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'aim r . nn*.^W^ajriV iltflT'itfiiY'iiiifk- J :5 30 ROBERT A. GDYER AND BONNIE G. RHYNE A. Mo r p h o l o g y o f Er y t h r o c y t es In load-induced anemia, rod blood cells art; microcytic and hypochromic, as in iron deficiency, and usually reticulocytosis and basophilic stippling am also observed. Iron -deficiency may be a. coincident factor, but micro cytic hypochromic anemia is seen in children with lead poisoning even when serum iron is normal or elevated (Leikm and Eng, 1963b Basophilic stippling of red blood cells has long been recognized as a feature of lead-induced anemia and has been employed as a method of monitoring workers in lead industry (McCord el al., 1935), but this test has the disadvantages of being nonspecific and probably does notroorrelate well with levels of lead exposure (Griggs, 1964), Stippling is more common in erythroblastic cells in bone marrow than in cells in peripheral blood (Waldron, 1966). The nature of the basophilic stippling has received .considerable atten tion. Stipples are thought to represent clustered ribosomes (Jensen ef al., 1965) . They may or may not stain for iron (Waldron, 1966). Large concentrations of lead in blood in vivo (25-10.0 mg Pb* given intravenously) or added in vitro (20 ag per milliliter of blood) produce red cell shrinkage, distortion, and wrinkling of the membrane (Waldron, 1966) . B. Fu n c t io n a l Ef f e c t s o n Er y t h r o c y t es A number of reports following the early studies of Aub and his asso ciates (1925) have shovvn that the osmotic fragility of red blood cells from lead-intoxicated people or of cells exposed to lead in vitro is decreased or altered. However, osmotic fragility may be increased -after sterile in cubation for 24 hours. These studies are reviewed by Waldron (196.6), On the other hand, the mechanical fragility of leaded cells is increased. Whether this effect is related to lead-binding phosphate as suggested by Aub and associates (1925) or to other functional effects of lead on the red cell membrane is unclear. Prankerd (1961) has suggested that, decrease in red cell membrane integrity follows impairment by lead of glycolytic enzyme activity. Incubation of red blood cells from workers exposed to lead results in excessive potassium loss (Hasan et al., 19.67a), and may be related to inhibition by lead of .sodium- and potassium-dependent ATPase's (Hasan et ah, 1967b; Heraberg et al., 1967). C. He mo l y t ic Ef f e c t o f Le ad The anemia that occurs in lead poisoning results from two basic defects, shortened erythrocyte life-span and impairment of heme synthesis. saaiaas DUP040007029 a . . 5 -r= r - ~ h.-; y . PATHOLOGICAL EFFECTS OF LEAD 37 ing red cells in bone marrow or on the membrane pf the circulating cell is debated (Waldron, 1966). A recent study of heme and porphyrin metabo lism in an adult with lead poisoning (Berk el dl., 1970) has shown that there is a direct hemolytic effect of lead on mature red blood cells which is independent of effects on heme biosynthesis. Previous workers who postulated decreased erythrocyte survival on the basis of shortened halflife pf 5lCr-labeIed erythrocytes in lead poisoning, were misled by the fact that lead increases the rate of 5!Cr elution from tagged cells (Berk el al., 1970), This conclusion was based on the demonstration of an early excretion of 140-labeled stereobilin and on erythrokinetie studies with multiple tracers. D. In h ib it io n o f He me Sy n t h e s is A schematic presentation of the effect of lead on heme synthesis is shown in Fig, 16. At least three steps in heme synthesis may be affected by lead. d-Aminolevulinic acid dehydratase (ALA-D) is probably the enzyme in the heme pathway that is most sensitive to lead. Inhibition of this enzyme results in a block in utilization of d-ALA and in subsequent decline in heme synthesis. Second, in the scheme of negative feedback Mitochondrion Ferritin, ferruginous .micelles HEME Pb Ferrochelata.se 3 Fe2* PROTO Glycine + Succinyi-CoA ALA -synthetase- Pb PROTO'GEN + Fe2+- -CYTOC -ALA , ALA | dehydratase | Pb c o .p r o o e n ni PBG COPRO'GEN IU- UROPOR'GEN Hi - Fig . 16. Scheme of hemesynthesis showing .sites of lead effect. PBG, porphobilinogen; TROPOR til, uroporphyrinogen XII; COPRO lit, caprnporphyrinogen III; PROTO, protoporphyrin; CoA, coensyme A; ALA, aminolevulinic acid; CYTO C, cytochrome c. DUP040007030 :i , " ,,I\- ~*m `V-' f: 38 ROBERT A GOYER AND BONNIE C. RHYNE control of heme synthesis proposed by Granick and Levere (1964), d-ALA synthetase activity is dcrepressed, which results in increased activity of the enzyme and increased synthesis of d-ALA. Since utilization of d-ALA is blocked, urinary excretion of d-ALA is greatly increased, serves as a sensitive biochemical index of lead toxicity and is widely used as such (Haeger-Aronsen, 1960). A third abnormality of heme synthesis in lead intoxication is inhibition of the enzyme ferrochelatase (Ortzonsek, 1967), which is located on the inner membrane of mitochondria (Jones and Jones, .1968). This effect is particularly interesting because of associated ultrastructural changes in .. the mitochondria. Ferrochelatase catalyzes the incorporation of the ferrous x ion into the prophyrin ring structure. Bessis and Jensen (1965) have shown that iron in the form of apoferritin and ferruginous micelles may accumulate in mitochondria of bone marrow reticulocytes from leadpoisoned rats. Other steps in the biosynthetic pathway of heme may also be abnormal in lead toxicity, but the evidence for this is incomplete. Increase in uri nary excretion of coproporphyrin, the degradative product of copropor phyrinogen III, is a sensitive reflection of lead toxicity. Metabolism of porphobilinogen to coproporphyrinogen proceeds unimpaired. However, since ALA-D is an extramitoehondrial enzyme, and later steps in heme synthesis are intramitochondrial, coproporphyrinogen must reenter the mitochondrion to be metabolized further. It has been suggested that transport of metabolites like coproporphyrinogen into the mitochondrial matrix might be impaired in the presence of altered inner membrane permeability a.nd reduction in oxidation and phosphorylation (HaegerAronsen et al., 1968). Whether the increased urinary coporporphyrinogen occurring in lead poisoning is a reflection of a nonspecific alteration in mitochondrial membranes or reflects a more specific effect of lead on the intramitochondrial enzyme, coproporphyrmogenase, is not known. VII. Renal Effects of Lead A, Le a d Ne p h r o p at h y in Hu ma n Be in g s 1. Acute or Early Effects on the Kidney Aeute effects of lead on the kidney were distinguished from lead-induced chronic nephropathy more than 50 years ago by the English toxicologist Thomas Oliver (1914), Acute renal effects of lead are seen in persons 1< it i i* v' y y*; . .WAcVy-A^-^T-i-^.A.. PATHOLOGICAL EFFECTS OF LEAD 39 dying of acute lead poisoning or suffering from lead-induced anemia -and/pr encephalopathy, and are usually restricted to nonspecific degenerative changes in renal tubular lining cells, usually cloudy swelling and some degree of cellular necrosis. Cells of the proximal convoluted tubules are most severely affected. There is little evidence that the glomerulus is affected in acute lead poisoning, although a recent report suggests that ultrastructural changes in the glomerular basement membrane may occur (Macadam, 1969), These consist of complete fusion of epithelial cell foot processes and of increased cytoplasmic density of epithelial cells adjacent to a normal looking basement membrane. As long ago as 192S, Pejic emphasized that the degenerative changes id proximal tubules rather than the vascular changes often referred to in earlier studies, are primary evidence of injury to the kidney in lead poisoning. Many subse quent studies have shown at least three pathological alterations in the renal tubule, with onset during the "early" or the acute phase of lead intoxication in the kidney. These include the formation of inclusion bodies in nuclei of proximal tubular lining cells and the development of func tional as well as ultrastructural changes in renal tubular mitochondria. These have been discussed in Section IV, Dysfunction of proximal renal tubules (Faneoni's syndrome) is mani fested by aminoaciduria, glycosuria, and hyperphosphaturia, and was first noted in acute lead poisoning by Wilson and eo-wprkers in 1953. Plasma amino acids were normal, which suggested that the aminoaciduria and other functional abnormalities were of renal origin. Subsequently, aminoaciduria in children with acute lead poisoning was observed by Marsden and 'Wilson (1955) in England, and Chisolm (1962) found that 9 of 23 children with lead encephalopathy had aminoaciduria, glycosuria, and hypophosphatemia. The aminoaciduria was generalized in that the amino acids excreted in greatest amounts were those normally present in urine, and it was related to severity of clinical toxicity, most marked in children with encephalopathy. The aminoaciduria disappears after treat ment with chelating agents and clinical remission of other symptoms of lead toxicity (Chisolm, 1962, 1068). This is an important observation relative to the long-term or chronic effects of lead on the kidney. Restora tion of the functional integrity of renal tubular lining cells following treat ment of acute lead poisoning implies restoration of normal morphology, but this has Hot been confirmed experimentally. 2. Chronic Lead Nephropathy in Han The -.occurrence of a chronic form of renal disease in man is contro versial. There are numerous reports in the medical literature of the past r 40 ROBERT A. GOYER AND BONNIE C. RHYNE century which describe a form of end-stage renal disease and renal failure iii humans which is said to follow many years of excessive exposure to lead. The pathogenesis of chronic lead nephropathy expressed by Charcot and Gombault in 1881 (cited by Aub cl ai, 1925) relates renal effects of lead on the tubular lining cells resulting in diffuse renal fibrosis charac terized by "epithelial cirrhosis of the kidney." Later descriptions by Oliver (1914) and Aub el al, (1925) are consistent with this hypothesis, and emphasize tubular atrophy and dilatation with interstitial fibrosis, but with minimal inflammatory cell infiltration. There is progressive contraction of kidney size with subsequent sclerosis of glomeruli. These . descriptions have no specific pathological feature, so that the role of lead in the pathogenesis of diffuse chronic nephropathy in a particular person has always been uncertain. The implication of lead as etiological agent of chronic nephropathy is largely the result of association of chronic renal disease with chronic exposure to lead and signs and symptoms of a chronic lead poisoning, such as abdominal colic and peripheral neuropathy. a. Lead Intoxication in Childhood and Chronic Lead Nephropathy in Adulthood. A series of reports from Queensland, Australia, points to a strong association between severe lead poisoning in childhood associated with central nervous system symptoms and chronic nephritis in early adulthood. Henderson (1954) followed up 401 children who had been diagnosed as having lead poisoning in Brisbane between 1915 and 1935. Of these 165 had died, 108 from nephritis or hypertension. This is greatly in excess of expectation. Information, was obtained from 101 of the 187 living survivors, and of these 17 had hypertension and/or albuminuria. In a more recent study, Emmerson (1963) presented criteria for implicat ing lead as an etiological factor in such patients: the patients should have an excessive urinary excretion of lead following administration of calcium EDTA. In his study, 32 patients with chronic renal disease attributable to childhood lead poisoning showed increased excretion of lead. Only 4 of 19 patients with chronic renal disease not attributable to lead poisoning had similarly elevated excretion of lead. A photomicrograph of part of a kidney from a 26-year-old male with a childhood history of lead poisoning is shown in Fig. 17. The presence of intranuclear inclusion bodies is very helpful establishing a relationship between renal lesions and lead toxicity, but inclusion bodies are not always present in persons with chronic lead nephropathy^ Attempts to confirm the relationship between childhood lead intoxica tion and chronic nephropathy have not been successful in at least two studies in the United States. Tepper (1963) found no evidence of chronic renal disease in 42 persons with a well documented history of childhood plumbism 20-35 years previously at the Boston Children's Hospital. Likewise, Chisolm (1970) found no evidence of renal disease in 62. ado- - * - *- .!*'-'/ :> > r.-/.,%/ I'io . 17. Renal cortex from a 26-year-old male with history of childhood lead poisoning and chronic lead nephropathy. The patient was hypertensive and died in uremia. At autopsy the kidney was .small and fibrosed. Bone lead was high. The histological picture is a mixture of interstitial fibrosis anti dilated tubules. .Some tubules are atrophic (lower left). Intranuclear inclusion bodies are not present. X210. (Slide furnished by J. A, Inglis, M.D., Department of Pathology, University of Queensland, Australia.) 42 ROBERT A, COYER AND BONNIE C. RHYNE lesccnts known to have had intoxication 11-16 years earlier. An important distinction between the Australian group and American patients was that none, of Chisolm's (1970) subjects showed evidence of increased residual . body lead burden following the EDTA mobilization test. This difference has suggested to Chisolm (1970) that lead toxicity in the Australian childrcn must have been of a different type, with a more protracted course than that experienced by the American children. Most American children suffer from lead toxicity early in childhood, between the ages of one and four, the source being oral ingestion of flecks of wall paint and plaster containing lead. Australian children, at least at the time of the Nye (1929) and Henderson (1955) studies, ingested lead from powder or chalky paint on veranda rails of their homes while playing. They tended to be older than the American children, and had a more chronic form of lead poison* ing. 6s Occupational Exposure to Lead--Renal Hypertension and Chronic Lead Nephropathy. Several studies of workers in lead industries in the early part of this century showed an increased incidence of hypertension which appeared to correlate with exposure to lead (cited by Cantarow and Trumper, 1944). However, a relationship of hypertension to renal disease was not established. A retrospective study (Dingwall-Fordyee and Lane, 1963) reviews causes of death among men eligible for pension (65 years of age) who had worked in an accumulator factory in England between 1926' and 1960. The incidence of deaths from cerebral hemorrhage and from thrombosis or arteriosclerosis was higher than expected. All affected persons were employed for not less than 25 years. Again, a renal basis for the hypertension was not demonstrated. Control of occupational exposure to lead -has undergone continued improvement during the past 50 years, which may be responsible for the failure of other investigators (Belknap, 1936; R. E. Lane, 1949) to find an. increase in frequency of hypertension and chronic renal disease. More recently, Cramer and Dablberg (1966) did not find an excessive incidence of hypertension among workers in a Swedish accumulator factory in which 265 workers were employed for more than 10 years. On the other hand, in those parts of the world where occupational exposure to lead is not closely controlled, there continued to be a high incidence of chronic nephropathy and renal failure. In Yugoslavia, in a study of 53 patients with chronic exposure t,o lead (2 months to 35 years) and with clinically manifest lead poisoning, Radosevic et al. (1961) concluded that lead may induce functional and anatomical lesions of the kidneys. Studies of renal function in 102 patients admitted to the Occupational Diseases Clinic in Bucharest, Rumania, during a 10-year period (1957-1967) were reported by Lilis and co-workers (196S). Renal failure was found in 17 .. x . pati cxpt arte foJoc velc epis c. tion of ` are Dei Eng of 1 (An glas and C pro lent (Ov the tior pat chrwot 35of 1 fixe win an to 1 A San dep hac excanc diu of mf>co:- 1 x?&!* ' Af " -\ .;> - ^\ ^,*r t * r r`.v j/ri JV*V ;.;;<; ".- 'y - ''Tf'o-Tr ' pat h o l o g ic al ef f ec t s o f l ead 43 patients who had had several episodes of abdominal colie and occupational .exposure to lead for more than 10 years- Thirteen of these patients had arterial hypertension and evidence of renal disease preceding the rise in blood pressure by several years. The authors related the progressive de velopment of renal failure to prolonged exposure to lead, with repeated episodes of lead-induced abdominal colic. e. Illicit Whiskey and Renal Disease. Contamination with lead, inten tional or accidental, is a long-recognized risk attending the consumption of "home brew'" or illegally produced alcoholic beverages. The Romans are said to have added lead to wine to improve flavor (GilfiUan, 1965), Devonshire colic, an endemic disease in the County of Devonshire, England, in the middle of the 1.8th century, was found to be a symptom of lead intoxication caused by drinking cider contaminated with lead (Anonymous, 1968). Homemade wine may be contaminated by lead glaze in earthenware crocks (Whitehead and Prior, 196.0; C. R. Lane and Lawrence, 1961). Contamination of illicit whiskey by lead has been a problem of major proportions in the southeastern region of the United States, Lead is leached into the distilling alcohol from lead-soldered pipe joints. Hammack (Gwen et id., 1967) has recorded that over 250 patients were admitted to the Birmingham Alabama Veterans Administration Hospital for intoxica tion with lead in illicitly distilled whiskey This number of acutely ill patients suggests that many others must be affected with subelinical or chronic lead toxicity and continue to go unrecognized. Morgan and coworkers (1066) have described renal biopsies in 13 of such patients, aged .35-50, with early' renal failure, anemia, and increased urinary excretion of lead with or without provocation by EDTA. Two of the patients had fixed hypertension. The biopsies from all eases showed interstitial fibrosis with few' inflammatory cells. Some glomeruli were sclerosed; others showed a mild increase in basement membrane thickness. All cases were found to have intranuclear inclusion bodies. At the Veterans Administration Hospital in Nashville, Tennessee, Sandstead et at. (1970) studied the renin-aldosterone response to salt deprivation in 9 men with subelinical or "occult" lead poisoning. All nine had elevated body burdens of lead demonstrated by increased urinary excretion of lead .following administration of EDTA. Plasma renin activity and aldosterone secretory rate were measured after administration of the diuretic fjirosomide and ingestion of ,a low sodium diet for 5 days. Neither of the measured parameters increased to expected levels in most of the men. Lead toxicity is believed to be responsible for abnormal sodiumeonserving functions of the renal tubule. It cannot be proved unequivocally that lead in alcoholic beverages was 'X- ' 'rs DUP040007036 r 46 ROBERT A. GOYER AND BONNIE C. RHYNE since these aniiiriais toietate large doses of lead for long periods of time and since they both develop progressive structural and functional renal changes in response to lead. Dose-effect relationships can also be studied in animals. The progressive morphological and functional changes induced by lead in rat kidneys may be divided into three stages--primarily, for the pur pose of observing the development of lead effects and, secondarily, for making comparisons to observations in man. 1, Sfagt 1--Tubular Effects, Reversible y The .first stage of lead nephropathy in rats fed a diet containing 1% lead as lead acetate continues for about 20 weeks and is characterized by | the development of intranuclear inclusion bodies after about 4 or 5 weeks. No other changes are apparent by light microscopy. An electron micro graph of a nucleus of a proxirtial tubular Bning cell containing an inclusion body is shown in Fig. 3. Swelling of organelles and mitochondria is also seen by electron microscopy, as shown in Fig, 9B. Impairment of respira tory and phosphorylative abilities of mitochondria isolated from kidneys of rats fed a 1% lead acetate diet for .10 weeks are discussed in Section IV, B. The mitochondrial changes may be related to the triad of func tional defects in proximal renal tubules, that is, to aminoaciduria, glyco suria, and hyperphosphaturia, as noted in children with acute lead poison ing. a Excessive aminoaciduria .also occurs during stage I nephropathy in rats. After about 10 weeks on the experimental diet, nearly all amino a.? 'fl5 acids are excreted in greater amounts than in control rats. The amino aciduria is `(generalized," with greatest increases occurring in amino 4 acids normally present in urine in largest amounts. These are the'small neutral monoamino, monocarboxylic acids, e.g., glycine, serine, and alanine. Renal clearances for most individual amino acids (Fig. 18) increase approximately 1-3 times. Exceptions include a decreased clearance of tyrosine, little change in the clearance of glycine and valine, and a very large increase in the clearance of histidine. Plasma levels of nearly all amino acids from lead-fed rats axe either the same or less than plasma levels of control rats. Exceptions are increases in threonine, glycine, and lysine. Renal clearance of glycine is normally considerably larger than i that of other amino acids, but it does not increase appreciably in the leadI fed rats. This suggests a prerenal factor in the excessive glycinuria. The large increase in histidine clearance and the disproportionate increases in uninary excretion of other amino acids may also reflect eomplexing of lead with amino acids (Goyer, 1071b; Goyer et al., I970aj. D U P040007039 ;s in they .952) wred lead f'ater ssin. 3ueh >52), as 6 :ural itrayon eadraelgc-s 3m yer, tore Dry nat ihy ear are live -sly )hy ail., ied `ad ion ms ;en PATHOLOGICAL EFFECTS OF LEAD 49 Fig . 19. Renal cortex of rat fed a diet containing 1% lead acetate for 9 weeks. Many tubules, particularly in the deep cortex, are dilated and lined with atrophic epithelium. Cells lining other tubules are hyperplastic and contain hyperchromatie nuclei. Inter stitial fibrosis is present, but inflammatory cells are sparse, X150- From G.oyer (1971c), by permission of Springer-Verlag. Berlin and New York. 3. Stage HI---Renal Failure and Cancer Rats fed 1% lead as lead acetate in their diets for more,than tine year have progression of interstitial scarring and fibrosis, sclerotic glomeruli, and frequently develop renal failure and adenocarcinoma. Blood urea levels of six rats after *34 tveeks of ingesting a lead-containing diet ace shown in Fig. 21A, Eleyation of blood uric acid also occurs (Fig. 21B) and may be related to the renal failure, although in these 6 rats there was no clear relationship between the hyperuricemia and uremia. On the other hand, the elevated blood uric acids levels may be analogous to the hyperuricemia seen in human lead nephropathy (Seetion VII, A, 2, d). W imooot'Odna '(IZ6T ,`TO3B3[Kmj^} pT33] nrejtlOD Aaqj JBqj 3ntJSa33tlS `OptjpiS oaSbxpAq iqtAi trrejs stioijaxouoo aqj, -(gg 'Sk [) insBjdojAa aqj tn readde suoijaxonoo asnsp ;satpoq uoisiqatn XBapntrexjut paqixosap Apnaxje aqj <4 ttotjtpp'e ix| -sqaaAv gg jo potxad b x bao sqaaAv g tn aono notjrqos ajejaae psaj %i jo pn x qjiAt suotjaafin jBauojtxadBxjur aAtssaoottS gj StrtAtS Aq paonptn aq Ab u i spaa Sniaij xGptqnj jenax tn pGaj jo uotjtsodap xajBoxj) (mi ` p p ssBjj) sjiqqttx paj-pGaf jo sAauprq tn xnoao osps pnn `(W6T ``ft p ifqcLmj.q Igegx `aopjBj i ifQ\ `onijxeunxreg ptre ipoiqQ) sxaqjo Aq pajxodax s AjsraoiAajd uaaq aABq sqjtroui jBiaAas x q j pnaj PaJ s j bx UI sjoajja puaa aATSSaiSoad reptutg Aatreti3qBuiaxd sjsaSSns qatqxt 'aatrereadcfe tit pJotdAjB o x b put* taptra otjGtuoxqaxadAq aABq spaa asaqj jo Au bu i jnq `stioisnptii xeoprureijin utBjuoa jott op spaa Stntip xBptqrq. atjsBidxadAij -ssax3oxd AqdoxjB j b nqnj ptre Sbu x bo s s b sasnaiaap ptre j j ptre j o Sbj s tiaaAvjaq pttuixBUi- saiitoaaq; satpoq uotsrqout xBapnirexjut jo xaquinu aqj, -spaa AxojBtntiiBgoi *\vaj qjut ansstj enoxqtj jBtjtjsxajni tn asBaxani aAissaxSbxd <9 st axaqj, atjsBidxadAq sainoaaq saptqnj atnos jo Sutdq repqpa aqj, `(0X2,61 `taXoQ) (gp 'Stj) aStreqa atjsAa jenjiiaAa ptre norjejepp qjm `sapqttj atnos nt spaa Suing rejnqnj jo Aqdoxje tit sjjnsax pna[ jo Sutpaaj pairaijttoQ fii[pdoj.i[dahi ajqtsj-aaajdj `amoMjD--j j -g i -sqaaAv (jg jnoqe xajjB 5 so3treqo xBjiiqrtj ptre Snureas Juotreuixad jo jtiouidopAap aqj Aq pazixaj | -aejeqo Si qatq.vt AqjBdoiqdou jj o Sb Js oj ssoi3oxd soStreqa ptuax paanput | fptja] ZjxBo asaqx 'sqaaAt gx-^-8 W. 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's14r.1q4.rc XqnoS dojoAop as aud asraSrp |ruaa aiuoaqa qqiM squaiqrd av o j 4rq4 poqou srq (6961) Srcquuuijvj ajBJn.jo uopdaasqroa arplqnq aAissaaxo Xq poqripoui si 4110S poanpui-pra] qrqq qsogSns sqpisoa osaqx 'uoiqraquoouoo aquin ruisrfd oq4 u io j j pajaipoid oSura oqq mqjiAi sm aqran jo uopajoas jrqnqn; OApar sraaaqAi poqoodxa urqq aoqroaS oq 04 punoj suAv aqraii jo UOpdaosqraa Jtqnqnx 'u j u j u j o Uoyo-iaos .nqnqnj oAijor sqaojq qoiqA\ opiurruizr.iild Smp oqj jo ajtijn jo uoijxsodap 411110.1 uo jaajja aqj SuiAJasqo Xq jCi04rjrdas ajran jo uopsaous pur uoijcLiosqro.i rcjuquj j iu io j pajnsrara (uoi4roiuruauio3 puos.iod) uos.iauiuig `Aqirdoa *qdau. praj u; uorjaaoxa ajrju jo Xpujs 4uaaoj joqj&ur ui `j o ao aio j j `piar ojjn jo uopaioas Jtquqnj puiaa sjirduli praj 40144 4so28us sSuipuy asoqx pior aun jo uonanpoad-iaAO jo aauapiAa ou s o a\ aaaqx "Gimoax.m.iadXq oq; jo sisouaSoqjrd oqj ui sXaupiq- aq4 jo ajoj aq4 pauuyuoa sjuaprd asoq; jo daaqj uo prou o u r j o sarpu4s aijaunj; -ppaj qjp. pajruipurjuoa j.auiqs -uoorn,,, jo uopduinsuoa paSuopid 04 jfrcpuoaas so 41408 qypa sjuopird gp jo gg Xjissrja 04 aj'qt! oaaAi (6961) uasuaaog pur prg 'ir4idsojj suraoja^ rrarqrjy ureqSuiuiaig 394 qr 4.U0S aoj suoissirupr 440 jo AiaiAai r luoaq jnoS jo qaSuo aqq papaoaad iCqqrdoaqdau praj `asra qara uj "(9961 `'P P urSaoj^) 9f avau 40 sxoauaa iv o id o u o h x v u Ui'troi. - * ^- izoiooot-odna ;noS pin? BlinaaiaruadXq 3ABq o s j b pBaj Xq papmtuiB^Oa Xaqsnpw ;ioiqi jo uoxjsaSui q;m pa;BiaassB Xupedojqdau oiuoaqa qjpa s;uai;Bd XtrepI -;no oiqjBdoipi q;uv s;uat;Bd ui UBq; ;uanl)aaj ssaj 9J9AV si;uq;.iB X;noS jo sqo-Bjj-B pro `papaya Xpiommoa axoui 3J9av squiq jaMoj aq; `cs|V 'pooqppqo in Smuosiod pBaj jo Xao;siq B ua;jo s bax axaqx astvedoxioui aq; aaojaq xia;jo pro `po;oxyjB aaaAv u o u io av aaora ;Bq; in ;no3 ougadcnpi q;u\ asoq; raoij pojagrp spcMtjed siq ;Bq; ptfnoj uosiauiragi qndS jo- sqoB;;B a;nas araaj pa.ojjns 91 `Xq;Bdo.iqdau pByj q;m s;uoi; -Bd jo jCptijs (8961) s,uosjouitiig; ui spnpiAipm gg oq; Suouiy -pauodooj uosq: Xjjuooaa 5Bq XqjBdoaqdaxi paoxiptn-pBoi pro ;no3 jo mojqoid oqX diqsuoi;Bpa jttoS-pua] aq; suoi; -satife (S26T) 7 P quy Xq AvdiAai aq; pus s ibo X ;uaoai in uaos uooq aABq s o s bo aaA\aq yuisxjBmnaqj,, ;ua;sncaoo o; anp aq ppioa ;uamoA{OAUi ;mof jaq;aqAV pasrea s bax uox;sanb aq; `;jodo.i siq; ux u s a b ;xig qasuo Xj j bo j o s bav si;xxq;j:y quasajd s Xbax j b s bax Suraostod pBaj jo Birnaro aq; pUB `uotqsodsxp -ojd |Bi[iuix!j jo oauosqB s bav aiaq; 'BOiqppB uj qnoS XaBuipao treq; ojq ax laxpreo Sqtxxxioao s b ;noS amtunjes paqstdSaijstp aauiuo'q -Sxnuosiod. pwa| put; ;na3 jo sasuo /,oi jo (9881) s,jrouitJoq s Sa i Xpiqs Xpsa fSoxdX; y -(jog; `3iA'.pnq Xq poqo) ;noS q;iAt Suiuosiod pBa; jo diqsuoijBjaj. aq; pazlsBqduia `;noS m j o j o bj }b d iSo [o i;<> x ib s b bj o ao ] pxoB autx poojq pajeAUjo Sutziu -So o o j 1say xj ;x av paqxpaao st oqAx `pojJBQ SuuJBg poajjy axg uoAg -(itqg) SxAXpwq Xq pozxaBxumns 8o b ;noS q;pvv pB3[ Surquq Xan;uoo q;6l aq; jd s;aodoi asBa JBaaAOg -Xq;Bdoaqdaxi pBO[ oiuoaqa pux? ;no3 uoaA\;aq diqsxioi; -B{aj B ut Xi3x io i;s pqAoqdq Xan;nOQ q;6I m s;s^O|daxxo; pOB $txBtatsXqd jBu;stiipm `suaqjOAx Xa;snpux pBaj 3uomB ;xxo3 xptw ascasip {Bxxoa oraoaqd jo u o x j bx d o s s B ttoxBUioa oq; jo osrtBaog RyjDdmi&*{ P^ l: Puv P*o$ 'P pajaoxanaop tiooq OABq oudu q3noq;[B `sXaupxq o; oixo; o o b ;Bq; sojjundmr aoq;o surcjuoa Xaqsiq-tt paqrjsrp Xgiaiqt ;Bq; ajqxssod o s j b s i ;j -Xanfui jxqnjjaa jo ;uaraoanBq -no {xm;nui. b u i ;{nsoa Xbx u `uoupuoqao;im aq; `aj io u bSj o arnus aq; ;aajjB ^oq; cfvtfi ;o bj aq; `jopip X[qBqoad pBaj puB loqoojB jo X;io;xo; axg 3uiX{ ' -lapun suisixreqaam .xlqxxoajom aq; q3noq; u.)Ag -X;pixo; pxi.q o; X;i[xqx;dao -stxs Stipuaixyui jopnsj b SB joqo.qB jo suiaa; Ut x uoxpag ui passnosip si uopdmnsaad siq; aoj pstrq aqX `I0! treinn03 V s;aaya aiXq; jnqiuns omds aAB,q {oqoo[B ptrn pB,yq *(Q96T `J?wituQ) sau;snpui pBoi ui uoxuqaoAV Joj papuaxumooaa sr [oqoop jo aauBpiOAB puB `(p;6I `JOa ij o ) X;i:iix o ; pBaj xxauBxjua o; ;q3txoq; ua,}q 3uo( 0Aq saSBJOAaq oi[oqoa[y 'Xaupiq aq; UQ ;aajjaoiX0'; oi;si3aauXs B a^Bq[oqoap? puB proj ;t?qi ajqissod os{B si ;p pBq (tma-i. aAissaax.1 jo oouapiAa aaq;anj si soipoq uoisnjaui aBajanunajm jo SuipUTj aq; `os[y -s;uoi;Bd aq; jpi ui pa;Bj;sxioxuop m.i.w pua[ jo suapanq Xpoq p.Baaaui `safpnqs asaxp jo jaq;ia UI asw.isip j bu o j aq; j o j ajqisuotfeoa aNiiiu 'o apiiioa <mt uaxop -y xsaaoa' ff PATHOLOGICAL EFFECTS OF LEAP 51 .50 TT 6 40 - o E Z ID 20- CD 0 WEEKS A * 1 "T" 40 o 6 o p o 84 V3 s 3H o I0 WEEKS C9..7) (6.2)0 o A -i---- !' ~----i 40 84 Fig . 21. Blood urea (A) and uric acid (B) from control ( O) and lead-poisoned ( O) rats sacrificed after ingestion of diet containing 1% lead for 10, 40, and 84 weeks. From Cover (1971c), by permission of Springer-Verlag, Berlin and New York. Since hypertension may occur in persons with chronic lead nephropathy, there have been several studies of blood pressure levels in experimental lead poisoning. The results are inconsistent. Several years ago, Fouts and Page (1942) tried unsuccessfully to produce hypertension in dogs by chronic lead poisoning. Griffith and Lindauer (1944) showed a progressive increase in systolic blood pressure of lead-poisoned, rats over a 2-month period, but these results were not confirmed in similar studies by Pardoe (1952) and by Padilla et al- (1969). Renal adenomas pr carcinomas develop in 60-80% of rats fed for more than one year a diet- containing lead. Incidence and size of the tumors are related to duration of lead feeding (Fig, 22). By light microscopy, the tumors are adenocarcinomas, presumably arising from focal areas of hyperplasia of renarTabuIar lining cells (Fig. 23A)- The ultrastructure of the tumors (Mao and Molnar, 1967) is charac terized by cellular and nuclear hypertrophy, numerous Jysosomes and mierobodies, and absence of infolding of basal plasma membranes as normally seen in renal tabular lining cells. Tumor cells dp not contain intranuclear inclusion booties, and lead content of the' tumors is less than that of adjacent renal cortex. In our investigations, about one-fourth of the rats with tumors had metastatic foci in the. lungs, but not in other organs (Fig. 23B) (Coyer, 1971c). Renal tumors in lead poisoning were first observed in rats by Zollinger (19,53) following long-term injections of lead phosphate, and later by Kilham et al. (1962) in wild rats believed to have been exposed to lead fumes in burning refuse in a city dump. Bead-induced renal epithelial tumors! have, since been studied by a num ber of investigators (Boyland et al., 1962; Van Eseh et al., 19.62; Hass 52 ROBERT A. GOYER AND BONNIE C. RHYNE 20r + 15 + * X f'+ to X ox + OX + + 300 400 500 Opys of lead feeding 600 700 Fig . 22. Correlation of incidence of renal tumors with duration of lead feeding. Opencircles indicate rats without tumors (9); X, rats with microscopic turnon (14); 4*, rats. with gross tumors (17). From Mao.and MoInar ( 1967), by permission of Amer. /. Pathol., Durham, North Carolina. -2" ><v5v Fig . 23. (A) Renal adenocarcinoma in cortex of kidney of rat fed 1% lead acetate diet for 84 weeks. Hie tumor appears well demarcated from adjacent cortex, but the cells are poorly differentiated. From Goyer (1971c). X150. (B) Pulmonary metastases occur as small nests of cells in the periphery of the lung parenchyma,. X250. From Goyer (1971c), by permission of Springer-Verlag, Berlin and New York. DUP040007044 *t'V PATHOLOGICAL EFFECTS OF LEAD 53 et al., 1967). They have not been noted in. lead-intoxicated experimcnta] animals other than rats and mice. less frequently in the latter (Van Esch and Kroes, 1969). The tumors do not appear to have any obvious or im mediate relevance to man, since Tenal tumors have not been noted in industrial workers with chronie exposure to lead. Moreover, the incidence of carcinoma of any type in such workers is not greater than expected in the general population (Dingwall-Fordyee and Lane, 1963) . 4. Comparison of Experimental and Human Lead Nephropathy -Morphological and functional reactions of kidneys in experimental animals fed lead orally and in people, particularly children with acute lead toxicity, have features which are comparable. In both instances, proximal tubular lining cells are affected, intranuclear inclusion bodies are formed, and there is an associated aminoaciduria,. Impairment of mitochondrial function has not been demonstrated in man, but may be inferred from morphological changes in human biopsy material (Section IV, A). Recovery from the lead-induced acute tubular lesion in man certainly occurs. Excessive aminoaciduria returns to normal a few weeks after chelation therapy, but intranuclear inclusion bodies may persist for several years after acute lead poisoning (Galle and Morel-Maroger, 1965). Continued formation of inclusion bodies probably reflects a certain body burden of lead. In man, progression of acute effects of lead on renal tubular epithelial cells to chronic lead nephropathy has been less clearly documented. Morphological changes observed in kidneys of persons with histories of excessive exposure to lead are similar to the changes seen in kidneys of experimental animals. The problem is that in the absence of intranuclear inclusion bodies, the pathology of chronic lead nephropathy, like that of many other forms of chronic renal disease, lacks specificity. Hyperuricemia occurs in rats with lead poisoning and in persons with chronie lead neph ropathy. A major difference between the renal reaction to lead in man and m the rat is that rats develop renal adenocarcinoma. There is no evidence that lead enhances malignancy of any type in man. * ^ - ' " ' - -- nemin the understanding of me progression of acute renal effects in man to chronie renal disease is the paucity of renal biopsy material from persons With excessive exposure to lead. H a It appears, however, from reports of studies on man and on experimental animals that chronic effects of lead on the kidney are dependent on a Particular renal content of lead (hiring a prolonged period of time, and that lead is certainly capable of inducing a chronic nephropathy. .More information is needed about factors that influence susceptibility of the kidneys to effects of lead. PATHOLOGICAL EFFECTS OF LEAD 7i Concern for potential toxic effects of lead has arisen from growing rareness of the .relatively large amounts of lead in the environment, nere is no question that excessive exposure to lead results in elinical xicity. "there is uncertainty, however, regarding the potential harmful this problem will only be achieved with greater knowledge, of the Re f e r e n c e s eoeella, G. (1866). Ada Vitaminol. 20, 195. ngevine, J. M., Kappas, A., DeGowin, R. L.,.and Spargp, B. H. (1962). Arch. Pathol 73, 486. nonymous. (1968). J. Arrter. Med. Ass. 204, 541. sokan, S. 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