Document 3JM60Z3QZVz5RgD8GMDwrrYOJ

Page 1 Draft ~ Coyer and Six LEAD TOXICITY: SUSCEPTIBILITY AND TOLERANCE Piv;v~c:2> H:/t IMPLICATION \o h o.a The recognition of factors, which influence the toxicity of lead,'is essential to effective control of the influence of environmental lead on human health. Such understanding must, of course, be predicated on knowl edge of the mechanisms of .lead toxicity. The immense body of literature already written about lead contains many clues and impressions of various factors, both adverse and beneficial, which influence the toxicity Of lead. This brief discussion will review a number of such factors, few of which have been subjected to the rigors of experimental confirmation. A considera tion of possible antagonisms and synergisms must be based on certain assump tions with regard to the metabolism of lead, particularly concerning events at the cellular level. Lead is present in the body in two forms, a nondiffusible or fixed fraction and' a diffusible or transportable form of lead. Lead in bone is probably in the form of bone mineral and is nondiffusible. Also, 95 per cent or more of lead in whole blood is bound to red blood cells and is nondiffusible. Only the small plasma fraction bound to organic ligands is diffusible and, in a sense, is the only portion of lead that is biologically active. Only the diffusible fraction passes in and out of capillaries, permeates cell membranes, and enters the parenchymal cells of the central nervous system, liver, kidneys, and other organs. Lead within soft tissues may also become nondiffusible by forming insoluble complexes. Lead-protein N40683 Chapter 5 E Page 2 complexes appear as morphologically dense inclusion bodies in the nuclei of liver parenchymal cells and renal tubular lining cells of lead intoxicated people and animals. The inclusion body may serve to reduce the level of diffusible lead within the cell. Experimental studies suggest that any correlation between lead exposure and toxicity must be related to the soft tissue content of diffusible or ligand-bound lead (1). Clinical Susceptibility Age - The children brought to out-patient clinics and emergency rooms of large metropolitan medical centers with acute lead poisoning are usually between the ages of 2 and 5 years. Recent screening studies suggest that many times this number of urban children have evidence of subclinieal lead 4/ 53/ poisoning. (Rennerto^'1970; Blankma, et al.,1969). These numbers are in contrast to only sporadic occurrp^ce of lead poisoning in adults and the latter are usually associated with identifiable episodes of exposure to large amounts of lead. This difference in incidence of lead poisoning between children and adults is not, however, proof of greater biological susceptibility of children to the toxicity of lead. It may only mean that children are more prone to over-exposure to lead or the relation of their small body-size to dose. Pica and similar factors which contribute to the relatively more frequent high exposure of lead by young children probably accounts for the increased incidence of lead poisoning in early childhood. Greater incidence of lead poisoning,must, however, be distinguished from greater biological susceptibility. There are, nevertheless, many reasons why the young might DUP050055953 . Chapter 5 E Page 3 be expected to be more susceptible to lead. Many of these have been re4/ viewed by Harriet Hardy and include speculations that there may be greater vulnerability of young growing tissue, as evidenced by the "lead line*1 of arrested growth of long bone} the possibility that in children, lead may stay in the soft tissues in an active form; and greater variation in int estinal acidity or alkalinity into pH ranges that may tend to dissolve lead compounds and hence, increase the absorption of lead. Also, shifts of lead into and out of the growing bone of a child may be less predict able (5). If lead dosage in the child is considered on a weight basis, the greater susceptibility of children becomes less startling. Kehoe showed some years ago that young adults ingesting 0.3 to 0.4 mg/day of dietary lead excreted nearly the same amount, but if the diet was supple mented with 1 to 3 mg/ day, excretion was incomplete and accompanied over a period of months by progressively rising blood levels but without evidence of clinical lead toxicity (6). On the other hand Baritrop has documented clinical lead intoxication in a 2-year-old child from ingestion of only 1 mg/ day during a six month period (7). If the quantity of ingested lead is corrected for body weight the 1 mg/day ingested by the 2-year-old child be comes equivalent to 6 mg/day by a 180 lb. adult, a dose almost certain to result in clinical toxicity in the adult. Clinical manifestation of acute lead poisoning also appears to differ between the child and adult. A large percentage of children with acute lead poisoning are seen by clinicians with central nervous system disease, even coma, whereas in adults, anemia is the predominanting complaint in DUP050055954 Chapter 5 E Page 4 patients that have been exposed to a higher dose than children. Encephal opathy in the adults is rare except as the result of very large exposure to lead vapors or organic forms of lead . This difference may ref lect inherent sensitivity of the central nervous system of the child to lead, or to a less effective blood-brain barrier. Alternatively it may simply refelct the relatively greater capacity of the adult to store lead in an inactive form, in bone or in lead-protein complexes, which appear as nuclear inclusion bodies. Seasonal Variation - It is clear that clinical lead toxicity is more common in summer months although affected children are exposed to lead from indoor paint and it is not believed that such exposure varies seasonally. Studies y by Kehoe have shown that urinary lead excretion in a person subjected to increased dietary lead is also increased in the summer. It would seem, therefore, that this phenomenon must result from some seasonal metabolic increased difference. Two explanations, cited by Baetjer (8), include/vitamin D from radiation the sun's ultraviolet/and increased environmental temperature* This latter notion is supported by experimental studies showing that lead-poisoned rabbits subjected to 37 C die in about 4 days, whereas lead poisoned rats kept at room temperature survive. Mice exposed to high temperature and injected intraperitoneally with lead nitrate had a more rapid and higher mortality rate than similarly injected mice kept at room temperature. The added burden <8) of dehydration further lessens the survival of lead-injected mice although it is unlikely that dehydration is clinically relevant in lead poisoned children (9). Seasonal metabolic cycles might explain not only increased susceptibility to infectious disease but may influence nutritional and metabolic abnormalities, (10) ideas that have been reviewed by Sargent but have not been related to the DUP050055955 Chapter 5 E Page 5 problems of lead toxicity. DIETARY FACTORS Calcium, phosphorus and vitamin D - The absorption of lead from the g&stro-r intestinal tract as well as the partitioning of lead in various body com partments appears to be regulated by some of the same physiological mecha nisms that control the metabolism of calcium and phosphorus and the Ca: P ratio. Interest in the relationship of these minerals to lead metabolism has been directed toward their usefulness in the treatment of lead poisoning. Many of the early studies are summarized in papers by Lederer and Bing (11) and Shields and Mitchell (12). Absorption of lead from the gastrointestinal.' tract is impaired by amounts of dietary calcium and phosphorus above certain low limits. The drinking of large amounts of milk has been practiced as prophylaxis to lead poisoning bu^/the effectiveness of this custom has been questioned (13). 12/ Shields and Mitchell conclude that low dietary calcium or phosphorus or both, does itxduce a higher retention of lead in the body in comparison with diets containing higher levels of these minerals. Attempts to partition the enhanced retention of lead between bone and soft tissues were limited to a few experiments. More recently, the studies of Six and Goyer (14) have been directed toward c^termining the effect of a low-calcium, normal phosphorus diet on the adverse or pathological effects of lead and the partitioning of lead & between bone and specific tissue compartments. In rats given the same amount of lead Low calcium diets were specifically chosen for these studies because low dietary calcium (low milk ingestion) is thought to be clinically relevant. Nutritional studies (49), (50),(51) suggest that significant populations of urban children do ingest diets low in calcium, but it should be pointed out that some diets contain DUP050055956 Chapter 5 E Page 6 ill their drinking water (200 ppm) as the controls, low dietary calcium greatly enhanced the severity of anemia and biochemical parameters of lead poisoning including blood lead levels, urinary delta-aminolevulinic acid excretion, and aminoaci duria, The bone lead was higher and bone calcium lower than that found in rats given the same amount of lead and normal dietary calcium. These studies emphasize the correlation between soft tissue lead and severity of clinical 12/ toxicity. The conclusion of Shields and Mitchell that an adequate intake of calcium protects against unwarranted increases in the body burden of lead is also strengthened. In this sense, therefore, dietary calcium is antagonistic to the toxic effects of lead. Vitamin D, on the other hand, appears to worsen lead poisoning in experimental animals. Lead concentration in blood and bones is greater in animals receiving this vitamin hfian in those not receiving this addition (15) . Presumably, vitamin D enhances gastrointestinal absorption of lead as it does calcium. Whether increased bone deposition of lead during vitamin D administration reflects a specific effect on bone metabolism or merely reflects increased blood levels of lead is not clear, although the authors cited believe the evidence is in favor of the views that the major effect is on absorption, and hence higher blood levels. Protein:-Dietary protein is another factor that may influence lead intoxi cation. An early paper on this subject is that of Baernstein and Grand (16). Young rats were fed diets containing 1.5% lead chloride and 6, 13 or 20% casein. Decrease in rate of weight gain and mortality associated with lead \ toxicity diminished with diets containing higher protein levels . Addition DUP050055957 Chapter 5 E Page 7 of cystine or methionine to the 67c casein diet decreased mortality and improved weight gain in the lead-fed as well as in the control rats. Gontzea and coworkers (17) observed that pair-fed rats on a 9% casein diet showed greater susceptibility to lead intoxication (shown by the lead content of liver, kidney, and blood) as compared to rats fed diet containing 18% casein. Recently, DeBarreiro--52/ found that cysteine protected the depression of SALA dehydratase activity by Pb(CH3C00)^ rabbit liver. Ascorbic Acid; The addition of large amounts of ascorbic acid to the diet of industrial workers was suggested as a means of alleviating such symptoms of lead intoxication as basophilic stippling of the erythrocyte (18). Pillemer and coworkers (19) y DUP050055958 Chapter 5 E Page 8 found that lead-poisoned guinea pigs treated with a scorbutic diet developed neurological symptoms more readily than did lead-poisoned animals fed ascorbic acid adequate diets, A number of other investigators have found ascorbic acid to be without effect in lead toxicity (20,21). Nicotinic Acid - Several experimental studies suggested that nicotinic acid synthesis from tryptophan was impaired in experimental lead poisoning (22). Nicotinic acid may relieve some of the clinical.manifestations of experimental lead poisoning and reduced porphyrinuria in lead poisoned rabbits (22,24). This finding was not confirmed by similar studies in the rat (25) Other studies have found reduced nicotinic acid levels in blood and urine in lead poisoning along with increased uyinary excretion of xanthurenic acid suggesting impaired tryptophan metabolism in lead poisoning (22). However, using tryptophan load tests, Tenconi and Acocella (26) concluded that lead intoxication in rats did not cause changes in tryptophan metabolism similar to that seen in pyridoxine deficient states. Alcohol - It has long been believed that persons who are alcoholics are more susceptible to the toxic effects of lead. This relationship was clearly stated in Oliver's book on lead toxicity published more than 50 years ago and avoidance of alcoholic DUP050055959 Chapter 5 E Page 9 beverages is still re-commended for workmen In lead industries (27) . Cramer found that Swedish workers who consumed more than 7,5 liters of alcoholic beverage per month experienced a significantly greater incidence of clinical lead 'intoxication than moderate drinkers (less than 37 liters per month) or non-drinkers (28). Little is known about the basis for the apparent synergism between alcohol and lead, particularly at the molecular level. If the cellular pathology of lead and alcohol are compared, similarities are observed, for example, each produces mitochondrial Injury. In vitro studies of mitochondria from ethanol-treated rats show decreased oxidative properties and increased membrane permeability (29). Lead also produces mitochondrial swelling, particularly in reticulocytes of the V bone marrow (30), liver (31), and kidney (32), and also impairs respiratory abilities of mitochondria from these organs (33,34,35). Although the molecular mechanisms for the toxicity of alcohol and lead probably differ, effects on the same organelle, the mitochondrion, may i*esult in a mutual enhancement of cellular injury. Another probable mechanism for apparent synergism between lead and alcohol is through the introduction of nutritional deficiencies by alcoholism which enhance the toxicity of lead. These deficiencies include calcium, protein, and vitamins which have already been commented on. DUP050055960 Chapter 5 E Page 10 Other aspects of the subject of lead poisoning'from ingestion of illicit whiskey are discussed in detail elsewhere* Synergism with Other Metals It might be expected that the metabolism of different heavy metals is similar enough to have overlapping or similar toxic effects. There are few clear examples of such synergism. Several of the heavy metals bind in vivo to red blood cells* However, the attachment of lead to the red blood cell membrane is not influenced (in vitro) by the presence of other heavy metals including cadmium, mercury, zinc, and aluminum which suggests that lead may be metabolized independently of other metals (41) A recent study does demonstrate synergism between the teratogenic effects of lead and cadmium (43) Influence of cp~existant disease It is reasonable to expect that pre-existant disease of major organ systems might enhance the vulnerability of affected persons to the toxic effects of lead. Documentation of this type of synergism is limited0 Several reports from Europe point out the increased susceptibility of persons with hemoglobin anomalies, such as hemoglobin-S and C disease and thalessemia, to toxins like lead which affect red blood cell metabolism. Carriers of such defects must be recognized and protected from lead exposure (43). DUP050055961 Chapter 5 E Page 11 Glucose-6-phosphate dehyrogenase-deficlent Individuals also may show increased susceptibility to lead and should be identified by a screening test before employment in a lead industry (44). The- kidney has a key role in lead metabolism and chronic renal disease from any cause must reduce the lead excretory capacity of an individual. Again, there is little documentation of the contribution reduced renal function has in increasing susceptibility to the toxic effects of lead but studies in rats suggest that the immature kidney is more susceptible than the adult kidney and reduced renal excretory function as occurs in unilateral nephrectomy enhances the toxicity of lead (45). SUMMARY ^ Since many factors are suspected of influencing both the severity and clinical manifestations of lead toxicity, it would seem useful to he able to recognize common denominators. The common mode of action of a number of the factors discussed is the effect of mobilizing lead into a transportable or diffusible form. There is presently little known about the biochemical nature of diffusible lead. Likewise, the toxicology of lead at the cellular or molecular level , is ubiquitous, and probably entails a number of mechanisms, depending on the physiologic or biochemical process involved. Lead does interact with certain enzymes; those concerned with heme synthesis, particularly d-aminolevulinic acid dehydrase, are the best studied (46). DUP050055962  ' Chapter 5 E Page 12 Lead ions also impair the oxidative and phosphorylative functions of mitochondria (35) and it is also suggested that lead interferes with transmission of impulses at preganglionic nerve endings by reducing the output of acetylcholine (47). In vitro studies have shown that lead may impair protein synthesis by polyribosome disaggre gation (48). In spite of the sophistication of these studies, the present level of. knowledge for any of these lead effects is not complete enough to identify a common physico-chemical property of the lead ion. Understanding of synergistic and antagonistic factors in lead toxicity will be greatly enhanced when more basic knowledge of the metabolism of lead is known. \ DUP050055963 REFERENCES 1. Coyer, R. A, Lead toxicity: a problem in environmental pathology. Am. J. Path, in press. . 2. Christian, J. R., Cellwycz, B. S., Andelman, S, L., A three year study of lead poisoning in Chicago: Part I. Epidemiology; Part II. Case finding in asymptomatic children using coproporphyrin as a screening test, Amer. J, Public Health, 53:1241-1251, 1964. 3. Ingalls, T. H,, Tiboni, E. A., Herrin, M. Lead poisoning in Philadelphia 1955-1960, ' V' Arch. Environ. Health, 3:575-579, 1961. * 4. Rennert , O. M., Weiner, P. and Madden J. Asymptomatic lead poisoning in 85 Chicago Children. Clin. Pediat. 9:9-13, 1970. 5. Hardy, H. L. Editorial, what is the status of knowledge of the toxic effect of lead on identifiable groups in the population? Clin. Pharm. and Therap. 7: 713-722, 1966. 6. Kehoe, R. A. The metabolism of lead in man in health and disease; lecture II. J. Roy. Inst. Public Health Hyg. 24:101-120, 129-143, 1961. 7. Barltrop, D. and Killala, N.J.P. Fecal excretion of lead by children. Lancet 2:1017, 1967. 8. Baetjer, A. M. Effects of season and temperature on childhood plumbism. Indust. Med. and Surg. 28:137-140, 1959. 9. Chisolm, J. J., Jr. Discussion of Ref. 8. Indust. Med. and Surg. 28:140-142, 1959. 10. Sargent, II, F. A critique of homeostasis: season and metabolism. Arch. f. Meterologie, Geophysik u. Biokliraatologie, .Band III, 289-296j 1951. 11. Lederer, L. G. and Bing, F. C. Effect of calcium and phosphorus on retention of lead by growing organism. J.A.M.A, 114:2457-2461, 1940. 12. Shields, J. B. and Mitchell, H. H. The effect of calcium and phosphorus on the metabolism of lead. J, Nut. 21:541-552, 1941. 13. Longley, E. 0. Myth about milk. Factory and Plant, 5:55-58, 1967. DUP050055964 .I< 2 14. Six, K. M. and Goyer, R. A. Enhancement of subclinical lead toxicity by low calcium diet. Fed. Proc. 29:568, 1970 (abstract) 15. Sobel, A. E., Gawron, 0. and Kramer, B* Influence of vitamin D in experimental lead poisoning. Proc* Soc. Exp. Biol. Med. 38:433-435, 1938. 16. Baemstein, H. D. and Grand, J. A. The relation of protein intake to lead poisoning in rats. J. Pharm. Exp. Therap. 74:18-24, 1942. 17. Gontzea, I., Sutzesco, P., Cocora, D. and Lungu, D. Importance de I'apport de proteines sur la resistance de lVorganisme a 11intoxication par le plomb. Archives Set. Physiol., 18:211-224, 1964. 18. Holmes, H. N., Campbell, K. and Amberg, E. J. The effect of vitamin C on lead poisoning. J. Lab. Clin. Med. 24:1119-1127, 1939. 19. Pillemer, L., Seifter, J., Kuenn, A. 0. and Ecker, E. E, Vitamin C in chronic lead poisoning. Am.J. Med. Sci. 200:322-327, 1940. 20. Evans, E. E., Norwood, W. D., Kehoe, R. A. and Machle, W. The effects of ascorbic acid in relation to lead absorption* J. Amer. Med. Assn. 121: 501-504, 1943. 21. Banneberg, A. M., Widerman, A. H., and Friedman, P. S. Ascorbic acid in the treatment of chronic lead poisoning. Report of a clinical failure. J. A. M. A. 114:1439-1440, 1940. 22. Pecora, L., Silvestroni, A. and Brancaccio, A. Relations between the porphyrin metabolism and the nicotinic acid metabolism in saturnine poisoning. Panminerva Medica, 8:284-8, 1966. tfrf/rjtso abstract Vol. 3, No. 129, 1967. 23. Sales Vazquez, M., Elvaler antitoxico del acido hicotinico. Rev. Clin. Espanola, 10:40-43, 1943. Nutr. Abst. and Rev. 13:385, 1943-44, Abst, No. 2130. 24. BenkB, A. Die gemrinsame wirkung des nikotinsaureamids und cartijens auf die porphyrinurie die bleivergiftung. Deutsch. Med. Worchenschr. DUP050055965 ,,3-,. Goyer 68:271-272, 1942. Nutr. Abst, and Rev. 13:385, 1943-44. Abst, No. 2129. 25. Acocella, G. Chemotherapy of experimental lead poisoning. II. Effects of nicotinic acid on coproporphyrinuria in the lead-poisoned rat. Acta Vitamin- ologica. 20:195-202, 1966. Kettering Abst. No. 265, Vol. ? 26. Tenconi, L. T. and Acocella, G. Chemotherapy of experimental lead poisoning. I. Effects of lead poisoning on the metabolism of tryptophen nicotinic acid in the rat. Acta Vitaminologica. 20:189-94, 1966. Kettering Abst. No. 276, Vol. 7. 27. Oliver, T. Lead Poisoning, H. K. Lewis, London, 1914. . 28. Cramer, K. Predisposing factors for lead poisoning. Acta Med. Scand. 179:56-59, 1966. (Suppl. 445) 29. French, S. W. and Todoroff, T. Hepatic mitochondrial fragility and permeability. Arch. Path. 89:329-336, 1970. 30. Bessis, M. C. and Jensen, W. N. Sideroblastic anemia, mitochondria and erythroblastic iron. Brit. J. Haernat. 11:49-51, 1965. 31. Watrach, A. M. Degeneration of mitochondria in lead poisoning. J. Ultrastructural Res. 10:177-8, 1964. 32. Goyer, R. A. The renal tubule in lead poisoning. I. Mitochondrial swelling and aminoaciduria. Lab. Invest. 19:71-77, 1968. 33. Lessler, M. A., Cardona, E., Padilla, F. and Jensen, W. N. Effect of lead on reticulocyte respiratory activity. J. Cell Biol. 39:171a, 1968. 34. Teras, L. E. and Kakhn, K. A. Oxidative processes and phosphorylation in liver in lead intoxication. Vop. Med. Khimii, 12:40-45, 1967. 35. Goyer, R. A. and Krai 1, R. C. Ultrastructural transformation in mito chondria isolated from kidneys of normal and lead intoxicated rats. J. Cell. Biol. 41:393-400, 1969. 36. Owen, C., Dodson, W. N. and Hammack, W. J. Medical Grand Rounds from the University of Alabama Medical Center, South. Med. Journal 60:44-50, 1967 DUP050055966 4. '. , Goyer 37. Morris, C. E,, Heyman, A., Pozefsky, T. Lead encephalopathy caused by ingestion of illicitly distilled whiskey. Neurology 14:493-499, 1964. 38. Henderson, D. A, Chronic nephritis in Queensland. Aus. Ann; Med, 4:163-177, 1955. 39. Pepper, L. B. Renal function subsequent to childhood plumbism. Arch. Environ. Health, 7:76-85, 1963. 40. Goyer, R. A. The pathobiology of lead nephropathy. Proc. of Fourth Ann, Symposium on Trace Metals, Univ. of Mo., June 23-25, 1970 (Ip Press). 41. Clarkson, T. W, and Kench, J. E. Uptake of lead by human erythrocytes in vitro. Biochcm. J. 69:432-439, 1958. 42. Ferm, V, H. The synteratogenic effect of lead and cadmium. Experientia 25:56-57, 1969. 43. Gaultier, M., Gervais, P.,de Traverse, P.-M.,Founier, P. -E. Coquelet, M.-L., Loygue, A.-M., and Housset, H. Hemoglobin variation of genetic type in industry. Practical consequences. Arch, des Maladies Profess., de Med. du Trav. et de Sec. Soc. 29:197-203, 1968. Kettering abstract No. 407:vol. IV, 1968. 44. Stokinger, H. E. and Mounkin, Progress in detecting the worker hypersusceptible to industrial chemicals. J. Occup. Med. 9:537-42, 1967. 45. Tange, J. D., Hayward, N. J, and Bremer, D, A. Renal lesions in experimental plumbism and their clinical implications. Aust. Ann, Med, 14:49-56, 1965 46. Waldron, B. A. The anemia of lead poisoning, a review, Brit. J. Indust. Med. 23:83-100, 1966. 47. Kostial, K., Vouk, V, Lead ions and synaptic transmission in the superior cervical ganglion of the cat. Brit. J. Pharm. Chem. Th. 12:219-223, 1957. 48. Waxman, H, S. and Rabinovitz, M. Control of reticulocyte polyribosome content and hemoglobin synthesis by heme. Biochem. Biophys. acta. 129: 369-379, 1966. DUP050055967 GOYER Kelsay, J. L. A compendium of -nutritional studies in dietary jj7 ' evaluation studies. A study conducted in the U, S. 1957~1967. Journal of Nutrition, Vol. 99, p. 119, 1969. Stubbs, A. Food use in protein neutralizational level of 1225 Texas families* Texas A & H University, Ag College Station Bulletin, H-B 1033, 1965.. ................. Sh , Skidmore,'U1XJ.V41U.ULU.} K. Study of----- h-- e----a-----d-start pre-school children's food habits**,Baltimore^Maryland. cysteine mental in-------- UeBarreirop 0 G* Effect of DUP050055968