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CLINICAL TOXICOLOGY 9(1), pp. 3 3 - 5 1 (1976)

Lead Poisoning

VERNON A. GREEN, Ph.D.; GEORGE W. WISE, M.D.; and JOHN CALLENBACH, M.D. The Children's Mercy Hospital Kansas City, Missouri

Certainly mor e has been written concerning poisoning by lead than any other metallic material and perhaps m o r e than any other single toxicant. Th is is not surprising considering that the toxic properties of lead were known as ear l y a s the second century B. C. The ease of refining lead from galena and i t s malleable properties contributed much to the ear l y widespread us e of this metal. During the height of the Roman Empire, lead was used for plumbing, wine vessels, and cooking utensils by the wealthy. T hi s widespread use, with report s of now recognized signs of plumbism, has lead to speculation that chronic lead poisoning may have contributed to the fall of the Roman Empire [ 141. Lead poisoning is a vast, many faceted monster that h a s been around since antiquity. It is not the intent of this writing to discuss the historical, economic, political, and social aspects of the problem; therefore, discussion is limited to the medical aspect s of the lead poisoning problem. The limitation is not a n indication that the authors feel that the other aspects of the problem are of l e s s e r importance than the medical. In fact, al l of the many facets of the problem must be dealt with and actually are greatly overlapping and interrelated. T o complicate the discussion of lead intoxication further, the medical a sp e cts of the intoxication are neither as simple nor as straightforward as that of most toxicants. The difference between acute and chronic 33 Copyright 0 1976 by Marcel Dekker, Inc All Rights Reserved Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical. including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher

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GREEN, WISE, AND CALLENBACH

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poisoning and the even greater disparity between the chronic poisoning in adults and that of young children add complexities to the problem. Further, the toxic syndrome produced by lead, especially chonic lead intoxication, is made up of diverse signs resembling numerous diseases and physiologic abnormalities, making the e a r l y diagnosis very difficult. CHRONIC LEAD POISONING With the institution of lead screening programs in many of the l a r g e r cities, chronic lead poisoning, especially in children, has been confirmed to be a major medical problem, and the treatment of acute toxic episodes a medical emergency. Intoxication is identified most often in the 1- to 5-year old age group, with the highest incidence of disease in the 12- to 36-month old children, most of whom have a history of pica and who live in housing, o r regularly visit buildings, that were built prior to 1955. The normal average daily intake of lead in children is probably l e s s than 0.3 pg. Most children exhibiting symptoms have been regularly ingesting lead, contained in paint chips, for longer than three months with an intake in excess of 1.5 pg per day, resulting in a progressive increase in the body burden. One small paint chip may contain as much as 100 pg of lead. Children usually give up their pica by age 5 , but frequently teach the habit to younger siblings who are likely to continually return to the paint chips because of their sweet taste; therefore, the importance of screening siblings of patients with plumbism cannot be underestimated. Many children present during an acute episode, usually during the summer months, because the minor symptoms (anorexia, r e c u r r e n t sporadic vomiting, colicky abdominal pain, anemia with a hemoglobin l e s s than 10 gm, irritability, and constipation) are ignored until severe encephalopathic symptoms appear. These include hyperirritability, agitation, ataxia, weakness, paralysis of the upper motor neuron, stupor, convulsions, and coma associated with a high mortality rate and an even higher rate of morbidity. The reason for the summer toxicity has not been clearly determined. Kehoe [23] indicates that toxicity is favored by dehydration and acidosis. Toxicity induced by high ambient temperatures is accompanied by a d e c r e a s e in the excretion of lead in the feces and urine [21]. Solar irradiation and Vitamin D enhance absorption of lead from the intestine and cause an increase in both accumulation and excretion of prophyrin intermediates [4]. It is doubtful that either or both of these explanations fully account for the summer epidemics.

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LEAD POISONING

35

Lead poisoning should not be considered a summertime disease. At present, a large number of c a s e s a r e being reported in the winter months due to health workers becoming aware of this problem. Some c a s e s have occurred during the winter when leaded battery casings were burned for fuel and the fumes inhaled o r there was prolonged contact with the a s h e s [2, 301. Epidemiologic studies indicate that lead encephalopathy is more frequent during the summer; however, asymptomatic lead poisoning is a year-round disease [ 181. The absorption, metabolism, and excretion of lead has been worked out by Kehoe and his associates. The major routes of entry a r e the gastrointestinal tract and the lungs, with dermal absorption being relatively insignificant in most cases. Approximately 10% of the intestinal lead is absorbed and Vitamin D appears to be involved, as is competition with calcium. Lead appears as a t r a c e metal in v i r tually all foods and beverages and the average adult consumes approximately 0.3 pg of elemental lead per day, of which 10% is absorbed. Another 0.3 pg per day is extracted from the atmosphere by the lungs. Atmospheric lead is actively absorbed by the lung in relation to i t s particle size. Of the finely divided lead in the air, 70 to 75% is discharged in expired air [3]. Of the 25 to 30% not returned, those particles l e s s than 0.1 p in diameter are almost totally absorbed, whereas 40% of the retained lead of particle size 0.9 p o r g r e a t e r in diameter is trapped in the upper airways and swallowed where it follows the same pattern as ingested lead [21]. Intermittent exposure and absorption is usually associated with an occupational schedule, and there is a balance between absorption and excretion. During time of exposure, intake is high and output is relatively low. Once exposure is terminated, intake is low and excretion of lead rises. When a significant portion of the inspired lead is diverted to the intestinal tract, freedom from exposure is not eliminated as the gastrointestinal lead constitutes a source of continual absorption of lead, and the contribution of pulmonary absorbed lead equals that of actual intestinal absorption. It now appears that inspired lead, in some situations involving l a r g e r particle size, may even contribute additional lead to the intestine resulting in a prolonged exposure. Once absorbed, lead is distributed initially to the body tissues in accordance with vascularity and tissue affinity (see Table 1). During periods of recent absorption, lead is initially deposited in the soft tissues and flat bones. Over a period of time, with proper freedom from continuing exposure, the lead is gradually incorporated into the long bones where a considerable pool may be built up. T h i s appears as "lead lines" in the metaphyseal a r m s of the long bones and the width is related more to the duration of exposure than to the severity of symptoms. There is no known toxic significance of lead

GREEN, WISE, AND CALLENBACH

36

TABLE la

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Individuals with no exposure, mg/100 gm tissue

Individuals with severe exposure, mg/IOO gm tissue

Kidney

0.05

0.22

Liver

0.12

0.71

Spleen

0.03

0.86

Muscle

0.03

0.10

Lungs

0.03

0.08

Brain

0.04

0.35

Flat bones

0.65

13.00

Long bones

1.78

8.00

aReference [ 131.

as a component of bone, but it can serve as a source that can be mobilized during acidosis, alcoholism, and fractures. Of the lead present in the circulation, over 90% i s associated with the red cell membrane as lead phosphate. Kehoe has shown that during times of consistent excessive daily intake, there is a relatively rapid attainment of a plateau in the blood lead level. In contrast, the total body burden of lead continues to increase until exposure is terminated [16, 211. It therefore appears that over a long period of time the concentration of lead in the body i s not directly proportional to the concentration of lead in the blood. Neither, however, is the total body burden directly proportional to the clinical severity of intoxication. Much of this lead is eventually stored in the bone. Severity of symptoms i s related to the general level of concentration of lead in the soft tissues, which is related primarily to the immediate exposure dose and the speed of absorption [21], and secondarily to bone reabsorption. The excretion of lead is primarily through the gastrointestinal tract, and bile i s the vehicle of excretion. Of the total average daily intake of 0.33 pg of lead, 0.30 pg i s excreted in the feces [22]. A smaller amount i s voided via the kidneys with the amount being proportional to glomerular filtration rate, except at higher concentrations where tubular reabsorption may play a role [31]. Approximately 0.35 pg

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LEAD POISONING

of the average daily dose is eliminated in this way [221. Because most of the body burden is stored in the bone, the excretion of this burden takes approximately twice as long a s it did to accumulate [21]. Chelating agents a r e relatively ineffective in removing a significant portion of this bone lead. The diagnosis is usually made on the b a s i s of blood lead levels, although as previously stated, this does not give an accurate estimate of the total body burden. Since much of the lead is attached to the red cell membrane, one must also consider the hematocrit prior to comparison with the levels on Table 2. Early diagnosis is certainly preferable, and followup s e r v i c e s should include those of a doctor, social worker, psychiatrist, child guidance counselor, health department, and visiting nurse association [ 101. The child should be immediately removed from the source of exposure and further pica prevented. Treatment is indicated in Table 3. All levels greater than 80yg% with symptoms should be considered medical emergencies since the onset of acute encephalitis can be both unpredictable and fulminant. Occasionally blood lead levels a r e not readily attainable and other emergency tests can be employed. Many of these t e s t s are based on the interference with synthesis by lead (Fig. 1). Although it is recognized that several sulfhydryl enzymes are inhibited in heme synthesis, the rate-limiting step appears to be the inhibition of the incorporation of iron into protoporphyrin. Recent investigation of this one enzymatic reaction has led to a microphotofluorometric a s s a y for protoprophyrin which some individuals believe to be the most sensitive and practical indicator of lead toxicity as yet TABLE 2 Blood lead level, mcg% 0-20 20-40 >60a

> 80 without symptoms > 80 with symptoms > 100

Normal for most areas. Abnormal-suspect

pica, water, vapors.

Follow blood levels; do provocative test. Provocative test indicated. Treatment indicated. Treatment indicated.

asurgeon General's Office has recommended 50 pg% as the intoxication level.

GREEN, WISE, AND CALLENBACH

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Normal pathway

Step inhibited by lead

Intermediate accumulation

( Kreb's

cycle Succinyl CoA and glycine

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Pb

I - 1 PorphobiIinogen

6-Aminolevulinic acid

Pb

-

Rise in urine and blood

1

Urophorphyrinogen II I

I - I

Coproporphyrinogen I I I

Pb

-

Protoporphyrinogen I X

I

Protoporphyrin IX & Fe -Rise Pb

Rise in urine and blood

-

in blood

I

Heme

FIG. 1. Modified from Chisolm [ 4 ] . devised [ 6 ] . The relative newness of this test means that most laboratories a r e not yet equipped to perform it. Qualitative urinary coproporphyrin levels a r e perhaps the fastest and simplest test. A 3 + to 4+ test may roughly correspond to a blood level of lead in excess of 100 pg% [ 11. There appears to be a direct linear relationship between the pretreatment UCP level and the quantitative lead output in the first 24 hr of treatment, The test has a good correlation with the metabolically active (delta aminolevulinic acid) fraction of lead in the soft tissues [ 4 ] . Urinary ALA levels a r e perhaps someNhat more sensitive, but they a r e more difficult to perform. Lead determination on whole blood is probably the most effective means of showing recent increased lead intake. Less specific tests include an abdominal film, which may reveal opacities in the bowel, and X-rays of the wrists and knees demonstrating "lead lines," especially in the 2- to 5-year age range. Again, width is related to duration of exposure rather than severity of s y m p toms. "Lead lines" will continue to increase in width even after termination of exposure as soft tissue lead is transported to the cancellous matrix. Presence of these lines in children less than 2 years of age a r e unpredictable and variable [8]. Lines in older bones

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LEAD POISONING

39

(74 y r ) may not be prominent. The blood s m e a r may show a microcytic ( r a r e l y normocytic) hypochromic anemia with hemoglobin l e s s than 10 gm. The reticulocyte count i s usually elevated, which distinguishes it from iron deficiency anemia. Basophilic stippling in the peripheral s m e a r is extremely variable. It was once thought that the anemia was due to removal of stippled cells by the spleen. It now appears that the spleen s e r v e s to mature the cells resulting in disappearance of the stippling rather than RBC destruction [32]. Examination of the bone marrow shows stippling in excess of 50% of the RBCs [4]. Urinalysis reveals glycosuria, proteinuria, cellular casts, elevated ALA greater than 6 mg/liter, and aminoaciduria. A confirmatory provocative lead excretion test can be done by measuring the 24-hr urine lead excretion provoked by BAL/EDTA chelation therapy. Levels greater than 1.5 mg Pb/24 h r in the adult and 1.0 mg Pb/24 hr in the child a r e indicative of lead intoxication [3]. The basic principles of treatment have been set down by Chisolm [ 51. Treatment should be begun immediately. Adequate urine output should be established over a 1- to 2-hr period. Should this fail to adequately initiate urination a judicious use of mannitol 1 gm/kg in a 20% solution given a t 1 ml/min may be employed. Since these patients occasionally exhibit an inappropriate antidiuretic hormonetype syndrome, once urine output has been established, the patient should be placed on maintenance fluids to maintain a urine flow of 350-500 ml/m2/24 h r or 0.35 to 0.50 ml urine secreted/ calorie metabolized in 24 hr. The use of diazepam and phenobarbital certainly, is probably not advisable in the face of disturbed porphyrin metabolism. Paraldehyde may be the mainstay of seizure control during the first several days, being implemented a t the first suggestion of increased intracranial pressure, which should be avoided. Osmotic diuresis may be helpful. Steroid therapy has not proven to be any benefit and may actually increase the renal toxicity of EDTA (Table 3). Treatment usually depends upon the severity of symptoms and available laboratory data. Exposed individuals should be followed closely with repeat blood levels and removed from continued exposure. Those persons with increased blood levels, either symptomatic o r asymptomatic, should be treated according to the recommended treatment schedule (see Table 3). Such persons should be removed from the source of exposure and followed on a regular basis. The BAL/EDTA combination has been in use since 1964. P r i o r to that date, children with encephalopathy had a 25 to 30% mortality rate when treated with EDTA alone [5]. In fact, there was occasionally a prompt deterioration of their clinical condition associated with an increased level of ALA in the urine and plasma 48 to 72 h r after

b. Blood level < l o 0

a. Blood level > 100

2. Asymptomatic

b. Without encephalopathy

a. With encephalopathy

1. Symptomatic

IM. See part (a) above. PO. 3-6 months' course. IM. 3-5 days.

BAL/EDT A, D- Penicillamine, 30-40 mg/kg/day EDTA only, 50 mg/kg/day b.i.d.

5-day treatment course.

IM. See part (a) above. IM. Divided into 2-4 doses/day

BAL in oil every 4 hr EDTA in 0.5% procaine aoo ++++

> 19

> 13 ~ 5 0 0

+++

< 13

13

150

Hemoglobin, gm/100 ml

\

a0

55-80

Lead poisoning.

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