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Chelating agents in treatment of lead intoxication
322
February, 1969 T h e Journal o[ P E D I A T R I C S
Letters to the Editor Chelating agents in treatment of lead intoxication
To the Editor: Lead intoxication in childhood is a serious disease and Dr. Chisolm is to be congratulated on his timely and excellent review on the use of chelating agents, in the July, 1968, issue of your JOURNAL.
Chronic lead poisoning in children was very common in the early part of the century in the state of Queensland, Australia, and many of these children developed chronic lead nephropathy in adult life.a, 2 Following legislation restricting the use of lead paint in Queensland, there have been very few cases. There is no similar legislation in the state of New South Wales, and in Sydney we are finding an increasing number of children with lead intoxication. There have been 42 cases in the past 5 years, which may seem small by Baltimore standards. I share Dr. Chisolm's approach to long-term treatment with d-penicillamine, and for the past 18 months all new cases have been treated in this manner. Once the acute stage of lead poisoning has passed, the lead which is stored in the skeleton is presumed to be removed over a period of several years. However, the bone-lead levels in adults with chronic lead nephropathy in Queensland, even 30 years or more after the initial lead exposure, were significantly elevated?, ~ Perhaps lead intoxication in Australia runs a different pattern to that in the United States, where chronic renal disease as a sequela to childhood plumbism has not been apparent. This may be related to climatic conclitions and/or the nature and duration of exposure to lead; or perhaps a longer period of follow-up is necessary in the United States. With the use of the bloodqead concentration, endogenous urinary-lead excretion, and the EDTA mobilization test as parameters, Dr. Chisolm found no increased burden of lead in the body in a group of adolescents who had plum_bism in childhood. One would agree that the latter test should provide a fairly sensitive index of
Vol. 74, No. 2, pp. 322-325
the lead burden, but one might question the reliability of the test as used by Dr. Chisohn. How does Dr, Chisolm correlate a normal E D T A mobilization test in Patient S. W. (Table V I I I ) in the face of an increased lead excretion with d-penicillamine? Emmerson 5 is one of those quoted as indicating a figure of 600 /xg Pb per 24 hours as the upper limit of urinary-lead output for the E D T A mobilization test in "normals." This figure, however, Emmerson related to the excretion of lead over a 4 day period following EDTA. The method of the test also differs from that used by Dr. Chisolm, but perhaps the main point is that a more prolonged period of lead excretion was used with the object of measuring the total amount of lead mobilized by the EDTA. He found that 600 ~g of lead was the upper limit in "normals" over 4 days. The increased amount of lead excreted after the fourth day was not significant. The importance of discovering the presence of an increased burden of lead in the body may be more applicable in this country, as prolonged treatment with d-penicillamine of children with ptumbism, or even young adults with past Iead intoxication, may avoid renal damage in later life. As bone biopsy is not a readily acceptable investigation, the prolonged lead excretion after EDTA, as described by Emmerson, may be the most reliable index of an increased body burden of lead. DR. RONALD FREEMAN~ DEPARTMENT OF PAEDIATRICS, PRINCE OF WALES HOSPITAL,
s-zvNzv, N.S.W. 2031, AUSTRALIA
REFERENCES 1. Henderson, D. A.: Follow-up of cases of plumbism in childhood, Australasian Ann. Med. 3: 219, 1954. 2. Henderson, D. A.: Chronic nephritis in Queensland, Australasian Ann. Med. 4: 163, 1955. 3. Henderson, D. A,, and Inglis, J. A.: Australasian Ann. Med. 6: 145, 1957. 4. Emmerson, B. T., and Lecky, D. S.: The lead content of bone in subjects without recognized past lead exposure and in patients with renal disease, Australasian Ann. Med. 12: 139, 1963.
VOlume 74 Number 2
5. Emmerson, B. T.: Chronic lead nephropathy: the diagnostic use of calcium EDTA and the association with gout, Australasian Ann. Med. 12" 310, 1963.
Reply To the Editor: I am glad to respond to the several points raised in Dr. Freeman's letter. His letter provides us with yet another reminder of the restrictive but apparently highly effective public health program started some years ago in the state of Queensland, Australia, for the prevention of plumbism in children. In essence, legislation in Queensland provides for the inspection of all housing where a young infant resides: Any hazardous lead sources found must be removed during the first few months of the infant's life. Should an infant later develop pica, flaking lead pigment paints will not be among the risks that he encounters in his home during the toddler stage. Public health officials elsewhere would do welt to place at least as much emphasis on this truly preventive approach as is now placed on case-finding and mass-screening techniques for plumbism in children. The observation that late lead nephropathy has been found as a sequel of plumbism during early childhood in Queensland, but not elsewhere, remains a mystery. I can add nothing to the possibilities mentioned by Dr. Freeman. I can only say that we have not found it in a group of adolescents studied in Baltimore. The report of Henderson* from Queensland indicated that late lead nephropathy became clinically manifest during adolescence in a small portion of their cases. Had circumstances been comparable in the group studied in Baltimore, at least a few cases of nephropathy should have been found. The most serious question raised by Dr. Freeman is that of the validity of the 24- hour EDTA mobilization test for lead. He suggests, on the basis of Emmerson's2 report, that a 4 day collection of urine following a single infusion of EDTA is necessary to determine the total amount of lead so mobilized. This, in turn, might provide a more accurate index of the body-lead burden as measured by this parameter. Emmerson's data are based on the study of adults with chronic renal disease, most of whom had severe impairment of renal function at the time of study. Under these conditions, urinal-y excretion of lead
Letters to the editor
3 23
continued at a markedly increased level for several days after the injection and in some instances, peak excretion did not occur until the second or third day. In Emmerson's control subjects with normal renal function, peak excretion of lead in the urine occurred in the first 24 hours with return toward values only slightly increased above the control values by the second day. This is in accord with the report of Teisinger and Srbov&,s who studied adults both with and without past occupational exposure to lead. All of their subjects had normal renal function. They showed, on the basis of fractional collections of urine during the first 24 hours, that maximum excretion of lead occurred during the first 6 to 12 hours, with rapid decline toward control levels by the end of the 24 hour period. Experimental studies4 indicate that following an early peak, the excretion of heavy metals in response to a single injection of EDTA decreases exponentially with the passage of time. Fractional collection of urine in the adolescents mentioned by myself5 (all of whom had normal renal function as judged by the usual parameters at the time of study) showed a decreasing rate of excretion of lead in the urine after the first 6 hours. Taken in sum, these and other data indicate that a 4 day collection period is essential in patients with impaired renal function, but that little is to be gained by extending the collection period beyond 24 hours in subjects with normal renal function. In the presence of normal renal function, it would appear that only an insignificantly small fraction of the total lead mobilized by a single dose of EDTA will appear in the urine after 24 hours. Comparison of the results obtained by various authors would be greatly facilitated if a more standardized technique for the administration of the EDTA mobilization test were adopted. The amount of lead mobilized into the urine varies according to the dose of EDTA employed6 and the rate and route of administration of this chelating agent, r, s Various experimental studies suggest that infusion of EDTA as employed by Emmerson rather than rapid intravenous injection should yield a more meaningful result. In children, we have tried to emulate the infusion technique by intramuscular injection. Beyond considerations of technique, there is, of course, the question of what precisely is being measured by the EDTA mobilization test. What portion of the total lead excreted in urine following a single dose of EDTA is mobilized from storage
February, 1969 T h e Journal o[ P E D I A T R I C S
Letters to the Editor Chelating agents in treatment of lead intoxication
To the Editor: Lead intoxication in childhood is a serious disease and Dr. Chisolm is to be congratulated on his timely and excellent review on the use of chelating agents, in the July, 1968, issue of your JOURNAL.
Chronic lead poisoning in children was very common in the early part of the century in the state of Queensland, Australia, and many of these children developed chronic lead nephropathy in adult life.a, 2 Following legislation restricting the use of lead paint in Queensland, there have been very few cases. There is no similar legislation in the state of New South Wales, and in Sydney we are finding an increasing number of children with lead intoxication. There have been 42 cases in the past 5 years, which may seem small by Baltimore standards. I share Dr. Chisolm's approach to long-term treatment with d-penicillamine, and for the past 18 months all new cases have been treated in this manner. Once the acute stage of lead poisoning has passed, the lead which is stored in the skeleton is presumed to be removed over a period of several years. However, the bone-lead levels in adults with chronic lead nephropathy in Queensland, even 30 years or more after the initial lead exposure, were significantly elevated?, ~ Perhaps lead intoxication in Australia runs a different pattern to that in the United States, where chronic renal disease as a sequela to childhood plumbism has not been apparent. This may be related to climatic conclitions and/or the nature and duration of exposure to lead; or perhaps a longer period of follow-up is necessary in the United States. With the use of the bloodqead concentration, endogenous urinary-lead excretion, and the EDTA mobilization test as parameters, Dr. Chisolm found no increased burden of lead in the body in a group of adolescents who had plum_bism in childhood. One would agree that the latter test should provide a fairly sensitive index of
Vol. 74, No. 2, pp. 322-325
the lead burden, but one might question the reliability of the test as used by Dr. Chisohn. How does Dr, Chisolm correlate a normal E D T A mobilization test in Patient S. W. (Table V I I I ) in the face of an increased lead excretion with d-penicillamine? Emmerson 5 is one of those quoted as indicating a figure of 600 /xg Pb per 24 hours as the upper limit of urinary-lead output for the E D T A mobilization test in "normals." This figure, however, Emmerson related to the excretion of lead over a 4 day period following EDTA. The method of the test also differs from that used by Dr. Chisolm, but perhaps the main point is that a more prolonged period of lead excretion was used with the object of measuring the total amount of lead mobilized by the EDTA. He found that 600 ~g of lead was the upper limit in "normals" over 4 days. The increased amount of lead excreted after the fourth day was not significant. The importance of discovering the presence of an increased burden of lead in the body may be more applicable in this country, as prolonged treatment with d-penicillamine of children with ptumbism, or even young adults with past Iead intoxication, may avoid renal damage in later life. As bone biopsy is not a readily acceptable investigation, the prolonged lead excretion after EDTA, as described by Emmerson, may be the most reliable index of an increased body burden of lead. DR. RONALD FREEMAN~ DEPARTMENT OF PAEDIATRICS, PRINCE OF WALES HOSPITAL,
s-zvNzv, N.S.W. 2031, AUSTRALIA
REFERENCES 1. Henderson, D. A.: Follow-up of cases of plumbism in childhood, Australasian Ann. Med. 3: 219, 1954. 2. Henderson, D. A.: Chronic nephritis in Queensland, Australasian Ann. Med. 4: 163, 1955. 3. Henderson, D. A,, and Inglis, J. A.: Australasian Ann. Med. 6: 145, 1957. 4. Emmerson, B. T., and Lecky, D. S.: The lead content of bone in subjects without recognized past lead exposure and in patients with renal disease, Australasian Ann. Med. 12: 139, 1963.
VOlume 74 Number 2
5. Emmerson, B. T.: Chronic lead nephropathy: the diagnostic use of calcium EDTA and the association with gout, Australasian Ann. Med. 12" 310, 1963.
Reply To the Editor: I am glad to respond to the several points raised in Dr. Freeman's letter. His letter provides us with yet another reminder of the restrictive but apparently highly effective public health program started some years ago in the state of Queensland, Australia, for the prevention of plumbism in children. In essence, legislation in Queensland provides for the inspection of all housing where a young infant resides: Any hazardous lead sources found must be removed during the first few months of the infant's life. Should an infant later develop pica, flaking lead pigment paints will not be among the risks that he encounters in his home during the toddler stage. Public health officials elsewhere would do welt to place at least as much emphasis on this truly preventive approach as is now placed on case-finding and mass-screening techniques for plumbism in children. The observation that late lead nephropathy has been found as a sequel of plumbism during early childhood in Queensland, but not elsewhere, remains a mystery. I can add nothing to the possibilities mentioned by Dr. Freeman. I can only say that we have not found it in a group of adolescents studied in Baltimore. The report of Henderson* from Queensland indicated that late lead nephropathy became clinically manifest during adolescence in a small portion of their cases. Had circumstances been comparable in the group studied in Baltimore, at least a few cases of nephropathy should have been found. The most serious question raised by Dr. Freeman is that of the validity of the 24- hour EDTA mobilization test for lead. He suggests, on the basis of Emmerson's2 report, that a 4 day collection of urine following a single infusion of EDTA is necessary to determine the total amount of lead so mobilized. This, in turn, might provide a more accurate index of the body-lead burden as measured by this parameter. Emmerson's data are based on the study of adults with chronic renal disease, most of whom had severe impairment of renal function at the time of study. Under these conditions, urinal-y excretion of lead
Letters to the editor
3 23
continued at a markedly increased level for several days after the injection and in some instances, peak excretion did not occur until the second or third day. In Emmerson's control subjects with normal renal function, peak excretion of lead in the urine occurred in the first 24 hours with return toward values only slightly increased above the control values by the second day. This is in accord with the report of Teisinger and Srbov&,s who studied adults both with and without past occupational exposure to lead. All of their subjects had normal renal function. They showed, on the basis of fractional collections of urine during the first 24 hours, that maximum excretion of lead occurred during the first 6 to 12 hours, with rapid decline toward control levels by the end of the 24 hour period. Experimental studies4 indicate that following an early peak, the excretion of heavy metals in response to a single injection of EDTA decreases exponentially with the passage of time. Fractional collection of urine in the adolescents mentioned by myself5 (all of whom had normal renal function as judged by the usual parameters at the time of study) showed a decreasing rate of excretion of lead in the urine after the first 6 hours. Taken in sum, these and other data indicate that a 4 day collection period is essential in patients with impaired renal function, but that little is to be gained by extending the collection period beyond 24 hours in subjects with normal renal function. In the presence of normal renal function, it would appear that only an insignificantly small fraction of the total lead mobilized by a single dose of EDTA will appear in the urine after 24 hours. Comparison of the results obtained by various authors would be greatly facilitated if a more standardized technique for the administration of the EDTA mobilization test were adopted. The amount of lead mobilized into the urine varies according to the dose of EDTA employed6 and the rate and route of administration of this chelating agent, r, s Various experimental studies suggest that infusion of EDTA as employed by Emmerson rather than rapid intravenous injection should yield a more meaningful result. In children, we have tried to emulate the infusion technique by intramuscular injection. Beyond considerations of technique, there is, of course, the question of what precisely is being measured by the EDTA mobilization test. What portion of the total lead excreted in urine following a single dose of EDTA is mobilized from storage