Document NGkQBE3qaq4vQM8exyzeo2Z0E

N40686 Chapter e /a Page 1 First Draft - Chisolm Sandstead PRIVILEGED INFORMATION ^ ; ; Chapter 6. Appraisal Of Impact in Man ROT FOR PUBLICATION OR PUBLICATION REFERENCES Treatment. The management of clinical and subclinical plumbism consists of two interrelated components: A. Chelation therapy and B. Control of excessive exposure. Chelation therapy does effect Sharp and prompt reduction in tissue levels of lead; however, there is no evidence that it can even under prolonged administration remove all Of the lead in the body. Experimental evidence would indicate that -> ' calcareous lead incorporated into A bone is not accessible to chelating agents. Chelating agents therefore seem indicated and effective for^reducing potentially toxic levels of lead^ principally h h x in the soft tissues^rapidly^)to less toxic or v"'~ -- ethylenediamine tetra nontoxic levels. Three chelating agents are now in wide use. They are^ acetic acid salt of Ca versinate ' - , the calcium disodium/\fKH CaEDTAi, 2,3-dimercaptopropdnal (BAL) and d-penicillamine ms (d-pen, PCA), DPTA and have received brief clinical trials but their effectiveness relative to the agents in wide use in humans has not been adequateljjassessed. The preliminary data indicate that they are not significantly more effective. As dis cussed elsewhere (1) an adequate tnolar excess of chelating agent over lead is apparently essential for effective therapy. Under this principle the higher the estimate of body lead content the higher the dosage and intensity of chelation therapy. In the patients with the most severe degree of acute plumbism the highest doses of chelating agents consistent with safety are indicated. DUP050056025 unapcer o f\ Page 2 An. example of the effectiveness of prolonged calcium versmate therapy is shown in the two figures which illustrates the major laboratory changes that occurred in a sixty year old man who had had a seventeen-year exposure to lead dust and fumes while employed at a smelting plant. The patient presented to the hospital with a myelopathy and t periieral neuropathy affecting the shoulder girdle bilaterally and the distal muscle groups of both upper extremities* His whole blood lead concentration was 67 pg%. Following an extensive evaluation of his endocrine status gDTA he was given sixty-four grams of calcium intravenously in two-gram doses and his response to therapy observed. Electromyographic studies demonstrated a disappearence of increased insertional potentials and uJ ^ fibrillations which present initially. His strength improved markedly in muscle groups which had been quite weak on admission. His hematocrit and mean corpuscular hemoglobin concentration rose to normal (Figure I); while his reticulocyte countywhich was as high as 4. 6% initially when his red cell survival time was decreased to 17 days, decreased to the normal range. DUP050056026 20 Squnry. whc Inch *' $ i:uBl B\'% e* DUP050056027 PLASMA RENIN ACTIVITY (ng/100cc) (Bui) 3NIrt Nl QV31 3AIIVlfWno DUP050056028 Chapter 8 fK Page 3 It appeared that therapy was associated with a mild increase in impairment of his renal function as judged by an increase in his blood urea nitrogren and serum creatinine concentration from the initial levels. Excretions of lead appeared to be decreasing by the end of the thirty--seven days, but was still greater than 1500 jag/24 hours. Figure II illustrates his plasma renin response to acute sodium deprivation and erect posture. before and following therapy. Both supine and erect plasma renin activity increased into the normal range following removal of lead. This finding hmh-4ms--heeB--submittefL~for"pabl-ication| s ugge s ts that lead may impair rnuVss the normal metabolism of the juxtaglomeni^ apparatus. . From the treatment point of view, these observations illustrate that responses to therapy may be slow in occuring in patients with large body burdens of lead. They also suggest that renal functional impairment may occur, and that renal function should be carefully monitored while giving therapy* Even though our previous experience suggests that these impairments are temporary, caution is certainly indicated. DUP050056029 Chapter 8 A Page 4 The control a far of hazardous exposure is in the long run fch& more important aspect of therapy. Repeated brief courses of chelation therapy instituted after the onset of severe clinical symptoms will apparently not prevent the occurrence of permanent injury to the nervous system and the kidney * . No therapeutic agent is currently available which could be safely administered on a long term basis for the purpose of minimizing the absorption in the face of continued hazardous exposure. Current therapy may now be evaluated in terms of its efficacy, direct medical cost for acute and after care^ and damage costs. % DUP050056030 Chapter 8 A Page 5 Efficacy of Chelation Therapy. The efficacy of chelating agents may be evaluated in terms of their influence on the mortality and known adverse health effects of lead on the nervous system, kidney and hematopoietic system. Prior to the advent of chelating agents in 1946 the mortality of severe acute lead encephalopathy was 66%. With BAL first and SBSAx Ca-EDTA a few years later the mortality from encephalopathy was reduced to 25 to 35%. With combined adminis tration of BAL and Ca-EDTA this mortality can apparently be reduced to less than 5% provided that certain important supportive measures are incorporated in the therapeutic regime. 1*2 These critical supportive measures are as follows: 1. Prompt institution of chelation therapy, 2. Withholding of all otal fluids and restriction of parenteral fluid administration to basal requirements and minimal estimates for the replacement of fluid losses, 3. Prompt adequate and continuous control of seizures and 4. Maintenance of a patent airway and adequate ventilation, 3 9 4 lead Severe/encephalopathy may be defined as the presence of intractible seizures .for a period of 24 hours or longer. In such patients the immediate threat to life abates after 48 to 72 hours except in those o maintained in a vegetative state by means of artificial cardiopulmipary assistance. Acute illness of lesser severity (gastrointestinal symptoms, peripheral neuropathy) and subclinical manifestations of lead toxicity do not pose an immediate threat to life and can be treated satisfactorily with either Ca-EDTA (parenteral administration) or d-penici 1 lamine (parenteral or oral administration) in lesser dose than that required for those patients with higher tissue levels of lead with or without central nervous system symptoms, * * Since several of the biochemical and metabolic parameters of acute lead toxicity are promptly suppressed toward normal levels the duration of a course of c helat io^:herapy is best monitored by quantitative measurement of urinary lead excretion during therapy,** When the DUP050056031 unapcer o j*i j Page 6 diuresis of lead under the influence of chelation therapy has pnrHry largely ska subsided the course of therapy is terminated. Adverse side effect's of chelating agents are described elsewhere. ^ d-penicillamine is widely used in Europe but in the United States its use is currently restricted and when used for the treatment of lead poisoning it is currently considered by the ^DA^as an investigational drug. Certain acute toxic biochemical and metabolic effects of lead as well as promptly acute clinical symptoms are rather jOEapsadgc reversed with chelation therapy within' a period of hours. Complete reversal at the subclinical level may require up to two months. (Without therapy such effects may subside slowly over a period of several months provided that excessive exposure is immediately terminated.) * But, the anemia o plumbism and the hematopoietic paramenters of lead toxicity (excess sive^excretion of ALA and coproporphyrin are promptly suppressed and the iron-deficient patient Vs response to iron therapy is restored.^*** The effect of therapy on elevated levels of free erythrocyte as above has not been adequately/ studied. Long term d-penicillamine therapy in children^ and adults^ can maintain normal hematologic indices in the face of continued diuresis of lead. With respect to acute renal injury the Fanconi syndrome (generalized amino aciduria of the renal type, k k &h x mellituria^ and hypopho sp ha'temia with hyperphosf hpturxa) is also reversed without apparent residual injury.^ Normal mineralization of bone is restored following the return of serum phosphorus levels to normal. Similarly subclinical manifestation of deranged endocrine function and metabolism and plasma renin activity return to normal following chelation 8> 0 therapy. * It should be stated, however, that modern more sophisticafeed means \ DUP050056032 vuttp u c j l p r\ Page 7 of assessing renal function have not been systematically applied on a long terra basis in either children or adults to determine whether subclinical impairment of renal function persists following acute renal injury in the absence of continued excessive exposure * Although the toxic effects of lead xx&x on the hematopoietic system are apparently conpletely reversible certain toxic effects of lead on the nervous system and kidney are not completely reversed by chelation therapy. There is in the medical literature no report/of any beneficial effect of chelation therapy xiaxkfag^ciifeKXXfcHKg pn the .nephropathy late lead (with or without secondary gout), nor would any beneficial effect be anticipated in view of the profound impairment of renal function and the profound tissue injury found in the kidneys of such patients.10 * 11* 12 9 13 The responsiveness of impairment of peripheral nerve conduction14 to therapy has not yet been assessed in either children or adults. However, the presence of pes cavus deformities in some patients with late lead nephropathy*^ and the preliminary finding of decreased peripheral nerve conduction velocity in the peroneal nerve of 3 institutionalized children 3 to 10 years after chelation therapy for acute lead encephalopathy*^ suggest that there is a point beyond which injury to peripheral nerves is not completely reversible by chelation therapy. All reported clinical studies in children relative to central nervous system injury are of necessity retrospective in nature. Nevertheless, there is clear clinical evidence that at least 25% of children who survive an episode of acute encephalopathy sustain severe central nervous system injury and that such injury is permanent (profound mental retardation, seizure disorders, gross behavior disorders, atropKv o/vtd paralyses. A paresis) 1 The results of followup studes in 425 children surviving plumbism reported by Peristein and Attala are summarized in Table JET Perlstein and Attala18 observed that the severity and frequency of permanent brain damage appeared to be related to the mode of onset of acute plumbism: for example. DUP050056033 TABLED SEQUELAE OF PIUMBISMBY MODE OF ONSET IN 425 PATIENTS Mode q f Onset Total Encepb. Seizures Ataxia G .l Febrile Asymptomatic 0 *----" *' , ... - o o o * 8 z icno4') *o oQ o I po X? z coirs *0$^ f* z <-- <n z rs $ a 8<fc8 c z 2^s 2^8 z =^8 .O-f$cV-SNM z ts& g> o o o tf 8 oOb sf CM . *ol c"8i c 2 O o .O*** e 8Oo 4? D2 *4* 1 n o o +r as & . E ,r- ; S :c C 2 . *** ; JO0 T5 a. 4> o o o *fe* 3s? .s? 0 ;Ti X CD JO 4OOcG/*>r t--* o o D E *<5 JOo> CO MO s .2<CO : cn. ou o z CM 00 CO a? 8 4 : J 8 CM - . 42 g0 b 8 O <n 1 r Q> z &. s8in -1f- -sJl 0-v fis 8* a z&- s s s N V$ J* t 8 CL e J a u 1 I *2 cL O a Sfl S \ DUP050056034 Chapter 8 A . Page 8 82% of 59 children presenting with acute encephalopathy were left with permanent and often multiple disabilities, while 13% of 159 children presenting with^nT) complaints only were left with seizure disorders. These authors concluded that "the nature and incidence of sequelae seems to be unrelated to the type of treatment employedV 18 These reports just cited refer to the analysis of patients treated 2 permanent with either Ca-EDTA or BAL alone. Coffin, et al. found pSOTSBCEfc residual nervous system injury in 7 of 21 children with acute encephalopathy who were treated with combined BAL and ELTA* Childholni^ currently has 10 childhood survivors of childhood encephalopathy treated with BAL and EDTA under followup. Of .these 10, 5 are severely damaged despite therapy and despite rigorous prevention of further abnormal environmental exposure. One of the 5 is blind, one institutionalized, two have already been excluded from school while only one of the ten is of above average intelligence and functioning at a superior level in school. There are no detailed reports available which attest the relationship between chelation therapy and persistent but nevertheless significant nervous system handicaps such as perseveration, visual motor coordination, fexxgx fine motor control, reaction time, etc in either children or adults. Clearly the limits of efficacy of therapy with respect to centra:! and peripheral nervous function in both children and adults remains to be determined, Control of Exposure. Haeger-Aaronsen19 reported in occupationally exposed adult workers that urinary ALA excretion was quite sensitive to varying levels of exposure* In serial studies on a few individual workers she noted prompt decrease in ALA output on weekends and during vacations and conversely, she noted sharp increases j &j when available safety procedures at the plant were temporarily disregarded. S^lander and Cramer20 instituted an occupational rotation plan whereby workers alternated on a regular basis between tasks with unavoidable high exposure and no exposure. They were. DUP050056035 Chapter 8 Page 9 able to show that mean urinary ALA levels were lower in such rotated groups. But environmental hygiene, automation of hazardous industrial steps, personal good personal hygiene and rotation can apparently minimize metabolic abnormalities and the occurrence of overt illness in occupational situations. In children it is clear that re-exposure to lead in deteriorated housing fete following a single known bout of acute encephalopathy increases the risk of permanent brain damage to virtually 100% (Table M) . 21 This observation has been confirmed by Byers22 and others. Byers and Lord23 noted the occurrence of mental handicaps in 19 of 20 children who did not have classical clinical encephalopathy: a careful re-reading of this report reveals that at least 13 of the 20 had long continued exposure to lead and recurrent episodes of plumbism throughout the pre-school years. It is likely that the data shown in Table I represent the outcome in children exposed to lead in hid housing throughout the pre-school years: Perlstein and Attala XKfeK report continued pica and continued exposure in many of their patients without houi&Xp# stating exact figures. A similar principle applies to the consumers of ivkh fex Brief courses of chelation therapy followed by continued consumption of lead- contaminated moonshine will not prevent the risk of permanent nervous system and renal injury as described by Emspssjmx Emmerson11 , Morgan12 and others. In some, control of excess exposure is the only known effective means of preventing serious functional impairment due to either very intense or very prolonged hazardous environmental exposure. It is clear that chelation therapy is not fully effdctive in reversing injury to the nervous system and kidney once it has occurred. In this light, chelating agents are seen as a useful but limited adjunct to adequate environmental hygiene: they are principally useful and effective for rapid reduction in high soft tissue levels of lead and should be administered on the basis of subclinical evidence of lead toxicity and prior to the onset of obvious clinical * symptoms. The extent to which they may reverse minor functional impairment if administered at this level is not known at this time. DUP050056036 TABLE ^ RELATION BETWEEN INCIDENCE OF SEVERE SEQUELAE* IN THE CENTRAL NERVOUS SYSTEM AND RE-EXPOSURE TO LEAD FOLLOWING RECOVERY FROM AN I NITIAL EPISODE OF ACUTE LEAD ENCEPHALOPATHY. Acute Lead Encephalopathy Severe Casesf Mild Cases 0'. Known re-exposure to lead No known re-exposure to lead With Sequelhoff Sggere. Sequelae , Ah&ertt 70 36 X^M. 89; P<0.05 With Sequelae* Sequelae- , Absent 70 2 17 X2=l 4.135;P<p.01 tFour survivors of severe acute lead encephalopathy who sustained sequelae,.but in whom reexposure to lead was uncertain, are omitted from the table. ftSequelae "^severe, permanent, residual damage to the brain (severe mental retardation, con vulsive disorder, severe behavior disturbance). From: Chisolm, J.J., Jr. and Harrison, H.E.: The Exposure of Children to Lead, Ped. 18:943. 1956. * DUP050056037 />* - * ruu- "t <r 1 <1*^X1 Posts . Treatment costs may be divided into four components: 1) direct medical costs for acute and convalescent care, 2) after care, excess school costs and custodial care for the permanently injured, 3) correction of hazards in housing and 4) preventive health supervision/ Children and adults are considered separately because of differences in exposure and other etiologic considerations (i.4., pica in children ) In young children since separation from exposure is the essential component of therapy, hospitalization is indicated. Out-patient treatment with daily injections of chelating agents into children with persistent pica and continued in tense environmental exposure cannot be condoned as either effective or humane management* While out-patient treatment may kx reduce public medical expense^ it increases costs to parents of the effected children in the form of transportation costs, loss of work and neglect of other members of the family. Thus the epidemiology of childhood plumbism is such that these costs fall most heavily and directly on the poor who are least able to pay. Nevertheless, one treatment center24 reports the treatment of even mild cases of acute encephalopathy on an ambulatory out-patient basis: presumably, this approach reflects the utter hopelessness and futility oil the part of the fcx physician that correction of the lead hazard in substandard housing can ever be attained. The city of Baltimore is unique in the United States in having an "extended pediatric care facility,, Jtor convalescent home where children can be replaced and ^ where they remain until a safe dwelling is found for the family. DUP050056038 The term "safe dwelling" is here defined as modern public housing or an adequately repaired old house. Table 13EX lists actual direct medical costs under field operating conditions incurred between 1965 and 1970 in a group of 45 children wtfcfcfcx with increased body lead burden. SkaocgKHHpx This group of 45 includes 10 survivors of encephalopathy. In this group average total days of acute and convalescent hospitaliza*tion was 100 days - and average direct hospital cost in 34 patients was $2,749. Virtually all of these children were hospitalized at public expense in hospitals that have a blanket basic charge and do not make charges for extras such as special nursing and intensive care. Not shown in Tablelife are the two highest hospital bills which were over $8,000 a piece. In one instance the high cost xas&x resulted from repeated hospitalization for complications of encephalopathy and in the other instance because of an excessively long wait for admission to public housing. This experience is not unique and the cost would be greater in other cities where children are retained in general hospitals for periods of from one to 3 months while an informal quest for * safe housing goes on. In view of the rapid rate of rise of hospital costs during the past 5 years it can be estimated that direct hospital costs for the 45 children Caee Table TL) shown in Table Hi would in 1970 cost $5,498 on the average. Chelation therapy with A BAL and EDTA followed by aMx oral administration of d-penicillamine requires an average of 10 days of hospitalization only. Asymptomatic dhildren do not require treatment in a general hospital but can be handled in a a convalescent facility at reduced cost* Thus, under this approach hospital costs beyond 10 days are directly attributable to delays in the completion of necessary housing repairs. Baltimore allows up to 6 weeks for completion of housing repairs before legal action is taken. New York and Philadelphia now limit the time allowed for compliance, repair the apartment at municipal expense and take out a lien on the property to recover the costs. DUP050056039 I To.We TP Title: Total Days of Hospitalization and Estimated Direct Medical Costs in 45 Children with Initial Blood Lead Levels Greater than BO Micrograms Pb per 100 grams Whole Blood (Including 10 Children with Acute Encephalopathy) Who are not Discharged to Home until after Completion of Removal of Old Lead Pigment Paints from the: Home Environment - Baltimore, Maryland, 1965-1970 Days of Hospitalization A Acute Care (General Hospital) (days) B Convalescent Care (Happy Hills Hospital) (days) No. of Patients (45) Total Days 1108 3402 Mean (Days/patient) 24.7 75.7' Median (Days/patient) 21 Range (80% of Patients) 4 - 70 20 - 203 Actual Costs* (1965 - 1970) No. of Patients (34) Total Cos ts/patient-mean) median 90% range i! Om Total A+ B (days) 4510 100.4 71 25 - 253 93,377.16 2,749.34 2,175.00 1,068.42 - 4,813.95 *Actual costs - Note that basic hospital rates virtually doubled between 1965 and 1970. Most of the 34 children for whom complete hoppital charges could he verified were hospitalized during 1965, 1966, and 1967 at public expense. DUP050056040 Table, 'VC 4r Estimated Current Average Direct Medical Costs to Above <% Children Based on 1970 Basic Hospital Rates in Baltimore, Maryland A Acute Care Unit Cost $100/day Total (45 chil- $110,800 dren) (1108 days) Mean cost/child $2470 (24.7 days) .B Convalescent Care $40/day $136,000 (3402 days) $3028 (75.7 days) * Total (A + B) $246,800 (4510 days) $5,498 (100.4 days) n.b. tue SinceAabove childrenAhandled under general policy that no child is discharged until either home is "deleaded" or family moves into safe modem housing, length of hospitalization is determined by this factor eatUer 4U.vo severity of acute illness. *Actual Costs - Note that basic hospital rates virtually doubled between 1965 and 1970. Most of the 34 children for whom hospital charges could be verified were hospitalized in 1965, 1966, 1967, at public expense. DUP050056041 Sustained medical followup for children with pica who live in substandard old housing is indicated for preventive purposes throughout the years of pica or for an average period of 3 years. The current costs for this are estimated at $120 based on a fee of $15 per out-patient clinic visit. For those with plumbism follow-up period ranges from 2 to 10 years for $225 to $675 per patient. The salary .of a medical social worker or comparable paramedical personnel at one worker per 50 cases should be added to this figure. For children with moderately severe permanent brain damage who require special schooling excess school costs related to transportation costs and smaller class size are currently estimated at $1200 per pupil per year, for$14,400 for ii: years of school through high school per damaged child. For those children requiring institutionalization for custodial care, current costs at the Rosewood State Hospital in Maryland arejapproximately $4000 per year per patient. Data for other institutions in Maryland where such patients have been hospitalized in the past are not available and comparable data from other parts of the country are likewise not immediately available to the Committee. During the past 13 years 19 children had been admitted to the Rosewood State Hospital as a result of lead encephalopathy during early childhood one has died, two have recently been given leave of absence, leaving 16 children in residence at a current cost of $64,000 pet annum. These patients have been hospitalized for a total of 148 patient years or 7.7 years per patient. Nxax None of the 16 remaining in residence are considered suitable for discharge. Should each one survive to 65 years Of age the expenditure of 60 years of institutionalxxafcmxx care at $4000 per annum is estimated at $240,000 per severely damaged child. The total direct medical cost can therefore be estimated according to the final clinical outcome as follows: 1) asymptomatic increased kiHjadx lead absorption without obvious residual permanent injury - $1500 to $2000 per patient; 2) moderate permanent brain damage special schooling required) $18,000 per patient and 3) severe permanent brain damage (insti* tutional car required) $245,000 per patient at current medical costs. DUP050056042 These direct treatment costs may be contrasted with the cost of the repairs to substandard housing to eliminate the * paint hazard. In Baltimore estimated costs range from $150 to $1200 per apartment depending upon the extent of repairs needed, New York City estimates costs at $1263 per apartment25 . Since New Yorkjcity repairs many apartments itself through the municipal emergency repair program, actual figures may shortly be available as the result of the program insti tuted in April 1970* Adequate housing repair is therefore comparable in dollars to the direct medical costs of treatment of a single asymptomatic child with increased body lead burden. Also repairs to substandard housing can prevent lead intoxication in xx the total number of children that may live in that house during the remainder of the house's useful existence. Were houses inspected and repaired prior to the onset of pica,/meSfcal costs could be totally eliminated. Preventive health care costs for children cannot be precisely estimated at this time. With the exception of New York no comprehensive programs are in existence* at. New York City Kxkmxx estimates such costs sas. $12.50 per child for initial case finding and $6,51 per child for each follow-up visit, including blood lead tests. Current research is aimed at reducing the cost of screening both children and housing through improved techniques with a potential for automation and portability for field testing. Treatment costs for adults can be considerably less. In the case of occupational exposure patients can be treated on an ambulatory basis because they can be easily and quickly separated from excessive exposure. Only in the case of severe illness is hospitalization required. In one instance the total hospitalization cost was 07 V $6693.95 . In the case of plumbism due to lead contaminated ,,moonshine,, liquor repeated hospitalization occurred because of recurred ingestion and ready availability of "moonshine,fl specially in the Southeastern part of the United States. Late DUP050056043 ,1 t lead nepropathyJL/t can lead to total costs comparable to those in severely Man damaged children.. Cost in adults might better be estimated on the* basis of an impaired working efficiency and productivity were that data available. 'b DUP050056044 Chisolm - Sandstead Chapter 8 Page References: 1. Chisholm, J. J*, Jr.: The Use of Chelating Agents in the Treatment of Acute and Chronic Lead Intoxication in Childhood, J. of Pediat. 73:1, 1968. 2. Coffin, R., Phillips, J. L. , Staples, W, I. and Spector, S.: Treatment of Lead Encephalopathy in Children, J. Pediat. 69:198, 1966. 3. Chisholm, J, J., Jr. and Harrison, H. E. Treatment of Lead Poisoning in Current Pediatric Therapy , 3rd Edition , W.B. Saunders, Philadelphia, 1968 pp. 918-923. 4. Chisholm, J. J., Jr, Treatment of Acute Lead Intoxication,Choice of Chelating Agents and Supportive Therapeutic Measures. Clinical Toxicology 3:527, 1970. 5. Selander, S* Treatment of Lead Poisoning : A Conparison between the Effects of Sodiumf Calcium Edatate and gang Penicillamine Administered orally and intra venously, Brit, J. Industrial Med. 24:272. 1967. 6. Goldberg, A., Smith, J. A. and Lochhead, A. C. Treatment of Lead-Poisoning with Oral Penicillamine. Brit. Med. J, 1^: 1270, 1963. 7. Chisholm, J. J., Jr, Amino Aciduria as a Manifestation of Renal Tubular Injury in Lead Intoxication and a Comparison with Patterns of Amino Aciduria seen in other Diseases. J. Pediat. 60:1. 1962. 8. McAllister, R, G., Jr., Michelakis, A. M. and Sandstead, H. H. Plasma Renin Activity in Chronic Plumbism. Arch. Int. Med. 123:632. 1965, I Berk, P. D., Tschudy, D. P., Shepley, L. A., Waggoner, J. G., and Berlin, M. I. i* Hemotologic and Biochemical Studies in a Case of Lead Poisoning. Amer. J. Med, [48:137, 1970. 1 _ ..... 10, EmmerSon, B. T.: Chronic Lead Nephropathy: The Diagnostic Use of Calcium EDTA and the Association with Gout, Australian Annals Med. 12:310, 1963, DUP050056045 Chisolm - Sandstead Chapter 8 Page iy 11. Emmerson, B, T.: The Clinical Differentiation of Lead Gout from Primary Gout. Arthritis and Rheumatism 11:623 % 1968* 12. Morgan* J. M., Hartley, M. W. and Miller, R. E. t Nephropathy in Chronic Lead Poisoning* Arch. Intern. Med . (Chicago) 118 :17% 3056. t 7 k 13. Richet, E. G., Albahary, C,, Ardaillou,* R., Sultan, C. and Morel-Maroger, A.: Le Rein du Satumisme Chronique. Rev. Franc. Rdxif Btud. Clin. Biol. -9:188, 1964. 14. Catton, M. J*, Harrison, M. J. G., Fullerton, T. M. and iforysngtnrT^YYYYYyygic^^ Kazantzis, G.: Subclinical Neuropathy in Lead Workers. Brit. Med. J. 2.: 80, 1970. 15. Feldman, R. G., and Chisholm, J. J.,' Jr. t/r^ublished data, 16. Chisholm', J. J., Jr.* Unpublished data. 17. Smith, H. D. Pediatric^ead Poisoning. Arch. Environment.Hlth. 8:256, 1964. 18. Perlstein, M. A. and of Attala, R. Neurologic Sequelae in Plumbism in Children Clin. Pediatrics 5x292, 1966. 19. Ha^KansixanBBasxxHaege r-Aronsen JJ, Studies on Urinary Excretion of Amino phonetic ' Lebulinic Acid and other Hk h h Heme Precursors in Lead Workers and Lead intoxicated Rabbits. Scandinav. J. Clin, and Lab. Invest. 12^ 47, 1, 1960 (Suppl.) Lou's note. Find Selander and Crame-from other reference and 20. Selander, Rx S. and Crame, R. cban8e of Crame Interrelationships between Lead in Blood, Lead in Urine, and ALA in Urine during Lead Work* Brit. J. Mkix Indust, Med. 27:28. 1970. 21. Chisholm, J. J., Jr., and Harrison, H. E, The Exposure of Children to Lead. Pediatrics 18:943. 1956. 22. Byers, R, K. Lead Poisoning: Review of the Literature and Report on 45 Cases. Pediatrics 23^:585, 1959. 23. Byers, R. K. and Lord, E. E. : .1kkx Late Effects of Lead Poisoning on Mental Development. Amer* J* Die. Child. 66:471. 1943. DUP050056046 ^-2. / ^ L. 24, Sachs, R. K, Blanksma, %. A,, Murray, E. F., and OfConnell, M, J, Ambulatory Treatment of Lead Poisoning: Report of i&fiQx 1, ISSCases*. Pediatrics 46:389, 1970. 25, Guinea - Personal Communication For exact reference for paper recently presented at APHA 26, Tyler, R, G, Personal Communication For reference to be supplied by lim for me 27, Sandstead Personal Communication V \ DUP050056047