Document YDK7M4Lx6yz5Oqyw2mpvE49zD

,/ > Me'Cliono t?eOorwfmenntt of Mediciine Division Of Neurology 1 March 1968 MISSISSIPPI MEDICAL CENTER 2500 North State Street JACKSON 6, MISSISSIPPI Area Code 601 362-4411 Robert A. Kehoe, M. D. Professor Emeritus of Occupational Medicine Kettering Laboratory > College of Medicine University of,Cincinnati Eden Avenue Cincinnati, Ohio 45219 Dear Dr. Kehoe: Enclosed is a report of the studies we have done on patients with amyotrophic lateral sclerosis concerning which we have been in correspondence with you for the last several years. We would appre ciate your reading the paper and giving us the benefits of any comments you might have on it. We are particularly interested in your comments on what we have said about the normal levels quoted by most laboratories for lead and mercury as discussed on pages 5 and 6 of the text. We wonder if what we have said is correct. We certainly appreciate your helping us by reading this paper and will look forward to any comments you may have on it. With kindest regards, I am Yours sincerely. Robert D. Uurrier, M. D RDC/lh HE 0015969 1 Amyotrophic Lateral. Sclerosis and Metallic Toxins by Robert D. Currier and Armin F. Haerer In a recent survey of amyotrophic lateral sclerosis (ALS) and multiple sclerosis in Mississippi^ it was noted that amyotrophic lateral sclerosis was more common in persons who had engaged in neavy onysical labor, particularly farming. As a consequence of ana in addition to the history of heavy labor an apparently, dispro portionate number appeared to have been exposed to metal-containing toxins in their work. References regarding a possible relationship between metal toxicity and amyotrophy can be found in the literature dating back to the work of Wilson in 1907^ who reported ALS-like amyotrophy from chronic lead poisoning. Chronic mercurialism in farmers was incriminated by Brown as a possible cause for a syndrome resembling ALS. Kantarjian 4 more recently described a similar syndrome which followed poisoning by ingestion of mercurials. There do not appear to be any reports of an acute or delayed amyotrophic syndrome as a consequence of exposure to gold, silver, zinc or arsenic. However, no detailed investigation of chronic or acut'd intoxication by heavy From the Division of Neurology, Department of Medicine, Univ. of Mississippi Medical Center, Jackson, Mississippi, 39216. Partially supported, by NIH grants NBO 5215 and FR 00091. Read in part at the 2nd Pan American Congress of Neurology; 1967, San Juan, Puerto Rico. HE 0015 70 N20242.01 T--T 2 metal compounds or arsenicals as a possible cause of clinically typical ALS ap.oears to have been undertaken. Heavy metal analyses on tissues from such patients have not. been reported in detail, possibly because V reliable nietnods for testing are of-meg recent development. Because of the frequent positive history of exposure to substances containing metallic compounds in the present series of patients witn ALS it was felt that a systematic search for traces of these substances in the urne and tissues might oe worthwhile and that empirical therapeutic trials with various chelating agents might be justified, even though there might not be increased concentrations of these metals in the oody fluids. C Reports by Steinke ant others have hintetl that an association may exist oetween ALS and abnormal carbohydrate metabolism. Pyruvate repre sents a focal point in intracellular carbohydrate metabolism which may oe deranged as well in some metal intoxications, notably arsenic, but also in lead and mercury poisoning to some degree. Since a possible abnormality of carbohydrate metabolism might therefore exist in ALS patients due to metal exposure, the serum and cerebrospinal fluid pyru- ' vatu in a portion of the present group of patients was also investigated. Methods Over a four year period (1962-1966) 31 patients were examined and i found to have definite ALS arid were thus included in this series. The toxicity studies omit 10 of the 31 because no specimens were obtained for various reasons. Letailed histories were obtained with special emphasis on exposure to metals, and neurologic examinations were done on all. patients. The K* 0015171 H -Li i-L i? g L j ;? - ;? * usual baseline investigations for establishing the diagnosis of ALS Deyond reasonable doubt were carried out, including x-rays, electromyonraphv, cerebrospinal fluid examinations, etc. Analyses for lead, mercury and arsenic were done on 24 hour urine spec-mens that had been collected so that the urine never touched metal and shat were stored in washed metal-free containers. Three laboratories empl yving different methods performed the analyses. Bio-Science Labora tories of Van Nuys, California used a modification of Hubbard's method6 - -'or mercury analysis, their own unpublished method for analysis of lead, and a spectrophotometric method for the determination of arsenic. The Tnirc United States Army Medical Laboratory at Fort McPherson, Georgia usea a modification of the method of Cholak for lead determination and O the mercury determination method of Nobel and Nobel. The methods used oy trie Mississippi State Chemical Laboratory were those of Elkins^ and the Chemical Rubber Company. Therapeutic courses of versenate, penicillamine and thioctic (lipoic) acid were given to several patients. The details are described under re sults. Lead and mercury analyses on autopsy tissues were performed by the Kettering Laboratory of Cincinnati (Drs. Kehoe and Tepper). Results i A total of 31 patients with definite ALS were studied. An additional 15 patients with probable, rather than definite ALS in whom the history and results were similar were also studied but will not be reported in detail at this. time. The majority of the patients listed in Table 1 were males as is true in most other series. The division between whites and Negroes corresponded to the population distribution in the state of Kir 0015072 4. Mississippi (58% ;hite). The age of onset (54 years) and duration of disease (3 years) correspond well with those of other series. None of the patients had significant abnormalities on x-rays of the spine and skull. Eighteen of the 31 were studied with electromyography which in all cases was consistent with ALS. The cerebrospinal fluid was normal in 23 patients and showed a slight increase in protein in five. Three patients had myelograms which were normal. Postmortem examinations on 7 patients were consistent grossly and microscopically with a diagnosis of ALS. Table 2 summarizes the occupational data. Ten patients were fulltime fanners growing cotton and other crops. Eight other patients were part-time farmers. Thirteen performed non-farming heavy manual labor throughout most: of their lives. Seven patients had occupations witn only slight or moderate physical exertion, and several others did part-time work involving heavy physical labor. There is obviously some overlap between these groups. Table 3 details the history of .exposure to toxic agents. Sixteen patients, about half, had a definite prolonged exposure to toxic materials Nine of these were exposed to sprays and/or compounds used in treating cotton seed (seed disinfectants) which contained various mercurial com pounds. Five of the 16 worked with substances containing lead and two i were exposed to other metals. In addition, ten other patients had pro bable exposure to metals as listed under II in this Table. Seven patients (tad no definite history of exposure to toxic agents or-the history was un certain. Several patients had more than one type of exposure. Metal_ detenninations. Table 4 summarizes the concent -ations of lead, mercury and arsenic in urines of the patients before treatment with HP 0015073 crslatinq agents. Six arsenic determinations, 20 lead determinations, and lb mercur determinations were done. The average concentrations in micro grams per liter of urine are fisted with the range in micrograms per liter a; a the n-.mber of patients who showed excretions above the "normal" limit given by he laboratories. There were two patients with elevated urinary It ad concentrations and one with an elevated urinary mercury concentration. Tab! ; 5 compares the heavy metal excretions of patients with a posi tive expo .ure history to the excretions of those who were not exposed. For arsenic, there were no values above the "normal" upper limits in the u''ir.es of patients with or without a history of exposure. Two patients nid slightly elevated urinary lead concentrations, one of whom had a positive exposure history and one who did not give such a history. The one nation1. with elevated mercury values stated that he had not been ex cised to 2' ' mercurial compound. In all patients with a history of exposore witn f)ur exceptions (patients #1, 22, 28 and 30, Table 6) the ex posure rad continued until the onset of the disease. The urine sample was obtainei during the usual diagnostic hospitalization period at an average time of one year after onset. Table 6 summarizes the exposure history, treatment regimens and metal determinations in all exposed patients. Thus, it appears that although there is frequently a history of t-<posure these substances are not often present in abnormal amounts in 21 hour urine specimens and there appears to be no correlation of the history of exposure to the amount of toxin found. It cat be seen that the laboratories give different values for the upper limf.s of normal for heavy metals in the urine. In the present study each value is considered normal or abnormal in relation to the 0015074 6 -tVt; However it must be remembered that upper limits of normal for these elements are related to levels set with consideration of the possible production of symptoms in patients with a history of known exposure. Tne true normal excretions of lead and mercury in non-exposed per sons are considerably lower; lead being 32 /jg/L urine (S.D. 10/jg)^ and tne total daily output of mercury in the urine being 10 to 50pug.^ > Hi If and Castano state that "because of the discrepancy in the literature as to the normal urinary lead content we have assumed that any urine containing more than 50 micrograms of lead per liter is worthy of notation." In the light of this comment, it might be pointed out that snore were five different patients before treatment in our series with one or more values each that exceeded 50 micrograms of lead per liter of urine. Pyruvate studies. Studies of the blood pyruvate concentration on fasting specimens were done on five patients and spinal fluid pyruvate was measured in 7 patients. These were all within the normal ranges. Treatment^ it was felt that perhaps a single urinary 24 hour sampling for arsenic, lead or mercury might not reflect adequately the body stores if these substances. For this reason, and since ALS is a relentlessly orogressive disease it was decided that treatment .with chelating agents might be 'worthwhile. Five patients received therapeutic courses of ver- i. senate, four received penicillamine and three received thioctic (Ifpole acid. Of those patients with consistently normal lead levels before treatment, urinary load concentrations rose after treatment in three cases, fell in two, but remained "normal" at all times. Of the two patients with lead values above "normal", the level dropped to normal before treatment in one, and treatment did not change it. The other KB 0015075 i i 6. t- l I 7 patient's lead value dropped after treatment. The patient who had elevated mercury levels showed a lower urit ary concentration a few days after treatment, but the concentration had risen almost to the pretreatment level 3 months later. In none of the patients did the treatment appear to change the course of the disease. Post mortem studies. Tissues obtained at autopsy from 2 patients of the group were sent for lead and mercury analyses to the Kettering Laboratory. One of these patients had no exposure to heavy metals but tne otner had a definite history of exposure to various cotton poisons N. on several occasions. Both had normal amounts of heavy metals in their urines done prior to death and both had pa.hoTogically verified ALS. Analysis of spinal cord, liver, and kidney in one, and bone, brain, liver, kidney and spinal cord in the other patienr revealed normal concentrations of lead and mercury with the exception of a slightly increased amount of mercury in one patient's kidneys. This wa: interpreted as possibly secon dary to administrat'on of a mercurial diuretic, although there was no definite history the-1 the patient ever had been so treated. It should be notea that one patient had been treated with thioctic acid and versenate and tra other with \ enici11 amine. Discussion i It appears that no correlation can be made between the amount of lead and mercury in any of these patients' tissues and their ALS. Tne normal amounts of pyruvate in the blood and spinal fluids would tend only to rule out acute arsenic or heavy metal intoxication since the pyruvate (ioes not remain elevated for long after these toxins are removed. 1 be possibility must be considered that exposure to heavy metals or j</ 0015 ^7 fi mmism 4< y !'l r*: > v: arsen.ic at an earlier time in life may then or later initiate a process of abiotroohy which becomes evident clinically at a time vhen pathologic concentrations of such substamos are no longer detectable in the body fInins or tissues. It appears difficult to prove or disprove this at i-':. om-vmit time. This is esp; cially pertinent since the present studies obtained from one to 20 yt ars after contact with the possibly toxic 00000asees. It thus is not unexpected that most of the evidence had disaon/c-aro .i if indeed it -had ever existed. Perhaps study of tissues from oatienos with fulminating ALS r of some who died early in their disease rroi.. unrelated causes might gi e added information. The changes in lead and m rcury concentrations following the thera- oio trials uo not seem to p esent any consistent pattern. it cun be concluded from he present data that no relationship nas oe-ju shown- between exposure to the substances analyzed and amyotrophic laceral sclerosis in this pati nt group. ummary Tiie maj rity in this seri s of 31 patients with Alt had been exposed so metal lie .oxins in their wc--k but no convincing evidence could be found of abn srrnal amounts of 1 ad, mercury or arsenic in their urine or in necropsy .issues. i K'E' 0015 77 9 Bibliography 1. Breland, A.E., and Currier, R. D.: Multiple sclerosis and amyotropnic lateral sclerosis in Mississippi, Neurology, 17:1011/1016, 1967, 2. Wilson, S. A. K.: The amyotrophy of chronic lead poisoning: /toyotrophic lateral sclerosis of toxic origin. Rev. Neurol. & Psychiat., `5:441 , 1907. 3. Brown, I. A.: Chronic mercurial ism: A cause of the clinical syndrome of amyotrophic lateral sclerosis. Arch. Neurol. & Psychiat., '2:674, 1954. 4. Kantarjian, A. D.: A syndrome clinically resembling amyotrophic '.ateral sclerosis following chronic mercurial ism. Neurology, 11:639, 1961. 5. Steinke, J., and Tyler, H. R.: The association of amyotrophic lateral sclerosis (motor neuron disease) and carbohydrate intolerance, a clinical study. Metabolism, 13:1376, 1964. 6. Hubbard, D. N.: Determination of mercury in urine. Anal. Chem., 12:768, 1940. 7. Cholak, J., Hubbard, D. N., and Burkey, R. E.: The determination, of lead in freshly voided urine. A rapid screening test. J. Ind. Hyg. & Tox., 30:59, 1948. i 8. Nobel, S., and Nobel, D.: Determination of mercury in urine. Clin. Chem., 4:150, 1958. 9. Elkins, H. B.: The Chemistry of Industrial Toxicology, 1950, John Wiley & Sons, Inc., New York. 10. Kehoe, R. A.: The metabolism of lead in man in health and disease. The Harben Lectures, 1960. J. of the Royal Institute of K& 00151? 8- Public Health and Hygiene, 1961. 11. Poison, C. J. and Tattersall, R. N.: Clinical Toxicology, 1969, J. B. Lippincott Co., Philadelphia. 12. Hilf, R., and Castano, F. F.: A simplified method of deter mination of urinary lead. Clin. Chem., 9:163, 1963. 0015079 I ALS S eries, General Data 'b ~o o o S CO CO o to ft- CO -n CO ~n c+ fD ZT O ' "O _! 3 X3 _i. 3 3 X3 3 c4 ft) fD O "5 3 o O^ ^o --s XX c+ 3 CO = 1 1 fD 3 (D CL> _j . -- in 3 *< -s 3 o Q> Cd to << x: "3 (/) to Ol to o 3 _i. a' "C 3 3 ~- O o a O 3 zz CD s 00 to CD CD r+ c+ o CD O O to 3 -+i O a. --h --j . to CL fD --j . 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