Document XnnmKkDQ3vmJMQ9GRQvYXb7G

>' M 'CJic i n e t i e pLo r t; m,o not fo f M ediciin e D ivision Of N eu ro lo g y 1 March 1968 . MISSISSIPPI M EDICAL CENTER 2500 N orth State Street JA CKSO N 6, M ISSISSIPPI Area Gode 60] 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. Currier, M. D. RDC/lh KE 0015069 Amyotrophic Lat eral. Sclerosis and M et allic Toxins ' by Robert D. Currier and Armin F. Haerer In a recent survey of amyotrophic lat eral sclero sis (ALS) and mult iple sclero sis in M ississippi^ i t was noted t hat amyotrophic lat eral sclero sis was more common in persons who had engaged in nc-avy onysical labor, p art icu lar ly farming. As a consequence of ana in aadit ion to the hist ory of heavy labor an apparently, dispro portionat e number appeared to have been exposed to met al- cont aining t oxins in t heir work. .. References regarding a possible relat ionship between metal t o xicit y and amyotrophy can be found in the lit er at u r e dating back to the work of Wilson in 1907^ who reported ALS- like amyotrophy from chronic lead poisoning. Chronic mercurialism in farmers was O incriminat ed by Brown as a possible cause f or a syndrome resembling MLS. Kant arjian 4 more recent ly described a sim ilar syndrome which followed poisoning by ingestion of m ercurials. There do not appear to ;ie any reports of an acute or delayed amyotrophic syndrome as a consequence of exposure to gold, si l v e r , zinc or arsenic. However, no det ailed invest igat ion of chronic or acutd int oxicat ion by heavy from the Division of Neurology, Department of M edicine, Univ. of M ississippi Medical Cent er, Jackson, M ississip p i, 39216. Pa r t ia lly 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. 2 met al compound 3 or arsenicals as a possible cause Of cl i n i ca l l y t ypical ALS apoears to have been undertaken. Heavy metal analyses on t issues from such pat ient s have not. been reported in d et ail, possibly because V reliab le nietnods f or t est ing are of-m*g recent development. Because of the frequent posit ive hist ory of exposure to substances containing m et allic compounds in the present series of pat ient s witn ALS i t was f e l t that a syst emat ic search f or t races of these substances in the u r n e and t issues might oe worthwhile and t hat empirical t herapeut ic t r i a l s with various chelat ing agents might be j u st i f i e d , even though there might not be increased concent rat ions of these metals in the body f lu id s. ' Reports by St einke ant others have hintetl t hat an associat ion may exist between ALS and abnormal carbohydrate metabolism. Pyruvate repre sents a focal point in in t r a ce llu la r carbohydrate metabolism which may ce deranged as well in some metal int oxicat ions, notably arsenic, but also in lead and mercury poisoning to some degree. Since a possible abnormality of carbohydrate metabolism might t heref ore exist in ALS pat ient s due to metal exposure, the serum and cerebrospinal f lu id pyru- ' vate in a portion of the present group of pat ient s was also invest igat ed. Methods Over a four year period (1962-1966) 31 pat ient s were examined and i found to have def init e ALS arid were thus included in t his ser ies. The t oxicit y st udies omit 10 of the 31 because no specimens were obtained for various reasons. .. det ailed hist o ries were obtained with special emphasis on exposure to metals, and neurologic examinations were done on all. pat ient s. The KE" 0015171 -in it -1} ; t f! -1 ` w l usual baseline invest igat ions f or est ablishing the diagnosis of ALS beyond reasonable doubt were carried out, including x- rays, electromyo- nraphv, cerebrospinal f lu id examinations, et c. .' Analyses for lead, mercury and arsenic were done on 24 hour urine specimens that had been collect ed so t hat the urine never touched metal and shat were stored in washed met al- free cont ainers. Three laborat ories empl jying dif f erent methods performed the analyses. Bio- Science Labora t ories of Van Nuys, Calif ornia used a modificat ion of Hubbard's method^ - *or mercury an alysis, t heir own unpublished method f or analysis of lead, and a spectrophotometric method f or the determination of arsenic. The y Tnirc United St at es Army Medical Laboratory at Fort McPherson, Georgia usee a modificat ion of the method of Cholak f or lead determination and O the mercury determination method of Nobel and Nobel. The methods used oy trie M ississippi St at e Chemical Laboratory were those of Elkins^ and the Chemical Rubber Company. Therapeutic courses of versenat e, penicillamine and t h io ct ic ( lip o ic) acid were given to several pat ient s, The d et ails are described under re su lt s. Lead and mercury analyses on autopsy t issues were performed by the Ket tering Laboratory of Cincinnat i (Drs. Kehoe and Tepper). Resul t s i A t ot al of 31 pat ient s with d ef init e ALS were st udied. An addit ional 15 pat ient s with piobable, rat her than def init e ALS in whom the hist ory and result s were sim ilar were also st udied but w ill not be reported in det ail at t his. time. The majorit y of the pat ient s list ed in Table 1 were males as is t rue in most ot her ser ies. The division between whites and Negroes corresponded to the population dist ribut ion in the st at e of ^r 0015072 4. Mi ssi ssi p p i (58% ;h it e) . The age of onset (54 years) and duration of disease (3 years) correspond well with those of ot her ser ies. None of the p at i e n t s had sig nif icant abnormalit ies on x- rays of the spine and sk u ll. Eighteen of the 31 were st udied with electromyography which in all cases was consist ent with ALS. The cerebrospinal f lu id was normal in 23 pat ient s and showed a slig h t increase in prot ein in f iv e . Three pat ient s had myelograms which were normal. Postmortem examinations on 7 pat ient s were consist ent grossly and m icroscopically with a diagnosis of ALS. Table 2 summarizes the occupational data. Ten pat ient s were f u l l time fanners growing cotton and other crops. Eight ot her pat ient s were part - t ime farmers. Thirt een performed non-farming heavy manual labor throughout most: of t heir l iv e s. Seven pat ient s had occupations witn only slig ht or moderate physical exert ion, and several others did part-cime work involving heavy physical labor. There is obviously some overlap between these groups. Table 3 d et ails the hist ory of exposure to t oxic agents. Sixteen pat ient s, about half , had a d ef init e prolonged exposure to toxic m at erials Nine of these were exposed to sprays and/ or compounds used in t reat ing cotton seed (seed d isinf ect ant s) which contained- various mercurial com pounds. Five of the 16 worked with substances cont aining lead and two i were exposed to other met als. In addit ion, ten ot her pat ient s had pro bable exposure to metals as list e d under I I in t his Table. Seven pat ient s (tad no d ef init e hist ory of exposure to t oxic agents or- t he hist ory was un cert ain. Several pat ient s had more than one type of exposure. MetaJ det enninat io ns. Table 4 summarizes the concent -ations of lead, mercury and arsenic in urines of the pat ient s before treatment with crelat inu agents. Six arsenic det erminat ions, 20 lead det erminat ions, and lb mercur determinations were done. The average concent rat ions in micro grams per l i t e r of urine are f ist ed with the range in micrograms per l i t e r a? a the n-.mber of pat ient s who showed excret ions above the "normal" lim it given by -.he laborat ories. There were two pat ient s with elevat ed urinary k ad concent rat ions and one with an elevat ed urinary mercury concent rat ion. Tab! ; 5 compares the heavy metal excret ions of pat ient s with a posi t ive expo .ure hist ory to the excret ions of those who were not exposed. F:.r arsenic, there were no values above the "normal" upper lim it s in the u-'ir.es of pat ient s with or without a hist ory of exposure. Two pat ient s nid slig h t ly elevat ed urinary lead concent rat ions, one of whom had a posit ive exposure hist ory and one who did not give such a hist ory. The one nat ion1, with elevat ed mercury values st at ed t hat he had not been ex cised to a- ' mercurial compound. In a ll pat ient s with a hist ory of expo sure witn f ) ur exceptions (pat ient s #1, 22, 28 and 30, Table 6) the ex posure had continued unt il the onset of the disease. The urine sample was obtaine i d-uring the usual diagnost ic hospit alizat ion period at an average time of one year af t er onset . Table 6 summarizes the exposure hist ory, treatment regimens and metal determinations in a ll exposed pat ient s. *" Thus, it appears t hat although t here is frequent ly a hist ory of i o<posure these substances are not often present in abnormal amounts in 21 hour urine specimens and there appears to be no correlat ion of the hist ory of exposure to the amount of t oxin found. ' I t cat be seen t hat the laborat ories give dif f erent values for the upper lirnics of normal for heavy metals in the urine. In the present study each value is considered normal or abnormal in relat ion to the 0015074 figures Given by the lab o rat o ry perform ing t he t e st . However i t must be remembered t hat upper lim it s of normal f or these elements are relat ed to levels set with considerat ion of the possible production of symptoms in pat ient s with a hist ory of known exposure. Tne t rue normal excret ions of lead and mercury in non-exposed per sons are considerably lower; lead being 32 / jg/ L urine (S.D. 10 / ig ) ^ and tne t ot al daily output of mercury in the urine being 10 to 50/ jgJ"* >' l i i l f and Castano st at e t hat "because of the discrepancy in the lit erat u re as to the normal urinary lead content we have assumed that any urine cont aining more than 50 micrograms of lead per l i t e r is worthy of not at ion." In the light of t his comment, i t might be pointed out t hat mere 'were f ive dif f erent pat ient s before treatment in our series with one or more- values each that exceeded 50 micrograms of lead per l i t e r of urine. Pyruvate st ud ies. St udies of the blood pyruvate concent rat ion on fast ing specimens were done on f ive pat ient s and spinal f luid pyruvate was measured in 7 pat ient s. These were all wit hin the normal ranges. Treatment. I t was f e l t t hat perhaps a single urinary 24 hour sampling for arsenic, lead or mercury might not r ef lect adequately the body st ores of these substances. For t his reason, and since ALS is a r elen t lessly orogressive disease i t was decided t hat treatment .with chelat ing agents night be worthwhile. Five pat ient s received t herapeut ic courses of ver ' V I. senat e, four received penicillamine and t hree received t h io ct ic ( lip o ic) acid. Of those pat ient s with consist ent ly normal lead levels before treatment, urinary load concent rat ions rose af t er treatment in three cases, f e ll in two, but remained "normal" at all t imes. Of the two pat ient s with lead values above "normal", the level dropped to normal before treatment in one, and treatment did not change i t . The other 0015 r\ T ( i ^ > 7 '`pat ient ' s lead value dropped af t er t reatment. The pat ient who had elevat ed mercury levels showed a lower urit ary concent rat ion a few days af t er t reatment, but the concent rat ion had risen almost to the pretreatment level 3 months lat er . In none of the pat ient s did the treatment appear to change the course of the disease. , Post mortem st u d ies. Tissues obtained at autopsy from 2 pat ient s of the group were sent for lead and mercury analyses to the Kett ering Laboratory. One of t hese pat ient s had no exposure to heavy metals but tne otner had a d ef init e hist ory of exposure to various cotton poisons on several occasions. Both had normal amounts of heavy metals in t heir urines done prior to death and both had pa.hoTogically verif ied ALS. Analysis of spinal cord, l i v e r , and kidney in one, and bone, brain, l i v e r , kidney and spinal cord in the ot her pat ienr revealed normal concent rat ions of lead and mercury with the exception of a slig h t ly increased amount of mercury in one pat ient ' s kidneys. This wa: int erpret ed as possibly secon dary to adm inist rt ' on of a mercurial d iu r et ic, although t here was no def init e hist ory th; t the pat ient ever had been so t reat ed. I t should be notea that one pat ient had been t reat ed with t h io ct ic acid and versenate and t ra other with ; enici 11 ami ne. Discussion ,,` I I t appears that no correlat ion can be made between the amount of lead and mercury in any of these pat ient s' t issues and t heir ALS. Tne normal amounts of pyruvate in the blood and spinal f luid s would tend only to rule out acute arsenic or heavy metal int oxicat ion since the pyruvate (ioes not remain elevat ed f or long if t e r these t oxins are removed. I ne p o ssib ilit y must be considered t hat exposure to heavy metals or O O lsm arsenic at an. e a r lie r time in l i f e may then or lat er i n it ia t e a process of abiotroohy which becomes evident cl i n i ca l l y at a time vhen pathologic concent rat ions of such substances are no longer det ectable in the body orf 1ui*is t issues. I t appears d i f f i cu l t to prove or disprove t his at t ime. This is esp ecially pert inent since the present st udies obtained from one to 20 years af t er contact with the possibly t oxic .......r^ rr- s. I t thus is not un'xpected t hat most of the evidence had d is ; i f indeed it- had ever exist ed. Perhaps study of t issues from oatienos with fulminating ALS r of some who died early in t heir disease \'o\.. unrelated causes might gi e added informat ion. The changes in lead and m rcury concentrations following the thera;x_^ i ; t r i a l s uo not seem to p esent any consist ent pat t ern. it Can be concluded from he present data that no relat ionship nas oe-jo shown between exposure to the substances analyzed and amyotrophic 1acoral sclerosis in this pati -nt group. .ummary The mai r i t v in t his seri s of 31 pat ient s with ALo had been exposed so metallic oxins in t heir wo -k but no convincing evidence could be 1fouua of abnormal amounts of ad, mercury or arsenic in t heir urine or in nccroosv ..issues. \ K F 0015 71 9 Bibliography 1. Breland, A . E. , and Currier, R. D.: M ult iple scler o sis and amyotropnic lat eral scler o sis in M ississip p i, Neurology, 17:1011/ 1016, 1967, 2. Wilson, S. A. K.: The amyotrophy of chronic lead poisoning: / toyotrophic lat eral sclero sis of t oxic origin. Rev. Neurol. & Psychiat ., ` 5:441 , 1907. - 3. Brown, I . A.: Chronic mercurial ism: A cause of the clin ica l syndrome of amyotrophic lat eral scle r o sis. Arch. Neurol. & Psychiat ., ' 2:674, 1954. 4. Kant arjian, A. D.: A syndrome cl i n i ca l l y resembling amyotrophic ' .at eral sclero sis following chronic mercurial ism. Neurology, 11:639, 1961. 5. St einke, J. , and Tyler, H. R.: The associat ion of amyotrophic lat eral sclero sis (motor neuron disease) and carbohydrate int olerance, a clin ica l 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 f reshly voided urine. A rapid screening t est . 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. Elk in s, H. B.: The Chemistry of I ndust rial Toxicology, 1950, John Wiley & Sons, I n c., New York. 10. Kehoe, R. A.: The metabolism of lead in man in health and disease. The Harben Lect ures, 1960. J. of the Royal I n st it u t e of Public Health and Hygiene, 1961. 11. Poison, C. J. and T a t t e r sa l l, R. N.: Clin ical Toxicology, 1959, J. B. Lippincot t Co., Philadelphia. 12. H ilf , R., and Castano, F. F.: A sim plif ied method of deter mi nation of urinary lead. Clin . Chem., 9:163, 1963. 0015079 I TABLL 1 ALS Series, General Data Total patients Males Whites Negroes , Onset of disease, age Duration of disease, average years Spine x- rays normal Spine x- rays mild degenerative changes Electromyography done ana compatiole with ALS 4 CSF normal CSF prot ein slig h t ly up Postmortems done (ALS proven) 31 26 . 19 12 25-76 3 (range 1-8) 24 4 18 23 5 7 AO j\ t!\\Ui>L. r U 9 V- Occupational Dato, Pat ient s with A.L.S. (31 patients) Primary Occupation of Pat ient s Secondary Occupation, i f any Farmer 10 Part - time Farmer (cot ton- chief ly) Railroad worker M inist er Manual Heavy Labor 13 Pai nt er (not farming) Secret ary Factory 'worker (2) ' Elect r ician (1) Dental t echnician Service SudiiOii accenudnt Meat packer 0) Welder - Athlete (1) Weider Carpent er (2) (1) 3 Paint er 42) Cook O) Const ruct i on 0) Wood work 0) Other Occupations _ X-ray t echnician Housewi fe (o4)r Regist ered nurse 0 ) Barber 0) 7 4 .Unknown ' 1 - ...... Igr.^ '^ v'.rv *** ' * U * *, < *<. '. : *` '*" ' `'f- . - \ differ ::m m m - '!' ;r.-,f>" '' ' ' ' TABLE 3 . History o.f Exposure to Toxic Agents, Pat ient s with A.L.S. ' (31 pat ient s) Number o f : pat ient s I . Def init e exposure by hist ory Cotton sprays and/ or t reat ed seeds _ Lead (soldering, welding, and paint ing Silv er (x- ray developer) Various metals (amalgams, et c.) t- I I . Probable exposure by hist ory Cotton sprays and/ or t reated seeds Lead (paint , et c.) > I I I . No def init e hist ory of exposure to t oxic agents, or unknown 9 5 * 1 ' J. Tot al ' 16 A6 ' 4/ Tot al ' T 7 (NOTE: Tot als exceed t ot al number of pat ient s, as several had * more than one type of exposure.) *f TABLE 4 Excret ions of heavy metals (before treatment) of ' all pat ient s with ALS t est ed Pat ient s ' >ug/L urine excret ed, average range, xtg/ L number above "normal" lim it s * All but one were below 20/ jg/ L Arseni c 6 5 0-30 *o Lead 20 37 0-212 2 Mercury 15 \ 23* * 0-365* ; `I TABLE 5 Heavy metal excret ions of pat ient s with and without hist ory of exposure to each metal /' \ # Patients Average urinary levels, >ug/L Range , xig/ L # Pat ient s above "normal" lim it s for t est s Arseni c Exposed Not Exposed 42 0.7 5' 0-3 0-10 00 Lead Exposed Not Exposed 7 13 42 39 0-205 1 0-212 '1 Mercury Exposed Not v 4. \- \4 . x 0-17 '0 0.