Document Vjg5YnJaVNyBJjwZMQor6byL4

L LOU IS IA H A D e lta - A m in o le v u lin ic A cid (ALA) a n d L e a d in U rin e o f W o rk e rs E x p o s e d to O rg a n ic L e a d in th e Form o f T e tr a e th y lle a d (TEL) an d T etram eth y llead (TML). T heodore R. R o b in so n , M D , IMD Staff Physician ' M edical D epartm ent Ethyl C orporation Baton R ouge, L o u isian a t Reprint req u ests to M edical D epartm ent, Ethyl C orporation, PC Box 341, Baton Rouge, L ou isian a 70821 . ALA an d O rg a n ic L e a d -----R o b in so n Synopsis-A bstract ' D e lta - a m i n o le v u li n ic a c id (ALA) a n d le a d w e re m e a s u re d in th e u rin e o f w o rk e rs e x p o s e d to o rg a n ic le a d in th e form o f te tr a e t h y lle a d (TEL) a n d te tr a m e th y lle a d (TM L). T he l e v e l s o f ALA an d le a d in u rin e w e re found to have a rela tiv e ly low p o sitiv e co rrelatio n of r=0.33. T hese re su lts are q u alitativ ely sim ilar to , but may be q u an titativ ely different from , re su lts reported by others for persons exposed to inor ganic forms of le a d . The m echanism through w hich the absorbed organic le a d e x e r ts i t s e f f e c t on u rin a ry ALA i s n o t in d ic a te d by th is s tu d y . U rin a ry ALA v a lu e s w e re fo u n d to b e s ig n if ic a n tly l e s s s e n s i t i v e th a n urinary lead values as an indication of in creased absorption of organic le a d in th e form of TEL an d TM L. . ALA an d O rg a n ic L e a d -----R o b in so n 3 E le v a tio n of th e d e lta - a m in o le v u l in ic a c id (ALA) l e v e l in u rin e h a s been reported to be a se n sitiv e and, except for certain rare disorders of porphyrin m etabolism , sp ecific in d icatio n of in creased absorption of le a d ' . The e le v a tio n is th o u g h t to re s u lt from a p a rtia l in h ib itio n by le a d o f th e c o n v e r s io n of ALA in to p o rp h o b ilin o g e n a s o n e o f th e s t e p s in the norm al b io sy n th esis of hem oglobin. Such an elevation is an indication of a biological resp o n se to the absorbed m a te ria l. The u su al c lin ic a l p ictu re a ss o c ia te d w ith in to x icatio n due to in o rg an ic lead ^ is q u ite d ifferen t from th a t produced by organic lead in the 4 form o f te tr a e t h y lle a d (TEL) . T he b io c h e m ic a l m e c h a n is m s u n d e rly in g th ese differences are not understood. The reports that have been published c o n c e rn in g th e e f f e c t o f l e a d o n u rin a ry ALA l e v e l s h a v e d e a l t w ith e x p o s u r e s to in o rg a n ic form s o f le a d . An in v e s tig a tio n of the p o s s ib le e ffe c ts of a b s o r p tio n o f a n o rg a n ic form o f le a d u p o n u rin a ry ALA le v e l s w a s c o n s id e r e d to be of in te re st. M aterials and M ethods S u b je c ts -----O ne h u n d re d t w e n t y - s i x a d u lt m a le s o f v a rio u s a g e s an d len g th s of se rv ic e , a ll w orking as operators or m aintenance men in an area of production of lead alkyl antiknock com pounds , provided the specim ens of urine used in this study. M ost of th e se men have a relativ ely much g re a te r p o te n tia l fo r o c c u p a tio n a l e x p o su re to o rg an ic le a d in th e form of t e tr a e t h y lle a d (TEL) a n d te tr a m e th y ile a d (TML) th a n to in o rg a n ic form s o f ALA an d O rg a n ic L e a d -----R o b in so n 4 l e a d . E x p o s u re s m u s t b e c o n s id e r e d to b e to a m ix tu re o f TEL a n d TM L, w ith the relativ e am ounts of each com ponent being variable and unknown for a given in d iv id u al. The su b jects w ere seen as part of a routine program of m edical su rv eillan ce of em ployees w orking in th is area of production. None of the su b jects were c lin ically ill and none w ere on any type of "deleading" therapy. U rin e S p e c im e n s .-----E a c h u rin e s p e c im e n c o n s i s t e d o f a s in g le v o id in g of 75 mi or more o b tain ed a t som e tim e during the em p lo y e e's norm al w orking d a y . M o st of the sp ecim en s w ere o b tain ed from th o se w orkers thought to have the g re a te st p o ten tial for in creased absorption of o rg an ic le a d . A few sp ecim en s w ere o b ta in e d from su b je c ts w hose work w as thought to offer relativ ely little opportunity for occupational exposure to le a d in an y form . A sm a ll p o rtio n (ab o u t 2 ml) of e a c h sp ec im e n w as s e t a s i d e fo r d e te r m in a tio n o f ALA c o n c e n tr a tio n a n d w a s s to re d a t 5 F (-1 5 C ) u n til a n a ly s is . No m easurem ent or adjustm ent of urinary pH w as done prior to sto ra g e . The rem ainder of each specim en w as u sed for determ ina tio n of le a d co n cen tratio n . A to tal of 280 urine specim ens w ere analyzed fo r b o th ALA a n d l e a d . A n a ly s e s . -----All ALA d e te r m in a tio n s w e re d o n e in th e c lin ic a l laboratory of the p lan t m edical fa c ility , using the m odification by D avis et a l5 of the m ethod of M au zerail and G ranick6 . D isp o sab le io n -ex ch an g e chrom atographic colum ns and re a g en ts w ere o b tain ed com m ercially (Bio-Rad ALA an d O rg a n ic L e a d -----R o b in so n 5 L ab o rato ries, Richm ond, C alifo rn ia). Standards w ere run w ith each group of specim ens an aly zed . It should be reco g n ized th at the low er ("norm al") v a lu e s fo r u rin a ry ALA in d ic a te d b y th e m e th o d u s e d a re o n ly in p a rt (10-20% ) d u e to ALA, w ith th e b a la n c e p re s u m a b ly b e in g d u e to a r e s id u e of am ino keto n es and glucosam ine . H ow ever, th is m ethod has been shown, to be s p e c if ic fo r e le v a te d v a lu e s o f ALA fo u n d in s u b j e c t s h a v in g a d is o r d e r o f p o rp h y rin m e ta b o lism ^ ' , a n d in s u b je c ts h a v in g e x c e s s i v e a b s o r p tio n of inorganic lead^ . ' All le a d d eterm in atio n s w ere done by th e A n aly tical S ectio n of R & D S erv ices a t E th y l's Baton Rouge p la n t by a m o d ificatio n (Ethyl A nalytical Procedure N o. 138, Baton Rouge) of th e d ith iazo n e m ethod of Snyder . This m ethod determ ines to ta l lead in the urine. R esults The v a lu e s o b ta in e d in th is s tu d y fo r ALA a n d le a d in u rin e a re show n in Figure 1. The ex p ec te d (normal) range of e ac h com ponent for p ersons not occup atio n ally exposed to lead are in d icated . For purposes of c a l c u l a t i o n , th e lo w e r (norm al) v a lu e s fo r ALA w e re u s e d a s if th e y w e re d u e e n tir e ly to ALA; th e r e s u ltin g c o r r e la tio n c o e f f ic ie n t i s r = 0 . 3 3 . F ig u re 2 s h o w s th e u rin a ry ALA an d le a d v a lu e s o v e r tim e fo r e a c h o f s i x w o rk e rs w ho h a v e b e e n fo llo w e d fo r a n u m b e r o f m o n th s . U rin a ry ALA and lead are seen to vary concom m itantly over tim e in th e se w orkers. Of the m en s tu d ie d in t h i s m a n n e r, o n e (S u b je c t # 7 0 , F ig u re 2) s h o w s a n a p p a r e n t ALA an d O rg a n ic L e a d -----R o b in so n 6 q u a n tita tiv e d ifferen ce from the o th ers in h is urinary ALA-lead re la tio n s h ip s. . D iscussion The degree of disp ersio n of the resu lts reported here is such that no single line or curve is thought to be ju stified as portraying the relatio n s h ip b e tw e e n ALA a n d le a d in th e u rin e o f t h e s e w o rk e rs . It i s n o t c l e a r w hether this d isp ersio n is prim arily due to innate v ariab ility of resp o n se of in d iv id u als to absorbed organic le a d , to d ifferen ces in the com position of th e TEL-TML m ixture to w hich in d iv id u a ls w ere e x p o se d , to d iffe re n c e s in the exposure / no exposure tim e re la tio n sh ip s, to d ifferences in in terv als betw een exposure and sam pling, or to other p o ssib le v ariab le fa c to rs. B ecause of this degree of d isp ersio n , p recise quantitative com parison of th e se re su lts w ith the re su lts others have reported for exposures involving inorganic -lead^'8 ,9 ,1 0 cannot be m ade. H ow ever, com parison of such r e s u l t s by s im p le in s p e c tio n (F ig u re 3) s u g g e s ts t h a t a g iv e n e le v a tio n of urinary lead excretion probably is a sso c iate d w ith a low er lev el of urinary ALA e x c r e tio n w h e n e x p o s u r e i s to o rg a n ic le a d (TEL,TML) th a n w h en exposure is to inorganic le a d . It is not c le a r w hether th is d ifferen ce m ight be re la ted prim arily to d ifferen ces in circu m stan ces of exposure or to d ifferen ces in m etabolism (biotransform ation) of the d ifferent forms of lead to w hich exposure occurred. In vitro and in vivo stu d ies by C rem er*1 and in vivo stu d ies by ALA a n d O rg a n ic L e a d -----R o b in so n 7 B o la n o w s k a 12 s u g g e s t th a t TEL is c o n v e r te d , a t l e a s t in p a r t , in th e b o d y to trie th y ile a d and th a t th is la tte r form of lead p ro d u ces a d istu rb a n c e in cen tral nervous system function sim ilar to th at observed in in to x icatio n due to TEL. Unconfirm ed re s u lts by B olanow ska in d ic a te th at trieth y ilea d may be ex creted as such in urine and feces q uite slow ly and w ithout evidence of fu rth er d eg rad atio n by the body . A portion of B olanow ska's w ork su g g e s ts t h a t so m e p a rt ( le s s th a n 20%) o f a b s o r b e d TEL m ay b e c o n v e r te d d ir e c tly to inorganic lead by the body. This portion of le ad presum ably w ould b eh av e in a m anner p h y sio lo g ic a lly the sam e as le ad d eriv ed from ino rg an ic le a d e x p o s u r e s , in c lu d in g e f f e c t s on p o rp h y rin m e ta b o lis m a n d u rin a ry ALA ex cretio n . This su g g ests also th at the urine of p ersons who have absorbed TEL c o n ta in s o rg a n ic a s w e ll a s in o rg a n ic l e a d . In v iv o a n d in v itr o s tu d ie s by C re m e r a n d C a llo w a y 3-2 s u g g e s t th a t TML may undergo a re la tiv e ly slow co n v ersio n in th e body to (the more toxic) trim eth y llead . No evidence has been reported to in d icate w hether or not som e portion o f ab so rb ed TML m ight be co n v erted d ire c tly to in o rg an ic lead w ith in th e bo d y . The e x c re tio n p ro d u ct(s) of TML is (are) n o t know n. There have been no stu d ies reported to in d icate w hat e ffe c t, if any, trieth y ilea d or trim eth y llead per se m ight have on porphyrin m etabolism and h e n c e o n u rin a ry ALA e x c r e tio n . It is im possible at p re sen t, therefore, to a s s e s s the relativ e im p o rta n c e of TEL a n d TML (and p o s s ib le m e ta b o lite s o f th o s e c o m p o u n d s: U RINARY ALA , m g/ 100 ml F ig u re 3. C o m p a ris o n of R ep o rted U rin a ry ALA. : L ead R e la tio n s h ip s for E x p o su r 2.5 URINARY ALA, m g/ lOOm ! 2.0 NORMAL RANGE FOR URINARY LEAD t.5 tMMtlM'ItMtt 0.5 ~j" * * Ht K I HIHlUlHI I * (M > <H H tm n H IH tetS M H n tu n tt itit#u H i Htes *c n L*.*e9 * t I ' I I 1 _L .L 0.05 0. 10 0.15 0.20 URINARY LEAD, m g/ l 0.25 I NORMAL RAN FOR URINA ALA I -L____ t ___ 0.30 F ig u re 1. ALA an d L ead in th e U rine o f O rg a n ic L ead (TEL,TML) W o rk e rs . ' URINARY ALA, mg/100 ml ~ . . :/.r y LEAD rr-o/l n 3.0 2.5 -- 2 .0 'n ? 1.5 >1.0 < z 0.5 TIME, MONTHS ....~... URINARY ALA, mg/ IOOml URINARY" l.EAD,rrig/l ' URINARY ALA, mg/ IOOml ui\iw /vi;r 1_L>i .> : / I 0.6 SUBJECT NO. 51 3.0 0.5 OUT OF _ H LEAD Sir AREA ALA 0.3 LEAD 0.2 "\ 0.1 \ N it 12 ii ii 34 56 TIME, MONTHS 7 0 Lar ge ur i ne sampl e 0.11 mg, Pb / I I 8 oo 2.0^; 1.5 3 < 1.0 z<c>c C 0. 5 9 TIME, MONTHS F ig u re 2 . T re n d s in U rin a ry ALA an d L e a d L e v e ls O v er T im e in -I 3.0 2. 5 1.0 0. 5 ALA an d O rg a n ic L e a d -----R o b in so n 8 trie th y ile a d , trim ethyllead and inorganic lead) in producing the deviations from n o rm al of u rin a ry ALA v a lu e s o b s e r v e d i n th e p r e s e n t s tu d y . F u rth e r in v estig atio n m ust be done if the roles of the various com pounds m entioned are to be understood. An in c re a se in urinary ex cretio n of porphyrins h as not been noted follow ing exposure to TEL^, in c o n tra st to the elev atio n found follow ing absorption of inorganic lead . The re su lts of the present study suggest that p o rp h y rin m e ta b o lis m i s a f f e c te d a t th e ALA le v e l ( i . e . , p rio r to th e fo rm a tio n of porphyrins) by ab so rp tio n of one or the o th er (or perhaps both) of the form s o f o rg a n ic le a d (TEL,TML) in v o lv e d in th is s tu d y . S u b je c t # 7 0 , w h o se u rinary ALA:lead re la tio n sh ip seem s to d iffer from the other su b jec ts in th is study (Figure 2), w orks in the lead recovery (furnaces) area of the p lan t. H is job may en tail a greater poten tial for exposure to inorganic lead than,do other job assig n m en ts in the organic lead p ro d u ctio n a re a . This s u b je c t's u rinary ALA:lead p a tte rn is q u a n tita tiv e ly q u ite sim ilar to th o se reported by others for w orkers exposed to inorganic le a d ^ '8 '9 . None of the other furnace w orkers seen during the course of the p resen t study exhibited a sig n ifican t elev atio n of eith er urinary lead or u rin a ry ALA a n d th u s do n o t f u r n is h in fo rm a tio n to e v a lu a te t h i s p o in t m ore d e fin itiv e ly . . D e te r m in a tio n o f ALA in u rin e h a s b e e n c o n s id e r e d b y so m e a u th o rs to be of co n sid erab le value in the routine m onitoring of w orkers exposed to ALA a n d O rg a n ic L e a d -.--R o b in s o n 9 inorganic lead 1 ,1 4 ,15. It has been suggested that determ ination of u rin a ry ALA, a m e a s u re m e n t o f b io lo g ic a l r e s p o n s e , s h o u ld r e p la c e d e te r m ination o f lead in blood or urine in th e m onitoring of w orkers exposed to inorganic le a d . This probably w ould be unw ise in m ost circu m stan ces. Blood and u rin ary le a d v a lu e s not only s p e c ific a lly id e n tify and e stim a te the m agnitude of the absorption of lead by individuals but a lso , when co llected sy stem atically over a period of tim e, can be of great u tility in the a sse ssm e n t of the hygienic sig n ifican ce of changes in work procedures and p r a c t i c e s , e q u ip m e n t c h a n g e s , e t c . ALA an d le a d d e te r m in a tio n s s u p p ly differen t types of inform ation, both of w hich are needed for the proper . '_ t evaluation of many situ a tio n s . The one is com plim entary to , but cannot re p la ce , the other. T he p r e s e n t s tu d y in d ic a te s th a t u rin a ry ALA d e te r m in a tio n s a re o f re la tiv e ly lim ited value in a m onitoring program w here the p o ten tial for e x p o su re is p rim arily to o rg an ic le a d (TEL,TM L), due to th e re la tiv e in s e n s itiv ity of th is te s t under su ch c irc u m sta n c e s. As can be seen in the group r e s u l t s (F ig u re 1) a n d in r e s u l t s fo r in d iv id u a ls (F ig u re 2 , S u b je c t #51 a n d #101), le v e ls of urinary lead show n by long experience to in d ic a te the d e sirab ility for reduction of exposure to lead (i.e . , a c o n siste n t urinary lead le v e l of 0 .1 8 m g/1 o r more) m ay b e a s s o c i a t e d w ith l e v e l s o f u rin a ry ALA th a t are w ithin normal lim its. U ntil and u n less an ex ten siv e background of c l i n i c a l e x p e r ie n c e c o n firm s th e s a f e ty o f th e u s e o f u rin a ry ALA l e v e l s fo r ALA a n d O rg a n ic L e a d -----R o b in so n 10 th e m ed ical co n tro l of w orkers e x p o se d to o rg an ic le ad (TEL,TM L), th e p resen t stan d ard s, b ased upon urinary lead v a lu e s, should continue to be used in such control program s. The determ ination of lead in urine m ust s till be co nsidered to be the m ost useful laboratory tool in the routine m ed ical m onitoring of .w orkers having a p o te n tia l for exposure to organic le a d i n th e form o f TEL a n d TM L. As a relativ ely early o b jectiv e ind icatio n of a resp o n se to the in creased absorption of le a d , co n sid eratio n should be given to the determ ina tio n o f u rin a ry ALA a s a p a r t o f th e m e d ic a l m o n ito rin g o f w o rk e rs h a v in g a p o ten tial for exposure to lead in any form . Inform ation of th is type should be of v alu e in long term c lin ic a l and epid em io lo g ical stu d ie s and may be u sefu l in the evaluation of such additional in d icatio n s of biological resp o n se as may be developed in the future. In sum m ary, the p resen t study show s th at absorption of organic lead in th e form o f TEL a n d TM L, a s in d ic a te d b y in c r e a s e d u rin a ry le a d l e v e l s , i s a s s o c i a t e d w ith a n i n c r e a s e in u rin a ry ALA l e v e l s . The m e c h a n is m through w hich th is effect is produced is not rev ealed in th is stu d y . U rinary ALA d o e s n o t a p p e a r to b e a s s e n s i t i v e a n in d ic a to r o f a b s o r p tio n o f TEL an d TML as is urinary le a d and is th u s of a n c illa ry , ra th e r th an prim ary, v alu e in the routine m edical m onitoring of w orkers having p o ten tial for exposure to th e se forms of organic le a d . ALA an d O rg a n ic L e a d -- -R o b in s o n 11 R eferen ces f 1 H a e g e r-A ro n s e n , B .: S tu d ie s on U rin a ry E x c re tio n of D elta-A rain o lev u lic Acid and O ther H aem P recu rso rs in Lead W orkers and L ead -In to x icated R abbits , Scand J C lin Lab In v est 12:(suppl 47): 1-128, 1960. 2. C hisolm . J .J .,J r .: D isturbances in the B iosynthesis of H em e in L ead In to x ic a tio n , I P e d ia t 6 4 :1 7 4 -1 8 7 (Feb) 1964. 3. Johnstone, R .T .: C linical Inorganic Lead Intoxication, Arch E nviron H e a lth 8 :2 5 0 -2 5 5 (Feb) 1964. 4 . S an d ers, L .W .: T etraeth y llead In to x ica tio n , Arch Environ H e alth 8 :2 7 0 -2 7 7 (Feb) 1964. 5 . D a v is, J.R . , e t al: U rinary D elta-A m in o lev u lin ic Acid (ALA) L e v e ls in L e a d P o is o n in g : I I . C o r r e la tio n o f A la V a lu e s W ith C lin ical Findings in 250 C hildren W ith S uspected Lead In g e s tio n , Arch Environ H e alth 17:164-171 (July) 19 68. 6 . M a u z e ra ll, D . , an d G ra n ic k , S-.: The O c cu rren c e and D eterm ination of D elta-A m inolevulinic Acid and Porphobilinogen in U rin e, J Biol C hem 2 1 9 :4 3 5 -4 4 6 (M arch) 1956. 7. Snyder, L .J .: Improved D ithizone M ethod for D eterm ination of Lead: M ixed-C olor M icrom ethod at H igh pH , Industr Enqin Chem A nal Ed 1 9 :6 8 4 -6 8 7 (Sept) 1947. 8 . S to p p s, G .J .: Sym posium on Air Q u ality C rite ria -L e a d , ALA an d O rg a n ic L e a d -----R o b in so n 12 JOM 19:550-564 (Sept) 1968. 9 . .deK retser, A .J ,, and W aldron, H .A .: U rinary D elta A m inolevulinic Acid and Porphobilinogen in L ead-E xposed W orkers, Brit J In d u str M ed 2 0 :3 5 -4 0 , 1963. 10. D av is, J .R ., and Andelm an, S. L .: U rinary D e lta - A m in o le v u lin ic A cid (ALA) L e v e ls in L e a d P o is o n in g : I.A M o d ifie d M ethod for th e Rapid D eterm ination of U rinary D elta-A m inolevulinic Acid U sing D isp o sa b le Ion-E xchange C hrom atography C o lum ns, Arch Environ H e a lth 1 5 :5 3 -5 9 (July) 19 6 7 . 11. C rem er, J .E .: B iochem ical Studies on the T oxicity of T e tra e th y l Lead and O th er O rg an o -L ead C o m p o u n d s, Brit J In d u str M ed 16:191-199, 1959. 12. B olanow ska, W .: D istribution and E xcretion of T riethyllead in R a ts, Brit J In d u str M ed 2 5 :2 0 3 -2 0 8 (July) 1968. 13. C rem er, J.E. , and C allaw ay, S .: Further Studies on the T o x icity of Some T etra and T rialk y l Lead C o m p o u n d s, Brit J In d u str M ed 18:277-282, 1961. 14. G ibson, S . L . , M ack en zie, J . C . , and G oldberg, A .: The D ia g n o sis o f In d u s tria l L ead P o iso n in g , Brit J In d u str M ed 25:40-51 (Jan) 19 6 8 . . 15. C ram er,K . , and S e la n d e r,S .: L etters to th e E ditor, D etectio n o f I n d u s tr ia l L e a d P o is o n in g , L a n c e t i : 5 4 4 -5 4 5 (M a rch 5) 196 6 . ALA; a n d O rg a n ic L ead - - - R o b in so n 13 Legend for Illu stratio n s 1 . ALA a n d L e a d in th e U rin e o f O rg a n ic L e a d (TEL,TML) W o rk e rs . 2 . T re n d s in U rin a ry ALA an d L e a d L e v e ls O v e r T im e in C e r ta in O rg a n ic L ead (TEL,TML) W o rk e rs. 3. C o m p ariso n of R eported U rinary ALA:Lead R e la tio n sh ip s for E xposures to Inorganic Lead W ith R esults of P resen t Study Involving O rganic L ead (TEL,TML). . 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