Document 6wxLvKG54zVMOxgb0rgr9jBq9

The Diagnosis oi' Lead Poisoning in the Light of eoent Information \ :7 Ro b e rt hm ilohoe Frocn the Ke t t e r i n g La b o r a t o ry o f Ap p lie d P h y s i o lo g y o f the U n i v e r s i t y o f Ci n c i n n a t i , Ci n c i n n a t i , Ohio The l a r g e fu s s ie r o f r o o e n t l y pun 1 1 sho d a r t i c l e s on lo a d p o is o n 'lig t e s t i f i e s to a g r e a t l y h e igh te n e d In t e r e s t ' n w hat n u at be l i s t e d as on o f o u r o l d e s t c l i n i c a l p ro bl * U n fo r t u n a t e l y , the amount o f l i g h t w hich has been she d upon the probleat does n o t c o r r e la te c l o s e l y ' th fc>ie vo lum e o f th e l i t e r a r y o u tp u t In d e e d , I t w ould s o o n r> th a t an a cto n p t on the p a rt o f the p r a c t it io n e r o f re d lo in o to examine and in te rp re t the cu rre n t lit e r a tu r e would r e s u lt a lio a t In e v ita b ly in 3 uch d i s c o ur n gn e n t and o o n fu s lo n as t o ca u s e Mm to r e t u r n t o t i vusm honored co n ce p ts and p ro ce d u re s . Kve n the casual reader w ill note . t h a'^t E/ my o f th a r t i c l e s p u b lis h e d r e c e n t l y d e a l p r i m a r i ly w it h la b o r n tn r y m e tho ds o f d la -n o s n r o n t* apicare nt as s u m p tio n t h a t th e u n d e r ly i n g p a th o lo gica l phye io lo ry o f load in to x ica tio n has been co m ple te ly e lu cid a te and n a y , t h e r e fo r e , be take n fo r .gra n te d , o r ttm t i t tieed n o t be take n i n t o a c c o u n t In th e In t e r p r e t a t i o n o f fi n d i n g s <>n ul,;hfc bo l e d t o b e lie v e th a t la b o ra to ry procedures nay be s u b s titu te d fo r c l i n i c a l s tu d y In f a c t th e re i s an i n s i s t e n t demand, n o t o n ly in u ctd io o -*le gal bu t in ge n e ral p r a c t ic e , fo r a la b o ra to ry te s t w h ich , s tan d in g a lo n e , w i l l have a p o s i t i v e d i a g n o s t i c s i g n i f i c a n c e . The re i s go^.d ro u s o n , t h e r e fo r e , to c o n c e r n * \ ui -o r a t o r y clia ;;n o 8i s , an d t o a p p r a is e in a a o n e ^ h a t c a u t io u s and o r l t i c a l man e r th e e x t e n t t o w h ich la b o r a t o r y o b s e r v a t io n s an d the i n t e r p r e t a t io n s w h ich a r e d e r iv e d fr o t h e n may ' e aocep fced a t r u s t w o r t h y I n view o f t h e im p o sa i^ l l .r t y o f r e v ie w in g t h e l i t e r a t u r e e ve n i n a c u r s o r y man t ie r , o r e ve n o f m e n t io n in g m a y m a t t e r s w h ich a r e o f p h y s io lo g ! c a l im p o r t a n c e , in t h e s h o r t t im e a v a i l a b l e , I s h a l l a t t e m p t t o c l a r i f y & few p o in t s w h ich seem t o bo o f Im m ediate p r a c t ic a l im p or ta n ce to th e p r oblem o f d ia gn o sis* Norm al Le a d Me t a b o lis m The in g e s t io n (a n d p r o b a b ly th e i n h a la t io n ) , a b s o r p t io n , an d e x c r e t io n o f le a d h ave b een shown to be nor m al phenomena o f human l i f e * ( l a ,b ,c ,d ) .* The l i m i t s o f t h e n or m a l v a lu e s fo r le a d in g e s t io n a n d fo r le a d e x c r e t io n in th e fe o e s and u r in e o f p e r son s in th e Un it e d St a t e s may b e d e fin e d in s u b s t a n t ia lly a b s o lu t e t o m a *( ii) * The v a lu e s fo r th e b lo o d , s p i n a l f l u i d an d t i s s us e s a r e nob s o S a t i s f a c t o r i l y e s t a b l i s h e d , in t h a t t h e f u l l r a n g e o f nojr m al v a r i a b i l i t y la in a d e q u a t e ly d e fin e d * {lt t e,a) ^ Th is is p a r t ic u la r ly tr u e in the case o f th e a k in , and u n fo r t u n a t e ly s o , sin ce ^ u n w ar ran ted c lin ic a l s ig n ifica n ce h a s| r e ce n tly/ been a t t r ib u t e d to apparent v a r i a t i o n s in t h e le a d c o n t e n t o f thm t i s s u e * ( 3) .) The e v id e n c e i n d i c a t e s t h a t w it h in t h e somewhat in c o m p le t e ly d e fin e d p h y a io lo g io a l lim it -**, a s t a t e o f dynam ic e q u ilib r iu m is m a in t a in e d in w hich l i t t l e or no p r o g r e s s iv e le a d a c c u m u la t io n In t h e t is s u e s o c c u r s , b u t , r a t h e r , it .c a k e an d o u t p u t come In t o a p p r o xim a t e b a la n c e a f t e r a c e r t a in Le v e l o f a b s o r p t io n i n t o t h e t is s u e s h a s b e e n r e a ch e d * (1 b ) * u c h d a t a a s iia ve a p p e a r e d t o in d ic a t e th a t th e r e Is a tendency toward p r o gr e s s ive a ccu m u la tio n in th e t i s s u e s , o h ie fly th e s k e le t o n , show t h a t th e a c t u a l c o n c e n t r a t io n d iffe r e n betw een you th and o ld age a r e a lig h t , - so a lig h t , in d aed as to r e q u ir e fu r t h e r p r o c f t h a t t h e y e x c e e d t h e l i m i t s o f ch a n ce v a r i a t i o n * {1^}* No e vid e n ce has b een d e ve lo p e d t o show t h a t u n u a u a l amounts o f le n d a ccu m u la t a b n o r m a l in t a k e * There* a r e , t o b e s u r e * s i g n i f i c a n t v a r i a t i o n s In a b s o r p t io n nnd e x c r e t io n fr om d ay t o d a y , b u t when com pared w it h t h e m e t a b o lis m o f t h e more common m e t a l l i c c o n s t it u e n t o f l i v i n g n a t e r l a l , t h e n o r m a l m e t a b o lis m o f le a d i s r e m a r k a b ly s t a b i l e , v ,b o t h e r o r n o t le a d is p h y s io lo g ica lly u s e fu l la a m atter fo r co n je ct u r e , bu t r e ga r d le ss o f the e v e n t u a l answ er bo t h is q u e s t io n the co n ce p t o f le a d as an accum ula fclve p o is o n , w ith o u t r e fe r e n ce to q u a n t it y , h as r e ce ive d a rude sh ock* O b v io u s ly , h e r e a f t e r , when we r e f e r t o t h e p o is o n o u s p r o p e r t ie s o f le n d i n a n im a l o r human m e t a b o lis m , we s h a l l h a ve t o make u s e o f q u a n t i t a t i v e terns* Th is p o in t o f view n e c e s s a r ily a lt e r s th e s ig n ific a n c e o f w hat lias lo n g ' eon r e ga r d e d a s an im p o r t a n t e le m e n t In th e d ia g n o s is o f plum bl n n m e l;', th e h is t o r y o f e x p o s u r e , The d is c o v e r y o f a p o t e n t ia l s o u r ce o f e x p o s u r e , w it h o u t r e fe r e n c e t o lfco i n t e n s i t y , h a s o ft e n b e e n a s i g n a l fo jr th e c e s s a t io n o f fu r t h e r c l i n i c a l stu d y o f a p a t ie n t * Su ch la p s e s o f ju d gem en t h ave b e e n e n co u r a ge d on t h e one hand b y th e f a c t t h a t th e c lin ic a l m a n ife s t a t io n s o f le a d In t o x ic a t io n a r c many, v a r ie d , and la r g e l n o n -s p e c ific , anti on th e o th e r b y th e b e lie f t h a t the a b so r p tio n o f any q u a n t it y o f le a d , however s m a ll, m igh t oause illn e s s i f exp osu r e were p r olo n ge d or i f an u n u su a l s u s c e p t ib ilit y e x is t e d , There can be l i t t l e e xcu s e f o r s u c h r e a s o n in g in t h e f u t u r e . The h i s t o r y o f la n d e x p o s u r e , i f i t is t o be t a k e ir 'a a r io u s ly , m usthnve some q u a n t it a t iv e m e a n in g, I t i s n o t enough t o know t h e t r a d e o r o ccu p a t io n o f th e p a t ie n t . In d u s t r ia l c o n d it io n s ch a n ge r a p i d ly , Lr n d h a z a r d s e x i s t in t r a d e s s u p p o s e d ly fr e e o f e xp o s u r e , and co n v e r s e ly , some p o t e n t ia lly d an ger ou s o ccu p a t io n s a r e s o s a fe g u a r d e d *s t o b e fr e e o f s i g n i f i c a n t e x p o s u r e . The c l i n i c a l h i s t o o f e x p o s u r e , t o b e u s e f u l , m u s t t h e r e fo r e b e p r e c is e and s p e e l*. i c in d e ve lo p ln g a b a s is fo r an e s tim a tio n o f the o xte n t o f exp osu r e e it h e r in r e la -t io n to o t h e r e xp o su r e c o n d it io n s w h ich a r e w e ll known to th e e xa m in or in terms o f the e ffe c t s o f the exposure upon oth er persons s im ila r ly cccu p !ed Th e r e I s a t l e s a t one t y p e o r p o t e n t ia l- le n d ox* u a u r e t o w hich th e above r e a o r v a t lo n a sh o u ld n ot ap p ly In p r a ct ice # d e s p it e t h e ir v a li d i t y in p r in c ip le . Th er e Is e ve r y ro'-sor. fo r s u s p e c t in g th e e x is t e n c e c f s i g n i f i c a n t and d a n ge r o u s le a d e xp o s u r e In t h e o&se o f c h i ld r e n w it h a h is t o r y o f p ica * Ih e o ccu r r e n ce o f le a d -o o n fcu ln tn g com m od ities and th e u se o f le a d p a in t s on fu r n it u r e # toys# and o t h e r o b je cts# w it h in th e r each o f s m a ll c h i ld r e n I s much t o o common t o ig n o r e * 'The* e x i s t e n c e o f sym n tor x even s li g h t ly s u gge s t iv e o f p lu m b isa sh o u ld r e s u lt In prompt In v e s t ig a t io n o f the c h ild and h is su r r ou n d in gs* Ab n or m al h e a d M e t a b u lla g The li m it s b eyon d w h ich human le n d a b s o r p t io n com es t o be a s s o cia t e d w ith In ju r io u s e ffe c t s can n ot lo d e fin e d p r e c is e ly a t presen t# and u n t il c e r t a in d e t a ils o f th e b e h a vio r o f le a d a r e u n d e r sto o d more c l e a r l y i t l a n o t l i k e l y t h a t t h e q u e s t io n 117 b e a n s w e r e d s a t i s f a c t o r i l y Ce r t a in c r it e r ia # w h ich a r e In lin e w it h sound c li n i c a l p r a c t ic e In o th e r fie ld s # may be ad op ted * In d u s t r y p r o vid e s n any and v a r ie d exam p les o f /` gr o u p xp e a u r e to lo a d compounds* Ca r e fu l s t u d y o f r e p r e s e n t a t iv e gr ou p s o f exposed persons w ill e v e n t u a lly give a cle a r In d ica t io n o f the q u a n t it a t iv e r e la t io n s h ip s w h ich e x is t betw een e x osura# a b s o r p t io n , d is t r ib u t io n . '\ w it h in th e t is s u e s # e xcr e t io n # und in t o x ic a t io n * IS is p r o b a b le t h a t lo n g b e fo r e we h a ve le a r n e d t h e d e t a i l s o f t h e p h y s io lo g ic a l m e ch a n ism s w h ich fir e r e s p o n s ib le f o r le a d I n t o x i c a t i o n in a n y in d iv id u a l# wo s h a l l h a ve a c l e a r id e a o f t h e t y p e s anct d e g r e e s o f le a d e xp o s u r e an d a b s o r p t io n w h ich ar e a s s o cia t e d w ith the p r o d u ctio n o f in t o x ic a t io n 41t h in th e gr ou p , lio r e o v o r we s h a ll kn ov th e r a n ge o f th e c o n c e n t r a t io n s o f len d # In e xcr e t a # blood # s p in a l flu id # and t is s u e s # w h ich a r e a s s o c ia t e d w it h t h e o ccu r r e n ce o f i lln e s s among a d e fin it e p r o p o r t io n o f human b e in gs * Do u b tle ss# a lso # in th e p r o ce s s o f o b t a in in g th co o p r a c t ic a lly u s e fu l d ata# much w i l l have been le a r n e d o f th e n a t u r e o f th e m echanism s in v o lv e d * 16 l a n o t t o b o s u p p o s e d t h a t vie a r e e n t i r e l y lu c k in g in in fo r m a t io n o f t h e t yp o d e s c r ib e d a b o ve A v e r y 'r e n t erao-mt o f wor k lia s b een done in t h ia d ir e c t io n * What m ust be r e a liz e d la t h a t o n ly a b e g in n in g h a s b e e n m a d e , a n d t h a t we a r e a l.io s t t h o u gh n o t q u it e in t h e d a r k aa t o t h e a c t u a l m echanism s o f le a d in t o x ic a t io n * I t la a ls o t r u e , u n fo r t u n a t e ly , t h a t th e v a r io u s m ethods w hich h ave b ee n u aed in o b t a in in g the a v a ila b le d a ta have been so la ck in g in u n ifo r m it y , and so v a r ia b le in t h e ir s e n s it iv it y , th a t the r e s p e ctiv e s e ta o f r e s u lt s can n ot be put on an a b s o lu t e b a s t s fo r com p ar ison or c l i n i c a l u se* Am b igu it ie s o f t h ia typ e a r e b e in g e lim in a t e d in some o f t h e m or e r e o e n t afcu i e s b u t t h e y a r e s t i l l a s u r c e o f c o n fu s io n * T h e r e fo r t h e c l i n i c i a n may w e ll be somewhat c a u t io u s in h is in t e r p r e t a t io n o f t h e in f^ r m a t ic n w h ich he r e c e iv e s fr om the la b o r a to r y* Fo r p r e s e n t p u r p o s e s , we m u s t r e g a r d fin d i n g s b e yo n d t h e r a n ge o f norm al va lu e s as abnorm al in the sen se th a t they In d ica t e the occu rren c o f a n u n u s u a l and t h e r e fo r e p r a g m a t ic a lly a b n o r m a l lo a d m e t a b o lis m * No r c lo a n -c u t c o r r e la t io n has been shown tw e x i s t b e t -e e n th e o ccu r r e n ce o f /' c l i n i c a l s ym p t o m s , an d t h e o c c u r r e n c e o f a. s p e o l fi o c o n c e n t r a t io n o f lo a d ir . the e x c r e t a , or in any t is s u e or body flu id * rf z n e r an d .ve yr .a u ch \{$) ;ll e v o t h e y h a ve d e m o n s t r a t e d a co n a t a n t r e la t io n s h ip b etw een th e le v o l o f lo a d c o n c e n t r a t io n It: b lo o d and the p r e se n ce o f symptoms* How ever, th ey have n o t do term ned a -ie q u a te ly th o rang o f v a r i a b i li t y o f ' th o lo a d co n c e n t r a t io n iu th e b lo o d o f norm al in d iv id u a ls , and t h e ir d ict u m c a n n o t , t h **r o fo r e , be a cce p t e d a s e s t a b lis h e How ever i t h a s been 3hown t h a t lo a d ui s o r p t io n , a s e vid e n ce d b y th e le n d co n te n t o f the b lo o d and c e r t a in oth er t is s u e s , as w e ll as a lim e n ta r y and u r in a r y le n d e x c r e t io n var y; r aettsu r eably in a cco r d a n ce w ttn th e s e v e r it y o f e xp o s u r e t o lo a d com poun ds* ( 6) Ab n o r m a lly h ig h fin d in g s m ay t h u s be r e g a r d e d o n ly a s e v id e n c e o f a b n o r m a l le a d e xp o s u r e * On t h e o t h e r h a n d , d e s p it e the fa c t o f v a r ia b le in d iv id u a l response to le a d a b s o r p t io n , th er e i s a. t h r e s h o ld o f a b s o r p t io n ( e v id e n c e d b y e xor e fc? u) a b o ve w n ich s o e p r o p o r t io n o f e xp o se d p e r s o n a become i l l tho c l i n i c a l s e v e r it y o f the in a b s o r p t io n . ( 6) . T h e r e fo r e , a lt h o u g h t h e r e l a n o c l i n i c a l Ju s fci f l e a fci o fo r th e assu m p tion th a t abnorm al a n a ly t ic a l r e s u lt s prove tho e xis t e n ce o f le a d in t o x ic a t io n , th e d em on str ation o f abnorm al fin d in g s w ith in the range o f v a lu e s w h ich h a v e b e e n show n t o o o e u r among e xp o s e d p e r s o n s some o f who? have d e ve lo p e d le a d in t o x ic a t io n e s t a b lis h e s th e p o t e n t ia l c li n ic a l a ig n iflc a n c e o f th e e xp o su r e ! tho h igh e r tho le v e l o f le a d a b s o r p tio n and e x c r e t io n , th e more c e r t a in is i t s p o t e n t ia l s i g n i fic a n c e , "ihere i s no c e r t a in t y , h o w e ve r , t h a t symptoms shown b y th e p e r son iri q u e s t io n a r e due t o l e a d . In d e e d , t h e d ia g n o s is o f Xe**d i n t o x i c a t i o n ca n b e made w it h r e a s o n a b le c e r t a in t y on ly on th e b a s is o f sym ptom and s ig n s o f illn e s s wh c o in c id e **lt h t h e known c l i n i c n l p i c t u r e o f le a d i n t o x i c a t i o n . Thus f a r we h a ve sp o k e n ox* a b n o r m a l le a d m e t a b o lis m a s t h o u gh 'the r e la t io n s h ip between a b so r p tio n , d is t r ib u t io n in the t is s u e s , and ex c r e t io n r em ain ed u n a lt e r e d b y an in cr e a s e d le v e l o f in g e s t io n or in h a la t io n i .e . as though i t r e p r e se n te d th e norm al type o f e q u ilib r iu m m a in ta in e d a t a h igh e r le v e l. There ar e c e r t a in e vid e n ce s t h a t t ills is n o t tho c a s e , bu t h a t t h e r e i s a typ e o f le a d m eta b olism w hich in I t s e l f la p a t h o lo g ic a l. Ap p a r e n tly the u r in a r y le a d e xcr e t io n does not In or e n se p r o p o r t io n a lly w it in c r e a s e d le a d e x p o s u r e , b e yo n d a c e r t a i n p o i n t . ( 6) . Va r io u s h y p o t h e s e s m igh t be advanoed in e xp la n a tio n o f t h is phenomenon, as a w or kin g b a s is fo r fu r t h e r s t u d y , b u t r e g a r d le s s o f t h e e x p la n a t io n i t w ou ld a p p e n r t h a t t h is is an in d ic a t io n o f a ohonge in th e m e ta b o iio p a t t e r n , - a ch an ge a s s o cia t e d w ith a p r o gr e s s ive a ccu m u la tio n o f le a d w it h in th e o r ga n ism . There is l i t t l e ad eq u ate e vid e n ce t h a t such a ccu m u la tio n is a a a o cin t e d w ith a change ir ^ h e manner o f d is t r ib u t io n o f le a d in the t is s u e s o f the b o d y, b u t fu r t h e r in v s t l g a t l o n i s n e e d e d t o s e t t l e t h i s im p o r t a n t quer f; i o n . Ad d it io n a l e vid en ce o f a q u a lit a t iv e change in the ch a r a ct e r o f 7 t h e a q u ' li' r r iu m 1etrm-on h* ;h l e v e l s o f la n d c o n c e n t r n * l j u in t h e t is s u e s and t h e le a " e o n co n t r s t io n in the a d o r a t io n s Is to bo fou n d In th e fa c t th a t the u r in a r y e xcr e to r y r a t e drops r a p id ly fo r a t ir e a ft e r the ce s s n t l o f s e v e r e e xp o s u r e an d th e n co n t in u e s a t a much lo e r b u t s t i l l d lm in is h l r a t e fo r a le n g t h o f t in e fe h a t ^ ^ j^ e s ^ w lth the s e v e r it y o f the p r e vio u s e xp o s u r e ( 7) * a p p a r e n t ly u n t i l t h e n o r m a l r e l a t i o n s h i p b e t w e e n le a d ln t a k i le a d co n te n t o f t is s u e s and le a d o u tp u t h as been r e -e s t a b lis h e d * Evid e n tly when th e r a t e o f a b s o r p t io n i s h igh some o f th e le a d la d is t r ib u t e d In t o th e t is s u e s In su ch a way a s to be r e le a s e d le s s r e a d ily th an t h a t w h ich la in vo lve d In a norm al or o n ly s lig h t ly in cr e a s e d r a t e o f a b so r p tio n * Aub h a s p r o v id e d e v id e n c e t h a t a m or e a c t i v e c a lc iu m a n d le a d m e t a b o lis m ta k e s p la ce in th e fe n e s t r a t e d p o r t io n o f o e r t n ln bones a s com pared w ith t h e ir s o lid p o r t io n *(8) I t may l e t h a t su o h d iffe r e n c e s e x e r t a p r ofou n d In flu e n c e upon th e m anner In w hich v a r y in g co n ce n t r a t io n s o f c ir c u la t in g le a d come t o h a d e p o s it e d In t;h s k e le t o n * W h a t e ve r m ay be i t s Ca u s e t h e sh arp d e clin e in the e xcr e to r y r ^ te a ft e r ttyr ce s s a t io n o f se ve r e exposure m ust be r e ck o n e d w it h In d ia g n o a t io p r a c t ic e * Thus c o n c lu s iv e e v id e n ce o f a b n or m a l le a d a b s o r p t io n in t h e for m o f a s i g n i f i c a n t l y h e ig h t e n e d e x c r o t o r a t e I s m ost r e a d ily fou n d w it h in a s h o r t tim e a ft e r t h e c e s s a t io n o f ab n o r m a l e x p o s u r e . The lo n g e r t h e i n t e r v a l b e t w e e n t h e c e s s a t i o n o f e x p o s u r and t h e e xa m in a t io n o f t h e e x c r e t a th o g r o t .t a r w ill b e th e d i f f i c u l t y in in t e r p r e t in g th e r e s u lt s * h ve n tu a ily a ll e vid e n ce w ill d isa p p e a r and n o t even th e a n a ly s is o f the t is s u e s can be r e lie d upon to show t h a t nn a b n o r m a l e x p o s u r e h ad o c c u r r e d * ( 7 ) On t h e o t h e r h a n d o n ly n s l ' g h t in cr e a s e In le a d a b so r p tio n r e s u lt s in tho prompt e le v a t io n o f the r a t e o f le a d e x c r e t i o n (1 b ) s o t h a t t h e a n a l y t i c a l s t u d y o f t h e e x c r e t a c a r r ie ou t In c lo s e tim e r e la t io n to a su sp e cte d exp osu r e w ill e s t a b lis h th e a ig - y n lflo a n e e or in a ig n iflc s n o e o f the exp osu re* In our exp e r ie n ce th e e xcr a r a t e alw ays co n t in u e s a t nn e le v a t e d le v e l fo r some tim e a ft e r th e sub 0a id e n ce o f a c t iv e symptoms o f in fco xlo a t lu r j h a d l o l o r l c an d M ic r o s c o p ic e v id e n c e s o f iib n cr m a l Lord. Ab s o r p t io n I t la e v id e n t fr o m th e fo r e g o in g p a r a gr a p h s t h a t a n a ly t ic a l p r oced u r e or e u s e fu l aa d ia g n o s t ic m oosurea on ly t o the e xt e n t t h a t they a r e meana o f e s t im a t in g th e s ig n ific a n c e o f exp osu r e t o le n d com pounds. Th ey h a ve t h e a d v a n t a g e o v e r ofchor c l i n i c a l m e t h o d s o f b e in g e n t i r e l y s p e c i ft o * an d t h i s a d v a n t a g e g iv e s them a u n iq u e u s e fu l n e s s . No d i s c u s s ! o f th e la : o r a t o r y s ig n s o f ab n or m a l le a d a b s o r p t io n w ould ho co m p le t e * however* w ith ou t r e fe r r in g to r e c e n t ly d isco ve r e d r a d io lo g ic e vid e n ce * and to the w id e ly a cce p te d b u t somewhat ill d e fin e d s ign ifica n ce o f c e r t a in b lood ch a n ge (9)a r k , and a l ' t t le la t e r Vo gt, (10) d ir e ct e d a t t e n t io n to a s h a r p ly d e fin e d lin e o f in cr e a s e d d e n s it y a t th e m ar gin o f m axim al grow th in the bones o f ch ild r e n * a s s o cia t e d w ith the lo c a l d e p o s it io n o f abnorm a amounts o f le a d . Th e ir fu r t h e r o b se r va tio n s have p r ovid ed a means fo r the prompt d e t e ct io n o f abnorm al le a d a b so r p tio n in the ca se o f young c h ild r e n . The d e n s it y p r o d u ce d b y le a d d e p o s it io n i s n o t s o s p e c i fi c in /: ' c h a r a c t o r a s t o d i ff e r e n t i a t e i t In e v e r y in s t a n c e fr om t h o s e w h ich may r e s u lt fr om o t h e r p a t h o lo g ic p r o ce s s e s * b u t i t may be s o s t r i k i n g in an o t h e r w is e a p p a r e n t ly norm al bone as to c a ll a t t e n t io n to p r e v io u s ly un~ s u s p e ct e d le a d a b s o r p t io n * The c h a r a c t e r o f th e lin e ch a n ge s w it h th e la p s e o f tim e* becom in g le s s in t e n s e ns th e le a d is give n up by th e bone a ft e r d is co n t in u a n ce o f exp o u r e* and a ls o becom in g more w id e ly s e p a r a t e d fr om t h e a c t iv e gr o w t h a r e a a s th e l a t t e r n ovee p r o g r e s s iv e ly fo r w a r d . Ho s u ch l i n e l a fo r m e d in a d u lt b o n e s * s o t h a t t h e u s e fu ln e s s o f t h e p r o ce d u r e is lim it e d t o th e s t u d y o f c h ild r e n . Po sifcivo fin d in g s m ust be in t e r p r e t e d w ith th e same d e gr e e o f ca u t io n t h a t is r e q u ir e d in th e ca se o f o t h e r in d ic a t io n s o f abnorm al le a d a b s o r p t io n . Moreover I t Is to be d oubted i f n e g a t iv e fin d in g s cun be a cce p te d as p r o o f th a t n o r e ce n t s ig n ific a n t a b s o r p tio n o f le a d has o ccu r r e d . Th is Is e s p e c ia lly to be - 9t a k e n in t o a c c o u n t In vie w oi* t h e o c c a s io n a l c a s e o f a c u t e le a d i n t o x i c a t io n fr om th e a c c id e n t a l in g e s t io n o f la r g e m ounts o f le a d . Til n u m e r ou s b lo o d ch a n ge s a s s o c ia t e d w it h a b n o r m a l le a d a b a o r p t ; have boon t h e s u b je c t oi' e x t e n s iv e In q u ir y and abun d an t co n t r o v e r s y fo r many y e a r s . The g r e a t e r p o r t io n o f th e p r e s e n t d is a gr e e m e n t i s con ce r n e d w ith the s ig n ific a n c e o f v a r ia t io n s in the numbers o f va r io u s typ es o f e r y t h r o c y t e s . The r e t ic u lo c y t e s h a ve been shown t o u n d e r go ch a n ge s In number under the in flu e n ce o f le e d a b s o r p t io n . Like w ise b a s o p h ilic s t lp p ll o f th e e r y t h r o c y t e s h a s lo n g been known ns an accom p an im en t o f le n d a b so r p tio n and in t o xica t io n * Va r io u s m e t h o d s f o r s t a i n i n g an d c o u n t in g on e op she o t h e r or b o th o f th e s e typ e c e lls h a ve been d e vis e d and recomm ended, and a la r g e number o f e x p o r ln e n t a lla t a and c li n ic i a n s , w or kin g w ith w id e ly v a r ia n t methods and groups o f p a t ie n t s , have s e t up stan d ard s fo r the d iffe r e n b in t o f n or m al fr o n a b n or m a l fi n d i n g s . I t w ould be d i f f i c u l t i f n o t Im p o s s ib le t o b r in g an y o r d e r o u t o f th e ch a o s w h ich has r e s u lt e d , o r t o har m ohlze the d ia m e t r ic a lly opposed p o in t s o f view in t o a g e n e r a lly a cce p t a b le s t a t e m ent o f t h e f a c t s Ac c o r d in g ly I s h a l l m e n t io n w ily a few o p in io n s , and 3 h a ll co n fin e m y s e lf la r g e ly to th e p r e s e n t a t io n o f th e r e s u lt s w h ich have b e e n o b t a in e d b y L . V/ . h a n d e r s , o f t h e l e t t e r i n g La b o r a t o r y , t h r o u g h t h e co n s is t e n t use o f one sim p le c lin ic a l method as a p p lie d to th e otu d y o f th occu r r en ce o f s t ip p le d e r yth r o cyt e s in the b lood o f norm al and abnorm al in d iv id u a ls . Lehm an ( 1 1 ) b e l i e v e s t h a t s t i p p l i n g o f th e e r y t h r o c y t e s o c c u r s in what is u s u a lly regar d ed as s ig n ific a n t numbers In co n d it io n s o th e r than le a d p o is o n in g o r t h e w e ll r e c o g n is e d a n e m ia s . He b e l i e v e s t h a t h e h a s d e m o n s t r a t e d t h a t e xp o s u r e t o hum id a t m o s p h e r e , a lc o h o l, an d ce m e n t d u s t r e s u lt s in th e p r o d u ct io n o f in cr e a s e d s t i p p li n g . The m a jo r it y o f' e x p e r i m en tal w orkers den y th e o ccu r r e n ce o f n ore than a ver y sm a ll number o f s t ip p le d c e llo in n or m al b lo o d . Th ose who a d m it t h e ir n or m al o ccu r r e n ce r-.p.C up a n s x i r n l U n i t o f fr o m 100 no $00 p e r n i l l i o h , ;ioh w ar s ( 12) n a ln t ft ln a t h a t "c o n s id e r a b le q u a n t it ie s e r e n e ve r fou n d In th e r e a lly h e a lt h y " Ko ch (1 3 ) r e g a r d s 100 s t ip p le d e r y t h r o e ;;t e a p e r m illio n ns s u s p ic io u s o f p lu r a b ism , an d 500 p e r m illio n na d i a g n o s t i c , Helm ( li*} s t a t e s t h a t s t ip p lin g i s n o t fo u n d in c a s e s o t h e r t h a n le a d in t o x ic a t io n , s e v e r e a n e m ia s , an d g r a v e I n t o x i c a t i o n s , fc h a i d t ( 15) h a s e s t a b li s h e d a fi g u r e o f 1)0 p e r m i l l i o n a a u s e fu l c o n fir r s a t o r y e v id e n c e o f le n d in t o x io a t io n an d 1000 p e r m i l l i o n a s s h o v in g a "d e e p s e a t e d c o n d i t i o n " . An in c c n p le t e d s t u d y o f o u r d a t a a ccu m u la t e d o v e r a p e r io d o f t e n y e a r s , w h ich i s n ov b e in g made b y Thv Sa n d e r s , shows t h a t th e p r e se n ce o f s fcip o le d e r y t h r o cy t e s is o f fr e q u e n t o ccu r r e n ce in th e b lo o d o f persona who a r e a p p a r e n t ly n o r m a l d n d h e a l t h y , an d who a r e fr e e fr o m a b n o r m a l le n d e b a o r o t io n , I n a a e r ie s o f JQU. p e r s o n s w hose c a r e f u l l y t a k e n h i s t o r i e s showed no e vid e n ce o f o ccu p a t io n a l le a d e xp o s u r e , the mean number o f a t ip p e r y t h r o c y t e s p e r m illio n was fou n d t o b e 3 3 9 l8 w it h a p r o b a b le s t a t i s t i c a e r r o r o f 9 *7 2 , and a s t a n d a r d d e v i a t i o n o f i*05*ti {e q u iv a le n t t o a b o u t 1 3t i p p le d e r y t h r o c y t e in o v a r y 12 f i e l d s w h e r e e a c h f i e l d c o n t a in s a p p r o x i r ia t e ly 250 e r y t h r o c y t e s ) j up* o f t h o a e n e n g a v e r e s u l t s v a r y in g fr o m lol*Q t o 11*1*0 p e r m i l l i o n e r y t h r o c y t e s , o v e r 2% r a n fr o m 1520 t o 1 9 2 0 p e r m i l li o an d t h e u p p e r l i m i t w as n e a r cOOO p e r m i l l i o n , .\ I t fo llo w s fr o n th ese o b s e r va tio n s th a t the mere ocourrcnc o f a t t p le d e r y t h r o cy t e s in th e b lood is n ot in d ic a t iv e o f abnorm al le n d a b s o r p tio n and t h a t th e mere d em on str ation o f s t ip p lin g, has no d ia g n o s t ic v a lu e . The r a n ge o f n or m a l v a lu e s m ust be e s t a b lis h e d fo r a n y m ethod o f e x a ia in a t i <>n o f t h e b l o o d , an d t h e m ethod i t s e l f m u s t b e s o s t a n d a r d is e d as to y ie ld c o n s is t e n t and com p ar ab le r e s u lt s . Ou r d a t a on p e r s o n a a b n o r m a lly e x ;o a e d t o le a d an d t o o e r t n in o th e r a ge n ts have n ot been so worked up as to Ju s t ify a com p le te sta te m e n o f t h e ir s ig n ific a n c e . N e v e r t h e le s s c e r t a in fa c t s w h ich have a b e a r in g u d i a g n o s i s , h a ve becom e o b vio u s fr om th e n a t u r e o f t h e in d iv id u a l r e s u l t s . 11 V l t h d u e r e g a r d fco t h e t e c h n iq u e w h ich we h n ve oysd , the fa llo w in g co n clu s io n s ere ju s t ifie d (a) There la a d e fin it e o ve r la p p in g o f the n or m al and ab n or m al r an ge o f s t i p p li n g , due to w ide In d iv id u a l v a r i a b i l i t y , b o t h among n o r m a l a n d a b n o r m a l ,;r o u ; s . (b ) Le a d a b s o r p t io n l a b u t ono o f a number o f fa c t o r s w hich may ca u se an in cr e a s e In th e number o f s t ip p le d e r y t h r o c y t e s w it h o u t In d u c in g s u b je c t i v e I l l n e s s ( e ) Loa d a b s o r p t io n t e n d s In the In d iv id u a l ca se to cau se in cr e a se d s t ip p lin g o f the e r yth r o cyte s {b e h a ve s e e n a s many a s 19000 s t i p p le d c e l l s p e r m i l li o n e r y t h r o c y t e s In s u b j e c t i v e l y w e ll b u t le a d e d p e r s o n s ) ( d ) Th e x t e n t o f t h e In c r e a s e p r od u ced by le a d a b s o r p t io n la n o t n e c e s s a r ily r e la t e d to th e m agn itu d e o f t h e le a d e x p o s u r e , o r t o t h e r c t e a n d magr! fcude o f t h e lo a d a b s o r p t io n (a ) Th er a la no n e ce s s a r y c o r r e la t i on b e t w e e n th e nuau o r o f s t ip p le d e r yt h r o cyt e s and th e on se t o r s e v e r it y o f lo a d in t o x ic a t io n ( In a c t iv e le a d 1u t o x le o t io n wo h a ve fo u n d u p t o ^ 8,000 p o r m i l li o n e r y t h r o c y t e s ) ( f) In o u r e x p e r i e n c e , t h u s f a r , le a d in t o x ic n <:i on I s a lw a ys a s s o c ia t e d w it h th .p r e s e n ce o f come d e g r e e o f s t i p p l i n g * a lt h o u g h In c e r t a i n ca s e s w it h ' a b r u p t o n s e t fo llo w in g p r o m p t ly upon a b r i e f m a s s ive e xp o s u r e , I t may n ot a p p e a r p r om p tly r a n t in g the v a lid it y o f th e so co n o lu sio r ia , tho e xa m in a tio n o f th e b lo o d f r s t ip p lin g by m ethods o f e q u iva le n t s e n s it iv it y to th ose w h ich we h a v e e m p lo y e d , l a u s e fu l n s a n ou n s o f e x c lu d in g l o r d c.o a f a t e r In s u s p e ct e d o a se s o f le a d In t o x ic a t io n , when th e r e s u lt s a r e n e g a t iv e , and a s a moans o f p r o v id in g co n fir m a t o r y e vid e n co whan p o s it iv e Re fVr ^ n ce s l,** K*snotj A ThABtann, F . , a ir ; Ch o la k , J* t on t h e n o m a l air s o r p t io n and o xcr f/ tio ii o f lo a d (a ) I . Le a d a b s o r p t ?u n and e x c r e t io n In p r im it iv e l i f e * J , In d u c t . Hyg. 1 * 257 (1953) (b ) I I , Le a d a b s o r p t io n a n d le n d e x c r e t i o n In m oder n Arao? le a n l i f e , it ;la 5. * 273 (1933) ( c) I I I , The s o u r ce o f n or m al le a d a b s o r p t io n I b i d , * 290 (192 (d ) I V , Le a d a b s o r p t io n and e x c r e t io n in I n fa n t s and c h ild r e n . I b i d , 15, * 301 (1 9 3 3 ) ( Fo o t n o t e * E xt e n s iv e r e fe r e n c e t o th e lit e r a t u r e o f th e s u b je c t may be fo u n d in t h i s s e r i e s o f p a p e r s ,) 2, Kehoe, t?. A, Thcuaann F, and Cholak, J.* Normal absorption and excretion oi lead cT,A,$4, , XO|j^t 90 119)5) 3 . Ga u l L ,K , a n d B t a u d , A.1 U* C l i n i c a l s p e c t r o s c o p y * s p e c t r o m e t r io a n a ly s is o f b io p a y s p e cim e n s o b t a in e d fr om o a s e s o f p lu a b ls m an d workmen in d a ily c o n t a c t w it h le a d p a in t s J , N e r v , and Mo n t , D la , 51 t 205 (1 7 3 5 ) lk . B a r t h , .,* Un t e r s u ch u n g e n {bar d e n B l e i g e h a l t d e r m e n e c h lic h e n Kn och e n Vir ch o w s Ar c h , f , p a t h , / . a t ,, 281 : li+o ( 1 9 3 1 ) 5, Lifc e n c r , M . an d 7 / e yr a u oh , F ,* Un t e r a u o h u n . on b e r d e n E l e i g e h a l t d e s M u t e s u n d Ka r n s , s e in e Be z ie h u n ge n zum Au ft r e t e n k li n i^ b h e r > Kr a n k h e lt s e r s c h e im m g e n s o w ie s e in e d ln g n o *t is c h e r e d e u t u n g , r ,r c h *f b e w e r b e p a fch . u . 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Uyg, u , In fe k 13 13* Koci'.p * /a u * Vr a n ciar H &a a t o lo g ls o h e n D ia g n o s e s t e llu n g b e l ile lv ilr k u i/ j Vo r s c h la g e i n e r Clu vu lm clfiirbu n g d e r g r a n u la po l yo iir one ..ry tro a y tim p Arch * f * Hy g . 2 k 1 3O0 (192+)* li ;* H'ln do a la s e * ** / ;&a a s e ~ La fo n t l\ p a ir i i 'e l l a * s Co n t r ib u t io n a l f eftu 4o du s n t u m la n o p r ot e s s i u n s i ; 1 d e p is t a g e u n r le a ^ w cth od e dned*la*b oi-raartt aoi r e* j di up3r e sUa9t2u2m*ls n e et du satu r n ism e co n fir a * i u ll, 1 5 * -Oh aft Pmi t e u e r e / e r a e h u n ge n Sb e r d a ' o e n d e r B le iv e r g ift u n g * HXn * / s e h r ** u s 36 7 ( 1 9 2 7 ) / / n 1 5^ 3