Document On49p0yEVqqM6Lg0RBxZOdxQ

December 13* 1 9 3 8 D r . Ann S . Min o t Departm ent o f P e d ia t r ic s Sch o o l o f Med icin e Va n d e r b ilt Un iv e r s it y H a s h v ille , Tennessee Dear Do cto r M in o t :- I am s o r r y I f my r e c e n t c r it ic is m s o f you r r e vie w o f "The P h y s io lo g ic a l E ffe c t s o f Sm a ll An o u n t s o f Le a d " co n ve ye d t h e im p r e s s io n t h a t I d id n o t b e lie v e i t t o b e u s e f u l . On t h e c o n t r a r y I th ou gh t w e ll o f I t in many r e s p e ct s or I sh ou ld n ot have taken the tr o u b le to c r i t i c i z e i t a t a l l . I o n ly b e lie v e d I t somewhat le s s u s e fu l and le s s r e v e a lin g o f th e a c t u a l s t a t u s o f t h e pr oblem th an i t r e a s o n a b ly co u ld b e e xp e ct e d t o b e . I d id n o t com p lain t h a t i t was in a ccu r a t e e xce p t in so fa r as i t was le s s com p lete than i t sh ou ld have b e e n . I a gr e e e n t ir e ly w ith you in your fe e lin g th a t any d e t a ile d d is cu s s io n of methods of a n a lys is would h a ve b e e n r e d u n d a n t in s u ch a r e v ie w , b u t , on t h e o t h e r h a n d , s in c e t h e u s e o f new and h ig h ly s e n s it iv e m eth od s h a s don e s o much t o a l t e r p r e v io u s ly a cce p t e d fa c t s in many sp o ts o f t h is p h y s io lo g ic a l f i e l d , one ca n n o t ig n o r e t h e i r p r a c t i c a l im p o r t a n c e . The a v a i la b le d a t a m ust be e v a lu a t e d on the b a s is o f th e s e n s it iv it y and a ccu r a cy o f th e m eth od s em ployed in o b t a in in g them o r t h e w hole l i t e r a t u r e o f t h e s u b je c t becom es a m a ze . T h is , I ad m it, is d i ffi c u lt , h u t i t is n ot im p o s s ib le , I t is not fa ir to s a y, m oreover, th a t the advocates of v a r io u s r e ce n t m ethods o f a n a ly s is ar e in an y ve r y gr e a t d is a gr e e m e n t among t h e m s e lve s as t o t h e e s s e n t ia l a ccu r a cy o f t h e i r r e s u l t s . D o u b t le s s D r . F a i r h a l l * w i t h whom I d is c u s s e d t h is q u e s t io n some tim e a go , is in t e r e s t e d , as I am, In the u tm ost p r e cis io n in th e a p p lic a t io n o f some m o d i fic a t i o n o f t h e " d i t h iz o n e 1' m e t h o d , and d o u b t le s s in h is o ffic ia l ca p a cit y and w ith h is p r e se n t r e s p o n s ib ilit ie s he can a ffo r d no more than I , to sp on sor any method fo r u se w ith o u t the m ost r ig id and d ir e c t exam in ation o f it s m e r it s . And y e t I do n o t b e l i e v e t h a t h e w ou ld h a v e t h e s l i g h t e s t r e s e r v a t io n in a gr e e in g t h a t in d e a lin g w ith the m in u te q u a n t it ie s o f le a d encountered in b io lo g ic a l m a te r ia l s e v e r a l of th e p u b lish e d m o d ifica t io n s o f th a t method ar e fa r s u p e r io r b o th in s e n s it iv it y and In fin a l a ccu r a cy to any one o f the more t y p ic a lly a n a ly t ic a l p r oce d u r e s u se d b y a n y o f u s some y e a r s a g o . He i s q u it e p r o p e r ly c a u t io u s in co n s id e r in g th e p o t fa lls a s s o cia t e d w ith th e extrem e a s e n s it iv it y o f t ; ose methods b u t I do not th in k he r egar d s t h e s e as in s u r m o u n t a b le in vies? o f h is kn ow led ge o f t h e ir u s e b y W illo u g h b y e t a l , b y C l i f f o r d and Wlchmann and b y o u r s e lv e s . Th e men in h i s la b o r a t o r y a r e now f a m i l i a r w it h these m ethods, and h is a s s o cia te s ar e a ls o q u ite fa m ilia r w ith s p e ct r o gr a p h ic m ethods ve r y s im ila r to o u r 3 . I t m ust b e r e c o g n iz e d , h o w e ve r , t h a t a much w id e r and lo n g e r e xp e r ie n ce w ith th e se m ethods has been had h y o th e r w o r k e r s. I was s u r p r is e d , t h e r e fo r e , t h a t you had n o t had some r e co u r s e t o t h e o p in io n s o f p e r s o n s who li k e W illo u g h b y , Wlchm ann, Ca lv e r y and c e r t a in o f my a s s o c ia t e s , have had th e b e n e fit o f t h a t lo n g e r e x p e r ie n c e , e s p e c ia lly so s in c e Ch o la k and Hubbar d in t h is la b o r a t o r y had a lr e a d y c a r r ie d ou t th e com p ar ison o f c e r t a in m e t h o d s w h ich F a i r h a l l i s now m a k in g. As t o t h e q u e s t io n o f yo u r c a s t i n g d o u b t on th e a c c u r a c y o f c e r t a in p u b lis h e d d a t a , I would be the la s t person to argue a ga in s t t h is d u ty o f a r eview er to do t h i s j u s t t o t h e d e g r e e o f h is own d o u b t . Ho w e ve r , I b e lie ve th at d ata o f s u ffic ie n t accu r acy were a v a ila b le to d is p e l your doubt - d ata ob tain ed by s e ve r a l r e lia b le w orkers w hich ar e in su ch e s s e n t ia l agr eem en t as to le a v e l i t t l e room fo r d ou b t co n ce r n in g t h e ir v a li d i t y . ( I may s a y , h e r e , t h a t I do n o t r e g a r d t h e i n c r e d i b ly b a d p a p e r s o f Myer s e t al"'. a s s u ffi c i e n t b a s is fo r in c r e d u lit y as to t h e r e s u lt s o f o t h e r s .) Hone o f t h e s e m a t t e r s w ou ld be o f gr e a t im p or tan ce as grounds fo r c r it ic is m e xce p t fo r t h e ir r e l a t i o n t o w h at I r e g a r d a s on o f t h e m o s t fu n d a m e n t a l p h ases o f th e p r oblem you were d is c u s s in g , n a m e ly, th e p h y s io lo g ica l a s p e cts o f le a d m e ta b o lism . I f I sp eak in a p e r fe c t ly fr a n k manner about th e im p or tan ce o f a p r ocess w hich was f i r s t r e co gn ize d in t h is la b o r a t o r y , I t r u s t I s h a l l n o t be t h o u g h t la c k i n g in m o d e s t y . As a m a t t e r o f f a c t , no g r e a t m o d e st y i s r e q u ir e d on my p a r t in r e s p e c t t o t h is m a t t e r s in c e i t came o u t o f no b r i l l i a n t l y c r e a t iv e m e n t a l e f f o r t , b u t r a t h e r fr om t h e o ve r w h e lm in g e v id e n ce o f a la r g e m ass o f d a t a # I t a p p e a r e d fr om ou r s t u d ie s a s o u t lin e d in 1933 ( J* I* H y g .) t h a t n or m al le a d m e t a b o lis m was an e q u ilib r a t e d p h y s io lo g ic a l p r o c e s s , in w hich a s u b s t a n t ia lly co n s t a n t le v e l o f le a d co n ce n t r a t io n in the t is s u e s was m ain ta in e d over lo n g p e r io d s o f tim e th r ou gh b a la n ce d in t a k e and cu t p u t * I t a ls o ..a p p e a r e d t h a t in c r e a s e d le a d i n t a k e , u p t o a ce r t a in in co m p le te ly d e fin e d p o in t , r e s u lt e d in an in cr e a s e in the le a d co n te n t o f th e t is s u e s and a cor r e sp o n d in g in cr e a s e in th e le a d e x c r e t io n . Ih e m agn itu d e o f th e In cr e a s e in the le a d co n t e n t o f the t is s u e s and in th e e x cr e t o r y r a t e was r o u gh ly p r o p o r t io n a l to th e m agn itu d e o f th e in cr e a s e d in ta k d w it h in ce r t a in lim it s . There was e v id e n ce , t h e r e fo r e , o f th e m ain ten an ce o f a b a la n ce d e q u ilib r iu m a t le v e ls above t h a t n or m a lly e n co u n te r e d . Gr a n t in g th e coorrectn ess o f th ese fa c t s , i t is s ca r ce ly to be exp ected th a t any d e le te r io u s e ffe c t s w ould o ccu r w it h in t h e li m it s o f a p h y s io lo g ic a l le a d in ta k e - i# e . th a t u n a vo id a b ly a s s o cia t e d w ith the n a t u r a l le a d co n t e n t o f fo o d and d r in k * F u r t h e r , w it h in a 3 su ch a s th e am ounts o f le a d fou n d in th e d ie t s o f random Am e r ica n s, as w e ll as t h a t o f our e xp e r im e n ta l s u b je ct s o ve r p e r io d s o f many m o n t h s , no u n tow ar d e ffe c t s w ould r e a s o n a b ly be a n t ic ip a t e d . I t sh ou ld be ad d e d , t h a t w ith r e sp e ct to s t i l l h igh e r le v e ls of exp osu r e, In d u s t r ia l e xp e r ie n ce had p r ovid ed co n s id e r a b le evid e n ce fo r a d e fin it e d iffe r e n t ia t io n o f h a r m le ss and in ju r io u s exp osu r e w hich in d ica t e d t h a t somewhat la r g e r q u a n t it ie s co u ld be absorbed over in d e fin it e p e r io d s o f tim e w ith o u t t o x ic e ffe c t s * One c o u ld s c o f f a t s u ch e v id e n c e a s b a s e d on in a c c u r a t e o b s e r v a t io n , unsound ju d gm e n t, and in d iffe r e n c e to th e r is k s o f o ccu p a tio n , u n t il a ccu r a te c lin ic a l stu d ie s com bined w ith p r e c is e a ir a n a ly s e s and c a r e fu l"e x c r e t o r y d a t a on e xp o s e d workmen p r o v id e d q u a n t it a t iv e c r i t e r i a fo r th e d e fin it io n of s a fe o ccu p a tio n a l co n d it io n s . In terms o f our o b s e r v a t io n s , and o f th e con cep t d er ived t h e r e fr o m , a l l o f th ese s it u a t io n s co u ld be d e s cr ib e d and c la s s ifie d under the categor y o f normal l ,e , p h y s io lo gica l, le a d m e ta b o lism , as a b a la n ce d p r ocess a s s o cia t e d w ith non in ju r io u s c o n c e n t r a t io n s o f le a d in t h e t i s s u e s . The l e v e l o f human le a d in t a k e a t w hich th e m e t a b o lic p a t t e r n ch an ges or a t w hich tb e co n ce n t r a t io n o f le a d as a m e t a b o lit e becomes h a r m fu l to t i s s u e s , h a s n o t been d e fin e d w it h th e r e q u ir e d a ccu r a cy, bu t th at th ere is such a le v e l and th a t i t is am enable to p r e cis e d e fin it io n seems w e ll a s s u r e d * No th in g h a s c o n t r ib u t e d to t h is e n co u r a g in g p r o s p e c t so much a s t h e d evelop m en t o f co m p a r a t ive ly s im p le and h ig h ly p r e c is e a n a l y t i c a l m e t h o d s , By means o f s u ch m e t h o d s , t h e p a t t e r n o f t h e p r o ce s s m e n t io n e d a b o v e , w h ich o r ig in a t e d fr om d a t a o b t a in e d la b o r io u s ly on v e r y la r g e sa m p le s o f t is s u e s and e x c r e t a , h as b een e lu c id a t e d w it h much g r e a t e r p r e c is io n th r ou gh t h e ir a p p lic a t io n to m a t e r ia ls t h a t co u ld n o t be a n a lys e d a c c u r a t e ly b y o ld e r m e th o d s, an d h a s been co n fir m e d a t ce r t a in e s s e n t ia l p o in ts b y the ob se r va tio n s o f a number o f w o r k e r s who h a ve n o t b e e n co n ce r n e d w it h t h e e n t i r e p r o b le m . I t was on a cco u n t o f su ch c o n s id e r a t io n s t h a t I r e g r e t t e d so much you r f a i l u r e p r o p e r ly t o e v a lu a t e t h e new m ethod s and t h e d a t a o b t a in e d b y t h e ir u s e . You may n o t b e c o n v in ce d o f t h e v a lid it y of the gen er al concept s ta te d ab ove. In th at case I do n o t w ish t o a r gu e *, b u t m e r e ly to ob se r ve t h a t my c r i t i c a l com m ents w e r e b a s e d on ray b e l i e f t h a t you w ou ld h a ve b e e n f u l l y co n vin ce d I f you had g iv e n ad eq u ate co n s id e r a t io n t o some o f th e r e ce n t co n t r ib u t io n s w hich I c it e d , 1 sh o u ld n o t w ish you t o ta k e what I have sa id as d e lib e r a t e ly ungenerous c r it ic is m , nor as the e xp r e ssio n o f an In t e r e s t in p o le m ics . Ra th e r have I attem p ted t o make as c o n s t r u c t iv e comments as I c a n , in r e la t i o n t o t h is im p or ta n t and in t e r e s t in g p r ob le m . With t h is Id e a u p p e r m ost, I am s e n d in g h e r e w it h some r e p r in t 3 o f a r t i c l e s w h ich may p r o ve t o be o f some i n t e r e s t t o you * You w i l l n o t be g r e a t l y I n t e r e s t e d , p e r h a p s , in t h o p r a c t i c a l d e t a i l s o f t h e s t u d y made on th e h a za r d s o f le a d e d g a s o lin e , b u t I t h in k th e r a t h e r com p lete s t u d ie s on n or m al le a d m e ta b o lism d e s cr ib e d t h e r e in w i ll be h w or th your c a r e fu l e xa m in a tio n * Ce r t a in fa c t o r s w hich In flu e n ce the r a t e o f u r in a r y le a d e xcr e t io n ar e r a t h e r w e ll d e m o n s t r a t e d . I sen d you a ls o typ ed co p ie s o f two papers w hich h ave been give n a t s c i e n t i fi c m e e tin gs b u t w h ich h a ve been w it h h e ld fr om p u b lic a t io n In o r d e r t o sa ve t h e d u p lic a t io n t h a t w ould r e s u lt fr om t h e f a c t th a t ce r t a in o b s e r va t io n s were in co m p le te * Th e s e , o f co u r s e , have no r e la t io n to you r r eview b u t th e y a r e , I t h i n k , o f i n t e r e s t . P le a s e r e t u r n them t o me when t h e y have se r ve d your p u r p ose. Co r d ia lly you r s, RAK j I s Ro b e r t A. Ke h o e , M .D . P .S . In r e la t io n t o th e pr oblem o f le a d m e t a b o lism t h e r e is one p o in t w hich I fin d no d ir e c t m en tion o f in the fo r e g o in g p a r agr ap h s and w hich I sh ou ld n o t have o m it t e d . Th er e is no d o u b t , fr e r .1 o u r o b s e r v a t io n s ( J,I .H .1 9 3 3 ) t h a t t h e word "s t o r e d " as a p p lie d to le a d in the s k e le t o n is a com p lete m is n o m e r . Le a d i s d e p o s it e d in t h e b o n e s in e q u ilib r iu m w it h o t h e r t is s u e s and t h e le a d s t r e a m . I t i s l o s t fr om t h e b on e s w hen ever th e le a d in t a k e is r e d u ce d . Va r io u s fa c t o r s may in flu e n ce the r a t e o f d e p o s itio n and lo s s to g r e a t e r or le s s e r d egr ee b u t the fin a l r e s u lt is e s s e n t ia lly in d ep en d en t o f th ese fa c t o r s , i t b e in g d eter m in ed la r g e ly by the e n vir on m en tal le a d exp osu r e and a b s o r p t io n . There m ay, o f co u r s e , be p a t h o lo g ic d is t u r b a n ce s in the ca se of le a d m e ta b olism , b u t th ese have n ot been a d e q u a te ly or even t e n t a t iv e ly in v e s t ig a t e d . A ll p r e se n t e vid en ces in d ica t e s a h igh d e gr e e o f p r e d ic t a b ilit y and s t a b ilit y in the p r o ce ss under o r d in a r y c o n d it io n s . K C 0 0 12422