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AR226-2761 LIVER STUDY OF WASHINGTON WORKS EMPLOYEES EXPOSED TO C-8: RESULTS OF BLOOD BIOCHEMISTRY TESTING WILLIAM E. FAYERWEATHER JANUARY 15, 1981 iompany Sanitized. Does not contain T SC A C 3 ! A cknow ledgem ents Sum m ary recent W a s h i n o f ^ 1'*1*0? ^ asfembled biochemical data on some o T t h e s ^ L a9 u ,npl0yeeS' BaSed on a crude ^ a l y s i s potential amm/C ^he res"^ts suggested that certain workers with S o w i n a liv^r rff"1 P erfl"orooctanoate (C-8) exposure might be have shownYthat C ^ n ^ o d * 150'ieVerf 1 unpublished animal studies moderateorhi produ?es liver damage when it is given at more d e t a i l s d *. A f a consequence of these findings, a WoiL assessment of C-8's health effects in Washington works employees was undertaken. yn compared aminr,frm rout4 ne blood tests were collected and workers^ ?? 95 "ps f >> a and non-Teflon area thise test! ana bilirubi" studied, since Within fh. t v ? generally good for detecting liver disease. wwoorrkk ^b iiissttoorrvy af indd" hby abi ?loao' ad Co~r8g ea n* Pics uf lrueo rgirdoeu plse vweelr.e d e f i n e d by These data provided no conclusive evidence of an occupationally related health problem among workers exposed be liver e f f ? ? a?aly ses suggested that there might . e tfccts attributable to C-8 exposure, further analyses did not support this position. analyses Background Teflon n o ? 6 T e f l ?.a irea consists of two divisions: the l7!!6 ?8 Dlvlslon and the Teflo n Copolymers D iyj; ^he Teflon P o l y m e r ^ ^ i s i o n p r o d u c e s j j * nneerrss. TTkhaegsae p o ly m e rs are made b y T a t ? ! ^ r o 5 l s s e s T. e fAlmomn^opni^ulmyallfiffhoCta? ate ( C ~ 8) 1 S a disP e r s ing agent added to nearly all f the polymer processes. The monomers do not contain Y Tha T e flo n * Polym ers D iv isio n makes th re e tyDes o f CC ^8e Ti ss " uuLserdd dff oo ri ^d-i s pf ei nr sei.oPn wtdhr a'n df o- Pr efri ns ieo np o, wadnedr pg rroa dn uu cl at sr.. More TTwwoo ^c on nntii-nPu o u sUCid Sr i-eUrSse rleemS SoveC" n8 etahral yn da ol l d tihs pe e Cr s-8i o nfropmr o fdiuncet s . !n i J ' i . i ndo Wf s i ln 9 and d r y i n * P r o c e s s e s rem ove e s s e n t i a l l y c o n fS fn I? Ck ? ^ S S ^ r a n u l a r p r o d u c t s . D i s p e r s i o n p r o d u c ts contain r o u g h ly 'g H lM N ( |c - 8 based on s o lid s . Tbe ^cflou Copolymers D iv isio n pro d u ces fo u r copoly- ? \ whlch c o n t a i r M Three o f th e se copolym ers a re c o n M n L b! tCh P r o c e s s e s * , The f o u r t h , T e fz e l , i s made by a all ^of ProcaaS * 13 added as a ,d is p e r s in g ag en t fo r j ^ ^ ^ o ^ t n ^ c o p Q l y m e r s e x c e p t T e fz e l . I j f t M H B i i M n i ---------- the m ajor polym er, makes^ up aboutl ^o^^he^ c o p o ly m e r p r o d u c e d . H P flnbcoo n s is ts o f ind Company Sanitized. Does not contain T SCA CBI . . . . . ThU ^ ^ P o l y n i e r i z a t i o n p r o c e s s a l s o g e n e r a t e s an in --u i s p e r s i n g a g e n t. In J u n e , 1976 th e p l a n t began a d d in g C-8 ag en t to in c re a se th e re a c tio n r a te . This change ed ced th e amount of tim e needed fo r the p ro c e ss and a ls o reduced th e amount o f in s i t u d is p e rs in g a g en t th a t was form ed. However, some in s i t u d i s p e r s in g a g e n t i s s t i l l form ed in a l l l p j l j a t c h e s . r U n til th e flJ H R o ly m e r re a c h e s th e humid h e a t t r e a t i n q AjjgAS, i t c o n t a i n s _in s i t u a s w e ll a s C-8 d i s p e r s i n g a g e n t . ^B ?ol3nner i s very d u s ty . So, in th e p ro c e ssin g s te p s between ^ ^ ^ P iy m e n z e r s and the ovens, th ere is s ig n ific a n t poten- i a l f o r e x p o s u re t o C -8 and iji s i t u d i s p e r s i n g a g e n t s . /*d r,o is p e r s i o n r > r o d u c t s c o n ta in in s i t u d i s p e r s i n g a g e n t a n clea b o u t C-8 based on s o lid s . s itu d isp e rsin g agent is not w ell c h a ra c te riz e d , i t i s b e l i e v e ^ t o be a m ix tu re o f homologs o f low m o le c u la r . e *g. . I j^ ^ ^ ^ ^ ^ ^ p c o m p o u n d s , some w ith a c id end g ro u p s . On a w eight b a sis i t is le s s su rfa ce a c tiv e than C-8. S e v e r a l u n p u b lis h e d a n im a l t o x i c i t y s t u d i e s d o n e a t 3M C o r p o r a tio n and a t Du P o n t have fo u n d t h a t m o d e ra te and h ig h dose le v e ls o f C-8 produced l i v e r damage. Both r e v e r s ib le and ir r e v e r s ib le l i v e r damage, e le v a te d l i v e r enzyme t e s t s , and e n la rg ed liv e r s were found. Study r e s u lts depended on th e dose l e v e l, ex p o su re ro u te , sex and s p e c ie s te s te d . Dr. Y. L. Power assem b led b io c h e m ic a l d a ta on some c u r r e n t W ashington Works em p lo y ees who had had company p h y s ic a l exam inations in 1978. Based on a p re lim in a ry a n a ly s is o f th ese d a ta , the r e s u lts suggested th a t c e rta in w orkers w ith p o te n tia l C--8 e x p o s u re m ig h t be show ing l i v e r e f f e c t s . , As a c o n se q u e n c e o f t h e p r e v i o u s a n im a l s t u d i e s o f C-8 and o f Dr. P o w e r's p re lim in a ry f in d in g s , a more d e ta il e d a s s e s s ment o f C-8 s h e a l th e f f e c t s in W ashington Works em ployees was undertaken. Study O b jectiv e The o b je c tiv e was to d e te rm in e w h eth er o c c u p a tio n a l exposure to C-8 a d v e rse ly a f f e c ts l i v e r fu n c tio n s as m easured by b lo o d le v e ls o f g lu ta m ic o x a lo a c e tic tra n s a m in a s e (SGOT), l a c t i c d e h y d ro g e n a s e ( LDH) , a l k a l i n e p h o s p h a ta s e (A P ), and b iliru b in . . N o te : T hese b lo o d t e s t s a r e n e i t h e r 100% s e n s i t i v e n o r 100% s p e c in c fo r d e te c tin g l iv e r d ise a s e . There are a number o f c irc u m s ta n c e s u n d e r w hich th e t e s t may g iv e f a l s e p o s i t i v e o r ^ ^ --negative r e s u lts . These circum stances are d iscu ssed the end of the p ap er under L iver fu n ctio n te s ts : lim ita tio n s . 4 Company Sanitized, Does .i contain TSCA CB* Methods 1. G eneral design . . . . . . R e c e n t b lo o d t e s t r e s u l t s f o r SGOT, AP, LDH, and l l i r u b m were compared betw een C-8 exposed and non-exposed w orkers a t W ashington Works. T e st r e s u l t s were s tu d ie d by s p e c if ic Teflon a re a jo b and by blood f lu o r id e le v e l. 2. S e le c tio n of study groups The i n i t i a l group c o n s is te d o f 96 W ashington W orksem ployees who w ere i n one o f th e fo llo w in g T eflon a re a jo b s as of O ctober, 1979: M ? rocess operator M p rocess operator m se rV i ce o p e r a to r m f t ^ ^ s e r v i c e o p e r a t o r L a b o r a to r ia n ; monomer o p e ra to r ; Teflon a re a e n g in e e r; chem ist, o r forem an. T h is group in c lu d e d 78 w o rk ers who had b een t e s t e d e a r l i e r in the year fo r blood flu o rid e le v e ls . n l y |H H ^ |p r o c e s s and se rv ic e o p e ra to rs were con sid ered to have had s ig n if ic a n t p o te n tia l fo r exposure to C-8. Monomer o p e r a t o r s , sem i-w o rk s l a b o r a t o r i a n s , and T eflon a re a oremen were k e p t as a se p a ra te com parison g ro u p , sin c e they worked m th e T e flo n a re a but had only lim ite d C-8 exposure p o ten tial. . The number in t h is g roup was l a t e r dropped to 88, sin c e 8 w orkers had n o t worked in th e Teflon a re a p r io r ' to th e ir most re c e n t blood t e s t . These 8 w orkers were added to the non-exposed group ( i . e . , the c o n tro l group). # For th e s e 88 em ployees, J . F. Doughty g a th e re d d e ta ile d Teflon a re a wprk h is to r ie s from p la n t rec o rd s and from p e r s o n a l i n t e r v i e w s . Work h i s t o r i e s w ere c o p ie d t o code sheets (tab le 1). . * 3. S e le c tio n o f a nonexposed c o n tro l group The c o n t r o l g ro u p c o n s i s t e d o f a 10% s y s t e m a t i c sam pl o f a l l a c t i v e W a sh in g to n Works e m p lo y ee s who, a s o f A u g u st, 19 . nad never w orked in th e T eflo n a rea . M echanics and la b o r a to r ia n s were excluded from th e c o n tr o l s , s in c e t h e i r ex p o su re p o te n tia ls could not be w e ll docum ented. Company oUililcU. 1/UCJ IW..U4H 1ai/M V^kil -j n> The g ro u p was s e l e c te d i n th e fo llo w in g m anner: Dr. Y. L. Pow er p u l le d e v e ry t e n t h r e c o r d from th e p l a n t ' s alphabetized m edical f i l e s fo r a c tiv e em ployees. These workers names were th e n g iv e n to J . F. D oughty. From p l a n t r e c o rd s and through p e rso n al in te rv ie w s , Doughty o b tain ed th e se w o rk ers' work h i s t o r i e s * W orkers who had w orked i n th e T eflon a r e a o r who had worked a s m e c h a n ic s o r l a b o r a t o r i a n s w ere th e n d ro p p ed from th e l i s t . The rem ain in g w o rk e rs c o n s t it u t e d th e c o n tr o l group. Eight- more w orkers were l a t e r tr a n s f e r r e d from th e exposed to th e c o n tro l group, because th ese 8 had had no poten t i a l C-8 ex p o su re p r io r to t h e i r m ost re c e n t blood t e s t . 4. Biochem ical blood te s ts As a p a r t o f r o u t i n e p h y s i c a l e x a m in a tio n s , e a c h w o r k e r 's b lo o d i s t e s t e d f o r 12 b io c h e m ic a l m a r k e r s . T h ese 12 t e s t s a re c a l l e d th e SMA-.12. From p l a n t m e d ic a l r e c o r d s , e v e ry SMA-12 on t h e exposed and c o n tr o l w o rk ers was co p ied to code s h e e ts ( ta b le 2 ) . A ll SMA-12 t e s t s had been p e rfo rm e d by th e same l a b o r a t o r y and by th e Same m eth o d s. Very few SM A-12's had been done b e f o r e 1 9 7 4 -7 5 . E very w o r k e r 's m o st r e c e n t SMA-12 had b een done sin c e 1977. Only t e s t s p e r ta in in g to th e l i v e r were s t u d i e d . T hese in c lu d e d t h e SGOT, AP, LDH, and b i l i r u b i n . 5. Blood flu o r id e le v e ls P rio r to th is study, blood flu o rid e le v e ls had been m easured on 78 o f th e p l a n t 's T eflon a re a w o rk e rs and on 25 W ilm ington o f f ic e w o rk ers. Blood flu o rid e m easurem ents had b e en made a t J a c k s o n L a b o r a to r y by th e 3M (bomb) m e th o d . Most o f th e w orkers te s te d a t the p la n t had had p o te n tia l C-8 expo su re . L iver fu n c tio n t e s t r e s u lts were analyzed acco rd in g to blood flu o rid e le v e ls . 6. S t a t i s t i c a l m ethods SMA-12 r e s u l t s were s t u d i e d by e x p o s u r e s t a t u s , by s p e c if ic Teflon a re a jo b , and by blood f lu o r id e d e c i l e . A nalyses were b ased on (1) t e s t means and (2) th e p ro p o rtio n f a l l i n g in to th e h ig h e s t l iv e r f u n c tio n t e s t d e c i l e . The h i g h e s t d e c i l e w as d e f i n e d as t h e ra n g e i n w h ic h t h e to p 10 percent of a ll c o n tro l and exposed groups' te s t values lie . On th e a v e r a g e , t h e n , one would e x p e c t t h a t 10 p e r c e n t o f th e c o n tro l g ro u p 's v a lu e s would f a l l , in to t h is d e c ile . U nless s ta te d o th e rw ise , t e s t v a lu e s were from th e w o rk e r's most r e c e n t SMA-12. Group d if f e r e n c e s in b io c h e m is try t e s t means w ere s tu d ie d by an aly sis of covariance and le a s t s ig n ific a n t d iffe re n c e te s ts (LSD). T h is a n a ly s is a d ju s te d f o r any g ro u p d if f e r e n c e s m age or se x . The s t a t i s t i c a l s ig n if ic a n c e o f d i f f e r e n c e s in p ro p o r tio n s was a s s e s s e d by F i s h e r 's e x a c t t e s t . T w o -ta il t e s t s were perform ed, and p -v a lu e s le s s th a n 0.10 were re p o rte d . Com pany Sanili: cd Does not contain T S C A CB? R esults 1. . T est v a lid a tio n D r. Y. L. Pow er p ro v id e d p r e l i m i n a r y d a ta on th e SMA-12 r e s u l ts f o r 1978 ( ta b le 3 ) . These d a ta showed th a t th e p la n t p o p u latio n as a whole had an u n u su a lly la rg e p e rc e n ta g e of e le v a t e d SG O T 's. SGOT's were e l e v a t e d i n 19 p e r c e n t o f th e w orkers w hereas e le v a tio n s would o n ly have been ex p ec ted in a b o u t 5% b a s e d on random s t a t i s t i c a l v a r i a t i o n . AP, b i l i r u b i n , and LDH t e s t s showed p l a n t - w i d e e l e v a t i o n s i n 8 , 4 , and 3 percent of the w orkers, resp ectiv ely . The l a r g e , p la n t- w id e e l e v a t i o n s i n SGOT's s u g g e s te d one o f two t h i n g s . E ith e r w o rk ers m many d i f f e r e n t a r e a s were a f f e c t e d , o r t h e p l a n t ' s SGOT t e s t was i n v a l i d . D r. Pow er to o k two s t e p s t o v a l i d a t e th e SGOT t e s t . F i r s t , he to o k b lo o d sam ples from a b o u t 100 w orkers and s e n t h a lf of each blood sam ple to th e sta n d a rd la b o ra to ry (G eneral C o n su lta n ts, I n c . ) and th e o th e r h a lf to an Upjohn L ab o rato ry t o be t e s t e d . When th e r e s u l t s o f th e s t a n d a r d l a b o r a t o r y were p l o t t e d a g a i n s t th e r e s u l t s o f U pjohn ( f i g u r e 1 ) , th e two l a b o r a t o r i e s w ere c o r r e l a t e d . High SGOT's a t th e s ta n d a r d la b o r a to r y w ere h ig h a t U pjohn, and low SGOT's a t th e s ta n d a rd were low a t U pjohn. How ever, a t a l l SGOT l e v e l s t h e s t a n d a r d l a b o r a t o r y 's v a lu e was h ig h e r th an U p jo h n 's . F u rth e rm o re , ab o u t 16 p e rc e n t o f th e sta n d a rd la b o r a to r y 's v a lu e s were "ab n o rm al," w hereas none from Upjohn f e l l in th e "abnorm al" ra n g e . Dr Pow er a l s o had th e s ta n d a r d l a b o r a to r y u s e a second method (manual en zy m atic) to re a n a ly z e sam ples th a t showed e le v a te d SGOT's by th e f i r s t m ethod (au to m ate d c o l o r i m e t r i c ) . In th e 22 r e t e s t e d s a m p le s , o n ly one sam ple was found t o be e l e v a t e d by t h e s e c o n d m ethod ( t a b l e 4 ) . When th e r e s u l t s o f th e f i r s t m ethod were p lo tte d a g a in s t th e second, th e r e s u lts were c o rre la te d (fig u re 2 ). g e ste d The in te r la b o r a to r y and in te rm e th o d com parisons sug th at ' SGOT's m easu red a t th e s ta n d a r d la b o r a to r y by th e sta n d a rd m ethod were s y s te m a tic a lly h ig h e r than the tru e blood le v e ls . By th e s ta n d a r d m ethod th e s ta n d a r d l a b o r a t o r y 's o b s e r v e d ra n g e f o r "n o rm a l" SGOT v a lu e s w as con s id e ra b ly h ig h e r th a n the s ta te d normal ran g e. . V a l id SGOT l e v e l c o m p a ris o n s c a n be made b e tw ee n exposed and nonexposed g ro u p s, provided th a t t e s t Company Sanitized. Does not contain T SC A CB1 means o r th e p ro p o rtio n f a l l i n g in to th e h ig h e s t t e s t d e c i l e a re u s e d . S in c e SGOT l e v e l s w ere c o rre la te d between la b o r a to r ie s and betw een m ethods, v a lid betw een-group com parisons are p o ss ib le . 2. L iv er t e s ts by jo b C ^ M jp r o c e s s w o rk e rs' meanSGOT o f 45 was h ig h e r th an . ^e. con^r l group s mean of 39 . Q B Q s e r v ic e and p ro c e s s w o r k e r s ' mean A P 's o f 101 and 8 r7 r e s p e c t i v e l y , w ere h i g h e r th a n th e c o n tr o l g r o u p 's mean o f 6 4 . T hese d i f f e r e n c e s w ere s ta tis tic a H y s ig n ific a n t at th e 0.05 p ro b a b ility le v e l (ta b le Sin,J i a " y /^ ^ ^ j|p r o c e s s an d fiB H |fcerv ice w o rk ers had s i g - i n t o th e h i g ?h <e 0s t*0t5e) s lt a rdgeec ri l ep r o( tpaobrltei o n6s) . o f th e AP v a lu e s f a l l i n g9 m c i * There were no o th e r s ig n if ic a n t d if f e r e n c e s betw een T e f lo n a r e a w o rk e rs and c o n t r o l s w ith r e s p e c t t o SGOT, AP. b i l i r u b i n , o r LDH. ' 3. L iver t e s ts by blood flu o rid e le v e l The mean SGOT. f o r th e h i g h e s t b lo o d o r g a n i c f l u o r i d e d e c ile was s i g n i f i c a n t l y h ig h e r th a n th e mean f o r th e lo w er n in e d e c ile s (52 vs 40, r e s p e c t i v e l y ) . However, when th e d a ta w ere broken down in to in d iv id u a l o rg a n ic f l u o r id e d e c i l e s , th e d a ta d id not show a ty p ic a l, s te a d ily r is in g d o se -resp o n se CUrVe. J i a ? l e s 7 and 8 ) * In f a c t , th e se c o n d and t h i r d h i g h e s t mean SCOT'S w ere fo u n d i n th e f i r s t and t h i r d d e c i l e s . I t i s s t i l l p o s s i b l e , how ever, t h a t th e h ig h SGOT's s e e n in th e h ig h e s t d e c ile a re somehow r e l a t e d to th e s e w o rk e rs ' o rg a n ic flu o rid e le v e ls -- the h ig h e st d e c ile could be th e e ffe c t/n o e ffe c t threshold. AP, LDH, and b i l i r u b i n showed no u n u s u a l e l e v a t i o n s when com pared by o r g a n i c f l u o r i d e d e c i l e . L ik e w is e SGOT, AP, LDH, and b i l i r u b i n showed no r e l a t i o n s h i p t o i n o r g a n i c f l u o r i d e lev els. 4. Blood f lu o rid e le v e l by jo b --------->rocefes o p e r a t o r s made up a b o u t one t h i r d o f th e 78 w o rk e rs t e s t e d f o r b lo o d f l u o r i d e s . B u t when th e 16 w o rk e rs from th e two to p o rg a n ic f l u o r id e d e c i le s w ere l i s t e d by e flo n a r e a , 12 o f th e w o rk e rs had b e e n M ^ iM p ro c e s s o p e r a t o r s a t th e tim e th ey were te s te d . Four o th e r s h a d worked a s d t* l p ro c e ss o p e ra to rs w ith in 1 to 2 y e a rs p r io r to th e tim e th ey J were te s te d . The number o f y e a rs o f w orking w ith C-8 o r o f working in th e Teflon a re a did not ap p ear to be r e la te d to organic flu o rid e lev el (tab le 9 ). In fa c t, the th ird hig h est o rg a n ic flu o rid e le v e l was m easured in a w orker having l=c than 3 years experience w ith C-8. V 0tVs ;b/ 7 These data suggest th a t& d p r o e e s s o p e ra to rs have C% c o ^ e l p o t* i t1 * 1 irVeT- iatntcd* t' h' a t o n-ly 3- y e a r s o f le v e ls s u ffic ie n t to e le v a te blood organ ic flu o rid e [ 4 i ^ S f f e t o ? s ^ " 31" 8 US" a l l y have - i c e than B lood i n o r g a n i c f l u o r i d e l e v e l and T e f lo n a re a a5Hnn- lev e ls^ o c c u rre d i^ a iffa n d iiiiflb ^ he h l9 h est inorganic flu o rid e operators, ^ T t llT lt l ~ J n t re not o c cu p a tio n ally exposed to flu o rid e s (ta b le 11). L iver t e s t s by jo b : a fte r exposure d iffe re n c e s betw een b e fo re and and f l f f o / 617 feW w r)c e rs had l i v e r t e s t s t h a t w ere done b e f o r e and a f t e r t i ? ? f Ure bf 9an* Since th e w r k e r s h av in g b o th b e fo r l th e s e c o m p a riso nns a syh ohuavlde bbeeent r eaa tseedl e wc tithg r oc ua pu ,t i othn e. r e s u l t s o f s u g q e s t thatC H aSS* a "d a f t e ^ c ~fi e x p o s u r e c o m p a ris o n s w eak ly h2 W & i l a T l and l s f r v i ce w o r k e r s ' AP l e v e l s may su o ^Jie ?hi 9 C: 8 e x P s u r e ( t a b l e ! 2 ) . T h is r e s u l t AfuPft l i v e Ls i lfr^ee hh li9qhhe er r thtahni 7t^h ei0 nc o tnhtar ot Pl "m<eta'n.^ e Hr so^w'evmero,st t hr ee scee n t two o b s e r v a t i o n s a r e n o t in d e p e n d e n t. hff?before J i F B f i OC^ L a n d f c r t S e r v i c e o p e r a t o r s showed no u n u su a l k - 3 u r d l f f e r e n c e s w ith r e s p e c t t o SCOT, AP LDH or >1 examination i ^ a t e l T p r ^ t o ^ f Discussion ` sssr m ^ h ^ c a i .'5 P h ySlCal of to Based on th e d a ta an occupationally re la te d C -8 0 above, h e a lth there is problem no co n clu siv e among w o rk e rs e v id e n c e exposed Some o f t h e SCOT d a t a s u g g e s te d t h a t t h e r e m ig h t ^ SGOTVf o r e t h 3 S ^ 8 n9 c e rfc a in C~8 e x p o se d w o r k e r s . The me a rT hink H B B 8> rocess o p e ra to rs was s i g n i f i c a n t l v (p<0 05) o ^ e r-to b le i i m - T e flc >n' c o n t r o l L a n . f * 4 , r o c s Md le v e l! B e L M a n ^ e M ^ r i h e 9 ? " * h I * h a r SG0T Company Sani|ijed, Doe? w ith H ow ever, in o t h e r r e s p e c t s SGOT showed p o o r organic flu o rid e lev e l and w ith OB ex p o su re. co rrelatio n Teflon a re a w orkers w ith l i t t l e o r no 0 8 e x p o s u r e h a ^ ^ e a n SGOT t h a t was n e a r l y a s high as th e |p M > ro c e s s o p e ra to rs ' mean. Since Teflon a re a w orkers w ith l i t t l e o r no 0 8 expo -su re a ls o had the low est blood o rg a n ic flu o rid e l e v e l s , t h e i r e le v a t e d SGOT c o u ld n o t r e a l i s t i c a l l y be caused by 0 8 exposure. W orkers from the th ir d low est blood o rg a n ic f l u o r i d e d e c i l e had an SGOT mean t h a t was nearly as high as th e top d e c ile 's mean. O th e r p u 2 z li n g f i n d i n g s w ere t h a t n e i t h e r AP, LDH, nor b ilir u b in means were e le v a te d am ongflB B fioperators. I f a p le n t t r u l y had a c h e m ic a lly in d u ced l i v e r d i s e a s e , one would expect one o r more o f th e se o th e r blood t e s t s to be e le v a te d . . M eanA P was s i g n i f i c a n t l y (p < 0 .0 5 ) h i g h e r among serv ice anP flP ^p > ro cess o p e ra to rs. Yet none of th e othe t e s t s were e le v a te d among th e s e w o rk e rs, l^ ts w ith blood o rg a n ic flu o rid e le v e ls . and AP d i d not c o rre - I t seem s v e ry u n lik e ly th a t a s in g le m a te ria l would r a i s e o n ly SGOT l e v e l s i n one w o rk e r g ro u p and r a i s e o n ly AP ^ Ve^ / J ; n a ^o t h e r w o rk e r g ro u p . More l i k e l y e x p l a n a t i o n s f o r th e SGOT and AP e l e v e a t i o n s a r e : The e le v a tio n s r e s u lte d from chance e v e n ts and ` were no t c a u sa lly r e la te d to C-8 ex p o su re. C e rta in unmeasured confounding f a c to r s such as a l c o h o l c o n su m p tio n o r d ru g u se may hav e i n f l u enced th e blood t e s t r e s u lts . I t is also p o s s ib le , however rem ote, th a t o ccu p atio n al exposures to o th e r to x ic m a te r ia ls were re s p o n s ib le f o r th e o bserved e le v a tio n s. For in s ta n c e , acute and ch ro n ic exposure to inorganic flu o rid e s can produce o steo m alacia, a bone d ise a s e . Tftis bone d is e a s e i s o f te n a s s o c ia te d w ith e le v a te d le v e ls o f serum AP. , ' .Liver fu n c tio n t e s t s : lim ita tio n s B i l i r u b i n , SGOT, AP, and LDH a s s e s s d i f f e r e n t compo n e n ts o f a l i v e r 's h e a lth and f u n c tio n . Only serum b i l i r u b i n i s a t r u e l i v e r f u n c t i o n t e s t . SGOT, AP, and LDH a r e a c t u a l l y enzymes th a t a re n o rm ally p rs s s n t s t Hiod6rst6 ig v c ig ip serum . They may a t t a i n h ig h e r l e v e l s a f t e r v a r io u s ty p e s o f l i v e r damage h av e o c c u r r e d . SGOT and LDH l e a k o u t 'o f dam aged l i v e r c e l l s and i n t o t h e b lo o d s t r e a m . E le v a te d AP l e v e l s , on th e o th e r h a n d , a p p e a r to r e s u l t from damaged l i v e r c e l l s s y n th e s iz in g and r e l e a s i n g more enzym e. Company Sanitized. Does not contain T SC A CBI ss ee vv ee rr aa ll p o i n t s s h o u ld be k oe ps ti t iivne mainndd: n e g a tiv e t e s t r e s u l t s , The l i v e r has a la rg e fu n c tio n a l re se rv e and a g reat capacity to reg en erate its e lf a fte r i t has a wwee^ke ka f^t ef ?r ^h a v" inugd ireesm ohvavede oshvoewr n80t h pa et r cweint ht i no f aab o u t - _a t s , l lv ? r / one can fin d a liv e r of e s s e n tia lly w eighi and f u n c t i o n . C o n se q u e n tly , m ild and so m etim es m o d era te l i v e r i n j u r y o f t e n may n o t be te s ts 3 tely refle c te d by G anges in liv e r function Some l i v e r f u n c t i o n s a r e much more s e n s i t i v e t o t h f " o t h e r s * T h u s' some l i v e r f u n c tio n s . do n o tU nCtl n t e s t s ^ may show changes w h ile o th e r s I10 ne s i n g l e t e s t o r p r o c e d u r e t h a t e ffe c tiv e ly m easures th e to ta l fu n ctio n o f th e liv e r. H T here i s no d ir e c t q u a n ti t a t iv e c o r r e l a t io n betw een th e amount o f liv e r c e l l in ju ry and th e h e ig h t of serum enzyme le v e ls . However, h ig h e r le v e ls are g e n e ra lly found w ith more se v e re in ju r y . I f th e serum enzymes a re m easured sometime a f t e r th e a c u te i n s u l t o r i n j u r y , t h e i n i t i a l r i s e may have been m issed. T hus, norm al o r low serum enzyme l e v e l s may be fo u n d a s a c o n se q u e n c e o f a decreased fu n ctio n in g liv e r c e ll m ass. Sim i- fv ' f e r ta f n types of c irrh o s is are asso c iated w ith o n ly s l i g h t l y e l e v a t e d o r e v e n no rm al SGOT lev els. SGOT, AP, and LDH may b e e l e v a t e d from c a u s e s than liv e r damage. For in sta n c e , most o f t h e AP p r e s e n t in n o rm a l serum i s d e r i v e d from t h e b o n e . H igh l e v e l s o f AP o c c u r i n p a t i e n t s w ith bone d is e a s e s c h a r a c te r iz e d by o s t e o b la s t i c aCj 1u l t Y- T hese i n c l u d e r i c k e t s , o s t e o m a l a c i a , and h e a lin g f r a c tu r e s . Growing c h ild re n and p r e g n a n t women in t h e t h i r d t r i m e s t e r h a v e e l e v a t e d seru m AP l e v e l s . SGOT and LDH may a l s o be e l e v a t e d i n p a t i e n t s d u rin g ep iso d es of acu te m yocardial in fa rc tio n card iac arrhythm ias, congestive h eart fa ilu re , p e r i c a r d i t i s , ana pulm onary in f a r c tio n . T here a re o th e r enzyme t e s t s th a t are more s e n s i- t ?oC ertf iP types of liv e r d isease than are SGOT, AP, and LDH. One o f t h e s e i s gam m aglutam yl t r a n s p e p t id a s e (GGT). T h is enzyme i s e le v a te d in Company Sanitized. Does not contain T SC A C3I th e serum o f alm ost a l l p a tie n ts w ith h e p a to b ilia ry d is o rd e rs . I t is th e most s e n s itiv e t e s t fo r alco h o lic liv e r disease. * A. i i y e r t e s t ' s s e n s i t i v i t y c an be d e f i n e d a s th e a b i l i t y to c o r r e c t l y i d e n t i f y p e rs o n s who have l i v e r d ise a se . S p e c ific ity can be d e fin ed as i ? c o r r e c t l y i d e n t i f y p e rs o n s who do not have liv e r d ise a s e . S e n s itiv ity and s p e c if ic ity have not been ad eq u ately stu d ie d fo r liv e r function te s ts . b?ilihfm ?niir9e amount f ^ fo rm a tio n is a v a ila b le concerning b io c h e m ic a l m e a s u re s o f a c u te h e p a t i c i n j u r y , we have l i m i t e d d ata about th e e ffe c ts of chronic lesio n s o n t h l biochem ical t e s ts and on th e s e n s itiv ity o f th e s e t e s t s in d e te c tin g chronic in ju ry or the sequelae of acute in ju ry " (G uidelines fo r the d e te c t i o n o f H e p a to to x ic i ty Due t o D r u g s ^ ' Z l l S Z J ? % P u b l i c a t i o n N o. 7 9 -3 1 3 . Oc t . 1979. p p . 3 3 -3 4 )? L iv e r fu n ctio n te s ts are most u se fu l i f they can be used s e ria lly to assess h ealth b e fo re , during, and a f t e r exposure. S o -c alled "abnorm al" values f o r one i n d iv i d u a l may be " n o rm a l" f o t a n o t h e r . Normal/abnorm al dichotom y vs th e c o n tin u o u s approach nr . Ti e b a s } s f o r c l a s s i f y i n g a l i v e r t e s t v a lu e a s norm al tL n e? C3n be e i t h e r f u n c t i o n a l o r s t a t i s t i c a l . On a fu n c - L b ' S1Sf a n v f 1,ue c o u ld be c o n s id e r e d n o rm al i f t h e r e w ere no i n c r e a s e d r i s k a s s o c i a t e d w ith i t . On a s t a t i s t i c a l ll iimm iiftcs m3 nCwTh?icahi Xv aplUe er c eCn Ut ld( eb.eg . ,any95%on) eo ft h tahte f ep lo1p uwliattbi oi nn ftheel l . m easuren,pn?!r ! = i s 3 " ? 3 r d/ s a d v a n ta 9e to c l a s s i f y i n g c o n tin u o u s Dlex nrohiiTM as norm3l o r abnorm al: i t o v e r s im p lif ie s a com- D l?ea?e and ^ a l t h l i e along a continuum . For h W ^ ' * 6Ven W1i h l n hhe c e n t r a l 95% o f t h e t o t a l ra n g e o f p r ? s s u r e s ' t h e r e 1S a g r a d i e n t such t h a t p e r s o n s a t th e stTM vo artu 3 9re a te r risk o f coronary h e art d isease or a l ^ h o i a 3? t h ? y e a t . th e lo w e r e n d .^ A s i m i l a r s i t u a t i o n may a lso hold fo r l i v e r fu n ctio n t e s t s . Thus, a n aly se s based on group means m ost o f te n -use the d a ta more e f f i c i e n t l y th an analyses based on the percent "abnorm al". ao n ro an h t c P? ? S b -? t h e o r e t i c a l a d v a n ta g e t o th e d ic h o to m o u s approach is th a t i t m ight be more s e n s itiv e to " o u tlie r s " , values on the h ig h sid e o f norm al, than is an a n a ly sis of Hor e v e r : l n a n in ,a l t o x i c i t y s t u d i e s p r a c t i c a l l y a l l I ? 31 a n a ly s e s o f b io c h e m ic a l t e s t s a re b ased on means a t ? * r fchan o n ' t h e P r P rfcfon above o r b elo w a c e r t a i n v a lu e of f rn ,0 re \ t h numbe r o f e x p e rim e n ta l o b s e r v a t i o n s needed to a r e a l e f f e c t i s c o n sid e ra b ly le s s when th e a n a ly s is is based on means th a n when i t is based on p ro p o rtio n s ( a l l e ls e being equal and assum ing an underly in g continuous v a ria b le ). . not contain TSCA CBI Company Sanitized. Does TABLE 1: C -B STUDY CODE SHEET FOR WORK H ISTO R IES ( Payclass (1 = wage, 2 = sa la ry ): _____ Date hired (month/year): / Name ( la s t, f i r s t i n t i t i a l , middle i n i t i a l ) : Sex (1 = male, 2 = fem ale): _____ SS t : __________ Birth date (month/year): / Current C-8 exposure (0 = no; 1 = y e s): Org. P = Inorg. F = Present or past Teflon area jobs or mechanic-type jobs (0 = no; 1 = yes): P aten tial present o r p a st C-8 exposure (0 = no, 1 = yes): Number o f jobs l i s t e d below ( l i s t a l l Teflon area and/or mechanic jo b s): C-8 P o te n tia l (0=none; l=some) Job code Date in Date out (mo./yr. ) (n o ./y r. ) Comments 1 2 3_ 5_ 6_ 1_ 9_ 10 11 12 13 14 15 16 17 at. 18 19 nolcnnlaln0* 0 S a n i la ) 0003 omPany TABLE 2 : C -8 STUDY CODE SHEET POR MEDICAL H ISTO R IES 'iame ( l a s t , f i r s t i n i t i a l , middle i n i t i a l ) ____ 5S # ; ___________________ 12 3 4 5 67 Current c ig a r e tte smoking s ta tu s : " 20 ixam; d a te / Blood p re s . / SMA-12 8 9~ B irth d a te : ____ i2 i r i r - T s Sex (l=male; 2=fem ale): Mo. Y r. 18 6 = non-smoker 1 - le s s than 1/2 pack a day 2 " 1/2 to 1 pack a day 3 = 1 - 2 packs a day 4 = 2 o r more packs a day 5 --smoker, no. packs unkown 7 = unknown 8 = pipe/cigar Payclass (1 = wage; 2 = s a l a r y ) : Current hypertensive statu s (1 h y p er.; 2 = norm al): ___ 22 Height: _________ 24 Weight: Company Sanitized. Does not contain TSCA CBI iroup utacite &P elrin ilam ents nei te* ?f lon* ftel chanical search chnical 's. Ser. P i. Rei. wer & Ser. No* o f T ests 197fl 119 78 82 131 71 212 241 380 77 251 103 32 63: ta l Plant 1840 tal Plant ss Teflon a 1628 TABLE 3: WASHINGTON WORKS 1978 Blood T est R esults SGOT (Nomai = 10-50) T o tal> 50 ALK. PHOS. (Nomai 30-85) Total>85 30 (25%) 14 (12%) 16 (21%) 6 (8%) 15 (18%) 7 (9%) 23 (18%) 11 (8%) 14 (20%) 7 (10%) 34 (16%) 23 (11%) 29 (12%) 8 (3%) 79 (21%) 16 (21%) 27 (7%) 4 (5%) 50 (20%) 15 (6%) 14 (14%) 8 (8%) 7 (22%) 3 (9%) 14 (22%) J L (11%) 341 (19%) 140 (8%) 307 (19%) i r '7) B ili (Nomai = 0-1.0) _ Total>l.n 6 (5%) 4 (5%) 1 (1%) 7 (5%) 3 (4%) 5 (2%) I l (5%) 16 (4%) 4 (5%) 11 (4%) 4 (4%) 3 (9%) -2J3% ! 77 (4%) IDH (Nomai 100-225) -- Total>225 2 (3%) 6 (8%) 1 (1%) 4 (3%) 2 (3%) 5 (2%) 6 (2%) 10 (3%) 0 (Oft) 6 (2ft) 1 d%) 0 (0% ) 5 (8%) 48 (3%) Company Sanitized. Docs not contain TSCA CBJ 72 (4%) TABLE 4: SGOT RESULTS FROM TWO DIFFFRFMT MF-runnc ' LRPORMED AT THE SAME LABORATORY (GENERAL C D l^Sw T S, INC.) Subject Date Standard SMA-12 (1) SOOT (normal = 10-50 ) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 11/12/79 11/14/79 11/26/79 11/27/79 12/10/79 12/10/79 12/10/79 12/10/79 12/10/79 12/10/79 12/11/79 12/11/79 12/11/79 12/13/79 12/11/79 12/12/79 12/18/79 12/20/79 12/26/79 12/28/79 12/31/79 12/31/79 60* 58* 150* 60* 55* 54* 51* 60* 62* 55* 54* 55* 63* 57* 85* 73* 52* 82* 57* 89* 60* 75* (1) Automated c o lo rim e tric method (2) Manual enzymatic method `Abnormally high based on lim its se t by the laboratory A ltern ate Method (2) SOOT (normal = 0-27> 19 17 42* 16 21 14 15 15 ' 19 13 14 17 19 23 23 21 15 ' 24 15 24 19 *3"7 Company Sanitised. Does oo. =on.aln T SC A C M TABLE 5: AGE AND BLOOD CHEMISTRY^MEANS BY OCCUPATIONAL GROUP^ Group Control (no Teflon, mechanic o r laboratory work)tc ' r^ 1 JH nprocess service H ^prooess ^m ^serv ice Monomer operator, semi-works laboratori an, foreman Group Size Age SGOT AP B ili IDH 80 38 39 64 0.7 156 13 49 37 81* 0.5 154 3 37 41 101* 0.6 146 25 45 45* 64 0.5 158 25 37 35 59 0.5 160 22 47 44 69 0.7 151 (a) Based on most re c en t SMA-12 as of October, 1979 (b) Based on job t i t l e a t th e tin e of the w orker's most recent SMA-12 (c) Ten percent sample o f cu rren t wage r o l l employees p lu s e ig h t workers cu rren tly exposed t o C-8 but who had never worked i n Teflon a t the time of th e ir most recent physicals. * f*9n ifican tly (p<0.05) higher than the control group a fte r adjusting (by an aly sis of covariance) fo r age. iomp ?ry..<Samtnwo Coes not ?oritelo T>Ca GBI ( TABLE 6: BLOOD CHEMISTRY ia) BY OCCUPATIONAL GROUP ib *: PROPORTION OF TEST VALUES FALLING INTO THE HIGHEST DECILE Group Group Size Control (no Teflon, mechanic . . or laboratory w ork)'c' ^V ^^rocess L ^^B pervice ^m Prooess ^^ jserv io e Monomer o p erato r, semi--works laboratorian, foreman 80 13 3 25 25 22 Mean Age 38 Proportion in Highest Decile SOOT AP B ili LDH 0.10 0.05 0.18 0.10 49 0.0B 0.31* 0.0 0.08 37 0.0 0.67* 0.0 0.0 45 0.20 0.12 0.08 0.12 37 0.04 0.12 0.0 0.16 47 0.23 0.14 0.18 0.09 (a) Based on most re c e n t SMA-12 as of October, 1979. (b) Based on job t i t l e a t the time of the w orker's most recent SMA-12. (c) Ten percent sample o f cu rren t wage r o l l employees p lu s e ig h t workers c u rren tly exposed t o C-8 b u t who had never worked in Teflon a t the time of th e ir most recent physicals. * S s t Lf t w nt a i l ) P<0`05) hi9her than *** ntro1 by F is h e r's exact impany Sanitized. Does not contain T SCA CBl TABLE 7: WORKERS GROUPED BY ORGANIC FLUORIDE DECILES - BIOCHEMISTRY TEST MEANS D ecile Group Size 0F(a) L im its Mean No. of Mean No. o f Yrs. Mean Years in C-8 in Teflon Aqe 1 2 3 4 5 6, 7 E 10 6 0.08-0.30 8 0.35-0.45 9 0.47-0.69 7 0.70-1.17 - 8 1.31-1.80 8 . 1.81-2.30 8 2.33-3.55 8 3.70-4.64 6 4.84-6.66 8 6.84-21.69 5 2 9 5 7 6 10 9 15 14 12 40 17 49 18 47 7 41 12 41 11 40 14 45 16 44 18 47 18 47 Mean Mean Mean Mear SOOT AP &i 14 Tr\tj 46 69 0.7 184 40 67 0.7 131 49 67 0.6 166 34 73 0.5 161 40 71 0.5 165 36 68 0.6 154 37 64 0.5 152 36 72 0.5 152 39 62 0.5 149 52* 63 0.5 169 igm fxcantly (p<0.05) higher than the mean o f the lower 9 d e c ile s The d ata 'r e * - * * * * by analysis of covariance before c e a ^ r i s S o S e . OF = organic flu o rid e M Company Sanitized. Does not contain T SCA C& TABLE 8: WORKERS GROUPED BY ORGANIC PrJY'rtJTnt? pnnTm n w P i l e Group Size OF Lim its 6 0.08- 0.30 8 0.35- 0.45 9 0.47- 0.69 7 0.70- 1.17 8 1.31- 1.80 8 1.81- 2.30 8 2.33- 3.55 8 3.70- 4.64 8 4.84- 6.66 8 | 6.84-21.69 Mean No. of Years in c -8 5 2 9 5 7 6 10 9 15 14 Mean No. of Years in Teflon 12 17 18 7 12 11 14 16 18 18 g n ific a n tly (p<0 . 06) higher then the lower 9 d eciles by F ish e r's exact t = organic fluoride Mean _Age 40 49 47 41 41 40 45 44 47 47 Proportion in .Highest Decile SGOT AP B ili LDH 0.17 0.17 0.33 0.3: 0.0 0.13 0.25 0.0 0.33 0.0 0.22 0.1] 0.0 0.14 0.0 o .n 0.0 0.25 0.13 o .i: 0.0 0.25 0.13 0.13 0.0 0.13 0.13 0.13 0.0 0.0 0.0 0.0 1 0.13 0.0 0.25 0.0 0.38* 0.13 0.13 0.13 (two t a i l ) . Company Sanitized. Does not contain TSCAC m TABLE 9 : TEFLON AREA WORKERS W ira TOE 16 HIGHEST ORGANIC FLOURIDE LEV ELS Worker Age Years in C-8 Years in Teflon Blood Organic Flouride Level Job A 50 20.5 B 59 23.8 C 36 2.8 D 60 23.2 E 53 4.0 F 48 23.4 . G 42 2.6 H #I 35 49 13.4 21.7 J 53 K 44 20.3 16.1 L 56 M 42 24.5 14.8 N 37 ' 5.6 O 42 p 55 11.8 3.2 23.4 25.8 4.1 23.9 22.3 23.4 4.8 14.6 23.9 20.3 17.2 24.5 17.5 13.6 20.4 3.2 21.69 . 20.81 16.89 14.38 9.63 8.89 6.91 6.84 6.66 5.90 5.64 5.61 5.29 4.97 4.96 4.84 process 'T il 10/78 [process >rocess ' l l 11/77 j^ fl^ p ro c e s s IjH D prooess ^ t i l l 5/77 process H 11 10/78 M process m (service Company Sanitized. Does not contain T SC A CBI i-tt'LCN AREA WDRKERS WITH THE 16 HIGHEST BIXOD INORGANIC FLUORIDE LEVELS Worker Age Years in C-8 Years in Teflon* A B C D E F G H I J K L M N 0 35 48 51 58 49 53 53 61 42 26 30 56 35 24 35 51 4.0 19.9 7.8 11.3 3.5 1.8 20.3 11.8 11.5 3.2 0.7 0.4 4.8 3.1 4.3 2.6 12.5 23.1 25.8 26.3 3.5 24.0 20.3 22.3 13.8 3.2 3.0 29.7 4.8 3.1 ' 11.7 2.6 Blood Organic Fluoride Lev 0.42 0.41 0.40 0.39 0.39 0.38 0.37 0.37 0.34 0.31 0.29 0.28 0.27 0.26 0.25 0.24 i 'rocess I pprocess Monerer > M process , Semiworks laboratorian Morener , process rocess rocess . ^ B ^ s e r v i ce rocess 4 Monomer fa ^ rv ic e ^ ^ ^ serv iae * p ttt s e r v ic e Semiworks laboratorian TABLE 11: Sample # 60 61 66 72 73 76 77 78 79 80 81 82 92* 93 94 95 96 97 101 102 103 106 107 109 111 TABULATION . OF BLOOD SAMPLES FROM WILMINGTON PERSONNEL (25 TOTAL) Total PPm 0.28 0.31 0.23 0.20 0.23 0.23 0.33 0.24 0.30 0.19 0.21 0.18 10.6 0.18 0.18 0.49 0.25 0.18 0.26 0.30 0.26 0.23 0.31 0.12 1.13 Inorganic F PPn 0.19 0.09 0.16 0.10 0.12 0.17 0.15 0.25 0.24 0.14 0.15 0.27 0 0.12 0.03 0.11 0.05 0.16 0.16 0.16 0.10 00..2127 0.11 0.35 . Organic F PPTM (by difference) 0.09 0.22 0.07 0.10 0.11 0.06 0.08 - 0.01 0.06 0.05 0.06 . -0.09 10.6 0.06 0.15 0.38 0.20 0.02 0.10 0.14 0.16 0.06 0.09 0.01 0.78 f c u S i ' f '5 " a re d K d l o f t h i s ^ n ' s b l * Recheck f 92 Itotal F - 0.33 Inorganic F ppm 0.09 Organic F PPm 0.24 Company Sanitized. Dogs not contain TSCAC8< TABLE 12; MEAN DIFFERENCES IN SCOT AND AP RESULTS WHEN THE FIRST TEST IS IfSF?A*FTER 1(b7EVX1NPOGSUIORTEOtfc'ic-- EXPOSURE JOB AND TOE SECOND TEST Group Control FEP process op erato r FEP service o perator TFE process op erato r TFE service op erato r Group size 45 3 2 2 7 AP<d > - 3.3 + 11.7 + 8.0 - 3.0 - 0.4 o T (d) - 4.7 - 4.0 + 7.5 - 11.5 ' - 8.1 ^ ^ Most recent SMA-12 p rio r to s ta rtin g C-8 exposure job ^ Most recent (p rim arily 1979) SMA-12 (c ) C-8 exposures ranged from 5 months to fiv e years between te s ts ^ Second t e s t minus f i r s t t e s t - Company Sanitized. Does not contain T SC A CBi <BflED83> RY SOOT ^ U | LEVEL bT ALTERNATE METHOD AT STANDARD i^ B FT < *>