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PROGRESS REPORT SUMMARY

PRINCIPAL INVESTIGATOR OR PROGRAM DIRECTOR

Dou~l ass Ches t er W.APPLICANT ORGANIZATION

Har var d School of Dent al Medi ci ne TITLE OF PROJ ECT (Repeat title shawn in item 1 on first page)

Fl uor i de Exposur e and Ost eosar coma(SEE INSTRUCTIONS)

'LNT NUMSER

ES06000- 02

9/ 30/ 92 9/ 29/ 93

PROGRESS REPORT SUMMARY

1. SPECI FI C AI MS

The Nat i onal Toxi col ogy pr ogr am ( NTP) f ound " equi vocalevi denceo , of car ci nogeni ci t y based on t he occur r ence of a smal lnumber of os teosar comas i n mal e r at s f ed doses of hi ghl yf l uor i dat ed wat er 1 A subcommi t t ee of t he Commi t t ee t o Coor di nat eEnvi r onment al H~ al t h and Rel at ed pr ogr ams ( CCEHRP) was t henconvened t o anal yze t he benef i t s and r i sks of f l uor i de i n dr i nki ngwat er .

An anal ys i s of 12 " f l uor i dat ed" count i es and 21 "non-f l uor i dat ed" count i es wi t hi n t wo SEER si t es used as t he basi s f ort he CCEHRP Fi nal Repor t t hat di r ect l y r ef ut ed t he NTP f i ndi ngs 2 Thi s st udy measur ed t he exposur e of i nt er est g i ngest i on of f l uor i dat ed wat er 9 onl y at t he count y l evel g and no at t empt wasmade t o capt ur e t he ef f ect of mi gr at i on. To achi eve t he or i gi nalgoal of t he Commi t t ee, t hi s nat i onwi de hospi t al - based case- cont r olst udy wi l l pr ovi de a mor e sci ent i f i cal l y concl usi ve assessment of r i sk f or ost eosar coma f r om t he i ngest i on of f l uor i dat ed wat er .Speci f i e ai ms addr essed i nt he on- goi ng st udy i ncl ude:

1. To compar e t he compl et e r esi dent i al f l uor i de hi s t or i es of ost eosar coma pat i ent s ( bot h pr eval ent and i nci dent cases) wi t ht he f l uor i de hi st or i es of hospi t al - based cont r ol s.

2. To compar e t ot al f l uor i de exposur e f r om or al hygi ene pr act i cesbet ween cases and cont r ol s; i ncl udi ng f l uor i de suppl ement s gsel f - appl i ed and pr of essi onal l y appl i ed t opi cal f l uor i des g andpar t i ci pat i on i n school based f l uor i de pr ogr ams.

3. To compar e t he f l uor i de cont ent i n bone and t oenai l s of ost eosar coma pat i ent swi t h t he f l uor i de cont ent i n bone andt oenai l s of hospi t al - based cont r ol s.

4. To cont r ol f or age g gender g and educat i on i n t he compar i son of cases and cont r ol s.

PHS 2590 (Rev. 9/91) (Form Page q) Paoe ~ (Use continuation pages if necessary)


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2. STUDI ES AND RESULTS

To accompl i sh t hese ai ms, a r et r ospect i ve and pr ospect i vehospi t al based case- cont r ol st udy was pr oposed and i mpl ement ed

dur i ng t he f i r s t year. The r et r os pect i ve as pect of t he cas econt r ol st udy col l ect ed dat a f r ompr eval ent cases and cont r ol s seenat 10 hospi t al snat i onwi de. Cases ar e def i ned as pat i ent s < 40year s of age di agnosed wi t h pr i mar y ost eosar coma f r om 11- 01- 89 t o12- 31- 92 by t he par t i ci pat i ng or t hopedi e sur geons. Non~ cancer ouscont r ol s mat ched by age, gender , and di st ance f r om t he hospi t alwer e chosen f r om t he i n- and out - pat i ent r ost er s of each of t hehospi t al s r sur ger y depar t ment . A 1: 2 r at i o of cases t o cont r ol swas enr ol l ed.

The f ol l owi ng hospi t aI s pr ovi ded access t o t he pat i ent senr ol l ed as a case or cont r ol i n t he r et r ospecti ve aspect of t hest udy:

Hospi t al i of Pr eval ent Cases/ Cont r ol s# Cases #Cont r ol s Tot al

Massachuset t s Gener al Hospi t al

Chi l dr en' s Hospi t al - Bost on

Cr ei ght on Uni ver si t y

Chi l dr en' s Hospi t al - DC

Memor i al Sl oan Ket t er i ng

Uni ver si t y of Chi cago

Rush Medi cal Col l ege

Uni ver si t y of Fl or i da

UCLA

Case West er n/ Cl evel and Cl i ni c

53

18

9

19

27

21

13

27

29

_1_8

226

90

36

18

38

54

42

26

54

58

_3_ 6

452

135

54

27

57

81

63

39

81

87

_5_4

678


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Ost eosar coma pat i ent s and t he mat ched cont r ol s wi t h anypr edi agnosi s hi st or y of t he known r i sk f act or , r adi at i on t her apy,ar e excl uded. l n addi t i on, pat i ent s wi t h a hi s t or y of ki dneydi al ysi s ar e excl uded as t hey chose t o dr i nk dei oni zed wat er f ormedi cal r easons. Bot h gender s and aI l r aces ar e i ncl uded f orst udy.

Pr ot ocol and Dat a Col l ect i on f or t he Ret r ospect i ve St udy

The Pr oj ect Di r ect or , Dr . McGui r e, t r avel ed t a each hospi t alt o r evi ew t he medi cal r ecor ds and det er mi ne t he el i gi bi l i t y of t hepr eval ent cases. Once t he age at di agnosi s, gender , and di st ancef r om t he hospi t al was t r anscr i bed f r om each el i gi bl e case medi calr ecor d, t he pr ocess t o chose t he cor r espondi ng cont r ol s was begun.Each hospi t al ( except ' f or Chi l dr en' s of DC) had t he capabi l i t y t ogener at e a comput er pr i nt out of t he i n- and/ or out - pat i ent r ost er s.A l i st i ng of t he pat i ent s mat chi ng t he age ( 5 year s) , gender , anddi s t ance f r om t he hospi t al of each of t he cases was r equest ed.Once t he l i st was r ecei ved, si x names wer e sel ect ed at r andom andt hei r medi cal r ecor ds wer e or der ed s o t hat abs t r act i on of demogr aphi c and medi cal i nf or mat i on coul d becompl et ed. Mor e t hanone r et ur n t r i p t o each hospi t al was necessar y t o r et r i eve t hei nf or mat i on f r om t he medi cal r ecor ds of t he qual i f yi ng mat chedcont r ol s because of t he t i mef r ame needed t o gener at e t he r ost er andor der t he medi cal r ecor ds.

The i nf or mat i on abst r act ed by Dr . McGui r e f r om t he medi calr ecor ds of t he el i gi bl e cases and qual i f i ed cont r aI s was ent er eddi r ect l y i nt o a sof t war e pr ogr am devel oped by New Engl and Resear chI nst i t ut e ( NERI ) . The dat a wer e t hen downl oaded ont o di sks andmai l ed t o NERI . Resear cher s at NERI pr oceeded t o send a l et t er of expl anat i on of t he r esear ch goal s of t he s tudy t o t he el i gi bl eost eosar coma pat i ent s and t he qual i f i ed mat ched cont r ol s ( SeeAppendi x A f or SAMPLE CASE LETTER and SAMPLE CONTROL LETTER) . Tel ephone cont act f ol l owed wi t hi n 10 days f or t he admi ni st r at i on of t he t el ephone quest i onnai r e ( See Appendi x B f or QUESTI ONNAI RE) . Apar ent was sur veyed i f t he case/ cont r ol was l ess t han 18 year s ol d.Appendi x C r epor t s t he st at us of t he di s posi t i ons ' f or t hecompl et i on of dat a col l ect i on f r om t he pr eval ent cases and cont r aI sas of t he end of t he Thi r d Quar t er ( 6/ 30/ 93)

Appr oxi mat el y 25 per cent of t he cases and cont r ol s used weI lwat er at sor nepoi nt i n t hei r r esi dent i al hi s t or y. Thi s r at e washi gher t han exper i enced dur i ng t he pi l ot phase. Har var d School of Dent al Medi ci ne pr oj ect st af f sent l et t er s and vi al s f or weI l wat ersampl e col l ect i on t o t he cases/ cont r ol s who r epor t ed weI l wat eruse. The par t i ci pant s ar e pr ovi ded wi t h a post age pai d car dboar d

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cont ai ner i n whi ch t o r et ur n t he weI l wat er sampl e. Dr . McGui r emeasur es t he l evel of f l uor i de i n each sampl e wi t h t he use of a DR100 Col or i met er .

Pr epar at i on f or Expanded Dat a Col l ect i on i n t he Pr ospect i ve st udy

Dur i ng Year 1, ar r angement s had been made t o coor di nat e t hest udy wi t h an expanded dat a col l ect i on ef f or t of t he et i ol ogy of ost eosar coma whi ch wi l l be conduct ed by t he Nat i onal Cancer

{I nst i t ut e ( NCI ) . The f undi ng pr ovi ded f or t oenai l anal ysi s i n Year1 wi l l be car r i ed over i n or der t o f ac i l i t at e t he col l ect i on of

' - t hese sampl es so t hat t hi s pr ocess can be i nt egr at ed wi t h t he NCIpar t i ci pant i nt er vi ews. We bel i eve t hat t he addi t i on of t he NCIbackgr ound dat a on st udy par t i ci pant s wi l l i ncr ease our abi l i t v t ocont r ol f or al t er nat i ve f act or s i n anal vz i ng t he l i nk bet weenf l uor i des and ost eosar coma.

As of t he end of t he Thi r d Quar t er of Year 1, f i nalar r angement s ar e under way t o expand t he pr ot ocol t o adj ust f or t hecol l ect i on of an i l i ac cr est bone sampl e f r om i nci dent cases. Thenon- t umor pi ece of bone wi l l pr ovi de a st andar di zed anat omi calposi t i on f r om whi ch a bone sampl e wi l l be t aken f r om bot h t he caseand cont r ol . The appr oval f or t he r evi s i on f r om each hospi t al ' shuman subj ect r evi ew commi t t ee has been acqui r ed and t her ecr ui t ment of r esear ch nur ses at each hospi t al has been compl et ed.3. SI GNI FI CANCE

When r est r i ct ed t o mal es under 20 wi t h ost eosar coma i n t heSEER st udy i n t he CCEHRP Fi nal Repor t , t he r at e of ost eosar comai ncr eased 79% i n t he f l uor i dat ed count i es and decr eased 4% i n t henon- f l uor i dat ed count i es f r om 1973- 80 t o 1981- 87. Ti me- t r endanal yses wer e per f or med and t he commi t t ee concl uded t hat f i ndi ngwas not si gni f i cant . However 0 as was st at ed pr evi ousl y 8 t hemeasur e of exposur e, dur at i on of i ngest i on of f l uor i dat ed wat er ,was onl y at t he count y l evel and no at t empt was made t o capt ur e t heef f ec t of t he mi gr at i on. Cases i n t he pi l ot s tudy case- cont r olstud y3 ( pr i mar i l y I owans) I i ved i n an aver age of 1. 7 di f f er entt owns pr i or t o di agnosi s. Thi s f i ndi ng weakens concl usi ons basedon t he assumpt i on of no mi gr at i on. The CCEHRP r epor t says " To t heext ent t hat mi gr at i on i s a f actor , i t i 5 l i kel y t o di mi ni sh. t hesensi t i vi t y of a geogr aphi c cor r el at i on st udy t o det ect possi bl eexcess r i sk . . . Fai l ur e t o obser ve exposur e- di sease associ at i on can

be at t r i but ed . .t o a communi t y l evel st udY . . Thi s i s especi al l y t r uef or mal i gnanci es wi t h a ver y l ow i nci dence such as ost eosar coma" .

Li nkage of f l uor i de i ngest i on and cancer i ni t i at i on coul dr esul t i n a l ar ge- scal e def l uor i dat i on of muni ci pal wat er syst emsunder t he Del aney cl ause. ( One aspect of t hi s EPA cl ause pr event st he addi t i on of car ci nogeni c agent s t o t he nat i on' s wat er suppl y) .

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Al t hough t he SEER st udy showed equi vocal evi dence, t he pi l ot st udyr esul t s f or t hi s gr ant showed no l i nkage of t he i nges t i on of f l uor i dat ed wat er t o t he occur r ence of ost eosar coma. Ther ef or e, ani ncor r ect i nf er ence i mpl i cat i : ngsyst emi c f l uor i de car ci nogeni ci t yand i t s r emoval f r om our wat er syst ems woul d be det r i ment al t o t heor al heal t h of most Amer i cans, par t i cul ar l y t hose who cannot af f or dt o pay f or i : ncr eas i ngl y expens i ver es tor at i ve dent al car e.Addi t i onal l y, a gr eat er under s t andi ng of t he et i ol ogy of ost eosar coma may pr event ot her s f r om ~ xper i enci ng i t .

4. PLANS

Dat a Col l ect i on f or Year 2

Pr eval ent Cases and Cont r oI s: Al I pr eval ent cases and cont r ol swer e accr ued i n t he f i r s t year . J udgi ng f r om t he f i naldi sposi t i ons at t he end of t he 3r d Quar t er , aI l pr eval entpar t i ci pant s wi l l have been cont act ed by NERI f or t he compl et i on of quest i onnai r e by t he end of Year 1. Because of . hi gher pr eval encet hen expect ed, t hewor k t o compl et e t he gat her i ng of aI l weI l wat ersampl es wi l l ext end i nt o Year 2.

I nci dent Cases and Cont r oI s: I nci dent cases and cont r ol s wi l laccr ue t hr oughout t he ent i r e per i od of Year 2. Resear ch nur ses ateach hospi t al wi l l per f or m t he f ol l owi ng dut i es:

1. assi st t he or t hopedi e sur geon i n gai ni ng i nf or medconsent f r om t he i nci dent cases,

2. l ocat e qual i f i ed cont r ol s f r om depar t ment alrosters ,3. admi ni st er t he quest i onnai r es t o and col l ect t oenai lsampl es f r om t he el i gi bl e cases and qual i f i edcont r ol s,

4. col l ect t he t umor sl i ce, bl ood speci men, and i l i accr es t bone bi ops y f r om t he cas e at t he t i me of sur ger y

5. col l ec t t he cont r ol aut opsy bone6. col l ect t he cont r ol bl ood speci men7. pr epar e aI l t he pat hol ogy speci mens f or

t r anspor t at i on ( See Appendi x D f or pr ot ocol )8. send t he t oenai l sampl es f or anal ysi s9. send t he quest i onnai r e dat a f or anal ysi s

The pr oj ect Di r ect or and Pr i nci pal I nvest i gat or wi l l conductt he t r ai ni ng s es si ons f or t he r es ear ch nur s es ; t r avel t o eachhospi t al annual l y t o moni t or 1) t he r el i abi l i t y of t he dat a, 2) t hepr ocess by whi ch t he cont r ol s ar e chosen and 3) pr ovi de gui dance ont he col l ect i on of speci mens; and moni t or t he col l ect i on of dat a at

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ADDI TI ON OF MI NORI TY RESEARCH TRAI NI NG PROTOCOL

Dur i ng year 1, a pr ot ocol was al so expanded t o f ac i l i t at e t her esear ch t r ai ni ng of a mi nor i t y f acul t y member .

Descr i pt i on of t he r esear ch exper i ence pr oposed f or t he mi nor i t yi ndi vi dua. l

Obj ect i ve:

To t est t he hypot hesi s t hatposi t i vel y associ at ed wi t host eosar coma.

Speci f i e Ai ms:

hi gherhi gher

soci oeconomi c st at usf l uor i de exposur e

i sand

1. To det er mi ne i f an as soci at i on exi s t s bet ween hi ghersoci oeconomi c st at us and hi gher f l uor i de exposur e.

2. To det er mi ne i f an as soci at i on exi s t s bet ween hi ghersoci oeconomi c st at us and t he r i sk f or ost eosar coma and i f t hi sr el at i onshi p i s medi at ed t hr ough hi gh f l uor i de exposur e.

Backgr ound and Si gni f i cance

The ef f i cacy of opt i mal wat er f l uor i dat i on f or t he pr event i onof car i es i n t he devel opi ng dent i t i on has been weI l est abl i shed, ashas t he use of f l uor i de suppl ement at i on i n ar eas wher e f l uor i del evel s i n t he wat er suppl y i s sub opt i mal . 1, 2 Ass oci at i ons bet weeni ndi cat or s of soci oeconomi c st at us, such as educat i on and i ncome~wi t h f l uor i de suppl ement at i on and f l uor osi s have been shown. 3, 4,I n a st udy of ei ght hundr ed and f i f t y 11- 14 year ol d r esi dent s of non f l uor i dat ed communi t i es i n Connect i cut and Massachuset t s,Pendr ys and Kat z 6 , f ound t hat mi l d t o moder at e enamel f l uor osi s wasst r ongl y associ at ed wi t h f l uor i de suppl ement at i on and medi anhousehol d i ncome. The odds r at i o f or t he i ncr eased r i sk of f l uor osi s and f l uor i de suppl ement at i on was 4. 0. The odds r at i o( OR) f or t he i ncreased r i sk of f l uor osi s and medi an househol di ncome was 6. 6. Those subj ect s i n t he mi ddl e medi an househol di ncome gr oup, who had used f l uor i de suppl ement s dur i ng t he f i r sts i x year s of l i f e, had a 28 - f ol d i ncr eas ed r i s k of f l uor os i scompar ed t o subj ect s i n t he l ow medi an househol d i ncome obt ai nedf r om census t r act dat a. Accor di ng t o t he aut hor s i 1t heseval uesmust be consi der ed conser vat i ve est i mat es of t he t r ue st r engt h of associ at i on wi t h soci oeconomi c st at us ( SES) , si nce gr oup dat a t oi dent i f y subj ect s! soci oeconomi c st at us woul d be expect ed t o be

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l ess pr eci se t han subj ect speci f i e i ncome val ues. ,,6 Anot heri ndi cat or of SES, par ent al educat i on, has been posi t i vel y r el at edt o bot h pr eval ence of f l uor osi s ( OR = 2. 2) and use of f l uor i desuppl ement s ( OR = 2. 7) . 7

The et i ol ogy of ost eosar coma r emai ns unknown. Al t hough ar el at i vel y r ar e t umor wi t h l ess t han 2100 new cases occur r i ng peryear i n t he Uni t ed St at es 8 , ost eosar coma i s t he most commonl yoccur r i nw mal i gnant t umor of t he bone 9 Radi at i on 1o , 11, 12, vi ralact i on. l , 14, genet i c f act or s 15 , and ot her exogenous f act or s havebeen i mpl i cat ed i n t he devel opment of ost eosar comas 16 Radi at i oni nduct i on of ost eosar coma i s at pr esent an accept ed pr i nci pl e. Ar ecent Semi nar s i n Oncol oqy r evi ew of t he epi demi ol ogy of bonesar comas however r epor t ed t hat conf l i ct i ng st udy r esul t s exi st f oraI l ot her et i ol ogi c agent s 12

Met hods

A t el ephone i nt er vi ew of 320 i nci dent cases and 640 mat chedcont r ol s wi l l be conduct ed. Cont r ol s wi l l be mat ched by age( 3 year s) , gender , and geogr aphi c r esi dence. The t el ephonei nt er vi ew t o be conduct ed byNew Engl and Resear ch I nst i t ut e ( NERI )wi l l be des i gned f or t he pr i mar y pr oj ect . The par ent gr anti ncl uded case cont r ol mat chi ng on r es i dence di s t ance f r omhospi t al . Not mat chi ng on communi t y of r esi dence decr eases t hel i kel i hood of si mi l ar soci oeconomi c st at us bet ween cases andcont r ol s . Thi s pr oj ect wi l l expand t he i nt er vi ew t o i ncl udequest i ons r egar di ng f ami l y soci oeconomi c st at us. I nf or mat i on onpar ent al educat i on, i ncome and empl oyment wi l l be col l ect ed anduni f or ml y coded. Cases wi l l t hen be compar ed wi t h cont r ol s t odet er mi ne odds r at i os f or t he associ at i on bet ween soci oeconomi cst at us and ost eosar c oma. Dr. Da Si l va wi l l devel op t hequest i onnai r e i n conj unct i on wi t h t he Pr i nci pl e I nvest i gat or . Hewi l l al so vi s i t each cl i ni c s i t e t o assess t he r el i abi l i t y of t hedat a col l ect i on, ensur e compl et e dat a col l ect i on, i nt er vene whenpr obl ems occur , and assi s t i n ensur i ng s tudy pr ogr ess when,per sonnel changes occur at t he var i ous si t es.

How t he exper i ence wi l l f ost er t hecapabi l i t i es of t he mi nor i t y i ndi vi dual

i ndependent r esear ch

Thi s r esear ch exper i ence wi l l pr ovi de Dr . Da Si l va wi t h sever aloppor t uni t i es:1. To devel op and car r y out an i ndependent r esear ch pr oj ect t hat

i nt egr at es weI l wi t h an exi st i ng nat i onwi de st udy. Thi s wi l lal l ow par t i ci pat i on i n t he par ent pr oj ect whi l e t aki ng t hemai n r esponsi bi l i t y on t hi s pr oj ect .

2. Because t he par ent s tudy i s amuI t i cent er ed pr oj ect , t hi s

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pr oj ect wi l l pr ovi de Dr . Da Si l va wi t h t he oppor t uni t y t oi nt er act wi t h ot her es tabl i shed r esear cher s a t he ei ghtdi f f er ent par t i ci pat i ng si t es.

3. Dr . Da Si l va wi l l become an I nt egr al par t of t hepr oj ect ,wor ki ng cl osel y wi t h t he New Engl and Resear ch I nst i t ut e and

member s of t he Har var d School of Dent al Medi ci ne t o:i . Devel op t he t el ephone i nt er vi ew quest i onnai r e f or t hei nci dent st udy subj ect s.

On cl i ni cal si t e vi si t s he wi l l :i i . Coor di nat e cl i ni c s i t e s t af f

i i i . Ensur e st udy pr ogr ess as per sonnel t ur nover occur sI v. Moni t or t he sel ect i on of appr opr i at e cont r ol s and assess

dat a r el i abi l i t yv. Moni t or dat a col l ect i on

vi . Moni t or pr obl ems of non- r esponseAt Har var d and NERI :

vi i . Edi t and check aI l dat a f r om t he ei ght s tudy s i t es i ncol l abor at i on wi t h t he si t e cl i ni c st af f

vi i i . Devel op codi ng schemes f or dat ai x. Pr epar e dat a f i l es f or t r ansmi ssi on t o NERI and

cOl l abor at i ng i nvest i gat or s.x. pr oduce dat a management and pr ogr ess r epor t s

xi ~ Check ent r y of and f i nal di s pos i t i on of cas es andcont r ol s

xi i . Dat a anal ysi sxi i i . Manuscri pt pr epar at i on of st udy r esul t s

Thi s exper i ence g combi ned wi t h Dr . Da Si l va' s educat i onalbackgr ound wi l l hel p devel op hi s f ut ur e pot ent i al t o become ani ndependent i nves t i gat or wi t h a f i r s thand knowl edge andunder st andi ng of t he i nt r i caci es and pr obl ems associ at ed wi t h al ar ge mul t i cent er ed i nvest i gat i on. Dr . Da Si l va wi l l wor k wi t h t hepr i nci pl e i nvest i gat or g pr oj ect di r ector and st at i s t i c i an of t hepar ent gr ant t o under st and t he compl exi t i es of dat a col l ect i on andanal ysi s f or a l ar ge case- cont r ol s t udy. Thi s anal ysi s wi l l al sobe i mpor t ant i n t he devel opment of Dr . Da Si l va' s dat a anal ysi sski l l s . He wi l l al so gai n exper i ence i n t he pr epar at i on andpr oducti on of manuscr i pt s of s t udy r esul t s f or publ i cat i on. l nsumg t hi s oppor t uni t y woul d be i r nr nensel yusef ul because i t woul d bef aci l i t at e t he mi nor i t y f acul t y r nember ' s r esear ch exper i encesubst ant i al l y at t he begi nni ng of hi s academi c car eer .

How t he pr oposed exper i ence r el at es t o t he speci f i e r esear ch goal sand obj ect i ves of t he par ent gr ant :

The pr oposed exper i ence wi l l al l ow Dr . Da Si l va t o becor ne anI nt egr al par t of t he par ent pr oj ect as t he devel oper of t het el ephone i nt er vi ew f or t he i nci dent cases and t hei r cont r ol s. I naddi t i on g he wi l l assi st i n ensur i ng t hat cases have appr opr i at el y

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mat ch cont r ol s as out l i ned i n t he par ent gr ant . He wi l l al soassi s t i n coor di nat i ng t he dat a col l ect i on f r om t he var i ouspar t i ci pat i ng cl i ni cal si t es, Har var d school of Dent al Medi ci ne andNERI . One of t he goal s of t he par ent gr ant i s t o det er mi ne i f ar el at i onshi p exi st s bet ween ost eosar coma and an envi r onment alf act or - f l uor i de i ngest i on. Thi s r esear ch suppl ement woul d al l owt he el uci dat i on of an addi t i onal f act or ' s i nf l uence - soci oeconomi cst at us. Thi s may become an i mpor t ant f act or i n t he anal ysi s of t hepar ent pr oj ect . The i ssue of soci oeconomi c st at us hei ght ens ouri nt er est as pr ovi der s of heal t h car e, becaus e i t may bespeci f i cal l y associ at ed wi t h medi cal and dent al heal t h car epr ovi si on of f l uor i de suppl ement s 17 , 18. As a pr oj ect whose goal i ti s t o det er mi ne i f an i ncr eased r i sk exi st s bet ween anenvi r onment al f act or ( f l uor i de) and ost eosar coma u t hi s suppl ementwoul d al l ow t he i nt egr at i on of an i mpor t ant f act or t hat has beenshown t o be cor r el at ed wi t h f l uor i de i ngest i on. l n addi t i on

ut hi s

suppl ement wi l l af f or d a mi nor i t y i nvest i gat or u wi t h an excel l entbackgr ound u t he oppor t uni t y t o become i nt egr al t o t he par entpr oj ect as weI l as embar k on hi s own r esear ch/ academi c car eer .( For r ef er ences i n t hi s sect i on u see Appendi x F)

Det er mi nat i on of f l uor i de exposur e f r om r esi dent i al hi st or y

Pr eval ent and I nci dent Cases and Cont r ol s : The f l uor i del evel s of t he muni ci pal i t i es suppl yi ng wat er t o t he cases andcont r ol s ar e l i st ed i n t he CDC Fl uor i dat i on Census i n ppm. Year of f l uor i dat i on i s al so l i st ed. However u we have f ound t hat manyci t i es and t owns ar e not l i s t ed i n t he Census u even t hough t heyhave f l uor i dat ed wat er . pr obl em towns wer e i dent i f i ed i n Year 1and t he Depar t ment s of Heal t h i n t he f ol l owi ng st at es wer e cal l edt o obt ai n a s tat ewi de l i s t of t he f l uor i de l evel s f or aI l ci t i esand t owns i n t he st at e: Ar i zona u Ar kansas u Cal i f or ni a u Col or ado uConnect i cut , Del awar e, Fl or i da, Geor gi a, I l l i noi s, I ndi ana, I owa,Kansas, Kent uckyp Loui si anap Mai ne, Mar yl and p Massachuset t s p NewHampshi r e p Ohi o p Okl ahomap Pennsyl vani ap Rhode I sl and p Sout hCar ol i na p Texas p Tennesseep Ver mont p and Washi ngt on.

Wat er sampl e t ubes wi l l cont i nue t o be pr ovi ded by mai l t o t hepar t i ci pant s who use weI l wat er . The par t i ci pant s wi l l ber equest ed t o r et ur n a weI l wat er sampl e f or anal ysi s at t he Har var dSchool of Dent al Medi ci ne. Response r at e t o dat e has beenappr oxi mat el y 70% f or weI l wat er sampl e col l ect i on. We expect t hi st o i mpr ove p however 19 cases have been f ound i n whi ch t he weI l i nquest i on has been shut of f .

Col l ec t i on of t oenai l sampl e and det er mi nat i on of f l uor i deconcent r at i on

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) - _/ ~ I nci dent Cases and Cont r ol s: The r esear ch nur ses wi l l col l ect1\ s yt of t oenai l cl i ppi ngs f r om aI l 10 t oes f r om aI l i nci dent~ar t i ci pant s. The cl i ppi ngs wi l l be cl eaned i n dei oni zed wat er at

each hospi t al e Thi s pr ocedur e i s hi ghl y ef f ect i ve at r emovi ngsuper f i ci al cont ami nat i on. The cl i ppi ngs wi l l t hen be sent t o t he

l abor at or y of Dr . J St even Mor r i s at t he Uni ver si t y of Mi ssour iResear ch React or . The case cont r ol pai r s wi l l be anal yzed i n t hesame assay r un by neut r on act i vat i on anal ysi s; t he speci mens wi l lbe l abel ed by I D number onl y, and t he posi t i on of t he case andcont r ol speci men wi l l var y r andoml y. Af t er exposur e t o t her malneut r ons, gamma emi ssi ons f r om t he 2F i sot ope ( hal f - l i f e 11. 03seconds) ar e count ed and, wi t h t he use of a cer t i f i ed st andar d,conver t ed t o wei ght of f l uor i de. The coef f i ci ent of var i at i on f ort hese measur ement s on s epar at e nai l speci mens f r om t he same per s on( whi ch i ncl udes bi ol ogi cal var i at i on and t echni cal er r or ) i s 10-15%.

Det er mi nat i on of f l uor i de cont ent i n bone

About one cm- 3 of r esect ed bone f r om t he i nci dent ost eosar comat umor sur gi cal s i t e of pat i ent s wi l l be anal yzed f or f l uor i decont ent NMR i magi ng and spect r oscopy. Col l ect i ng t he r esect edspeci men wi l l not i n any way al t er t he t ype of sur gi cal pr ocedur et hat gi ven pat i ent wi l l r ecei ve. Addi t i onal l y, whi l e t he i nci dentcase i s under gener al anest hesi a f or t he t r eat ment of t he sar comal esi on, an i l i ac cr est bone bi opsy wi l l be obt ai ned. At a poi nt 2cm di st al and 2 cmpost er i or t o t he ant er i or - super i or i l i acspi ne,a 4 cm i nci s i on wi l l be made. t he sof t t i ssues wi l l be r et r actedt o expos e t he out er cor t ex of t he i l i um. The t r ochar i s t henposi t i oned so t hat t he needl e wi l l acqui r e a t r ansi l i ac bi cor t i cal

cor e bi opsy wi t h a di amet er of appr oxi mat el y 1 cm. Hemost asi s wi l lbe achi eved by el ect r ocoagul at i on or mi nor bl eeder s. The sof tt i ssues ar e al l owed t o f al l back i nt o pl ace. The wound i s cl osedi n a r out i ne f ashi on. The bone bi opsy f r om t he i nci dentost eosar coma pat i ent wi l l be anal yzed f or f l uor i de cont ent . ' Thenon- t umor pi ece of bonewi l l pr ovi de a st andar di zed anat omi calposi t i on f r om whi ch a bone sampl e wi l l be t aken f r om bot h t he caseand t he cont r ol . Cadaver i l i ac crest bone sampl es ( t he cont r olbone) mat ched by age and gender wi l l al so under go f l uor i neanal ysi s. Speci mens wi l l be st or ed at - 60 0 C and t hen t r anspor t edt o MGH i n dr y i ce unt i l r eady f or use.

The speci men wi l l be cl eaned of adher i ng sof t t i ssue andper i ost eum f ol l owi ng br i ef t hawi ng, pl aced under l i qui d ni t r ogen,and gr ound t o a f i ne powder wi t h a l ar ge cer ami c mor t ar and pest l e. The r esul t i ng powder wi l l be l yophi l i zed over ni ght at r oomt emper at ur e, and t hen ext r act ed wi t h chl or of or m- met hanol . Thi st r eat ment wi l l r emove most of t he wat er and l i pi ds, pr oduci ng a dr ypowder whi ch i s easy t o spi n at hi gh speed. The mi l dness of t he

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t r eat meht i nsur es t hat no chemi cal al t er at i on of t he mi ner aI wi l loccur . I n our exper i ence, gr ound but ot her wi se unt r eat ed speci mensof t en cannot be spun above about 1. 5 kHz, whi ch woul d be suf f i ci entf or f l uor apat i t e, but i nsuf f i ci ent f or cal ci um f l uor i de- t ypeconst i t uent s . Lyophi l i z i ng yi el ds a pas t y mat er i al t hat can

usual l y be coaxed above 2. 5 kHz. Removal of t he maj or i t y of t hel i pi d i s r equi r ed t o pr oduce a dr y, f r ee f l owi ng powder whi ch candynami cal l y bal ance i t sel f as t he spi nner appr oaches speeds above6 kHz. speci mens wi l l be equi l i br at ed t o l abor at or y t emper at ur eand humi di t y f or 24 hr pr i or t o NMR anal ysi s.

Quant i t at i ve 19 F MAS NMR spect r a of an accur at el y wei ghedsampl e of each powder ed speci men wi l l be obt ai ned on a Br uker MSL-400 NMR spect r omet er oper at i ng at a f i el d st r engt h of 9. 4 T and a19 F f r equency of 376 MHz. Spi nni ng speeds wi l l be pr eci sel y 7. 00kHz so t hat t he di s t r i but i on of s i gnal i nt ens i t i es among t hesi debands wi l l be f i xed f or aI l speci mens. Wei ght s wi l l be t akenbot h bef or e and af t er NMR anal ysi s t o check f or possi bl e wat erabsor pt i on. Quant i t at i on wi l l be per f or med by compar i son of t het ot al i nt egr al of t he basel i ne cor r ec ted spect r um wi t h t hat of ar eagent gr ade CaF 2 st andar d. CaF 2 i s chosen as a pr i mar y st andar dbecause i t may be accur at el y det er mi ned by gr avi met r y al one. Dat apr ocessi ng wi l l be per f or med of f l i ne f r om t he spect r omet er usi ngt he NMRI sof t war e package f r omNew Met hods Resear ch ( Syr acuse, NY) .Repl i cat e anal yses wi l l be per f or med f or each speci men on t wodi f f er ent days.

The f i gur e of 7 kHz r epr esent s t he appr oxi mat e maxi mumspi nni ng speed achi evabl e by our equi pment . As shown byKr ei nbr i nk, et a1 31 t hi s i s mor e t han adequat e t o f ul l y nar r ow

apat i t i c f l uor i de, and suf f i ci ent t o nar r ow CaF 2 - t ype r esonancesenough f or r easonabl e quant i t at i on. Al t hough combi ned MAS/ mul t i pl epul se met hods 4 pr ovi de t he shar pest , pot ent i al l y most usef ul ,r esonances, t her e i s of t en a l oss i n t ot al s i gnal / noi se r at i o, andso we wi l l avoi d t hese t echni ques because of t hei r somet i mesquest i onabl e absol ut e quant i t at i ve accur acy.

Pr i or t o t he st ar t of t hi s aspect of t he st udy, we wi l lchar act er i ze t he quant i t . at ive accur acy of our met . hods by bl i ndanal ysi s of a ser i es of wei ghed mi xt . ur es of hydr oxyapat i t . e,pr evi ousl y char act er i zed 5 f l uor apat i t e, and r eagent gr ade CaF 2 A st andar d set . of condi t i ons and i nst . r ument set . t . i ngs wi l l bedevel oped. Sampl es of t hese mi xt ur es and occasi onal bonesampl eswi l l be sent t o commer ci al l abor at or i es f or f l uor i de det . er mi nat i onby di ssol ut i on and pot ent i omet r i c anal ysi s i n or der t o est . abl i sh acompar i son bet ween NMR and convent i onal met hods. Occasi onal boneNMR and pot ent i omet r i c anal yses wi l l be checked by t he met . hod of st andar d addi t i ons usi ng r eagent gr ade CaF 2 0

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Repor t wr i t i ng

Af t er t he r et ur n of aI l obt ai nabl e weI l wat er sampl es f r om t hepr eval ent cases and cont r ol s, dat a col l ect i on f or t he r et r ospect i veaspect of t he st udy wi l l be compl et e. Anal ysi s wi l l commence

i mmedi at el y. Thus, . i n year 2, we wi l l have a pr el i mi nar y r epor t ont he f i ndi ngs f r om t he 226 r et r ospect i ve cases and 452 cont r ol s.Addi t i onal l y, an ar t i c l e i s i n pr ogr ess r evi ewi ng t he cur r entl i t er at ur e on t he genet i c r i sk f act or s f or ost eosar coma and ot herbone and sof t t i ssue t umor s. The def i ni t i ve dat a however , wi l laccr ue f r om t he f i ndi ngs of t he pr ospect i ve st udy.

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PROGRESS REPORT (Personnel and Study Subjects).,\J TNU MBER

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.11.11Personnel for the Currenl Budgel Periodand Any Planned Changes in Personnel for the Next Budgel Period

Use Iwo sections. ln the first section list Ali Current Personnel. ln the second section list Planned Personnel Changes.

l anned Per sonnel Chances

Name

Al I Cur r ent Per sonnel

Daugl ass, Chest er

Manki n, Henr yMcGui r e, Shei l aAcker r nan, J er omeHunt er , _Davi dPf l ei der er , Bet t i na

-e r r~l ; g, . I l onaDuf f y, Mar y

McGui r e, Shei l aoshi , Ani l

To Be Named

Degree(s)

DDS, PhD

MDDDS, DMScPhDPhDPhD

BDS. MPH

SSN Role on Project(e.g., PI, Res. Assoc.)

Pr i nci pal

\

I nvest i gat orI nvest i gat orpraj .Direct ..I nvest i gat orI nvest i gat orR 5'. Assac.Admi ni s t r at .Secr et ar y

Pr oj ect Di r .Pr ogr ammerSt at i st i ci an

Date of Birth(MMIDDfYY)

Annu% E

Provide the number of subjects enrol led in the s tudy 10 date according to the followlng categories . (See Page 8 for def ini t ions.)

American IndianAsian or Pacifie Black, not of White, nol of Other oror Alaskan Hispanie TOTAL

Native Islander Hispanie Origin Hispanie Origin Unknown

Female .1 19 205 13 238Male q 34 301 17 356Unknown

TOTAL 5 53 0 506 30 594PHS 2590 (Rev. 9/91) (Form Page 7) Page --6A- (Use contInuatIon page I f necessa


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5. HUNAN SUBJ ECTS

Pr ot ocol Changes

I n addi t i on t o t he dat a and pat hol ogy sampl es t hat weor i gi nal l y pr oposed, an i l i ac cr est bone bi opsy wi l l be per f or medat t he t i me of sur ger y t o gat her a non- t umor pi ece of bone at ast andar di zed anat omi cal posi t i on. A si mi l ar bone sampl e wi l l bet aken f r om an aut opsy cont r ol . The appr oval f or t he r evi s i on f r omeach hospi t al ' s human subj ect r evi ew commi t t ee has been acqui r ed.See Appendi x E f or a sampl e set of I nf or med Consent s submi t t ed f orsuccessf ul i nst i t ut i onal appr oval .

I ncl usi on of Women and Mi nor i t i es

Al I women and mi nor i t i es meet i ng t he el i gi bi l i t y cr i t er i a wi l lbe enr ol l ed i n t he pr oposed s tudy. The gender r at i o f ound bypr evi ous s tudi es f or t he occur r ence of os teosar comas i s 3: 2mal e: f emal e. Ost eosar coma, a r ar e bone cancer , has a l ow pr eval encer at e i n peopl e of col or .

6. VERTEBRATE ANI MALS

Not Appl i cabl e

7. PUBLI CATI ONS

Not Appl i cabl e

8. I NVENTI ONS AND PATENTS

Not Appl i cabl e

Li t er at ur e ci t ed

1. Nat i onal Toxi col ogy Pr ogr am. Toxi col ogy and c~ r ci nogenesi s of

sodi um f l uor i de i n F344J N r at s and B6C3FI ml ce. Techni calRepor t Ser i es 393, NI H Publ i cat i on No. 90- 2848, 1990.

2. Revi ew of Fl uor i de: Benef i t s and Ri sks. Repor t of t he Ad HocSubcommi t t ee on Fl uor i de of t he Commi t t ee t o coor di nat eEnvi r onment al Heal t h and Rel at ed pr ogr ams, Publ i c Heal t hSer vi ce, Depar t ment of Heal t h and Human Ser vi ces. 1991.

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3. McGui r e SM,Dougl ass CW.ost eosar coma?

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Vanabl e ED, McGui r e MH, Buckwal t er J A, andI s t her e a l i nk bet ween f l uor i dat ed wat er and J ADA 122: 39- 45, 1991.

4. Smi t h KA, Bur um DP. Appl i cat i ons of f l uor i ne- 19CRAMPS t o t heanal ysi s of cal ci um f l uor i dej f l uor apat i t e mi xt ur es. J MagnReson 84: 85- 94, 1989.

5. Shi moda S. , AohaR, Mor eno EC, Mi ake Y. Ef f ect of sol ut i oncomposi t i on on mor phol ogi cal and st r uctur al f eat ur es of car honat ed cal ci um apat i t es. J Dent Res. 69: 1731- 1740, 1990.

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fluoride bone cancer 8

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