am j clin nutr 1997 patriarca 616 21

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61 8 P T R I R E T L

I W I and W 2 are women and M 1 and M 2 are men.

T A BL E 1

General data on volunteers takingpart in the 62N i study

Subject

W M W2 M2

A ge (y) 30 28 21 30

Weight (kg) 66.2 77.5 59.2 86.5H eight (cm) 162 186 169 179Body surface area (m2) I .70 2.02 1 .68 2.06C reatinine clearance (niL mi n 1.73 m2) 89 1 12 92 22 84 6 100 IlT otal 62N i dose (pg) 670 760 57 1 879

I W I and W 2 are women and M 1 and M 2 are men.2t SD .

62Ni w ere added and analyzed together w ith the plasm a andurine sam ples obta ined from the subjects.

A d d it ion a l a n a lysis

Serum and urine creatin ine concentra tions were determ inedby th e Jaff { 233}25) method on an automated analyzer. Creatinine

clearance w as norm alized to body surfacearea, according to

G ow an and Fraser 26 .

R E S U LT S

D etails on each subject taking part in the study-including

sex, age, weight, height, body surface area ,average creatinineclearance, and 62Ni dose-are given inTable 1 The daily fecaloutput of the tracer 62N i and the excre tion of the fecal m arker(radioopaque pellets) for each volunteer are compared in T able

2. The plasma concentrations of 62N i observed in each of the

four volunteers at various tim e intervals are show n in F igure1

T h e co ncen tr ati on s of 62N i in plasm a and red cellsamples

taken at the sam e tim e intervals for one of the subjects are

compared in Table 3. Cumulative urinary excretion as a per-centage of the absorbed dose is plotted against tim e inFigure2. T he absorbed, excre ted ,and retained fractions ofthe dose of

62Ni for ea ch su b ject a r e sh ownin T a b le 4. T h e d a ta ob ta in ed

in th is study are com pared w ithdata from the study by Sun-

derman et al 10 in Ta b l e 5

D I S C U S S I O N

Th e 62Ni dose given in this s tudy T able 1 w as r ela tiv elysm all and com parable w ith the am ountof nickel that can be

ingested from diets rich in certain types of food, such as dark

chocolate , nuts, and soy products , although several studies

showed that n ickel absorption is greatly reduced w hen inges ted

w ith food (8, 10). The dose 0 .6-0 .9 m g) , al though not phys-io logic in form , w as the closest in s ize to a typical physiologic

dose used to date . S m aller doses eg ,0.4 and 0.6 mg N i) have

been adm inistered during studies of clin ical responses of nick

el-sensitive patien ts to oral nickel intake 7 , 9 , but thes

studies had only a lim ited num ber of nickel determ inations.Gastrointestinal absorption of 62N iwas estimated as the differ-

ence between ingested nickel and nickel excre ted in feces . Th

com pleteness of fecal excretion w asconfirmed by the com plete

recovery of all radioopaque pelle ts in the feces with in5 d ofingestion , although patternsof fecal excretion w ere different from

subject to subject Table 2 .O ne of the volunteers, w ho consum eda v eg etar ian diet, excreted 18 of the20 pe lle ts w ith in 24 h,

w hereas the others required a longer tim e. In all volunteers, the

pattern of excretion of the tracer closely follow ed that of the fec

marker and there w as no evidence of secondary peaks . T herefore,

w e are confident that the recovery of the dose of 62N i not absorbed

from the in tes tine w as also com plete and that reexcretion o

absorbed nickel via the gut w as negligible . T he average transit

time (A U ) ofthe digesta through th e gut w as 47.4 h (SD : 18.3 h;

SE M : 9.1 h a n d , a fter exclu sion of th ev eg eta ria n s ub je ct,54.4 h

(SD : 14.4 h;SEM : 8.3 h). Cummings et al(23) reported an A U

of 54.2 h (SEM : 2.6 h) in 50 subjects given a single dose of pellets

and a shorter A U was observed when additional fiber was in-

cluded in the diet .

T he m ean concentration of dietary nickel observed in th

feces of all subjects except in one basal sam ple, w hich w as

considered incom plete w as 2.2 1. 1 p.g /g w et w t range:

0 .9-5.0 ;.L g/g wet wt; n = 19) and 7.9 3.3 g/g dry wt

range: 3 .5-15 pg/g dry w t; n = 19). Daily fecal excretion of

T ABL E 2

Fecal marker and tracer excreted per day by each subject

W I M 1 W 2 M 2

Fecal Fecal Fecal Fecal

D ay marker T racer marker T racer marker T racer marker T racer

2 4 5 5 2

% o f t ot a ex cr e te d

6 9 9 7 2 5 2 2

3 4 3 6 2 5 9 2 9 5 7

4 2 2 3 5 3 8

5 2 2 5 2 3

r 0.982 0.965 0.953 0.947


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62 0 PATRIAR CA ET A L

T B L E 4

A bsorption, excretion, and retention of the 62N i dose in each of the four subjec ts, expressed as a percentage of the dose and a percentage

absorbed dose

W M W M i S

Percen tage of dose (% )

Total 62N i dose 100.0 100.0 100.0 100.0 -

Total fecal excretion 71 .3 67.6 59.9 68.7 66.9 4. 9

A bsorbed dose 28.7 32.4 40.1 31.3 33.1 4. 9Total urinary excretion 14.5 22.3 32.9 18.9 22.1 7.8

Retained am ount 14.2 10.1 7.2 12.4 1 1.0 3. 0

Percen tage of absorbed dose (% )

A bsorbed dose 100.0 100.0 100.0 100.0

Total urinary excretion 50 .4 68.5 82.0 59.8 65.2 13.4

Retained am ount 49.6 31.5 18.0 40.2 34.8 13.4

vitro s tud ie s o f cellu lar up take ofn ic ke l ind ic a te d tha t h ig h

c o nce ntra tio ns o f a lbum in a nd a m ino a c ids m a y pre ve nt nicke l

accum ulation in red cells (3 1, 32). In th is study we observed in

vivo the d is tribu tio n o f nic ke l be tw e e n re d c e lls a n d p la s m a .

The c o n c e n tra tio n o f 6 2 N i w a s d e te rm ine d in re d c e ll s a m ple s

taken from tw o of the volunteers (W 2a n d M2 ) o ve r aperiod of

tim e a fte r ing e s tio n o f th e is o to pe . F o r bo th s u bje c ts , th e

co nce ntra tio n o f 6 2 N i in re d c e lls w a s< 1 6 nm o l/L, ie , m uc h

low er than that in the corresponding p la s m a s a m p le s . B e c a u s e

t he c on ce nt ra ti on s o bs e rve d w e re c lo s e to the de te c tio n lim it o f

th e m e tho d, th e re s u lts c o uld be q ua ntifie d o n ly fo r o n e s u bje c t

(W 2; Table 3).The u pta ke o f 6 2 N i in re d c e lls w a s s m a ll,

d e s pite the hig h 6 2 N i c o nc e n tra tio n in th e s urro u nd in g p la s m a .

Th e peak w a s reached 48 h after ingestion. The d e c re a s e in

6 2 N i c o nc e n tra tio n started w hen th e c o rre s po nd in g p la s m a c o n -

c e n tra tio n s w e re lo w e r tha n tho s e ins id e th e re d c e lls .

As indicated byth e da ta in F ig u re 2 , the re w a s a la rg e be tw e e n -

s ubje ct va ria bility in urina ry nic ke l e xc re tio n, w hichw a s o nly

p a rtia lly e xpla in e d b y th e diffe re nc e s in u rin a ry vo lu m e s a nd

f lows. A verage da ily urina ry vo lu m e fo r a n in divid u a l ra ng e dfrom 1015 to 1755 m L an d th e a ve ra g e urina ry flo w w a s b e tw e e n

0.71 and 1.22 m lJm in. V alues for creatinine clearance and intra-

in div id ual v ar iab ilit y w e re w ith in th e e xp e c te d re fe re nc e ra ng e fo r

h e a lth y s u bje c ts 2 6 ) a n d in dic a te d no rm a l re n a l fun c tio n Ta ble

1 ). A lo w e r d a y -to -d a y va ria bility w a s o bs e rve d fo r th e v e g e ta ria n

su b jec t (W 2), according to the la c k o f d ie ta ry c re a tin in e in ta ke .

Five days after ing e s tio n, th e e lim in a tio n o f n ic ke l w a s n o t c o m -

p le te in a n y o f th e s u bje c ts . The a ve ra g e a m o u nt e xc re te d w a s

65.0 13.5 of the absorbed d o s e .

T B L E S

E stim ates of nickel absorption, excre tion, and retention determ ined by

using naturally occurring nickel or a stable isotope (62Ni)

Sunderman Ct al (

nickel2

10), This study,

62Ni3

% of ose

Fecal excretion 76 19 66.9 4. 9

Urinary excretion 26 14 22.1 7. 8

Total excretion 102 8 89.0 3. 1

A bsorbed frac tion 27 17 33.1 4.9

Retained fraction 0 1 1.0 3. 01 SD .

2 Length of study: 4 d.

Length of study: d.

In th is s tu dy, th e p e rc e n ta g e o f th e o ra l n ic ke l do s e a bs o rb e d

from the gu t w a s fa irly s im ila r in th re e o f th e vo lu n te e rs ,

w he re as the fo urth subject (W 2) had higher gastrointestinal

absorption 25 ) . S he is a yo u ng ve g e ta ria n w o m a n, w ho m a y

ha ve h a d ina de q ua te iro n inta ke . It h a s b e e n re po rte d th a t

n ic ke l a b s o rp tio n in c re a s e d in iro n-de fic ie n t ra ts 3 3 ). Th is

suggests that iro n s ta tu s s ho uld be assessed in volunteers cho-

s e n for studies o f nic ke l a b s o rp tio n . Th e p e rc e n ta g e o f the

absorbed d o s e e x c re te d in u rin e s ho w e d a w id e r va ria b ility

fro m s u b je c t to s u bje c t, w hic h w a s p a rtia lly e xp la in e d in te rm s

of the to ta l a m o un t o f u rin e pa s s e d . The pe rc e n ta g e o f th e d o s e

retained in the bo d y a t the e nd o f th e e xp e rim e nt ra n g e d fro m

1 8% to 49.6% of the absorbed dose (Table 4).

Biliary excretion hasb e en s ug g es te d as a ro u te o f n ic ke l

e lim ina tio n o n th e b a s is o f e v id e n c e o f b ilia ry e xc re tio n in ra t

a nd rabbits (2) a nd th e m e a s u re m e n t o f nic ke l in h u m a n bile

s pe c im e ns 3 4 ). Ho w e ve r, w e o b s e rve d n o e vid e n c e o f e nte ro -

path ic circulation ofn ic ke l, a s ju dg e d by th e a pp e a ra nc e o f

s e c o n da ry p e a ks o f pla s m a o rurinary n ic ke l c o nc e ntra tio ns .

The pattern o f fe c a l e x c re tio n o f nic ke l h a s be e n a s s e s s e d fo rth e firs t tim e b e c a u s e the tra c e r could be distinguished from

na tura lly a b u nd a n t n ic ke l in g e s te d w ith fo o d. Th e e lim in a tio n

of 62N i in fe c e s fo llo w e d thesam e pattern observed forth e

fecal m arker (Table 2) .This suggests tha t biliary excre tion of

nic ke l is ve ry s m a ll o r a b s e nt in hu m a ns .

The results of thisin ve s tig a tio n s ho w e d am uch low er be tw een -

s ub je ct va ria bility tha n that o bserv ed in e a rlie r s tu die s 8 -1 0 ),

which u s e d n a tu ra lly a b u nd a n t nic ke l. Th is is a ttribu te d to the

im proved ability to d is ting uis h th e tra c e r fro m o th e r s o u rc e s o f

e n viro n m e nta l n ic ke l. Th e e s tim a te s o f nic ke l a b s o rp tio n, e xc re

tio n , a n d re te n tio n o b ta in e d in th is s tud y a re c o m p a re d in Ta b le5

w ith those reported by Sunderm an e t a l 1 0 ), the o nly o the r

c o m ple te s tu d y o n hu m a n sub jects. W e observed a higher gastro-

in te s tin a l a b s o rptio n 6 ) a nd lo w e r fe c a l -9 ), u rina ry -4 ),and to tal nickel excretion 1 1 ). Th e m o s t s triking re s u lt ob -

s e rv e d in this s tu d y w a s th a t a c o n s ide ra b le fra c tio n o f theab -

sorbed n ic ke l do s e (34.8 13.4% ) w as s till retained d after

ing e s tio n. The s e re s ults fo r nic ke l re te ntio n a re co ns is te nt w it

th o s e o f re c e nt a n im a l s tu die s [m ic e fe d p hy s io lo g ic do s e s o f 5 7

5 )1 a nd a study by Te m p le to n e t a l 2 1 ), w h o , in a s in g le -s ub je c ts tudy found urinarye xc re tio n o f 6 tN i persis ting 96 h aftera n o ra l

dose of th e is o to pe .

The us e o f a s ta b le is o to pe to inv e s tig a te n ic ke l m e ta b o lis m

in hu m an s has several advan tages; the doses can be reduced

a m o unts c lo s e r to phys io lo g ic o ne s a nd c o nta m ina tio n is e


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NICKEL M ETA BO LISM IN H UM A NS 62 1

fectively re d u c e d b y a fa c to r o f 1 8 .5 , a llo w in g th e fa te o f th e

t racer to be follow ed for a long tim e.

O n the assum ption that nickel absorbed from aqueous solu-

tions during fasting behaves as does nickel absorbed fromth e

d ie t, th e re s u lts o f th is s tu d y s h o w th a t e lim in a tio n o f n ic k e l

fro m th e b o d y ta k e s lo n g e r th a n re p o rte d p re v io u s ly a n d tha t

nickel excretion a n d in te rin d iv id u a l v a ria b ility m ay h a ve b e e n

o v e r e s t i m a t e d . Estim ates of long-term retention o f th e a b -

sorbed nickel fraction shouldb e c o n s id e re d w ith c a u tio n b e -

cause th e n o n e x c h a n g e a b le o r s lo w ly e x c h a n g e a b le fra c tio n s

ca n a p p a re n tly b e in c re a s e d b y a n y lo s s e s o f n ic k e l d u e to

in c o m ple te fe c a l an d u rin e c o lle c tio n s . H o w e v e r, in th is s tu d y

the fecal m arker given with the n ickel dose was com plete ly

recovered from a ll sub jects and the retention of nickelw a s

co n firm ed b y its co n ce n tra tio n in p la s m a a n d u rin e .

T h e in ve s tig a tio n o f th e s ite s w h e re n ick e l is re ta in e d a n d th e

processes inv o lve d in th e s lo w e x ch a n g e o f n ick e l fro m tis s u e s

will re q u ire fu rth e r s tu d ie s . P re lim in a ry re s u lts o n th e k in e tic s

of nickel uptake fro m e ry th ro c y te s in v ivo h a v e b e e n re p o rte d .

A three-com partm ent m athem atical m odelfo r n ic k e l m e ta b -

olism ha s b e e n d e v e lo p e d w ith d a ta fro m th is s tu d y a n d p re -

l im inary results w e re p re s e n te d p re v io u s ly a t th e F ifth C O M -

T X Sym posium on T oxicology a n d C lin ica l C h e m is try o f

Metals (u n p u b lis h e d o b s e rv a tio n s , 1 9 9 5 ). A fu ll d e s c rip tion o f

the m odel w ill b e th e s u b je c t o f a fo rth c o m in g p a p e r. E l

W e are grateful to A ndrew D uncan, D ennis O Reilly , and Naveed S attar

from the G lasgow R oyal Infirm ary , w ho took part in the organization of the

m etabolic s tudy; to the partic ipants of the experim ent; and to Brian M cG aw

(Robert Gordons U nivers ity , A berdeen) for his advice on the isotopic-

dilution techniques. W e are indebted to Ian Brem ner for the use of the

ICP-MS facili ty at the Row ett Research Insti tute, Aberdeen, and to M artin

Reid for his skillful ass istance.

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