Biological Trace Element Research - American Chemical Society

Chapter 9

Trace Metal Analysis and Quality Assurance in Clinical Chemistry

Downloaded by UNIV MASSACHUSETTS AMHERST on August 2, 2012 | http://pubs.acs.org Publication Date: December 26, 1991 | doi: 10.1021/bk-1991-0445.ch009

J. Savory, M . G. Savory, and M . R. Wills Departments of Pathology, Biochemistry, and Internal Medicine, Health Sciences Center, University of Virginia, Charlottesville, VA 22908

The establishment of a trace element analysis laboratory requires many considerations. Specimen collection must be controlled and detailed protocols established. Sources of contamination in analysis are serious problems although some relatively inexpensive devices can help enormously. Of the instrumental techniques used for the analysis, electrothermal atomic absorption spectrometry has the widest applications. Sample preparation for analysis varies according to the biological material, element in question and instrumental technique. Minimizing the number of manipulations reduces the risk of contamination. Localization of trace elements in tissue requires special techniques which include laser microprobe, electron probe and electron energy loss microanalysis. Conventional clinical chemistry tools such as the use of standard reference materials, and internal and external quality assurance programs, are essential if satisfactory results are to be obtained in the long-term. The field of metal toxicology over the years has had to cope with many serious problems in order to advance the knowledge base. Foremost among these problems has been the development of suitable analytical methods having the necessary degree of precision, accuracy, and sensitivity. Since many of the inorganic analytes are present in body fluids and tissues in the parts per million and often only parts per billion range, it has taken a considerable degree of refinement to solve these analytical problems. Atomic spectroscopy has contributed most to providing satisfactory analytical methods, although the application of good analytical technique to avoid contamination has been of major importance. This review summarizes some of the more important considerations in the establishment of a trace metal clinical laboratory. 0097-6156/9iy0445-0113$06.00A) © 1991 American Chemical Society In Biological Trace Element Research; Subramanian, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

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Specimen

Collection

Many d i f f e r e n t types o f specimens a r e s u b m i t t e d f o r t r a c e element measurements. The most common a r e b i o l o g i c a l f l u i d s u s u a l l y serum (or plasma) and u r i n e , a l t h o u g h t h e r e i s sometimes i n t e r e s t i n c e r e b r o s p i n a l f l u i d . T i s s u e a n a l y s i s i s a l s o o f importance and t h e l a b o r a t o r y must be equipped t o a n a l y z e a wide v a r i e t y o f t i s s u e s such as bone, b r a i n , muscle, l i v e r , e t c . H a i r a n a l y s i s has g a i n e d some i n t e r e s t b u t i t s h o u l d be d i s c o u r a g e d i n most i n s t a n c e s s i n c e c o n t a m i n a t i o n from t h e environment i s a major problem. Recently, because o f t h e h i g h l e v e l o f i n t e r e s t i n aluminum t o x i c i t y i n h e m o d i a l y s i s p a t i e n t s , d i a l y s i s w a t e r and d i a l y s a t e s o l u t i o n s a r e commonly a n a l y z e d . General aspects o f specimen collection, p r o c e s s i n g and s t o r a g e have been r e v i e w e d by A i t i o and J a r i v i s a l o (2) and a l s o b y S e l l e r (2). The p r e s e n t a u t h o r s recommend f o r t r a c e m e t a l measurements such as aluminum, copper and z i n c t h a t an acid-washed p l a s t i c s y r i n g e be u s e d w i t h a s t a i n l e s s s t e e l n e e d l e and t h a t t h e b l o o d be t r a n s f e r r e d to a p o l y p r o p y l e n e tube ( F a l c o n , Oxnard CA) f o r p r o c e s s i n g and s t o r a g e . An a l t e r n a t e approach w h i c h i s s a t i s f a c t o r y f o r aluminum i s to use a p l a s t i c c o l l e c t i o n tube c o n t a i n i n g u n c o n t a m i n a t e d l i t h i u m h e p a r i n a t e as an a n t i c o a g u l a n t . Even g r e a t e r c a r e must be t a k e n f o r u l t r a t r a c e a n a l y s i s such as t h e measurement o f chromium, c o b a l t o r n i c k e l i n serum. The b l o o d c o l l e c t i o n t e c h n i q u e must n o t a l l o w t h e specimen t o come i n t o c o n t a c t w i t h a m e t a l n e e d l e , and t o c i r c u m v e n t this problem we collect o u r specimen into an acid-washed p o l y p r o p y l e n e t e s t tube u s i n g a n e e d l e w i t h a t e f l o n o r p o l y e t h y l e n e i n t r a v e n o u s c a t h e t e r (£). Procedures f o r t h e c o l l e c t i o n and s t o r a g e o f u r i n e and f e c a l specimens have been d e v e l o p e d i n o u r l a b o r a t o r y ( 4 ) . Twenty-four h o u r u r i n e specimens a r e c o l l e c t e d i n p l a s t i c c o n t a i n e r s ( S c i e n t i f i c P r o d u c t s , McGraw Park, I L ) and an a l i q u o t t r a n s f e r r e d and s t o r e d a t 4°C i n a p o l y p r o p y l e n e tube ( F a l c o n , Oxnard, CA). F e c a l specimens a r e c o l l e c t e d d i r e c t l y i n t o p l a s t i c bags, weighed and f r o z e n . Sources of Contamination i n Analysis Every item used d u r i n g a n a l y s i s i s a p o s s i b l e source o f t r a c e metal contamination. To be c o n s i d e r e d a r e such items as g l a s s and p l a s t i c w a r e , p i p e t t e t i p s , c o l l e c t i o n t u b e s , sample cups, p u r i t y o f r e a g e n t s , s t a n d a r d s , a c i d s , water and t h e w o r k i n g environment. C o n t a m i n a t i o n o f g l a s s and p l a s t i c w a r e i s removed b y a c i d washing and a l l a c i d s s h o u l d be u l t r a p u r e grade. Techniques f o r p r e p a r i n g e x c e p t i o n a l l y h i g h p u r i t y a c i d s have been r e p o r t e d (5^7). Water s h o u l d produce a r e s i s t i v i t y o f a t l e a s t 18 megohms and c o n t i n u o u s monitoring i s necessary. The room chosen f o r a n a l y s i s s h o u l d have l i m i t e d a c c e s s t o ensure a c l e a n w o r k i n g environment and powder-free g l o v e s must be worn a t a l l t i m e s . Sample p r e p a r a t i o n s h o u l d be c a r r i e d o u t i n an e n v i r o n m e n t a l l a m i n a r f l o w hood. We use a f i l t e r u n i t (122 χ 61 cm) suspended from t h e c e i l i n g w i t h p l a s t i c s h e e t i n g e n c l o s e d t o bench l e v e l . T h i s f i l t e r u n i t (MAC 10, E n v i r c o , Hagerstown, MD) i s i n e x p e n s i v e , c o n v e n i e n t and p r o v i d e s c l a s s 100

In Biological Trace Element Research; Subramanian, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

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a i r . S e v e r a l u n i t s can be used t o g e t h e r t o p r o v i d e more bench space h a v i n g a c l e a n a i r environment.


A n a l y t i c a l Techniques The o l d e r c h e m i c a l and p h y s i c o c h e m i c a l methods i n g e n e r a l have been r e p l a c e d by more s p e c i f i c and s e n s i t i v e new t e c h n i q u e s . X-ray fluorescence, neutron activation, atomic spectroscopic, e l e c t r o c h e m i c a l and, r e c e n t l y , mass s p e c t r o m e t r i c t e c h n i q u e s have a l l been a p p l i e d t o the measurement o f t r a c e elements i n b i o l o g i c a l specimens. Each o f these approaches has i t s own i n h e r e n t advantages and disadvantages. However, for most clinical chemistry a p p l i c a t i o n s , atomic a b s o r p t i o n s p e c t r o m e t r y has been most w i d e l y u s e d and can be recommended as a r e l i a b l e a n a l y t i c a l t e c h n i q u e . Flame a t o m i z a t i o n methods p e r f o r m w e l l f o r some o f the more commonly measured elements such as c a l c i u m , magnesium, z i n c and copper, b u t f o r t r a c e and u l t r a t r a c e a n a l y s i s e l e c t r o t h e r m a l a t o m i c a b s o r p t i o n s p e c t r o m e t r y (EAAS) i s the method o f c h o i c e . Advantages o f t h i s technique include: ( i ) sample p r e t r e a t m e n t u s u a l l y can be e l i m i n a t e d , ( i i ) sample r e q u i r e m e n t s a r e s m a l l (2-100 μΐ), ( i i i ) g r a p h i t e f u r n a c e s are c a p a b l e o f a t t a i n i n g the h i g h temperature needed t o form ground s t a t e atoms, and ( i v ) the atoms s t a y i n the l i g h t p a t h f o r a l o n g e r time t h a n flame a t o m i z a t i o n , r e s u l t i n g i n i n c r e a s e d c o n c e n t r a t i o n and thus g r e a t e r s e n s i t i v i t y . There are many f a c t o r s t o c o n s i d e r i n c h o o s i n g parameters f o r EAAS. The use o f p y r o l y t i c a l l y c o a t e d g r a p h i t e tubes t o m i n i m i z e r e a c t i o n s between the a n a l y t e and the tube i s an important c o n s i d e r a t i o n and such tubes used t o g e t h e r w i t h a p y r o l y t i c g r a p h i t e p l a t f o r m are recommended f o r o p t i m a l r e s u l t s . However, t h r o u g h p u t and o t h e r f i n a n c i a l c o n s i d e r a t i o n s sometimes f o r c e the a n a l y s t t o choose a l t e r n a t e approaches. Thus, r e g i o n a l l a b o r a t o r i e s p r o v i d i n g aluminum measurements f o r a l a r g e number o f r e n a l d i a l y s i s u n i t s are o f t e n f o r c e d t o d i s p e n s e w i t h the use o f the p l a t f o r m i n o r d e r t o p e r f o r m the l a r g e number o f a n a l y s e s r e q u e s t e d . Such a compromise does n o t appear t o j e o p a r d i z e p a t i e n t c a r e s i n c e the q u a l i t y o f the r e s u l t s can be m a i n t a i n e d a t a h i g h l e v e l p r o v i d e d o t h e r a n a l y t i c a l p r i n c i p l e s are n o t v i o l a t e d . Other c o n s i d e r a t i o n s i n e s t a b l i s h i n g a p r o c e d u r e f o r the measurement o f a t r a c e element a r e the use o f m a t r i x m o d i f i c a t i o n , background c o r r e c t i o n and sample p r e p a r a t i o n . These f a c t o r s e s p e c i a l l y as they p e r t a i n t o aluminum measurements have been r e v i e w e d by the p r e s e n t a u t h o r s (4) and by S l a v i n ( 5 ) . The use o f EAAS i s n o t i d e a l f o r a l l a p p l i c a t i o n s b u t , as mentioned e a r l i e r , t h e r e a r e d i s t i n c t advantages o v e r o t h e r methods. N e u t r o n a c t i v a t i o n a n a l y s i s i s v e r y s e n s i t i v e b u t i s a complex t e c h n i q u e r e q u i r i n g access t o a n u c l e a r r e a c t o r . A l s o f o r b i o l o g i c a l a n a l y s e s , the elements sodium, c h l o r i n e and bromine can cause problems o f masking, o f t e n making a s e p a r a t i o n s t e p n e c e s s a r y . X-ray f l u o r e s c e n c e i s s p e c i f i c b u t l a c k s s e n s i t i v i t y f o r many a n a l y t e s . I n d u c t i v e l y coupled plasma e m i s s i o n has advantages f o r very r e f r a c t o r y elements b u t o f t e n s e n s i t i v i t y i s l e s s t h a n EAAS. I n d u c t i v e l y c o u p l e d plasma i n t e r f a c e d w i t h mass s p e c t r o m e t r y (ICP/MS) i s r e l a t i v e l y new as a c o m m e r c i a l l y a v a i l a b l e t e c h n i q u e a l t h o u g h i t was f i r s t d e s c r i b e d o v e r a decade ago. ICP/MS i s a m u l t i e l e m e n t


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BIOLOGICAL TRACE ELEMENT RESEARCH t e c h n i q u e w h i c h p r o v i d e s the s p e c i f i c i t y i n h e r e n t i n i s o t o p e d i l u t i o n mass s p e c t r o m e t r y and w h i c h a l s o a l l o w s e l e m e n t a l b i o a v a i l a b i l i t y t o be s t u d i e d u s i n g s t a b l e i s o t o p e s . B i o m e d i c a l a p p l i c a t i o n s o f ICP/MS have been r e v i e w e d r e c e n t l y by Delves ( 9 ) .


Sample P r e p a r a t i o n f o r A n a l y s i s A wide v a r i e t y o f sample p r e p a r a t i o n methods have been used, the l e v e l o f c o m p l e x i t y b e i n g dependent on the f i n a l a n a l y t i c a l t e c h n i q u e used. For EAAS o f b i o l o g i c a l f l u i d s we use the f o l l o w i n g f o u r p r o c e d u r e s depending on the a n a l y t e : ( i ) d i l u t i o n and d i r e c t analysis with external calibration, ( i i ) direct analysis with s t a n d a r d a d d i t i o n s , ( i i i ) d i g e s t i o n and e x t r a c t i o n and ( i v ) p r o t e i n precipitation. The f i r s t o f these procedures i s the most s t r a i g h t f o r w a r d and s h o u l d be u s e d whenever p o s s i b l e . I d e a l l y the s t a n d a r d c u r v e i s c o n s t r u c t e d u s i n g aqueous s t a n d a r d s . However i f the sample m a t r i x causes problems t h e n m a t r i x based c a l i b r a t o r s may be used. Some w o r k e r s (10) have used t h i s approach f o r serum aluminum by p r e p a r i n g s t a n d a r d s i n a serum p o o l c o n t a i n i n g a m i n i m a l amount o f endogenous aluminum. S t a n d a r d a d d i t i o n s can be used t o m i n i m i z e m a t r i x e f f e c t s b u t t h i s approach i n h e r e n t l y i s i m p r e c i s e s i n c e m u l t i p l e a n a l y t i c a l measurements, each w i t h i t s own imprécisions, a r e made t o a c h i e v e the f i n a l r e s u l t . A v a l u a b l e t e c h n i q u e f o r the d e t e r m i n a t i o n o f n i c k e l , and aluminum i n serum i s t o p r e c i p i t a t e p r o t e i n s u s i n g a s m a l l amount o f u l t r a p u r e c o n c e n t r a t e d n i t r i c a c i d (11,12) . The f i n a l p r e p a r a t i o n w h i c h i s r e l a t i v e l y p r o t e i n f r e e has markedly reduced m a t r i x e f f e c t s . U r i n e samples s i m i l a r l y may be s i m p l y d i l u t e d p r i o r t o EAAS measurement ( 1 0 ) , a l t h o u g h a c i d d i g e s t i o n i s o f t e n n e c e s s a r y ( R a i n s , T.C., NIST, p e r s o n a l communication, 1988). A n a l y s i s o f f e c e s i s more c o m p l i c a t e d and the procedure we use i s as f o l l o w s (13). Frozen specimens a r e thawed and weighed i n the o r i g i n a l p l a s t i c c o n t a i n e r u s e d f o r c o l l e c t i o n . D e i o n i z e d water i s added (1 ml p e r 2 g f e c e s ) and the sample i s homogenized on a p a i n t shaker i n a s e a l e d p a i n t can. A 10-ml a l i q u o t i s ashed, d i s s o l v e d i n d i l u t e HN0 , and a n a l y z e d by EAAS. S o f t t i s s u e samples, such as b r a i n , l i v e r , o r muscle, must be homogenized b e f o r e p r o c e s s i n g , and t h i s can be a c c o m p l i s h e d e a s i l y by pummelling the t i s s u e i n a "Stomacher" b l e n d e r ( F i s h e r S c i e n t i f i c Company, P i t t s b u r g h , PA 15219). D e i o n i z e d w a t e r (5 ml) i s added t o the bag w i t h the t i s s u e . The s e a l e d bag i s p l a c e d i n the b l e n d e r and b l e n d e d f o r 5-15 min, w h i c h c o m p l e t e l y homogenizes the sample. The homogenate can t h e n be p r o c e s s e d f o r a n a l y s i s . Microwave d i g e s t i o n o f t i s s u e specimens i s a new technique w h i c h p r o v i d e s an e x c e l l e n t means o f p r e p a r i n g a sample f o r EAAS w i t h o u t r i s k i n g e x c e s s i v e c o n t a m i n a t i o n (14). We use a microwave d i g e s t i o n bomb ( P a r r Instrument Company, M o l i n e , I L 61265) w h i c h i s m o d i f i e d w i t h a t e f l o n l i n e r w i t h a s m a l l e r sample w e l l t h a n the s t a n d a r d l i n e r . A p p r o x i m a t e l y 50 mg (100 mg maximum) o f d r i e d t i s s u e p l u s 1 ml o f 50% n i t r i c a c i d a r e added t o the t e f l o n w e l l . The bomb i s s e a l e d and p l a c e d i n a s t a n d a r d microwave oven f o r a p p r o x i m a t e l y 1 m i n u t e . E l e v a t e d temperature and p r e s s u r e promote r a p i d d i g e s t i o n 3


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o f the t i s s u e , w h i l e the s e a l e d t e f l o n l i n e r e l i m i n a t e s e x t e r n a l c o n t a m i n a t i o n and l o s s due t o v o l a t i l i z a t i o n . Upon c o o l i n g the d i g e s t i s ready f o r EAAS a n a l y s i s .


Localization of Trace Elements i n Tissues There i s e x t e n s i v e l i t e r a t u r e on e l e m e n t a l m i c r o a n a l y s i s b u t f o r the purposes o f t h i s r e v i e w we p r e s e n t o n l y i n f o r m a t i o n on aluminum whose p r e s e n c e i n t i s s u e s , p a r t i c u l a r l y bone, i s d i a g n o s t i c o f aluminum t o x i c i t y . A h i s t o c h e m i c a l r e a c t i o n f o r the d e m o n s t r a t i o n o f aluminum i n t i s s u e s was d e v e l o p e d i n 1955 (15) u s i n g ammonium a u r i n t r i c a r b o x y l a t e (aluminon) which forms a l a k e w i t h a number o f m e t a l l i c i o n s ; aluminum produces a c h e r r y r e d c o l o r . T h i s t e c h n i q u e has been v a l i d a t e d by e l e c t r o n probe x - r a y m i c r o a n a l y s i s ( 1 6 ) . The s c a n n i n g e l e c t r o n microscope has been used t o d e t e c t aluminum d e p o s i t s by e n e r g y - d i s p e r s i v e x - r a y a n a l y s i s . Aluminum d e p o s i t s have been l o c a t e d w i t h i n the g l o m e r u l a r basement membrane (17). U s i n g t h i s same t e c h n i q u e , P e r l , e t a l . (18) examined b r a i n t i s s u e s from p a t i e n t s w i t h amyotrophic lateral sclerosis and parkinsonism-dementia, and l o c a t e d aluminum i n n e u r o f i b r i l l a r y t a n g l e - b e a r i n g hippocampal neurons. Other workers a l s o u s i n g t h i s t e c h n i q u e have l o c a l i z e d aluminum i n bone t i s s u e s (19,20). An a l t e r n a t i v e approach t o aluminum l o c a l i z a t i o n i n t i s s u e s i s to use the new t e c h n i q u e o f l a s e r microprobe mass s p e c t r o m e t r y (LAMMA). I n t h i s t e c h n i q u e an i n t e n s e l a s e r beam i s d i r e c t e d toward a s p e c i f i c o r g a n e l l e and m e t a l s l o c a l i z e d i n t h a t r e g i o n a r e a n a l y z e d i n a mass s p e c t r o m e t e r . T h i s t e c h n i q u e has been used t o l o c a l i z e aluminum i n the lysosomes o f h e p a t o c y t e s as w e l l as K u p f f e r c e l l s from l i v e r t i s s u e o f p a t i e n t s on c h r o n i c h e m o d i a l y s i s (21^22) . We r e c e n t l y have used LAMMA t o s t u d y the u l t r a s t r u c t u r a l l o c a l i z a t i o n o f aluminum i n l i v e r s o f aluminum m a l t o l - t r e a t e d r a b b i t s ( 2 3 ) . An even newer t e c h n i q u e i s t h a t o f e l e c t r o n energy l o s s s p e c t r o s c o p y (EELS) w h i c h p r o v i d e s e x c e p t i o n a l r e s o l u t i o n even though the o r i g i n a l promise o f e x c e l l e n t s e n s i t i v i t y has n o t m a t e r i a l i z e d . The p r i n c i p l e s o f the t e c h n i q u e are g i v e n i n two e x c e l l e n t r e v i e w s (24, 25) . We have a p p l i e d t h i s t e c h n i q u e t o the a n a l y s i s o f l i v e r from aluminum m a l t o l - t r e a t e d r a b b i t s ( 2 6 ) . A major problem w i t h m i c r o a n a l y s i s o f t i s s u e i s i n the p r o c e s s i n g o f the specimen. C o n v e n t i o n a l c h e m i c a l f i x a t i o n as developed f o r morphological s t u d i e s , i s not i d e a l f o r l o c a l i z i n g t r a c e elements. Movement o f m e t a l i o n s w i t h i n the c e l l must be a s e r i o u s c o n s i d e r a t i o n as t i s s u e s a r e l e f t f o r s e v e r a l days i n a f i x a t i v e . We p r e s e n t l y use r a p i d f r e e z i n g and f r e e z e s u b s t i t u t i o n as a means o f t i s s u e p r o c e s s i n g , b u t these t e c h n i q u e s a r e e x t r e m e l y difficult. A l t h o u g h b o t h the LAMMA and EELS r e q u i r e v e r y e x p e n s i v e s o p h i s t i c a t e d equipment, b o t h are e x t r e m e l y p o w e r f u l t e c h n i q u e s f o r s t u d y i n g m e t a l l o c a l i z a t i o n i n t i s s u e s . The s e n s i t i v i t y o f the LAMMA t e c h n i q u e appears t o be b e t t e r t h a n EELS b u t the r e s o l u t i o n o f the l a t t e r techniques i s b e t t e r . Our u n d e r s t a n d i n g o f the t o x i c i t y o f m e t a l s w i l l be a i d e d c o n s i d e r a b l y by the use o f such l o c a l i z a t i o n techniques.


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S t a n d a r d R e f e r e n c e M a t e r i a l s and Q u a l i t y A s s u r a n c e The a v a i l a b i l i t y o f s t a n d a r d r e f e r e n c e m a t e r i a l s i s o f c o n s i d e r a b l e importance i n t h e a p p l i c a t i o n o f r e l i a b l e a s s a y s f o r t r a c e a n d u l t r a t r a c e metals. The N a t i o n a l I n s t i t u t e o f Standards a n d Technology (NIST, Washington, DC 20234) p r o v i d e s aqueous s t a n d a r d s o l u t i o n s , w h i c h c o n t a i n 10 mg/mL o f a s t a n d a r d i n a c i d medium. I n a d d i t i o n , NIST o f f e r s o t h e r c e r t i f i e d r e f e r e n c e m a t e r i a l s f o r serum, u r i n e and o t h e r b i o l o g i c m a t r i c e s . These m a t e r i a l s are u s e f u l n o t o n l y i n e v a l u a t i n g a c c u r a c y b u t c a n a l s o be u s e d t o c a l i b r a t e instrumentation. The m a t e r i a l s are c e r t i f i e d f o r a c c u r a c y b a s e d on d e t e r m i n a t i o n s b y d e f i n i t i v e methods. Aqueous s t a n d a r d s a r e a l s o a v a i l a b l e from commercial s o u r c e s , one b e i n g F i s h e r Scientific Company. D i l u t i o n t o w o r k i n g s t a n d a r d s must i n c o r p o r a t e a n i n t e r m e d i a t e s t a n d a r d i f a c c u r a c y i s t o be m a i n t a i n e d . Quality assurance i n trace m e t a l measurements follows e s t a b l i s h e d p r i n c i p l e s used i n a l l a r e a s o f c l i n i c a l c h e m i s t r y . I n t e r n a l q u a l i t y c o n t r o l m a t e r i a l s , u s u a l l y serum from a human donor o r a n i m a l s o u r c e such as a cow o r s t e e r , a t two o r t h r e e d i f f e r e n t c o n c e n t r a t i o n s , s h o u l d be used on a d a i l y b a s i s . The c o n c e n t r a t i o n s i n these m a t e r i a l s should c o i n c i d e w i t h v a r i o u s d e c i s i o n l e v e l s . I n t e r l a b o r a t o r y c o n t r o l m a t e r i a l s a l s o are an i m p o r t a n t p a r t o f any q u a l i t y a s s u r a n c e scheme. P r e s e n t l y , such a program i s conducted by the Robens I n s t i t u t e ( U n i v e r s i t y o f S u r r e y , G u i l d f o r d , S u r r e y , GU2 5XY, U n i t e d Kingdom), f o r example. The i n s t i t u t e m a i l s samples monthly t o l a b o r a t o r i e s f o r s e l e c t e d t r a c e m e t a l a n a l y s e s . The d a t a and s t a t i s t i c a l i n f o r m a t i o n o f the 38 p a r t i c i p a t i n g l a b o r a t o r i e s are t h e n made a v a i l a b l e f o r r e v i e w . The c l i n i c a l chemist i n s p i r e d t o perform t r a c e element measurements must a p p r e c i a t e t h e s u b t l e t i e s needed t o p r o v i d e s a t i s f a c t o r y r e s u l t s . Not o n l y i s the i n s t r u m e n t a l method s e l e c t i o n , b u t a l s o specimen c o l l e c t i o n and p r o c e s s i n g o f samples are i m p o r t a n t . S t r i c t adherence t o b a s i c p r i n c i p l e s o f q u a n t i t a t i v e a n a l y s i s i s e s s e n t i a l i f the c l i n i c i a n and, o f c o u r s e , the p a t i e n t i s t o b e n e f i t from the e f f o r t s o f the l a b o r a t o r i a n .

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RECEIVED July

16, 1990


Biological Trace Element Research - American Chemical Society

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