Examples of Measuring Internal Dose for Assessing Exposure in

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Examples of Measuring Internal Dose for Assessing Exposure in Epidemiological Studies L a r r y L. Needham Division of Environmental Health Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, U.S. Department of Health and H u m a n Services, Atlanta, GA 30341-3724

Exposure to environmental contaminants occurs when the contaminant is present in the environment and humans have contact with that environment. Environmental

public health scientists, especially

epidemiologists, study the relationship between such exposure and any adverse health effects. The exposure is often assessed on the basis of measured concentrations of the contaminants in the environment and the estimated duration of human exposure. However,

frequently

these models are not predictive of the amount of toxicant absorbed in the human; thus, there is a need to measure the internal dose of these toxicants in humans. This measurement, along with pharmacokinetic information for the toxicant, is the best marker of exposure with which to relate adverse health effects. Several examples that illustrate the need for measuring the internal dose are presented.

E P I D E M I O L O G I S T S AND OTHER ENVIRONMENTAL p u b l i c h e a l t h scientists are i n t e r e s t e d i n the r e l a t i o n s h i p b e t w e e n e x p o s u r e assessment a n d a d v e r s e h e a l t h effects o r at least a b i o c h e m i c a l

c h a n g e that m a y b e a m a r k e r o f a

p o t e n t i a l adverse h e a l t h effect. T o s t u d y this r e l a t i o n s h i p , t h e y m a y

use

t h r e e basic types o f o b s e r v a t i o n a l a n a l y t i c a l investigations: the c a s e - c o n t r o l s t u d y ; the c o h o r t study, p r o s p e c t i v e a n d r e t r o s p e c t i v e ;

a n d the cross-sec-

t i o n a l study. I n a " c a s e - c o n t r o l s t u d y " , a case g r o u p that has the a d v e r s e h e a l t h effect a n d a c o n t r o l , or c o m p a r i s o n ,

g r o u p that does not h a v e the

effect are s e l e c t e d for i n v e s t i g a t i o n ; t h e p r o p o r t i o n s

w i t h the e x p o s u r e o f

i n t e r e s t i n each g r o u p are c o m p a r e d . T h u s , i n a c a s e - c o n t r o l study, t h e startThis chapter not subject to U.S. copyright Published 1994 American Chemical Society

Draper; Environmental Epidemiology Advances in Chemistry; American Chemical Society: Washington, DC, 1994.


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ENVIRONMENTAL EPIDEMIOLOGY

i n g p o i n t (the adverse h e a l t h effect that has o c c u r r e d p r i o r to the initiation of the study) is the adverse h e a l t h effect. E x p o s u r e s to several pollutants that m a y l e a d to t h e adverse effect can b e s t u d i e d . I n a " c o h o r t s t u d y " , however, participants are i d e n t i f i e d o n the basis o f t h e i r exposure status. I n a prospective cohort study, the adverse h e a l t h effect has not o c c u r r e d at the t i m e o f the initiation o f the study; i n a retrospective cohort study, the i n v e s tigation is i n i t i a t e d after t h e exposure a n d effect have o c c u r r e d . S e v e r a l health effects that m i g h t result f r o m exposure to the pollutant can b e s t u d i e d . F i n a l l y , i n the "cross-sectional s u r v e y " , the status o f an i n d i v i d u a l w i t h respect to the presence o r absence o f b o t h exposure a n d disease is assessed simultaneously. H o w e v e r , i n a l l of these studies, exposure a n d h e a l t h effects must b e assessed. I n e n v i r o n m e n t a l p u b l i c h e a l t h , t h e exposure is freq u e n t l y to ubiquitous e n v i r o n m e n t a l pollutants, i n c l u d i n g dioxins, p o l y c h l o r i n a t e d b i p h e n y l s , a n d volatile organic solvents. Therefore, because most a l l p e o p l e have b e e n i n contact w i t h these pollutants, exposure is not a q u a l i tative yes-qr-no d e c i s i o n ; ideally, i t is q u a n t i f i e d , b u t at least i t must b e "scientifically e s t i m a t e d . " W h a t is the best means o f d o i n g this? F i g u r e 1 illustrates the exposure a n d h e a l t h effects pathway (1,2), w h i c h w e have a m e n d e d (3). A s s h o w n i n F i g u r e 1, a pollutant originates f r o m a source a n d is e m i t t e d into the e n v i r o n m e n t , w h e r e it can u n d e r g o c h e m i c a l a n d p h y s i c a l interactions a n d w h e r e it m a y accumulate. H u m a n s are exposed w h e n , for an i n t e r v a l o f t i m e , they c o m e into contact w i t h that pollutant i n an e n v i r o n m e n t a l m e d i u m — s o i l , water, air, o r food. T h e concentration o f a g i v e n pollutant i n the e n v i r o n m e n t a l m e d i a w i t h w h i c h h u m a n s have c o n tact, integrated o v e r the t i m e o f contact, is c a l l e d the external dose (3) o r

1

Source emissions

|

Environmental media: air, water, food, soil

1

External dose: human contact with air, water, food, soil inhalation ingestion skin absorption

r

Internal dose

Biologically effective dose

Figure 1.

Health effect

Pathway of a contaminant from emission to resulting health effect.


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potential dose (2). W h e n h u m a n s have contact w i t h these e n v i r o n m e n t a l m e d i a , the pollutants enter the b o d y v i a i n h a l a t i o n , ingestion, or skin absorption. O n c e i n the body, a p o l l u t a n t m a y be d i s t r i b u t e d t h r o u g h o u t i t . T h e amount of contaminant absorbed i n b o d y tissue is c a l l e d the i n t e r n a l dose. C o m m o n measures of i n t e r n a l dose are the b l o o d a n d u r i n e levels of pollutants or t h e i r metabolites. A p o r t i o n of this i n t e r n a l dose may reach a n d interact w i t h a target site over a g i v e n p e r i o d so as to alter p h y s i o l o g i c a l function; this p o r t i o n is c a l l e d the biologically effective dose. T h u s , at least three measures or estimates of dose m a y be u s e d i n assessing h u m a n exposure. T h e s e are external dose, biologically effective dose, a n d i n t e r n a l dose. E a c h has c e r t a i n advantages a n d disadvantages.

External Dose Traditionally, e n v i r o n m e n t a l epidemiologists have assessed exposure b y est i m a t i n g the external dose, that is, the total concentration of a g i v e n toxicant i n the e n v i r o n m e n t a l m e d i a w i t h w h i c h h u m a n s c o m e into contact, i n t e grated over the t i m e of contact. T h e concentration of the p o l l u t a n t i n the e n v i r o n m e n t a l m e d i a is sometimes based o n analytical measurements of e n v i r o n m e n t a l samples—water, air, soil, a n d f o o d — c o l l e c t e d at the exposure site near the t i m e of exposure or as close to it as possible. Perhaps the " b e s t " e n v i r o n m e n t a l sample of an a i r b o r n e p o l l u t a n t w o u l d be an air sample c o l l e c t e d at the t i m e of exposure b y a p e r s o n a l air m o n i t o r located i n the b r e a t h i n g zone. C l e a r l y , this is n e v e r a c h i e v e d , except i n d e s i g n e d e x p e r i ments. T h e t i m e of contact w i t h the e n v i r o n m e n t a l m e d i a c o n t a i n i n g the pollutant is generally collected b y questionnaire a n d history. T h i s c o m b i n a t i o n of questionnaire and history a n d e n v i r o n m e n t a l measurements are t h e n w e i g h t e d into an exposure i n d e x , w h i c h is u s e d as an estimate of exposure for each person. E x p o s u r e indices have several p o t e n t i a l p r o b l e m s , p a r t i c u l a r l y bias of a d m i n i s t e r i n g a n d a n s w e r i n g the questionnaire. T h i s bias m a y arise w h e n ever noncomparable information is o b t a i n e d from the different study groups. T h i s may result from the i n t e r v i e w e r e l i c i t i n g or i n t e r p r e t i n g the i n f o r m a t i o n i n different ways (interviewer bias); it m a y also result f r o m the p a r t i c i pants i n t e n t i o n a l l y or u n i n t e n t i o n a l l y r e p o r t i n g the events i n n o n c o m p a r a b l e manners (recall bias), for example, h a v i n g p r o b l e m s r e c a l l i n g the frequency of w a l k i n g o n c o n t a m i n a t e d soil o r c o n s u m p t i o n of a c e r t a i n food. A n o t h e r source of e r r o r is the inability to adjust for i n d i v i d u a l factors r e l a t e d to h o w m u c h toxicant enters the b o d y a n d h o w m u c h is absorbed ( i n d i v i d u a l m e t a b o l i s m differences, i n d i v i d u a l n u t r i t i o n a l status d u r i n g exposure, a n d personal habits s u c h as h a n d - t o - m o u t h activities). A l t h o u g h generally fewer p r o b l e m s are associated w i t h the quantitative measurements i n the e n v i r o n m e n t a l m e d i a , these measurements m a y not b e representative of the d e g r e e of contamination at the t i m e the h u m a n exposure o c c u r r e d ; for example, the


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average l e v e l of a pollutant i n fish caught i n a r i v e r may not b e representative of all such fish i n that river. T h u s , w e b e l i e v e that estimates of the e x t e r n a l dose are not the best means of assessing exposure.


Biologically Effective Dose B y d e f i n i t i o n , the best measure of exposure for assessing d o s e - r e s p o n s e r e lationships is the " b i o l o g i c a l l y effective dose". Ideally, e n v i r o n m e n t a l h e a l t h scientists w o u l d l i k e to have sensitive a n d specific measurements of the b i o logically effective dose. H o w e v e r , i d e n t i f y i n g the target site of the toxicant is a major i m p e d i m e n t to u s i n g measures of the biologically effective dose to quantify exposure, a n d e v e n w h e n the target site is k n o w n , a h i g h l y i n vasive p r o c e d u r e may be r e q u i r e d to sample that site (e.g., l i v e r or brain). S o m e organic toxicants, or t h e i r metabolites, covalently b o n d to D N A , thus f o r m i n g a D N A adduct. If this adduct is at a site that leads to an a l t e r e d r e a d i n g of the genetic code, it m a y lead to m u t a g e n i c i t y a n d cancer i n h u mans. H o w e v e r , other adducts that lead to no such alteration may f o r m . Because w e cannot analytically d i s t i n g u i s h b e t w e e n these adducts, the a n a l yses of h u m a n samples, such as c i r c u l a t i n g l y m p h o c y t e s , for a l l such adducts are generally c o n s i d e r e d measurements of the biologically effective dose. L i k e w i s e , measurements of adducts w i t h h e m o g l o b i n a n d p r o t e i n s , such as a l b u m i n , have also b e e n c o n s i d e r e d measurements of the biologically effective dose (4). S o m e of these adducts are specific markers for toxicants (e.g., benzo(a)pyrene i n lymphocytes), whereas others are m u c h less specific (e.g., D N A adducts w i t h a l k y l groups). T h e m e a s u r e m e n t of adducts i n h u m a n s is still i n the e x p e r i m e n t a l d e v e l o p m e n t stage, a n d m u c h m o r e i n f o r m a t i o n is n e e d e d before it can b e u s e d as a quantitative m e a s u r e m e n t of exposure, although it can be u s e d as a m a r k e r of exposure. O t h e r disadvantages of these measurements are that sample t h r o u g h p u t is somewhat p r o b l e m a t i c for moderate-size epidemiological studies, and very sensitive analytical m e t h ods are r e q u i r e d .

Internal Dose T h e next most useful exposure measures are those of i n t e r n a l dose. T h e direct m e a s u r e m e n t of a toxicant or one of its metabolites i n b l o o d or u r i n e has significantly i m p r o v e d h u m a n exposure assessment a n d has thus i m p r o v e d h u m a n risk assessment for a n u m b e r of i m p o r t a n t toxicants. F o r exa m p l e , w i t h o u t b l o o d lead measurements, most of the c e n t r a l nervous syst e m effects of l o w - l e v e l lead exposure c o u l d not have b e e n detected. To i n t e r p r e t b l o o d or u r i n e toxicant levels accurately, analysts m u s t k n o w the pharmacokinetics of the toxicant a n d also m u s t k n o w the backg r o u n d levels f o u n d i n the general p o p u l a t i o n . F o r example, some toxicants, such as the volatile organic c o m p o u n d s , are r a p i d l y e l i m i n a t e d , whereas o t h ers, such as the c h l o r i n a t e d h y d r o c a r b o n pesticides, may have a half-life i n


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h u m a n s of m o r e than 5 years. T h u s , this i n f o r m a t i o n is c r i t i c a l for i n t e r p r e t i n g w h e t h e r the m e a s u r e d concentration reflects recent exposures or l o n g t e r m (chronic) exposures, o r b o t h . It is still essential that t h e e p i d e m i o l o g i s t collect, to t h e extent possible, nonbiased questionnaire a n d h i s t o r y data o n the p o t e n t i a l exposure. I f the c o m p o u n d can b e detected i n b l o o d o r its components, w e prefer these matrices because (1) t h e concentration o f the toxicant i n t h e u r i n e c a n vary greatly throughout t h e day; (2) t h e l e v e l i n t h e b l o o d m o r e l i k e l y r e flects the concentration available to the target site; a n d (3) a l t h o u g h t h e p a r ent c o m p o u n d is n o r m a l l y m e a s u r e d i n b l o o d , the metabolite is usually m e a s u r e d i n u r i n e , a n d that metabolite may not b e specific for o n l y one toxicant. A potential disadvantage for t h e m e a s u r e m e n t o f the i n t e r n a l dose i n b l o o d is that the concentration o f l i p o p h i l i c c o m p o u n d s i n a n i n d i v i d u a l can v a r y throughout t h e day, d e p e n d i n g o n t h e v a r i a b i l i t y i n t h e l i p i d content o f the s e r u m . H o w e v e r , expressing the concentration o f the toxicant o n a l i p i d w e i g h t basis, instead o f a w h o l e - w e i g h t basis, has p r o v e d to b e a n adequate adjustment (5). I n occupational studies, o n t h e other h a n d , u r i n e is the p r e f e r r e d b i o logical matrix, p r i m a r i l y because it can b e p r o c u r e d noninvasively. Its major advantage is t h e ease i n o b t a i n i n g t h e sample c o m p a r e d w i t h t h e difficulty of v e n i p u n c t u r e for o b t a i n i n g a s e r u m sample. T h e A m e r i c a n C o n f e r e n c e o f G o v e r n m e n t a l I n d u s t r i a l H y g i e n i s t s (6) p u b l i s h e s b i o l o g i c a l exposure i n dices ( B E I s ) for use i n assessing occupational exposure to selected chemicals. T h e B E I is a reference value that indicates t y p i c a l concentrations o f selected chemicals o r t h e i r metabolites, p r i m a r i l y i n u r i n e b u t also i n b l o o d o r exh a l e d air, for healthy workers w h o have b e e n exposed p r i m a r i l y b y i n h a l a t i o n to t h e selected c h e m i c a l at its t h r e s h o l d l i m i t values. It is generally b e l i e v e d that there is p o o r correlation b e t w e e n t h e levels o f contaminants i n t h e b l o o d a n d u r i n e ; however, w e f o u n d a h i g h c o r r e l a t i o n o f the levels of p e n t a c h l o r o p h e n o l i n these t w o matrices after the u r i n e was c o r r e c t e d for creatinine (7). W e r e c o g n i z e d the c r i t i c a l n e e d for sensitive a n d specific measurements of i n t e r n a l dose i n o r d e r to i m p r o v e h u m a n exposure assessment. O u r l a b oratory is c o m m i t t e d to d e v e l o p i n g such measurements a n d to a p p l y i n g t h e m to e p i d e m i o l o g i c a l studies, w h i c h s h o u l d substantially i m p r o v e h u m a n risk assessment. W e have d e v e l o p e d a n d a p p l i e d methods o f m e a s u r i n g t h e i n t e r n a l dose o f p o l y c h l o r i n a t e d a n d p o l y b r o m i n a t e d b i p h e n y l s i n s e r u m (8) as part o f the M i c h i g a n P o l y c h l o r i n a t e d B i p h e n y l - P o l y b r o m i n a t e d B i p h e n y l S t u d y (9); p e n t a c h l o r o p h e n o l (10) i n t h e u r i n e a n d s e r u m o f residents o f l o g houses (7); l o w - m o l e c u l a r - w e i g h t diols i n s e r u m (11) o f alcoholics (12); p h e n o l a n d cresols i n the u r i n e o f w o r k e r s (13); d i o x i n i n t h e adipose tissue (14) o f residents o f M i s s o u r i (15-18); d i o x i n i n t h e s e r u m (19) o f residents o f Seveso, Italy (20); p h e n o x y a c i d h e r b i c i d e s a n d c h l o r i n a t e d phenols i n u r i n e (21) o f residents l i v i n g near a S u p e r f u n d site (22); a n d the volatile organic



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c o m p o u n d s i n the b l o o d of U . S . residents (23). W e give o t h e r examples of internal-dose measurements f u r t h e r o n . S o m e t i m e s i n an e p i d e m i o l o g i c a l study, a n exposure i n d e x based o n measurements i n e n v i r o n m e n t a l m e d i a a n d o n questionnaire a n d h i s t o r y information is a l l that is practicable a n d m u s t be used. W h e n e v e r possible, this index should be c o m p a r e d w i t h measures of i n t e r n a l dose o n at least a subset of the exposed p o p u l a t i o n to validate the exposure i n d e x a n d to c a l i brate the levels of exposure b e i n g e x a m i n e d . T h i s was effectively d o n e i n s t u d y i n g w o r k e r exposure to d i o x i n (24). H o w e v e r , m e a s u r e m e n t of the i n t e r n a l dose is not the panacea for assessing exposure. A s p o i n t e d out b y H u l k a a n d M a r g o l i n (25), variability w i t h i n the laboratory a n d also b i o l o g i c a l variability, b o t h intraperson a n d i n t e r p e r s o n , can l e a d to errors i n the assessment of exposure. T h e laboratory p e r s o n n e l a n d epidemiologists m u s t attempt to m i n i m i z e these errors b y u s i n g , for example, p r o p e r s a m p l i n g design a n d quality assurance procedures. I n this chapter w e present examples of o u r experiences i n case-control a n d cohort e p i d e m i o l o g i c a l studies i n w h i c h w e c o u l d c o m p a r e m e a s u r e ments of i n t e r n a l dose w i t h exposure indices. T h e situations range f r o m occupational exposure to exposure a m o n g residents l i v i n g near hazardous waste sites.

Examples Operation Ranch H a n d Study. F r o m 1962 to 1970, d u r i n g the V i e t n a m conflict, the m a i n m i s s i o n of the U . S . A i r F o r c e s O p e r a t i o n R a n c h H a n d was to spray defoliants, such as A g e n t O r a n g e , o v e r densely vegetated areas of S o u t h V i e t n a m . A g e n t O r a n g e consisted of an e q u a l m i x t u r e of (2,4dichlorophenoxy)acetic a c i d (2,4,-D) a n d (2,4,5-trichlorophenoxy)acetic a c i d (2,4,5-T) i n d i e s e l o i l ; the 2 , 4 , 5 - T was c o n t a m i n a t e d w i t h 2,3,7,8-tetrachlorodibenzo[fc,e][l,4] d i o x i n ( 2 , 3 , 7 , 8 - T C D D [dioxin]) i n the p a r t s - p e r - m i l l i o n range. D i o x i n is l i p i d - s o l u b l e a n d thus tends to store i n the l i p i d - r i c h depots of the h u m a n b o d y ; it has a l o n g half-life of m o r e than 7 years i n h u m a n s (26). T h e r e f o r e , q u i t e a b i t is k n o w n about its p h a r m a c o k i n e t i c s i n h u m a n s . I n 1982, the A i r F o r c e d e s i g n e d a prospective cohort study, specifically to study h e a l t h outcomes that may be associated w i t h exposure to A g e n t O r ange a n d other h e r b i c i d e s c o n t a i n i n g d i o x i n . T h e s e h e a l t h studies w i l l be p e r f o r m e d o n the veterans of O p e r a t i o n R a n c h H a n d e v e r y 5 years t h r o u g h the year 2002. O n e of the first tasks was to d e v e l o p an exposure i n d e x , w h i c h is the concentration of the contaminant m u l t i p l i e d b y the t i m e of contact, to be the basis of assessing h u m a n exposure. T h i s exposure situation was similar to that of an occupational setting i n that the p r i m a r y exposure was thought to be d i r e c t exposure to the h e r b i c i d e itself, rather than i n d i r e c t exposure t h r o u g h a n e n v i r o n m e n t a l pathway. T h e A i r F o r c e k n e w the average concentration of d i o x i n i n the A g e n t O r a n g e


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d u r i n g various periods. T h e d u r a t i o n a n d frequency o f p o t e n t i a l exposure for the m e n i n different m i l i t a r y occupational groups w i t h i n t h e operation w e r e estimated o n the basis o f m i l i t a r y records. T h e n u m b e r o f m e n i n t h e study was l i m i t e d to t h e 1200-1300 survivors o f the operation. T h e U . S . A i r F o r c e a n d various r e v i e w boards b e l i e v e d n o t o n l y that this exposure i n d e x c o u l d serve as a reliable basis for assessing exposure to d i o x i n , b u t that any n o t e d adverse h e a l t h effects c o u l d b e r e l a t e d to this index. I n 1987, t h e U . S . A i r F o r c e contracted w i t h o u r laboratory to analyze 150 s e r u m samples from O p e r a t i o n R a n c h H a n d veterans i n o r d e r to c o m pare the A i r F o r c e s exposure i n d e x w i t h t h e m e a s u r e d i n t e r n a l dose o f the veterans. T h e r e was essentially n o correlation b e t w e e n t h e exposure i n d e x a n d t h e s e r u m d i o x i n l e v e l . T h e r e f o r e , t h e A i r F o r c e t h e n contracted w i t h the C e n t e r s for Disease C o n t r o l a n d P r e v e n t i o n ( C D C ) to analyze t h e s e r u m of all s u r v i v i n g m e m b e r s o f O p e r a t i o n R a n c h H a n d . T h i s lack o f c o r r e l a t i o n b e t w e e n t h e i n t e r n a l dose a n d t h e A i r F o r c e s exposure i n d e x c o n t i n u e d throughout t h e study (27). T h e r e m a y b e several reasons for this lack o f correlation; these i n c l u d e the A i r F o r c e not k n o w i n g w h i c h bases i n V i e t n a m h o u s e d t h e A g e n t O r a n g e d u r i n g a g i v e n t i m e p e r i o d a n d i n d i v i d u a l differences i n j o b performance a n d other exposure activities, s u c h as u s i n g A g e n t O r a n g e as a degreaser for o i l o n t h e body. T h e A i r F o r c e s u b s e q u e n t l y changed the basis o f its exposure assessment to t h e s e r u m d i o x i n m e a s u r e m e n t , a measure o f i n t e r n a l dose. H a d t h e A i r F o r c e u s e d its o r i g i n a l exposure i n d e x for the O p e r a t i o n R a n c h H a n d study, a n y conclusions about h e a l t h effects w o u l d have b e e n i n v a l i d .

U . S . Army Ground Troops in Vietnam. T h e contaminant o f c o n c e r n was d i o x i n i n A g e n t O r a n g e ; t h e p o t e n t i a l e n v i r o n m e n t a l pathways w e r e skin contact w i t h a n d i n h a l a t i o n o f the spray c o n t a i n i n g t h e h e r b i c i d e , s k i n contact w i t h sprayed vegetation a n d soil, a n d ingestion o f water a n d food that h a d b e e n sprayed. T h e amount o f d i o x i n i n the A g e n t O r a n g e f r o m 1966 to 1969 was k n o w n . T h e d u r a t i o n o f contact was gathered f r o m q u e s tionnaires g i v e n to t h e veterans a n d f r o m U . S . m i l i t a r y records o f the locations o f m i l i t a r y u n i t s , areas w h e r e h e r b i c i d e was s p r a y e d , a n d t h e dates w h e n h e r b i c i d e was sprayed. Six exposure indices w e r e generated f r o m this i n f o r m a t i o n ; four o f the indices w e r e based o n a s o l d i e r s p o t e n t i a l for exposure from d i r e c t spray o r o n h i s b e i n g i n a n area that h a d b e e n s p r a y e d w i t h i n t h e previous 6 days; the other t w o exposure indices u s e d self-reported data a n d i n c l u d e d a n i n dex based o n the v e t e r a n s p e r c e p t i o n o f h o w m u c h h e was exposed. T o test the v a l i d i t y o f these exposure i n d i c e s , w e m e a s u r e d b l o o d d i o x i n levels i n a sample o f e n l i s t e d g r o u n d troop veterans w h o h a d s e r v e d i n I I I C o r p s for an average o f 300 days d u r i n g 1966-1969. F o r c o m p a r i s o n , d i o x i n i n a sample of n o n - V i e t n a m U . S . A r m y veterans w h o s e r v e d d u r i n g t h e same t i m e was also m e a s u r e d (28).


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T h e results s h o w e d no m e a n i n g f u l association b e t w e e n d i o x i n levels a n d any of the exposure indices. T h e m e a n , m e d i a n , a n d frequency d i s t r i b u t i o n s for b o t h the V i e t n a m a n d n o n - V i e t n a m veterans w e r e r e m a r k a b l y similar, i n d i c a t i n g little, i f any, increased exposure to d i o x i n i n this p o p u l a t i o n (Table I). T h i s example illustrates the value of measurements of i n t e r n a l dose i n exposure assessment. It also shows the n e e d to d e v e l o p specific a n d sensitive methods: I f the detection l i m i t for d i o x i n h a d b e e n 20 p p t (lipid-adjusted), almost a l l the results w o u l d have b e e n " n o n d e t e c t . " F u r t h e r m o r e , because elevated exposures c o u l d not b e d o c u m e n t e d , plans for a prospective cohort h e a l t h study w e r e d r o p p e d .

Seveso, I t a l y . M o r e than 15 years have passed since the release of d i o x i n - e o n t a i n i n g materials f r o m the Icmesa c h e m i c a l plant near Seveso, I t aly. T h i s i n c i d e n t has r e c e i v e d perhaps m o r e p u b l i c attention a n d study t h a n any other r e s i d e n t i a l exposure to a synthetic e n v i r o n m e n t a l toxicant; yet no deaths have b e e n d i r e c t l y a t t r i b u t e d to it. I n fact, i n its last m e e t i n g of F e b ruary 1 9 - 2 1 , 1984, the I n t e r n a t i o n a l S t e e r i n g C o m m i t t e e of experts n o t e d that chloracne was the o n l y c l i n i c a l alteration to have a positive association w i t h soil levels of d i o x i n . T h e c o m m i t t e e also r e p o r t e d that no c o n c l u s i o n was yet possible about its association w i t h cancer, the study of w h i c h is still ongoing. F o l l o w i n g the 1976 to 1985 m e d i c a l examinations of the Seveso p e o p l e a n d a nearby c o m p a r i s o n g r o u p , s m a l l amounts of u n u s e d s e r u m w e r e frozen. I n 1988, w e met Italian officials a n d o u t l i n e d a protocol a i m e d at first d e t e r m i n i n g w h e t h e r w e c o u l d measure d i o x i n i n the s m a l l a m o u n t of r e s e r v e d s e r u m available f r o m the most exposed p o p u l a t i o n (based o n residential soil levels of dioxin); i f so, c o u l d w e d e t e r m i n e w h e t h e r t h e r e is a difference b e t w e e n the d i o x i n levels i n those w h o h a d d e v e l o p e d chloracne (10 people) a n d those w h o h a d not (10 people). M a n y factors w e r e s i m i l a r for the two groups (e.g., g e n d e r a n d d i o x i n soil levels), whereas other factors favored h i g h e r exposure of the nonchloracne group (e.g., greater t e n d e n c y to eat local p r o d u c e a n d p o u l t r y , average n u m b e r of days r e s i d i n g i n the most exposed zone f o l l o w i n g the explosion, a n d average l e n g t h of t i m e f r o m explosion to the b l o o d draw); these characteristics are s u m m a r i z e d i n T a b l e II. T h e other p r i m a r y difference is age at the t i m e of the explosion; for c h l o r acne cases, the range was 2 - 1 6 years w i t h a m e a n of 7.2 years, a n d for c o m parisons it was 15-71 years w i t h a m e a n of 42.6 years. I n d i v i d u a l s w h o h a d the highest l i p i d - a d j u s t e d s e r u m T C D D levels t e n d e d to d e v e l o p chloracne. H o w e v e r , there was no clear s e r u m T C D D l e v e l above w h i c h chloracne was p r o d u c e d a n d b e l o w w h i c h chloracne d i d not occur (20); such a result w o u l d have b e e n s u r p r i s i n g . T h e p o i n t is that there was no " m a g i c " l e v e l that p r o d u c e d chloracne. T h e best quantitative m a r k e r for exposure is not chloracne or r e s i d e n t i a l T C D D soil levels b u t rather the i n t e r n a l dose.


10.

NEEDHAM

Table I.

129


Distribution (1987) of 2,3,7,8-Tetrachlorodibenzo-p-dioxin i n Serum Lipids (PPT) of 743 Vietnam-Era Veterans Percentile

Place of Service

Non-Vietnam (n = 97) Vietnam (n = 646)


Measuring

Median

Mean ± SD

25th

50th

75th

90th

95th

3.8

4.1 ± 2.3

3.8

3.8

4.9

7.2

9.2

3.8

4.2 ± 2.6

2.8

3.8

5.1

6.8

7.8

Residents Living near Toxic Waste Sites. W o r k practices that i n v o l v e d electric transformers w i t h p o l y c h l o r i n a t e d b i p h e n y l ( P C B ) - c o n t a i n i n g d i e l e c t r i c f l u i d at a r e p a i r a n d maintenance facility i n P a o l i , P e n n s y l v a n i a , resulted i n extensive, h i g h - l e v e l P C B c o n t a m i n a t i o n o f soil a n d surfaces— u p to 420,000 p p m i n the w o r k area a n d 36,000 p p m i n soil. S o i l c o n t a m i nation i n nearby r e s i d e n t i a l neighborhoods r a n g e d f r o m less than 1 p p m to m o r e than 6400 p p m ; t h e n o r m a l l e v e l o f P C B s i n U . S . soil is less than 1 p p b . L o c a l creeks a n d trout i n those creeks also c o n t a i n e d elevated levels o f P C B s . I n this example, t h e frequency a n d d u r a t i o n o f contact w i t h t h e c o n taminant w e r e not estimated for each p e r s o n o r for groups. Rather, 6 2 p e r sons o l d e r than 3 years o f age, from neighborhoods adjacent to o r i m m e d i ately d o w n a gradient f r o m t h e r e p a i r facility w e r e selected b y u s i n g a p r o b a b i l i t y s a m p l i n g to represent t h e e n t i r e p o p u l a t i o n o f t h e n e i g h b o r hoods (396 persons). A second preselected group o f 85 was chosen f r o m persons w h o l i v e d i n homes w i t h yards that h a d at least o n e soil P C B m e a s u r e m e n t greater than 150 p p m . W e m e a s u r e d the P C B s i n t h e s e r u m (29) o f these 85 persons. I n the p r o b a b i l i t y s a m p l i n g group, the s e r u m P C B levels ranged f r o m less than 1 p p b to 23.7 p p b w i t h a geometric m e a n o f 4.3 p p b a n d an a r i t h m e t i c m e a n of 5.8 p p b . T h e geometric m e a n a n d a r i t h m e t i c m e a n o f the 2 3 s e r u m P C B concentrations i n the preselected group w e r e 5.9 p p b a n d 10.4 p p b , respect i v e l y — h i g h e r than t h e p r o b a b i l i t y s a m p l i n g g r o u p — b u t t h e geometric means w e r e not statistically significantly different. I f the o n e o u t l i e r value of 76.9 p p b is d i s c a r d e d , the geometric a n d a r i t h m e t i c means are 5.3 p p b Table II.

Characteristics (Mean ± SD) of Selected Seveso A Zone Residents Dioxin Soil Levels

Days in A Zone after Explosion

Group

N

Chloracne Nonchloracne

10 7.2 ± 4.2 10 ± 7.0 1071 ± 338 9 42.2 ± 16.1 1171 ± 26 16.1 ± 0.4

NOTES:

Age (Years)

f(xg/m2j

# Who Ate Local ProducePoultry

Dioxin Serum Levels—Lipid Adjusted (ppt)

6 9

19,144 ± 16,241 5240 ± 2946

SD is standard deviation; ppt is parts per trillion


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a n d 7.4 p p b , respectively. T h i s value was d i s c a r d e d because the person w i t h this value h a d b e e n occupationally exposed; P C B values for other m e m b e r s of his f a m i l y w e r e b e t w e e n 5 a n d 9 p p b , a n d the next highest P C B l e v e l found was less than half of this l e v e l . T h e authors c o n c l u d e d that the p o p u l a t i o n near the w o r k site i n P a o l i h a d exposure similar to that of populations w i t h t y p i c a l b a c k g r o u n d exposure elsewhere i n the U n i t e d States. M u l t i p l e l i n e a r regression analysis, c o n t r o l l e d for age, sex, years of residence near site, a n d other factors, found age to be the o n l y variable significantly associated w i t h s e r u m concentrations of P C B s (30), w h i c h , like d i o x i n , are l i p o p h i l i c a n d have l o n g biological halflives (31). O n e u n u s u a l f i n d i n g i n this study was that gas chromatographic peaks consistent w i t h a rarely u s e d A r o c l o r ( A R 1268) w e r e f o u n d i n three persons a n d i n 9 of 16 dogs (32). H o w e v e r , e n v i r o n m e n t a l testing d i d not reveal the presence of A R 1268. These P C B findings are similar to other site-specific investigations that we have c o n d u c t e d a r o u n d toxic waste sites. I n 1988, S t e h r - G r e e n et a l . (33) r e p o r t e d that i n 10 of 12 pilot exposure-assessment studies, w e f o u n d no excess p r o p o r t i o n of o v e r t l y exposed persons, i n spite of h i g h P C B levels i n soil or leachate o n the sites. T h e two sites w h e r e an elevated p r o p o r t i o n of exposed persons was f o u n d w e r e i n N e w p o r t C o u n t y ( N e w Bedford), M a s sachusetts, a n d M o n r o e C o u n t y (Bloomington), Indiana. A follow-up study of the p o p u l a t i o n a r o u n d B l o o m i n g t o n , I n d i a n a , has b e e n c o m p l e t e d , a n d the report is i n draft f o r m . T h e G r e a t e r N e w B e d f o r d S t u d y (34) was c o n d u c t e d from 1984 to 1987 to assess the prevalence of elevated levels of P C B s i n the s e r u m of persons aged 18 to 64 years w h o h a d r e s i d e d i n the area for at least 5 years. Because of d o c u m e n t e d e n v i r o n m e n t a l c o n t a m i n a t i o n b y P C B s i n the N e w B e d f o r d area, the practice of recreational fishing i n the harbor for food, a n d the findings f r o m a p i l o t study (35), researchers exp e c t e d to f i n d a significant n u m b e r of persons w i t h elevated P C B levels. Instead, they found that the P C B levels a m o n g the 840 participants w e r e similar to those found a m o n g persons i n other u r b a n U . S . populations; the geometric means of the samples w e r e 4.3 p p b a m o n g males a n d 4.2 p p b a m o n g females. H o w e v e r , persons w h o ate locally caught seafood f r o m i n n e r N e w B e d f o r d H a r b o r t e n d e d to have h i g h e r concentrations of s e r u m P C B s , although t h e i r m e a n value was less than 20 p p b , w h i c h is the u p p e r 9 5 % l e v e l of s e r u m P C B s i n the U n i t e d States (32). W e also collaborated i n an exposure assessment a n d h e a l t h effect study of p e o p l e l i v i n g near the H o l l y w o o d D u m p Site, i n M e m p h i s , Tennessee; this toxic waste site contains c h l o r i n a t e d h y d r o c a r b o n pesticides. T h e results of the analyses (36) of the s e r u m of 370 persons a n d the adipose tissue of 297 of t h e m revealed that persons l i v i n g a r o u n d the d u m p site h a d not b e e n overtly exposed to these c h l o r i n a t e d pesticides (37). I n each of these studies, i n t e r n a l dose measurements substantially clarified exposure assessment a n d thus h e l p e d guide the risk management policy.


10.

NEEDHAM


131

1,1, l-Trichloro-2 2-bis(p-chlorophenyl)ethane (DDT) i n Triana, Alabama. I n D e c e m b e r 1978, p u b l i c i t y c o n c e r n i n g h i g h D D T residues


5

i n fish caught i n I n d i a n C r e e k , d o w n s t r e a m f r o m a defunct D D T manufact u r i n g plant near Triana, A l a b a m a , raised the q u e s t i o n o f increased exposure for the large n u m b e r o f p e o p l e w h o ate locally caught fish. W e a n a l y z e d t h e e d i b l e portions o f several fish a n d t h e s e r u m o f 12 local residents, w h o ate several meals o f fish weekly, for D D T a n d its metabolites, l , l - d i c h l o r o - 2 , 2-bis(p-chlorophenyl)ethene ( D D E ) a n d l,l-dichloro-2,2-bis(p-chlorophenyl) ethane ( D D D ) . T h e average concentration o f total D D T (i.e., D D T + D D E + D D D ) i n t h e fish was 226 p p m — t h e F o o d a n d D r u g A d m i n i s t r a t i o n s action l e v e l is 5 p p m ; t h e 12 residents also h a d e x t r e m e l y h i g h levels of these c o m p o u n d s , i n c l u d i n g the highest l e v e l e v e r r e p o r t e d i n an i n d i v i d ual. Subsequently, a c o m m u n i t y - w i d e study was c o n d u c t e d (38). T h e 518 persons w h o r e g i s t e r e d for the study s e e m e d i d e a l to m o d e l for exposure to D D T , because t h e p r i m a r y e n v i r o n m e n t a l m e d i u m (food) a n d the approximate concentration o f the p o l l u t a n t i n that m e d i u m w e r e k n o w n , the p r i m a r y route o f e n t r y (ingestion) was k n o w n , a n d t h e n u m b e r o f meals eaten p e r w e e k o f locally caught fish c o u l d b e l e a r n e d f r o m questionnaires. T h e r e f o r e , this situation offered a good o p p o r t u n i t y to d e v e l o p a n exposure i n d e x i n a n e n v i r o n m e n t a l setting. W e m e a s u r e d D D T a n d its metabolites i n 499 persons o f a w i d e range of ages. T h e s e r u m levels r a n g e d from 0.6 to 2821 p p b w i t h a g e o m e t r i c m e a n o f 76.2 p p b , w h i c h is greater t h a n five times the g e o m e t r i c m e a n f o u n d in the U . S . population i n T h e Second National H e a l t h and Nutrition E x a m i n a t i o n S u r v e y ( N H A N E S II) (37). F o r t h e T r i a n a study, t h e exposure index o f concentration o f the p o l l u t a n t i n t h e e n v i r o n m e n t a l m e d i u m (fish) a n d t h e a m o u n t o f fish eaten p e r w e e k w e r e significantly r e l a t e d to i n t e r n a l dose; however, age was a n e v e n b e t t e r predictor. T h e s e findings e m p h a s i z e that for exposure to D D T a n d other l i p o p h i l i c toxicants, age must b e c o n s i d e r e d i n t h e i n t e r p r e t a t i o n o f measures o f i n t e r n a l dose. I n fact, P C B s w e r e subsequently m e a s u r e d (39) i n this p o p u l a t i o n , a n d age was f o u n d to b e t h e best p r e d i c t o r ( r = 0.56) o f the l o g P C B l e v e l (40). T h e Triana study d e m onstrated h o w measures o f i n t e r n a l dose c a n h e l p identify (1) p r e d i c t o r s o f exposure a n d (2) c o n f o u n d i n g factors that r e q u i r e adjustment i n exposure assessment.

Occupational Dioxin Study. T h e N a t i o n a l Institute for O c c u p a tional Safety a n d H e a l t h ( N I O S H ) o f t h e C D C c o n d u c t e d a retrospective cohort study o f 5172 w o r k e r s at 12 plants i n the U n i t e d States that p r o d u c e d chemicals c o n t a m i n a t e d w i t h 2 , 3 , 7 , 8 - T C D D (24). T h e exposure i n d e x was based o n t h e d u r a t i o n o f exposure that was calculated f r o m a careful a n d d e t a i l e d r e v i e w o f each worker's occupational records. W e t h e n m e a s u r e d (19) the s e r u m T C D D levels o f 253 o f these w o r k e r s a n d a c o m p a r i s o n group. T h e s e r u m d i o x i n levels w e r e significantly r e l a t e d to t h e exposure


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index (Pearson correlation coefficient of 0.72, p < .0001). O n t h e basis o f this correlation, t h e N I O S H exposure i n d e x c a n b e u s e d to assess a n y a d verse h e a l t h effects o b s e r v e d i n its p o p u l a t i o n . H o w e v e r , e v e n i n this study, the exposure i n d e x cannot b e u s e d to r e l i a b l y p r e d i c t t h e s e r u m l e v e l o f a given individual.


Conclusions W e have p r e s e n t e d six exposure situations. I n four o f these ( O p e r a t i o n R a n c h H a n d , Seveso, Triana, a n d t h e N I O S H O c c u p a t i o n a l D i o x i n Study), w e f o u n d h i g h l y exposed populations; i n t w o studies (the U . S . A r m y g r o u n d troops i n V i e t n a m a n d residents l i v i n g near hazardous waste sites), w e d i d not. T h e N I O S H S t u d y represents an occupational setting i n w h i c h the p o p ulation is d i r e c t l y exposed to t h e source o r t h e o r i g i n o f the pollutant. T h e O p e r a t i o n R a n c h H a n d study is somewhat s i m i l a r i n that m a n y o f the m e n s m i l i t a r y occupations caused t h e m to h a n d l e t h e h e r b i c i d e daily. I n t h e N I O S H study, t h e exposure i n d e x p r e d i c t e d t h e i n t e r n a l dose for t h e p o p ulation; i n t h e O p e r a t i o n R a n c h H a n d study, it d i d not. T h r e e other situations are m o r e representative o f c h r o n i c e n v i r o n m e n t a l exposure. I n Triana, the p r i m a r y route o f the D D T s e n t r y was ingestion o f h i g h l y c o n t a m i n a t e d fish, whereas i n the other two studies ( U . S . A r m y g r o u n d troops i n V i e t n a m a n d residents l i v i n g near toxic sites), t h e pollutants' routes o f e n t r y c o u l d have b e e n ingestion, i n h a l a t i o n , o r skin contact, o r a c o m b i n a t i o n o f these routes, a n d the e n v i r o n m e n t a l m e d i a c o u l d have b e e n air, soil, food, o r p e r haps water. F i n a l l y , Seveso is a n example o f an acute e n v i r o n m e n t a l exposure. T h e choice o f methods to assess exposure depends o n (1) i n t e n d e d use of the exposure data, (2) e c o n o m i c a n d logistic constraints, a n d (3) the a v a i l ability a n d i n t e r p r e t a b i l i t y o f measures o f exposure (external dose, i n t e r n a l dose, o r biologically effective dose) for the toxicant o f interest. E n v i r o n m e n tal measurements o f toxicant concentration i n air, water, food, a n d soil w i l l always b e i m p o r t a n t for regulatory purposes. T h e s e external dose m e a s u r e ments s h o u l d b e correlated to measurements o f the i n t e r n a l dose o r b i o l o g ically effective dose, w h e n e v e r possible. T h e assessment o f h u m a n exposure based o n e n v i r o n m e n t a l m o n i t o r i n g alone must b e done v e r y cautiously. F o r e p i d e m i o l o g i c a l studies o f the relationship b e t w e e n exposure a n d health effects, every effort s h o u l d b e made to use t h e exposure measures closest to t h e h e a l t h effect i n t h e pathway s h o w n i n F i g u r e 1. Usually, this is a m e a s u r e m e n t o f i n t e r n a l dose (e.g., t h e concentration o f the toxicant o r its p r i m a r y metabolite i n b l o o d o r urine). I f exposure indices based o n e n v i r o n m e n t a l measurements o r o n questionnaire a n d h i s t o r y information are to b e u s e d to d e t e r m i n e h u m a n exposure, rather than t h e d i r e c t m e a s u r e ments o f i n t e r n a l dose o r biologically effective dose, it is necessary to v a l i date a n d calibrate t h e exposure i n d e x against d i r e c t measurements o f i n t e r -



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n a l dose i n a subset o f the exposed p o p u l a t i o n , i f at a l l possible. C a l i b r a t i o n is n e e d e d so that investigators can compare the levels o f exposure to a g i v e n toxicant i n populations from different studies, s u c h that a " h i g h " l e v e l o f exposure i n o n e study is equivalent to a " h i g h " l e v e l i n another. F u t u r e efforts to characterize the pharmacokinetics o f measures o f i n t e r n a l dose a n d biologically effective dose are i m p o r t a n t . T h e p h a r m a c o k i n e t i c studies are especially i m p o r t a n t for those toxicants that have short half-lives i n h u m a n s . Because m a n y e n v i r o n m e n t a l toxicants are u b i q u i t o u s , it is also necessary to k n o w the n o r m a l concentration range o f these toxicants i n h u m a n s , stratified b y age, gender, race, a n d so forth. W e are c u r r e n t l y d e t e r m i n i n g these reference levels for 32 volatile organic c o m p o u n d s a n d 12 phenols a n d p h e n o x y acids i n a subset o f the T h i r d N a t i o n a l H e a l t h a n d N u t r i t i o n E x a m i n a t i o n Survey. W e are also a t t e m p t i n g to d e v e l o p sensitive, specific, r e l i a b l e , a n d affordable measures o f i n t e r n a l dose a n d biologically effective dose, w h i c h , c o m b i n e d w i t h s o u n d epidemiology, w i l l substantially i m p r o v e h u m a n e x posure assessment a n d h u m a n risk assessment.

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February 4, 1993.


Examples of Measuring Internal Dose for Assessing Exposure in

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