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Chapter 6

Validation of Environmental Monitoring by Biological Monitoring Fluorescent Tracer Technique and Patch Technique

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Richard A. Fenske New Jersey Agricultural Experiment Station, Department of Environmental Science, Rutgers University, New Brunswick, NJ 08903

Environmental monitoring of pesticide expo­ sure allows i d e n t i f i c a t i o n of exposure pathways and appropriate exposure reduction strategies. Biological monitoring studies which c o l l e c t t o t a l urinary metabolites from a s i n g l e exposure episode provide a r e l a t i v e index of exposure for evaluating the v a l i d i t y of environmental monitoring methods. Essential validation study design factors include selection of an appropriate p e s t i c i d e for b i o l o g i c a l monitoring, and elimination of extraneous and i n t e r f e r i n g exposures. Most studies which have r e ­ ported poor c o r r e l a t i o n s between patch estimates of dermal exposure and metabolite excretion e x h i b i t d e f i c i e n c i e s in one or more of these design factors. A recent study of malathion exposure during a i r b l a s t applications demonstrated a high correla­ tion between fluorescent tracer measure­ ments of dermal deposition and malathion metabolite excretion (r=.84). Patch depo­ s i t i o n values were a l s o c o r r e l a t e d with excretion (r=.71). Environmental and biological monitoring are complementary approaches to characterizing human exposure to chemicals in occupational and general populations. The combination of these two techniques provides a comprehensive evalua­ tion of exposure magnitude and the pathways by which exposure occurs. Biological monitoring has been an im­ portant part of pesticide exposure assessment for nearly forty years due to the importance of the dermal route of exposure (JL). Cholinesterase and urinary metabolite monitoring have often been conducted in conjunction with estimates of dermal deposition to determine the r e l a t i v e 0097-6156/89/0382-0070$06.00/0 ° 1989 American Chemical Society

Wang et al.; Biological Monitoring for Pesticide Exposure ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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c o n t r i b u t i o n of dermal exposure to t o t a l exposure, and t o determine the accuracy o f dermal exposure measurements.

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This paper examines the g e n e r a l p r i n c i p l e s i n v o l v e d i n f i e l d v a l i d a t i o n o f e n v i r o n m e n t a l m o n i t o r i n g methods/ and r e v i e w s s t u d i e s w h i c h have e m p l o y e d b i o l o g i c a l monitoring as a r e l a t i v e index of p e s t i c i d e exposure to evaluate dermal exposure estimates. Studies employing the p a t c h t e c h n i q u e a r e compared t o a r e c e n t study w h i c h m e a s u r e d p e s t i c i d e d e p o s i t i o n on t h e s k i n w i t h fluorescent t r a c e r s and video imaging. The s t r e n g t h s a n d l i m i t a t i o n s of these techniques a r e d i s c u s s e d together w i t h suggestions regarding future areas f o r research i n p e s t i cide exposure assessment. Human E x p o s u r e A s s e s s m e n t

Methods

Environmental m o n i t o r i n g p r o v i d e s a measure o f exposure; i.e./ amount o f m a t e r i a l r e a c h i n g a body b a r r i e r and a v a i l a b l e f o rabsorption. A i rsampling/ patch monitoring and handwashing a r e e x a m p l e s o f e n v i r o n m e n t a l monitoring methods employed r o u t i n e l y i n p e s t i c i d e exposure a s s e s s ment. Such t e c h n i q u e s a l l o w study o f the r e l a t i v e importance of routes of exposure and p r o v i d e the f o u n d a t i o n for the development of appropriate c o n t r o l strategies. Since environmental m o n i t o r i n g t e c h n i q u e s n e e d n o t be compound-specific/ t h e y h a v e o f t e n been e m p l o y e d t o meas u r e e n t i r e c l a s s e s o f c o m p o u n d s (e.g./ a i r s a m p l i n g o f v o l a t i l e organics)/ or to provide a generic examination of p r o d u c t i o n processes (e.g./ a u t o b o d y p a i n t i n g o r pesticide applications). F i n a l l y / environmental monitoring i s t h e o n l y m e a n s o f a s s e s s i n g e x p o s u r e f o r t h e many c h e m i c a l s w h i c h do n o t h a v e a r e l i a b l e b i o l o g i c a l e n d p o i n t t o measure. B i o l o g i c a l m o n i t o r i n g p r o v i d e s a measure o f a b s o r p t i o n i n body t i s s u e o r f l u i d s / or i n v o l v e s measuring change i n a p h y s i o l o g i c a l parameter. Such m o n i t o r i n g i n t e g r a t e s exposure from a l l r o u t e s and a l l o w s e s t i m a t i o n of an absorbed dose. S i n c e a dose e s t i m a t e i s the u l t i mate g o a l o f any e x p o s u r e a s s e s s m e n t / a w e l l - c o n d u c t e d b i o l o g i c a l monitoring procedure can provide important information unattainable with environmental monitoring. C l e a r l y both of these approaches a r e e s s e n t i a l t o reducing exposures and s e t t i n g a p p r o p r i a t e o c c u p a t i o n a l and environmental h e a l t h standards. U n d e r many c i r c u m s t a n c e s t h e y c a n be c o n d u c t e d s i m u l t a n e o u s l y t o p r o v i d e a c o m p r e hensive exposure assessment. The A m e r i c a n C o n f e r e n c e o f Governmental I n d u s t r i a l Hygienists considers biological m o n i t o r i n g t o be a n i m p o r t a n t s u p p l e m e n t t o e n v i r o n m e n t a l m o n i t o r i n g / and has r e c e n t l y e s t a b l i s h e d B i o l o g i c a l Expos u r e I n d i c e s t o p r o v i d e g u i d a n c e i n t h i s a r e a (2^). Simil a r b i o l o g i c a l e x p o s u r e g u i d e l i n e s have been d e v e l o p e d i n Europe/ where b i o l o g i c a l m o n i t o r i n g i s an e s t a b l i s h e d e x p o s u r e a s s e s s m e n t p r o c e d u r e (3^).

Wang et al.; Biological Monitoring for Pesticide Exposure ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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Exposure

Assessment

Method

Validation

The r e l a t i v e a c c u r a c y o f a n e x p o s u r e a s s e s s m e n t t e c h n i q u e c a n be e s t a b l i s h e d b y d e m o n s t r a t i n g i t s a b i l i t y t o m o n i t o r changes i n exposure c o n s i s t e n t l y . Measurements p r o d u c e d by t h e t e c h n i q u e a r e c o m p a r e d t o a r e l i a b l e m e a s u r e of exposure or exposure p o t e n t i a l . The a b s o l u t e a c c u r a c y o f a m e t h o d i s n o r m a l l y d e m o n s t r a t e d by c a l i b r a t i n g t h e measurement s y s t e m a g a i n s t a known s t a n d a r d . I f s u c h a standard i s not a v a i l a b l e / a c c u r a c y i s d e t e r m i n e d by c a l c u l a t i o n of e r r o r or uncertainty. V a l i d a t i o n of dermal e x p o s u r e a s s e s s m e n t methods has p r o v e n p r o b l e m a t i c . Laboratory f a c i l i t i e s which create w e l l - d e f i n e d exposures a r e commonly employed t o e v a l u a t e r e s p i r a t o r y measurement t e c h n i q u e s (e.g./ c o n t r o l l e d t e s t a t m o s p h e r e s a n d inhalat i o n chambers). No s u c h p r o c e d u r e s a r e a v a i l a b l e f o r t h e study of dermal exposure. Instead/ i n v e s t i g a t i o n s must be c o n d u c t e d i n t h e f i e l d w h e r e n u m e r o u s v a r i a b l e s c a n n o t be c o n t r o l l e d . As a r e s u l t / t h e d e r m a l e x p o s u r e a s s e s s ment methods i n c u r r e n t use h a v e n e v e r been v a l i d a t e d i n terms of a b s o l u t e a c c u r a c y . Dermal exposure validation s t u d i e s h a v e i n s t e a d f o c u s e d on r e l a t i v e a c c u r a c y by comparing environmental monitoring data to a r e l a t i v e index of exposure. Two f i e l d study parameters are often employed as r e l a t i v e i n d i c a t o r s of e x p o s u r e : work r a t e and active ingredient applied. I m p l i c i t i n the use of such v a r i a b l e s i s an a s s u m p t i o n t h a t a s t r o n g a s s o c i a t i o n e x i s t s between the v a r i a b l e and e x p o s u r e ; i . e . / e x p o s u r e i s proportional to time worked or amount of material handled. Work r a t e i s commonly e m p l o y e d i n i n d u s t r i a l s e t t i n g s w h e r e e x p o s u r e p o t e n t i a l i s p r e d i c t a b l e (e.g./ a m b i e n t a i r l e v e l s i n a f a c t o r y ) / and where work a c t i v i t y is routine. In a recent study of timber m i l l workers exposed to t e t r a c h l o r o p h e n o l / f o r example/ i t was d e m o n s t r a t e d t h a t s k i n d e p o s i t i o n o f t e t r a c h 1 o r o p h e n o l was d i r e c t l y r e l a t e d t o the amount o f time worked (4). This a s s o c i a t i o n was e x p e c t e d s i n c e w o r k e r s p u l l e d a n d sorted t i m b e r a t a r a t e c o n t r o l l e d by t h e s p e e d o f a c o n v e y o r belt. Such work c o n d i t i o n s c o n t r a s t s h a r p l y w i t h p e s t i c i d e m i x i n g and a p p l i c a t i o n i n a g r i c u l t u r e / where b o t h e x p o s u r e p o t e n t i a l and work r a t e a r e h i g h l y v a r i a b l e . A 1979 s t u d y o f s i x t e e n m i x e r / a p p l i c a t o r s demons t r a t e d t h a t w h e n w o r k e r s e m p l o y t h e i r own e q u i p m e n t and w o r k a t t h e i r own s p e e d / w o r k r a t e i s h i g h l y variable (J5). R e g r e s s i o n a n a l y s i s r e s u l t e d i n no significant c o r r e l a t i o n b e t w e e n t i m e w o r k e d a n d 48 h r e x c r e t i o n o f a z i n p h o s m e t h y l m e t a b o l i t e s (r=.43). However/ a s t r o n g c o r r e l a t i o n (r=.77) was f o u n d when t h e a m o u n t o f a c t i v e i n g r e d i e n t h a n d l e d by e a c h w o r k e r a n d 48 h r e x c r e t i o n were compared. S e v e r a l other i n v e s t i g a t o r s have conf i r m e d t h e s e r e s u l t s (6). Most r e c e n t l y a study of 2/4-D a p p l i c a t o r s i n Canada found s t r o n g c o r r e l a t i o n s between

Wang et al.; Biological Monitoring for Pesticide Exposure ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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the u r i n a r y e x c r e t i o n o f e i g h t w o r k e r s a n d amount s p r a y e d ( r = . 9 0 ) / a s w e l l a s w i t h s p r a y i n g t i m e ( r = . 9 3 ) (8). T h e a s s o c i a t i o n o f amount o f a c t i v e i n g r e d i e n t a p p l i e d a n d exposure suggests that this parameter i suseful a s a r e l a t i v e i n d i c a t o r o f exposure p o t e n t i a l . W o r k r a t e may be a n a p p r o p r i a t e i n d i c a t o r i n some c a s e s / b u t c a n b e highly variable for pesticide applications.

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Study Design f o r B i o l o g i c a l

Monitoring

Validation

Most p e s t i c i d e s t u d i e s aimed a t v a l i d a t i n g dermal exposure measurements have employed b i o l o g i c a l m o n i t o r i n g a s a r e l a t i v e index o f exposure. An i d e a l v a l i d a t i o n s t u d y design would attempt t o demonstrate a strong correspondence between dermal exposure a n d i n t e r n a l dose. In lieu o f a m e a s u r e o f i n t e r n a l dose f o r humans/ t h e u s e o f u r i n a r y m e t a b o l i t e e x c r e t i o n a s an i n d i c a t o r o f r e l a t i v e dose h a s g a i n e d w i d e s p r e a d u s e i n i n d u s t r i a l h y g i e n e a n d a p p l i e d t o x i c o l o g y (£). T h i s approach assumes a l i n e a r 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 a n d a b s o r b e d d o s e / a n d may n o t be a p p r o p r i a t e f o r a l l compounds. Most s u c c e s s f u l v a l i d a t i o n s t u d i e s a r e based on a "single exposure" design. S u b j e c t s work f o r a d e f i n e d exposure peciod/ and t o t a l urine samples are then c o l lected until metabolite excretion i s negligible. The duration of urine c o l l e c t i o n i s a function of the k i n e t i c s o f the a b s o r p t i o n ande x c r e t i o n o f the p e s t i c i d e applied. I fv i r t u a l l y a l l m e t a b o l i t e s are c o l l e c t e d / t h e amount o f p e s t i c i d e m e t a b o l i t e s e x c r e t e d i sa d i r e c t r e f l e c t i o n o f thes i n g l e period exposure/ though n o t n e c e s s a r i l y a measure o f a b s o r b e d dose. Three c r i t e r i a can be e m p l o y e d t o e v a l u a t e the soundness o f a v a l i d a t i o n s t u d y d e s i g n : (1) c o n t r o l o f e x t r a n e o u s e x p o s u r e b e f o r e a n d a f t e r t h e s t u d y p e r i o d / (2) c o n t r o l o f i n t e r f e r i n g e x p o s u r e d u r i n g t h e s t u d y p e r i o d / a n d (3) s e l e c t i o n o f a n appropriate pesticide for biological monitoring. Extraneous Exposure. S u b j e c t s a r e asked t oa v o i d expos u r e p r i o r t o t h es t u d y f o r a time s u f f i c i e n t t o a l l o w u r i n a r y m e t a b o l i t e l e v e l s o f the s t u d y compound o r i n t e r f e r i n g compounds t o r e a c h b a c k g r o u n d l e v e l s . Following the a p p l i c a t i o n p e r i o d no a d d i t i o n a l e x p o s u r e i s a l l o w e d u n t i l urine c o l l e c t i o n i s completed. This protocol i s d i f f i c u l t t o implement i f w o r k e r s must m a i n t a i n a r e g u l a r work s c h e d u l e . F u r t h e r m o r e / e v e n i f w o r k e r s do n o t m i x o r a p p l y p e s t i c i d e s b e f o r e a n d a f t e r t h e s t u d y / t h e y may come i n t o c o n t a c t w i t h c o n t a m i n a t e d e q u i p m e n t o r r e u s e exposed clothing. I n t e r f e r i n g Exposure. Biological monitoring integrates exposure from a l l sources. I f the e n v i r o n m e n t a l m o n i t o r ing technique under study measures o n l y a p o r t i o n o f t h e p o t e n t i a l e x p o s u r e / t h e n o t h e r e x p o s u r e s s h o u l d be m i n i mized. When d e r m a l e x p o s u r e i s o f i n t e r e s t / f o r e x a m p l e /

Wang et al.; Biological Monitoring for Pesticide Exposure ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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o r a l a n d r e s p i r a t o r y e x p o s u r e s h o u l d be c o n t r o l l e d f o r the study p e r i o d . S i m i l a r l y / a s t u d y of hand e x p o s u r e would r e q u i r e p r o t e c t i o n of a l l other dermal s u r f a c e s . Pesticide Selection. The c e n t r a l d e c i s i o n i n d e s i g n i n g a v a l i d a t i o n study i s the c h o i c e of the p e s t i c i d e to monitor. Compound s e l e c t i o n r e q u i r e s k n o w l e d g e o f the e x c r e t i o n k i n e t i c s f o l l o w i n g d o s i n g / i d e a l l y by t h e d e r m a l r o u t e i n humans. The c o m p o u n d s h o u l d be r a p i d l y e x c r e t e d i n the u r i n e e i t h e r unchanged or as a major m e t a b o l i t e . T a b l e I p r e s e n t s a b s o r p t i o n and e x c r e t i o n d a t a i n humans r e p o r t e d by F e l d m a n n a n d M a i b a c h f o r f o u r o f t h e compounds which have been employed i n v a l i d a t i o n s t u d i e s to d a t e (1_0). T h e s t u d y i n v o l v e d a n i n t r a v e n o u s d o s e f o l l o w e d by a s i n g l e t o p i c a l a p p l i c a t i o n l e f t on t h e s k i n f o r 24 h o u r s . T o t a l u r i n e was c o l l e c t e d f o r 5 d a y s i n each case. The i n t r a v e n o u s d o s e h a l f - l i v e s o f t h e compounds e x h i b i t e d n e a r l y a f i v e - f o l d range/ from 3 hours f o r m a l a t h i o n t o 14 h o u r s f o r e t h i o n . The p e r c e n t a g e of t h e d e r m a l d o s e e x c r e t e d r a n g e d f r o m 3.3% f o r e t h i o n t o 9.7% f o r parathion/ or n e a r l y t h r e e - f o l d . Column 3 of Table I was c a l c u l a t e d f r o m the 5 day e x c r e t i o n d a t a p r e s e n t e d i n the study. The v a l u e s a r e t h e percentages o f t h e t o t a l m e t a b o l i t e s w h i c h w e r e e x c r e t e d on t h e f i n a l day o f c o l l e c t i o n . L e s s t h a n 2% o f t h e m a l a t h i o n was e x c r e t e d o n d a y 5, w h e r e a s m o r e t h a n 1 1 % o f 2/4-D was e x c r e t e d on t h e f i n a l d a y o f s a m p l i n g . Data of t h i s k i n d a l l o w b a s i c c o m p a r i s o n s among p e s t i c i d e s i n t h e s e l e c t i o n of s u i t a b l e c a n d i d a t e s f o r b i o l o g i c a l m o n i t o r i n g . Table

I.

Compound

Dermal of

A b s o r p t i o n and E x c r e t i o n C h a r a c t e r i s t i c s F o u r P e s t i c i d e s i n Humans*

Half-life** (hours)

Ethion 2/4-D Para t h i o n Malathion

14 13 8 3

Data adapted from Half-life following

Patch Technique

Percent Dermal Dose Excreted 3.3 5.8 9.7 8.2

Day as

5 Excretion Percent of Total 8.0 11.1 7.2 1.5

; mean o f 6 s u b j e c t s intravenous administration

Va1idation

The p a t c h t e c h n i q u e has b e e n t h e m o s t w i d e l y e m p l o y e d method f o r e s t i m a t i n g dermal exposure s i n c e i t s f o r m a l p u b l i c a t i o n by i n v e s t i g a t o r s f r o m t h e U.S. P u b l i c H e a l t h S e r v i c e (1^1). I t i s now a n a p p r o v e d p r o t o c o l f o r b o t h t h e W o r l d H e a l t h O r g a n i z a t i o n a n d t h e U.S. Environmental P r o t e c t i o n Agency (12-13). However/ the method has n e v e r been v a l i d a t e d / a n d t h e r e a r e many i n v e s t i g a t o r s who

Wang et al.; Biological Monitoring for Pesticide Exposure ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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Validation of Environmental Monitoring

c o n s i d e r p a t c h t e c h n i q u e data i n a d e q u a t e (14-16). This j u d g m e n t i s b a s e d on t h e q u e s t i o n a b l e a c c u r a c y o f t h e method/ b u t a l s o stems from the r e p e a t e d o b s e r v a t i o n t h a t p a t c h d a t a do n o t c o r r e l a t e w i t h u r i n a r y m e t a b o l i t e e x ­ c r e t i o n data. A r e v i e w of p u b l i s h e d s t u d i e s which have attempted t o d e m o n s t r a t e a c o r r e l a t i o n between d e r m a l e x p o s u r e and m e t a b o l i t e e x c r e t i o n i n d i c a t e s shortcomings i n study design or e x e c u t i o n . The s t u d y d e s i g n c r i t e r i a d i s c u s s e d a b o v e a r e e m p l o y e d here t o examine f i v e s t u d i e s w h i c h have c o l l e c t e d p a t c h and m e t a b o l i t e d a t a s i m u l t a ­ neously. T h e s e s t u d i e s a r e summarized i n T a b l e I I .

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Table

II.

Patch Technique

Study P e s t i c i d e

18 19 20 21 22

parathion 2/4/5-T ethion phenoxy 2/4-D

N

r

11 21 17 17 8

.69 .45 .36 .67

—

Validation

Studies

Extraneous Exposure

Interfering Exposure

Urine Sample

possible yes possible possible no

hand hand/resp hand hand/resp resp

unknown 5 days spot spot 7 days

Durham a n d W o l f e f i r s t a t t e m p t e d to v a l i d a t e the p a t c h t e c h n i q u e by m o n i t o r i n g a s i n g l e e x p o s u r e a n d d e ­ t e r m i n i n g t o t a l p a r a t h i o n m e t a b o l i t e e x c r e t i o n (17). E x t r a n e o u s e x p o s u r e a p p a r e n t l y was n o t c o n t r o l l e d : no pre-exposure u r i n e s a m p l e s were r e p o r t e d and t h e l e n g t h o f u r i n e s a m p l i n g was e x p r e s s e d s i m p l y a s u n t i l "levels were no l o n g e r o f s i g n i f i c a n c e " . Interfering exposures were n o t c o n t r o l l e d : r e s p i r a t o r y e x p o s u r e a n d hand e x p o ­ sure both c o n t r i b u t e d to m e t a b o l i t e l e v e l s . Parathion a p p e a r s t o h a v e b e e n a g o o d c h o i c e a s a s t u d y compound due t o i t s r e l a t i v e l y r a p i d a b s o r p t i o n and e x c r e t i o n . The s t u d y r e p o r t e d a "good c o r r e l a t i o n " b e t w e e n p a t c h e x p o s u r e and e x c r e t i o n / b u t no s t a t i s t i c a l a n a l y s i s was c o n d u c t e d . A c o r r e l a t i o n c o e f f i c i e n t o f r=.69 f o r t h e 11 s u b j e c t s c a n be c a l c u l a t e d / b u t t h i s v a l u e i s h e a v i l y i n f l u e n c e d by v e r y h i g h r e s u l t s f o r one s u b j e c t . When t h i s s u b j e c t i s removed from t h e d a t a s e t / t h e r e i s no s i g n i f i c a n t c o r r e l a t i o n ( r = . 1 9 ) . The i n f l u e n c e o f a s i n g l e h i g h v a l u e i s an i n h e r e n t weakness o f t h e P e a r s o n c o r r e l a t i o n c o e f f i c i e n t / a n d c o r r e l a t i o n s b a s e d on one extreme v a l u e a r e g e n e r a l l y n o t c o n s i d e r e d adequate e v i ­ dence o f a p o s i t i v e a s s o c i a t i o n . thus/ t h e s e d a t a do n o t d e m o n s t r a t e a c o r r e l a t i o n between t h e two measures. A s t u d y by L a v y a n d c o - w o r k e r s o f 2/4/5-T e x p o s u r e was b a s e d on a s i n g l e e x p o s u r e d e s i g n a n d was c o n d u c t e d t w i c e (JJB). The i m p o r t a n c e o f r e d u c i n g e x t r a n e o u s e x p o ­ s u r e was c l e a r l y r e c o g n i z e d / a s i n d i c a t e d by t h e r e c r u i t ­ ment o f p a r t i c i p a n t s who h a d n o t u s e d 2/4/5-T f o r two weeks/ a n d t h e c o l l e c t i o n o f 24 h o u r p r e - e x p o s u r e u r i n e

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samples. U n f o r t u n a t e l y , b a c k g r o u n d l e v e l s o f 2,4,5-T were v e r y h i g h f o r a number o f t h e w o r k e r s , p a r t i c u l a r i n the second study, c a l l i n g i n t o q u e s t i o n the u t i l i t y of the e x c r e t i o n data f o rc o m p a r a t i v e purposes. In regard to i n t e r f e r i n g exposures, r e s p i r a t o r y e x p o s u r e w a s meas u r e d a n d was d e t e r m i n e d t o be o n l y a s m a l l f r a c t i o n o f the dermal exposure. H o w e v e r , hand e x p o s u r e was n o t measured o r c o n t r o l l e d . Thus, hand e x p o s u r e r e p r e s e n t s an i m p o r t a n t c o n f o u n d i n g f a c t o r , p a r t i c u l a r l y s i n c e a p p l i c a t i o n s w i t h b a c k p a c k s y s t e m s a n d m i s t b l o w e r s comm o n l y r e s u l t i n s i g n i f i c a n t hand e x p o s u r e . T h i s s t u d y was a l s o hampered by t h e c h o i c e o f compounds. T h e h e r b i c i d e 2,4,5-T i s e x c r e t e d a l m o s t t o t a l l y i n urine, but e x c r e t i o n f o l l o w i n g dermal exposure extends beyond 5 days. S e v e r a l workers e x h i b i t e d t h e i r highest e x c r e t i o n l e v e l s on t h e f i f t h a n d l a s t day o f c o l l e c t i o n . On a v e r a g e t h e e x c r e t i o n o n t h e l a s t d a y r e p r e s e n t e d 1 4 % of t h e t o t a l 5 day e x c r e t i o n , s u g g e s t i n g t h a t a s i g n i f i c a n t f r a c t i o n o f t h e compound c o n t i n u e d t o be e x c r e t e d beyond t h i s p e r i o d . The s t u d y r e p o r t s a l o w c o r r e l a t i o n c o e f f i c i e n t ( r = . 4 5 ) f o r t h e 21 w o r k e r s s t u d i e d . In l i g h t of problems w i t h extraneous exposure, interfering exposure, and i n c o m p l e t e m e t a b o l i t e c o l l e c t i o n , however, t h i s r e s u l t i s not unexpected. Thus, the study does n o t p r o v i d e c l e a r evidence that patche exposure e s t i m a t e s and excretion are not correlated. Wojeck and co-workers examined the r e l a t i o n s h i p between e t h i o n exposure and d i a I k y l p h o s p h a t e e x c r e t i o n i n 17 F l o r i d a c i t r u s m i x e r s a n d a p p l i c a t o r s (1_9). Extran e o u s e x p o s u r e was m o n i t o r e d by a s i n g l e u r i n e s a m p l e one week b e f o r e t h e s t u d y . M e t a b o l i t e l e v e l s on t h e day p r i o r t o the s t u d y were n o t measured. Spot sampling o f u r i n e w a s c o n d u c t e d r a t h e r t h a n t o t a l 24 h o u r collections. These s a m p l i n g p r o c e d u r e s c l e a r l y l i m i t the u t i l i t y o f the u r i n e v a l u e s as r e l a t i v e i n d i c a t o r s o f exposure. R e s p i r a t o r y e x p o s u r e was l i m i t e d by u s e o f r e s p i rators. C o t t o n g l o v e s w e r e w o r n by a l l w o r k e r s t o meas u r e hand e x p o s u r e , b u t w o r k e r s d i d n o t wear g l o v e s a s p r o t e c t i v e d e v i c e s . The u s e o f c o t t o n g l o v e s r e p r e s e n t s a p a r t i c u l a r l y complex confounding factor, wherein the dermal sampling procedure i t s e l f i s l i k e l y to a l t e r the b i o l o g i c a l m o n i t o r i n g d a t a i n u n p r e d i c t a b l e ways. Regression a n a l y s i s produced a low c o r r e l a t i o n coeff i c i e n t ( r = . 3 6 ) f o r t h e g r o u p mean t o t a l d e r m a l exposure ( d e r m a l p a t c h e s + h a n d s ) a n d t h e g r o u p mean m e t a b o l i t e c o n c e n t r a t i o n when t h e s e v a l u e s w e r e c o m p a r e d on a d a i l y basis. C o n s i d e r i n g the l i m i t a t i o n s i n urine sampling and the p o t e n t i a l confounding e f f e c t o f the c o t t o n g l o v e s , t h i s study does n o t p r o v i d e an adequate test of patch technique v a l i d i t y .

Wang et al.; Biological Monitoring for Pesticide Exposure ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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6.

FENSKE

Validation of Environmental Monitoring

11

Manninen and c o - w o r k e r s c o n d u c t e d a s t u d y of 17 workers exposed t o p h e n o x y a c i d h e r b i c i d e s (20)» No e v a l u a t i o n o f p r i o r e x p o s u r e among w o r k e r s i s m e n t i o n e d / a n d no p r e - e x p o s u r e u r i n e s a m p l e s w e r e c o l l e c t e d . Two s p o t s a m p l e s w e r e t a k e n : one a f t e r t h e w o r k i n g day i n t h e e v e n i n g a n d one on t h e f o l l o w i n g m o r n i n g . Respiratory e x p o s u r e and hand e x p o s u r e were l e f t u n c o n t r o l l e d . Some w o r k e r s wore r e s p i r a t o r s or g l o v e s but o t h e r s d i d not, i n t r o d u c i n g an unknown amount of v a r i a b i l i t y i n t o the t o t a l e x p o s u r e r e f l e c t e d by t h e m e t a b o l i t e s . This study a n a l y z e d u r i n e f o r four d i f f e r e n t phenoxy h e r b i c i d e s : MCPA/ d i c h l o r p r o p / m e c o p r o p / a n d d i c a m b a . Workers used f o r m u l a t i o n s w i t h d i f f e r e n t c o m b i n a t i o n s o f t h e s e compounds. C l e a r l y the v a r i a b l e dermal p e n e t r a t i o n and p h a r m a c o k i n e t i c s o f t h e s e c o m p o u n d s make t h e s p o t u r i n a r y e x c r e t i o n v a l u e s d i f f i c u l t to i n t e r p r e t . The a u t h o r s c o n d u c t e d a r e g r e s s i o n a n a l y s i s o f u r i n e e x c r e t i o n a n d d e r m a l p a t c h e s t i m a t e s f o r t h e 17 w o r k e r s / r e s u l t i n g i n a p o s i t i v e c o r r e l a t i o n c o e f f i c i e n t (r=.67). However/ v a r i a b i l i t y i n the h i g h e r e x p o s u r e v a l u e s were pronounced. H i g h l y exposed workers with s i m i l a r levels o f s k i n e x p o s u r e ( a p p r o x i m a t e l y 2 mg) v a r i e d b y m o r e t h a n an o r d e r of magnitude i n the e x c r e t i o n o f m e t a b o l i t e s ( 2 28 u m o l / L ) . The l a c k o f c o n t r o l o v e r e x t r a n e o u s a n d i n t e r f e r i n g exposures/ together with spot sampling of a v a r i e t y o f compounds r a i s e s q u e s t i o n s r e g a r d i n g the c o r r e l a t i o n of exposure and e x c r e t i o n . The f i n a l s t u d y t o be r e v i e w e d was conducted by C a n a d i a n r e s e a r c h e r s o n 8 f a r m e r s e x p o s e d t o 2,4-D amine (21). P r e - e x p o s u r e u r i n e samples were c o l l e c t e d to determine background l e v e l s . T o t a l 24 h o u r u r i n e samples w e r e c o l l e c t e d d u r i n g t h e s t u d y a n d f o r 4-7 d a y s t h e r e after. S o m e o f t h e p a r t i c i p a n t s s p r a y e d 2,4-D again w i t h i n a few days a f t e r the i n i t i a l s t u d y p e r i o d / p r e c l u d i n g use o f a s t r i c t s i n g l e e x p o s u r e d e s i g n . However/ a l l u r i n e was c o l l e c t e d f r o m t h e f i r s t e x p o s u r e t h r o u g h t h e l a s t a n d f o r 4-7 days a f t e r the l a s t / providing adequate data f o r d e v e l o p i n g a r e l a t i v e index of exposure. E a c h e x p o s u r e was m e a s u r e d by t h e p a t c h a n d h a n d wash t e c h n i q u e s . Workers d i d not use r e s p i r a t o r s or protective gloves. T h i s s t u d y was w e l l c o n d u c t e d / a v o i d ing problems r e g a r d i n g e x t r a n e o u s exposure seen i n the o t h e r s t u d i e s / and c o l l e c t i n g u r i n e f o r a p e r i o d a p p r o p r i a t e t o t h e e x c r e t i o n o f 2/4-D. C u m u l a t i v e u r i n a r y e x c r e t i o n was a s s o c i a t e d only w i t h hand e x p o s u r e (r=.67). P a t c h exposure e s t i m a t e s and t o t a l d e r m a l e x p o s u r e ( p a t c h e s t i m a t e s + hand e x p o s u r e ) did not c o r r e l a t e with u r i n a r y e x c r e t i o n . The a u t h o r s c o n c l u d e d t h a t the l a c k of c o r r e l a t i o n between total d e r m a l e x p o s u r e a n d u r i n a r y e x c r e t i o n was a t t r i b u t a b l e t o the v a r i a b l e n a t u r e of dermal d e p o s i t i o n and the i n a b i l i t y of the patch technique to e s t i m a t e such d e p o s i t i o n .

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In summary/ t h e s t u d i e s r e v i e w e d d e f i n i t i v e e v i d e n c e r e g a r d i n g the the patch technique. Confounding exposure/ i n t e r f e r i n g exposure and l e c t i o n i n t r o d u c e an unknown d e g r e e c a n n o t be s e p a r a t e d f r o m v a r i a b i l i t ment t e c h n i q u e .

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F l u o r e s c e n t Tracer Technique

h e r e do n o t p r o v i d e r e l a t i v e a c c u r a c y of f a c t o r s of extraneous inadequate urine colof v a r i a b i l i t y which y due t o t h e m e a s u r e -

Validation

Study

The f l u o r e s c e n t t r a c e r t e c h n i q u e was f i r s t e m p l o y e d i n f i e l d s t u d i e s i n 1 9 7 9 (j>). S u b s e q u e n t l y / a q u a n t i t a t i v e v i d e o i m a g i n g s y s t e m was d e v e l o p e d t o m e a s u r e dermal fluorescence. The r e l a t i o n s h i p b e t w e e n t h e t r a c e r a n d p e s t i c i d e s d u r i n g a p p l i c a t i o n was e x a m i n e d / a n d t h e t e c h n i q u e was f i e l d t e s t e d ( 2 2 - 2 4 ) . A d e t a i l e d account of the v a l i d a t i o n s t u d y d i s c u s s e d here has been r e p o r t e d recently ( F e n s k e / R.A. Am. I n d . Hyg. Assoc. J./ i n press). The s t u d y i n c l u d e d s e v e n m i x e r s a n d 14 a p p l i c a t o r s . E a c h a p p l i c a t o r s p r a y e d f o u r t a n k s on a h i g h - v o l u m e a i r b l a s t spray s c h e d u l e t y p i c a l f o r c i t r u s i n the r e g i o n . The f l u o r e s c e n t w h i t e n i n g a g e n t / 4-methy1-7-diethylaminoc o u m a r i n / was e m p l o y e d a s a t r a c e r . D e p o s i t i o n of the t r a c e r compound a n d m a l a t h i o n on g a u z e p a t c h e s a t t a c h e d to t h e s p r a y r i g was highly correlated (r=.94). The i n s t r u m e n t e m p l o y e d t o q u a n t i f y d e r m a l f l u o r e s c e n c e was a computer-based image p r o c e s s i n g s y s t e m i n t e r f a c e d w i t h a t e l e v i s i o n camera. T h e t r a d i t i o n a l p a t c h t e c h n i q u e was a l s o e m p l o y e d (2_5). Hand w a s h e s w e r e n o t c o n d u c t e d due to use o f t h e t r a c e r compound. The p r i m a r y c o n c e r n i n d e s i g n i n g t h i s s t u d y was t h e s e l e c t i o n o f a p e s t i c i d e w h i c h w o u l d be r a p i d l y e x c r e t e d i n the u r i n e p r o p o r t i o n a l to absorbed dose. Several l a b o r a t o r y s t u d i e s p r o v i d e s u p p o r t f o r the use o f o r g a n o phosphorus p e s t i c i d e m e t a b o l i t e l e v e l s e x c r e t e d i n the u r i n e as r e l a t i v e i n d i c a t o r s of exposure. A controlled s t u d y i n humans w i t h m e t h y l and e t h y l p a r a t h i o n demons t r a t e d a s t r o n g a s s o c i a t i o n b e t w e e n two o r a l d o s e levels a n d e x c r e t i o n l e v e l s (^26^). More r e c e n t l y a study of azinphosmethyl a p p l i e d d e r m a l l y to rats demonstrated that d i m e t h y 1 t h i o p h o s p h a t e e x c r e t i o n was p r o p o r t i o n a l t o d o s e o v e r a f o u r - f o l d dose range. S t u d i e s w i t h human v o l u n teers a l s o suggested a proportional dose-excretion patt e r n (27). One o f t h e m o s t r a p i d l y e x c r e t e d o r g a n o p h o s p h o r u s compounds i s m a l a t h i o n / due t o i t s h y d r o l y s i s i n mammals to f o r m c a r b o x y l i c a c i d m e t a b o l i t e s (^8). Feldman and Maibach demonstrated t h a t e x c r e t i o n of m a l a t h i o n metabol i t e s f o l l o w i n g dermal a p p l i c a t i o n i n acetone peaked w i t h i n 12 h o u r s f o l l o w i n g e x p o s u r e / a n d t h a t o v e r 9 0 % o f the i n t r a v e n o u s a d m i n i s t r a t i o n was r e c o v e r e d a s m e t a b o -

Wang et al.; Biological Monitoring for Pesticide Exposure ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

6.

FENSKE

79

Validation of Environmental Monitoring

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l i t e s i n u r i n e (3^0). B r a d w a y a n d S h a f i k d e m o n s t r a t e d a s i m i l a r pharmacokinetic p a t t e r n f o r malathion i n mice (29). T h u s , m a l a t h i o n a p p e a r e d t o be a n e x c e l l e n t c a n d i date f o r t h i s v a l i d a t i o n study. The s e c o n d s t u d y d e s i g n i s s u e i n v o l v e d m i n i m i z i n g extraneous exposures. S u b j e c t s were asked to a v o i d a l l e x p o s u r e t o m a l a t h i o n o r any o t h e r d i m e t h y l organophosp h o r u s compounds f o r a t l e a s t 3 days p r i o r t o the study. Pre-exposure s a m p l e s were c o l l e c t e d a t the b e g i n n i n g of the study p e r i o d to determine p r i o r exposure. In one c a s e m e t a b o l i t e l e v e l s w e r e f o u n d t o be a b o v e b a c k g r o u n d l e v e l s , n e c e s s i t a t i n g e x c l u s i o n of t h i s s u b j e c t ' s data from a n a l y s i s . A l l u r i n e was c o l l e c t e d f o r 72 h o u r s f r o m t h e commencement o f the s t u d y / and s u b j e c t s were r e m o v e d from any f u r t h e r e x p o s u r e d u r i n g t h i s c o l l e c t i o n p e r i o d . The r e l a t i v e l y s h o r t 3 day p e r i o d o f c o l l e c t i o n favored s u b j e c t c o o p e r a t i o n / a n d t h e t i m e p e r i o d was a d e q u a t e t o r e c o v e r a p p r o x i m a t e l y 95% o f the m e t a b o l i t e s w h i c h w o u l d b e e x c r e t e d i n 5 d a y s (,10). Thus/ the t o t a l amount of m a l a t h i o n m e t a b o l i t e s r e c o v e r e d i n t h e 3 day u r i n e s a m p l e a p p e a r e d to a c c u r a t e l y r e f l e c t the r e l a t i v e exposure which workers received. I n t e r f e r i n g e x p o s u r e was minim i z e d by p r o v i d i n g a l l w o r k e r s w i t h r e s p i r a t o r s a n d c h e m ical resistant gloves. D e r m a l e x p o s u r e was m o n i t o r e d by the f l u o r e s c e n t t r a c e r t e c h n i q u e (body + hands) and by the p a t c h t e c h n i q u e (body o n l y ) d u r i n g a s i n g l e study p e r i o d f o r each worker. Table

III.

C o r r e l a t i o n of Exposure Measurements w i t h 24-Hr M a l a t h i o n M e t a b o l i t e E x c r e t i o n

Exposure Measurements Fluorescent P a t c h : Mean P a t c h : Head * ** + ++

Tracer Value Exposure

Corr. Coeff.*

RSquared

Rank Corr.**

.84+ .71 + .63 +

.71 .51 .40

.62 + .39++ .33

Pearson c o r r e l a t i o n c o e f f i c i e n t Spearman rank c o r r e l a t i o n c o e f f i c i e n t S t a t i s t i c a l l y s i g n i f i c a n t ; p