Use of Biological Monitoring in the Regulatory Process - ACS

Chapter 27

Use of Biological Monitoring in the Regulatory Process

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Leonard Ritter and Claire A. Franklin Environmental and Occupational Toxicology Division, Environmental Health Directorate, Tunney's Pasture, Ottawa, Ontario K1A 0L2, Canada

Occupational risks associated with pesticide use can only be estimated if exposure can be quantified. Dermal exposure has historically been estimated from patches placed on the worker or his clothing while more recent advances have focused on the use of biological monitoring. Biological monitoring of pesticides can be carried out in a variety of body fluids including blood, urine, sweat, saliva, adipose tissue and exhaled breath; indeed, urinary concentration of the chemical or its metabolites has become one of the most frequently reported biological measures of exposure. For pesticides such as 2,4-D, which is excreted largely unmetabolized, urinary concentrations may be quantitatively related to exposure. Similarly, for organophosphorus compounds, data are presently available which establish the relationship between dermal dose and urinary metabolites. It has been postulated that this standard curve approach could then be utilized to estimate exposure in workers based on the metabolite excretion. There are many products, however, for which the metabolite excretion pattern is not known, thus severely limiting the usefulness of the biological monitoring approach as a measure of exposure to such products. O c c u p a t i o n a l exposure t o p e s t i c i d e s may p r e s e n t h e a l t h r i s k s t o b o t h a p p l i c a t o r s and a g r i c u l t u r a l w o r k e r s . I n order t o p r o p e r l y assess t h i s exposure and e s t i m a t e r i s k , a c c u r a t e d a t a on exposure and a b s o r p t i o n a r e n e c e s s a r y . I n a d d i t i o n t o q u a n t i f y i n g exposure, p r e c i s e i n f o r m a t i o n s h o u l d be a v a i l a b l e on the dose l e v e l s f o r b i o l o g i c a l e n d p o i n t s e s t a b l i s h e d through e x p e r i m e n t a l t o x i c i t y studies. This chapter not subject to U.S. copyright Published 1989 American Chemical Society

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

27.

RITTER AND FRANKLIN

Monitoring in Regulatory Process

355

H i s t o r i c a l l y , r i s k from p e s t i c i d e r e s i d u e s i n food has been e s t i m a t e d by comparing the t h e o r e t i c a l d a i l y i n t a k e of the p e s t i c i d e r e s i d u e t o the a c c e p t a b l e d a i l y i n t a k e . The a c c e p t a b l e e f f e c t l e v e l seen i n e x p e r i m e n t a l a n i m a l s t u d i e s and utilization of an a p p r o p r i a t e s a f e t y f a c t o r f o r the t o x i c o l o g i c end-point b e i n g c o n s i d e r e d . I f the t h e o r e t i c a l d a i l y i n t a k e i s determined to be l e s s than the a c c e p t a b l e d a i l y i n t a k e , the p e s t i c i d e i s g e n e r a l l y c o n s i d e r e d s a f e f o r use on f o o d . S i m i l a r l y , r i s k t o agricultural workers can be e s t i m a t e d by comparing the t h e o r e t i c a l d a i l y exposure to a p e s t i c i d e and the a c c e p t a b l e d a i l y exposure. As i s the case w i t h food r e s i d u e s , i f the t h e o r e t i c a l d a i l y exposure i s e s t i m a t e d to be l e s s than the a c c e p t a b l e d a i l y exposure, the p e s t i c i d e may be c o n s i d e r e d s a f e f o r use by a g r i c u l t u r a l w o r k e r s . These comparisons a r e summarized i n F i g u r e 1. From the f i g u r e i t can be seen t h a t f o r the d e t e r m i n a t i o n of a g r i c u l t u r a l worker s a f e t y t h e r e i s a need to o b t a i n r e l i a b l e and a c c u r a t e e s t i m a t e s of worker exposure. The m a j o r i t y of exposure i n p e s t i c i d e workers has been shown t o take p l a c e v i a the dermal r o u t e ( 1 - 3) and t h i s exposure was o f t e n e s t i m a t e d by the use of adsorbent patches l o c a t e d at v a r i o u s s i t e s on the w o r k e r s b o d i e s or c l o t h i n g . C l a s s i c a l p a t c h t e c h n i q u e s may o v e r e s t i m a t e exposure (4) l e a d i n g t o exaggerated r i s k e s t i m a t e s and improper r e s t r i c t i o n on r e g i s t r a t i o n and use of the p e s t i c i d e . More r e c e n t l y , c o n s i d e r a b l e i n t e r e s t has developed i n the t e c h n i q u e of human b i o l o g i c a l m o n i t o r i n g t o supplement or indeed r e p l a c e many of these o l d e r p a t c h t e c h n i q u e s f o r e s t i m a t i n g dermal exposure ( 5 ) . B i o l o g i c a l m o n i t o r i n g , a s p e c i f i c form of m o n i t o r i n g of human exposure, can be used to determine i f an a g r i c u l t u r a l worker has been exposed to a c h e m i c a l and, i n s e l e c t e d c a s e s , the e x t e n t t o which exposure may have taken p l a c e . Measurements can be made i n a v a r i e t y of b i o l o g i c a l f l u i d s i n c l u d i n g u r i n e and b l o o d . The advantages of b i o l o g i c a l m o n i t o r i n g , when compared to c l a s s i c a l p a t c h t e c h n i q u e , l i e i n the a b i l i t y of t h i s approach to more a c c u r a t e l y e s t i m a t e body burden of the c h e m i c a l from a l l r o u t e s of exposure. L i m i t a t i o n s of t h i s t e c h n i q u e i n c l u d e i n d i v i d u a l p h a r m a c o k i n e t i c v a r i a b i l i t y (6) and a requirement f o r e x t e n s i v e knowledge on metabolism and d i s p o s i t i o n of the c h e m i c a l . The r e l i a b i l i t y of t h i s t e c h n i q u e i s t h e r e f o r e l i m i t e d by the g e n e r a l u n a v a i l a b i l i t y of such e x t e n s i v e d a t a f o r the m a j o r i t y of p e s t i c i d e s i n use today. Low c o n c e n t r a t i o n s of a m e t a b o l i t e i n u r i n e c o u l d be the r e s u l t of any one or c o m b i n a t i o n of the f o l l o w i n g : ( i ) the c h e m i c a l i s not w e l l absorbed; ( i i ) the c h e m i c a l i s absorbed but i s s e q u e s t e r e d i n the body; ( i i i ) the c h e m i c a l i s m e t a b o l i z e d i n t o a number of d i f f e r e n t m e t a b o l i t e s a l l of w h i c h are e x c r e t e d at low l e v e l s . I f the k i n e t i c s and metabolism of the c h e m i c a l are not w e l l understood i t would be p o s s i b l e to i n c o r r e c t l y conclude t h a t low l e v e l s of the measured m e t a b o l i t e i n u r i n e i n d i c a t e t h a t o n l y a s m a l l amount of the c h e m i c a l was absorbed. T h i s i n t u r n would r e s u l t i n an u n d e r e s t i m a t e of r i s k . In t h i s paper we w i l l focus on the use of b i o l o g i c a l m o n i t o r i n g f o r q u a n t i f y i n g exposure and w i l l d i s c u s s these cases which show how p r i o r knowledge of the metabolism of the c h e m i c a l can i n f l u e n c e the s u i t a b i l i t y of b i o l o g i c a l m o n i t o r i n g to p r e d i c t exposure. 1


356

BIOLOGICAL MONITORING FOR PESTICIDE EXPOSURE

1. CHEMICALS WHICH ARE RAPIDLY ABSORBED, NOT SEQUESTERED, AND EXCRETED IN URINE LARGELY UNMETABOLIZED ARE GOOD CANDIDATES FOR ESTIMATING EXPOSURE (2,4-D), An example of a c h e m i c a l t h a t i s a good c a n d i d a t e f o r e s t i m a t i n g exposure from b i o l o g i c a l m o n i t o r i n g i s 2,4-D. I t i s a broad spectrum a g r i c u l t u r a l h e r b i c i d e w i d e l y used throughout the world. I t s a b s o r p t i o n , d i s t r i b u t i o n and metabolism i n animals have been s t u d i e d by s e v e r a l a u t h o r s and r e p o r t e d i n t h e l i t e r a t u r e (7-14). The a b s o r p t i o n and e x c r e t i o n o f 2,4-D i n humans v i a the o r a l r o u t e have been i n v e s t i g a t e d i n a c o n t r o l l e d l a b o r a t o r y s i t u a t i o n . The f i r s t o f these s t u d i e s ( 9 ) i n v o l v e d a s i n g l e o r a l dose of 5 mg 2,4-D a c i d / k g body weight t o each of 5 v o l u n t e e r s . U r i n e was c o l l e c t e d over a p e r i o d o f 144 hours f o l l o w i n g i n g e s t i o n and t h e p e r c e n t a g e o f the o r a l dose of 2,4-D e x c r e t e d was then c a l c u l a t e d . I t was shown t h a t 2,4-D was e x c r e t e d u n m e t a b o l i z e d as f r e e o r g l u c u r o n i d e c o n j u g a t e d 2,4-D ( 9 ) . As can be seen from T a b l e I , complete r e c o v e r y o f the i n i t i a l dose was p o s s i b l e i n the f i r s t 96 h o u r s . I n a d d i t i o n , 70 t o 83% o f the i n g e s t e d 2,4-D was r e c o v e r e d i n t h e f r e e form. A l t h o u g h two s u b j e c t s e x c r e t e d up t o 26% as t h e c o n j u g a t e d form, two o t h e r s u b j e c t s e x c r e t e d no more than 10% o f t h e c o n j u g a t e and t h e r e m a i n i n g s u b j e c t e x c r e t e d o n l y f r e e 2,4-D. T h i s study i n man shows t h a t 2,4-D i s absorbed f o l l o w i n g o r a l a d m i n i s t r a t i o n and e l i m i n a t e d l a r g e l y as unchanged parent compound. I t has a l s o been shown i n man t h a t 6% o f a d e r m a l l y a p p l i e d dose o f 2,4-D a c i d i s absorbed ( 1 5 ) . R e s u l t s from our own l a b o r a t o r y ( u n p u b l i s h e d ) have a l s o shown t h a t 15% o f a d e r m a l l y a p p l i e d dose o f 2,4-D a c i d i s absorbed from rhesus monkey forearm and t h a t 29% o f the a p p l i e d dose i s absorbed from the forehand ( F i g u r e 2 ) . I t was a l s o shown t h a t 100% of an i n t r a v e n o u s dose was e x c r e t e d i n d i c a t i n g t h a t the compound was not sequestered ( 1 5 ) . The r e s u l t s r e p o r t e d above show t h a t 2,4-D i s a compound which i s absorbed by t h e o r a l and dermal r o u t e s , i s e x c r e t e d l a r g e l y as unchanged parent compound and i s not s e q u e s t e r e d . Although a d e f i n e d r e l a t i o n s h i p between t h e amount o f 2,4-D a p p l i e d d e r m a l l y and the c o n c e n t r a t i o n o f u r i n a r y m e t a b o l i t e has not been e s t a b l i s h e d , t h e type of i n f o r m a t i o n d e s c r i b e d above g i v e s one some c o n f i d e n c e i n c o n c l u d i n g t h a t low u r i n a r y m e t a b o l i t e l e v e l s i n workers r e f l e c t low absorbed doses. The r e l a t i o n s h i p between dermal exposure and 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 under normal use c o n d i t i o n s has been i n v e s t i g a t e d by Grover and h i s co-workers ( 1 6 ) . I n t h i s s t u d y , a t o t a l o f 9 farmers who r e p e a t e d l y sprayed 2,4-D were m o n i t o r e d d u r i n g normal s p r a y a p p l i c a t i o n s . I n a l l cases the t o t a l amount of 2,4-D a v a i l a b l e f o r a b s o r p t i o n was e s t i m a t e d u t i l i z i n g a standard p a t c h t e c h n i q u e , w h i l e a b s o r p t i o n was e s t i m a t e d by measuring 2,4-D i n u r i n e c o l l e c t e d f o r 96 hours f o l l o w i n g the l a s t exposure t o t h e chemical. The r e s u l t s a r e summarized i n T a b l e I I . As can be seen from the t a b l e t h e r e was a v e r y wide range o f c a l c u l a t e d dermal d e p o s i t i o n i n workers a p p l y i n g 2,4-D (75 t o 13,286 ug 2,4-D/kg s p r a y e d ) w h i l e t h e r e was a much narrower range o f u r i n a r y e x c r e t i o n of 2,4-D i n these same w o r k e r s . I t i s noteworthy t h a t d e p o s i t i o n



hrs

82

Free

1

2

103

21

Conjugate

* adapted from (9)

Total

0-96

SUBJECT

88

Free

88

-

Conjugate

70

Free

3

96

26

Conjugate

87

Free

4

92

5

Conjugate

83

93

Free

5

10

Conjugate

Table I . Percentages of 2,4-D (Free and Conjugate) Excreted i n Urine Following A Single Oral Dose of 5 mg/kg 2,4-D*

358


Food

NOEL Safety Factor

• Acceptable D a i l y Intake

- animal t o x i c i t y data generated using o r a l route of exposure - o r a l route of exposure to humans through food and water - i f T h e o r e t i c a l D a i l y Intake (TDI) i s l e s s than Acceptable D a i l y Intake (ADI), p e s t i c i d e may be safe f o r use on food

Workers

NOEL Safety Factor

• Acceptable D a i l y Exposure

- animal t o x i c i t y data generated using o r a l route of exposure - dermal route of exposure g e n e r a l l y the greatest f o r workers and bystanders - i f T h e o r e t i c a l D a i l y Exposure (TDE) i s l e s s than Acceptable D a i l y Exposure (ADE), p e s t i c i d e may be safe f o r use by a g r i c u l t u r a l workers.

F i g u r e 1.

Risk Estimation

A B

S 0 R P T 1 0 N 0

1

2

3

4

5

6

7

8

9 10 11 12 13 14

TIME (DAYS) 0

FOREHEAD FOREARM F i g u r e 2.

2,4-D

A c i d - % Recovery i n Monkeys


Wang et al.; Biological Monitoring for Pesticide Exposure ACS Symposium Series; American Chemical Society: Washington, DC, 1988. 75 391 1,529 13,286 1,339 444 1,572 951

CALCULATED DERMAL DEPOSITION OF ug 2,4-Da.e/Kg sprayed

11 6 14 3 17 17 33 17

a

CUMULATIVE URINARY EXCRETION OF ug 2,4-Da.e. /kg sprayed

T o t a l amount excreted during exposure period and f o r 4 days a f t e r l a s t exposure.

24 35 49 127 89 102 186 71

AMOUNT SPRAYED (kg a.e.)

• adapted front (16)

* Acid equivalent

a

B B B F D A G E

SUBJECT

Table I I . Cumulative Estimates of Dermal 2,4-Da.e.* Deposition and Urinary 2,4-Da.e. Excretion f o r Farmers Involved i n Spraying of 2,4-D BY Ground Rig.*

360


l e v e l s were n o t n e c e s s a r i l y c o r r e l a t e d w i t h t h e amount o f 2,4-D sprayed. These d a t a suggest t h a t compounds t h a t a r e r a p i d l y absorbed, not s e q u e s t e r e d and e x c r e t e d i n an unchanged form are w e l l s u i t e d t o the p r i n c i p l e o f b i o l o g i c a l m o n i t o r i n g and t h a t u r i n a r y m e t a b o l i t e l e v e l s may more a c c u r a t e l y r e f l e c t both exposure and body burden than would be e s t i m a t e d by more c l a s s i c a l patch t e c h n i q u e s . 2.

CHEMICALS FOR WHICH URINARY METABOLITES ARE QUANTITATIVELY RELATED TO DERMAL DOSE. (AZINPHOS-METHYL) Azinphos-methyl i s an i n s e c t i c i d e w i d e l y used f o r t h e c o n t r o l o f a v a r i e t y o f o r c h a r d i n s e c t s . E a r l y work w i t h organophosphorus i n s e c t i c i d e s has demonstrated t h a t i n humans (17-20) and i n r a t s (21-22) a r e l a t i o n s h i p e x i s t s between exposure t o organophosphorus p e s t i c i d e s and e x c r e t i o n o f a l k y l phosphate m e t a b o l i t e s . S p e c i f i c a l l y , i t has been shown (23) t h a t a z i n p h o s - m e t h y l i s degraded p r i m a r i l y i n m i c r o s o m a l and s o l u b l e f r a c t i o n s t o d i m e t h y l t h i o p h o s p h a t e (DMTP), d i m e t h y l phosphate (DMP) and t h e oxygen a n a l o g . The s t r u c t u r e o f a z i n p h o s - m e t h y l and t h e s i t e o f h y d r o l y s i s a r e shown i n F i g u r e 3. S t u d i e s u n d e r t a k e n i n our l a b o r a t o r y have examined t h e r e l a t i o n s h i p between i n c r e a s i n g doses o f t o p i c a l l y a p p l i e d a z i n p h o s - m e t h y l and t h e u r i n a r y e x c r e t i o n o f t h i s dose as DMTP ( m e t a b o l i t e ) i n r a t s (24) and i n man ( 2 5 ) . As can be seen from T a b l e I I I , d e r m a l l y a p p l i e d doses o f between 100 and 800 microgram per r a t r e s u l t e d i n a p p r o x i m a t e l y 10% o f t h e a p p l i e d dose b e i n g e x c r e t e d as DMTP m e t a b o l i t e . F o l l o w i n g o u r i n i t i a l o b s e r v a t i o n s t h a t a p p r o x i m a t e l y 10% o f a t o p i c a l l y a p p l i e d a z i n p h o s - m e t h y l dose i n r a t s c o u l d be r e c o v e r e d as u r i n a r y DMTP, a s i m i l a r i n v e s t i g a t i o n was u n d e r t a k e n i n man ( T a b l e I V ) . I t was shown t h a t a s i m i l a r 10:1 p r o p o r t i o n o f t h e d e r m a l l y a p p l i e d dose i n humans c o u l d be r e c o v e r e d as u r i n a r y DMTP m e t a b o l i t e . F u r t h e r , as can be seen from Table V, the r e l a t i o n s h i p between d e r m a l l y a p p l i e d dose and t h e amount o f DMTP m e t a b o l i t e e x c r e t e d was r e l a t i v e l y l i n e a r over a dermal dosage range o f 500 t o 6000 micrograms p e r p e r s o n . The r e s u l t s o b t a i n e d from b o t h t h e r a t and human i n v e s t i g a t i o n s have suggested t h a t t h e r e i s a q u a n t i t a t i v e r e l a t i o n s h i p between dermal dose and t h e p r o p o r t i o n o f t h i s dose t h a t c a n be r e c o v e r e d i n u r i n e as a DMTP m e t a b o l i t e . S p e c i f i c a l l y , these r e s u l t s suggest t h a t t h e r e i s a p p r o x i m a t e l y a 10 t o 1 r e l a t i o n s h i p between t h e dose t h a t i s a p p l i e d and t h e c o n c e n t r a t i o n o f u r i n a r y m e t a b o l i t e s ( T a b l e V ) . T h i s r e l a t i o n s h i p c a n be v e r y u s e f u l i n f i e l d m o n i t o r i n g o f a g r i c u l t u r a l workers i n t h a t i t a l l o w s e s t i m a t i o n o f dermal exposure s i m p l y by the d e t e r m i n a t i o n o f l e v e l s o f u r i n a r y m e t a b o l i t e s . I t s h o u l d , however, be noted t h a t w h i l e t h i s method may be u s e f u l f o r e s t i m a t i o n o f dermal exposure l e v e l s , u r i n a r y m e t a b o l i t e s may not be u s e f u l f o r purposes of e s t i m a t i n g r i s k . DMTP r e p r e s e n t s o n l y one o f s e v e r a l m e t a b o l i t e s formed on exposure t o a z i n p h o s - m e t h y l and may not r e f l e c t r e l a t i v e c o n c e n t r a t i o n s o f o t h e r b i o l o g i c a l l y i m p o r t a n t metabolites i n various species. 3. CHEMICALS WHICH UNDERGO COMPLEX METABOLISM AND WHERE DOSE AND ROUTE OF ADMINISTRATION MAY QUALITATIVELY QUANTITATIVELY AFFECT METABOLISM AND BIOLOGICAL OUTCOME (METHYLENE CHLORIDE). Mice exposed t o 3500 and 7000 mg/kg/6 h r day methylene c h l o r i d e (MC) by



8

5

5

3

100

200

400

800

Dermal

Dermal

Dermal

Dermal

Route

* Adapted from (24)

N

Dose (ug/rat)

8.3 15.5 34.8 73.6

12.2 23.0 18.9

48 hours

6.9

24 hours

86.1

81.7

11

9

37.3

9

36.4

91.2

120 hours

X Dose Excreted As DMTP

8

96 hours

X Dose

16.0

8.8

72 hours

Cumulative T o t a l (ug DMTP)

Table I I I . Excretion of DMTP Following Dermal Application of Azinphos-methyl i n Male Rats*


52 140

36 76

188 120

122 184

1,000

2,000

4,000

6,000

* adapted from (24)

82 25

246 322

264 270

104 76

80 180

110 41

48 hours

278 368

454 354

148 90

92 212

123 41

72 hours

Cumulative Total (ug DMTP)

24 hours

500

Dose (ug/person)

323

404

119

152

85

Average Total

5

10

6

15

17

% dose excreted as DMTP

Table IV. Excretion of DMTP Following Dermal Application of Azinphos-methyl to the Forearm of Human Volunteers*

o

w w

3

W H O

o ^ o

2 3

o

H

S o

P

5

o

ON

27. RITTER AND FRANKLIN

Azinphos-methyl:

Monitoring in Regulatory Process

s-(3,4-dihydro-4-oxobenzo [d]~ [ 123]-triazin-3-yl methyl)-0,O-dimethyl phosphorodithioate

-|—S-CHj

1

hydrolysis

Metabolite:

DMTP

Analysis:

Azinphos-methyl by HPLC

:

Metabolite by a modified shafik method to derlvatize alkyl phosphates followed by G.C. analysis

Figure 3

Table V.

Analysis of Azinphos-methyl by HPLC

Relationship Between Amount of DMTP Excreted and the Amount of Azinphos-methyl (A.M.) Applied*

Dermal Dose Range

Metabolite Excretion/ Amount A.M. Applied

Rat

100 - 800 ug

1 ug DMTP/10 ug A.M.

Human

500 - 6000 ug

1 ug DMTP/10 ug A.M.

* adapted from (25)


363

364


i n h a l a t i o n f o r 5 days/week demonstrated an excess o f h e p a t o c e l l u l a r adenomas/carcinomas as compared t o unexposed c o n t r o l s ( 2 6 ) . These r e s u l t s c o n t r a s t e d w i t h an e a r l i e r study conducted by t h e N a t i o n a l C o f f e e A s s o c i a t i o n (27) i n w h i c h mice exposed t o MC i n d r i n k i n g water a t c o n c e n t r a t i o n s l e a d i n g t o exposure o f 250 mg/kg/day showed no i n c r e a s e i n t h e i n c i d e n c e o f l i v e r tumours. There a r e two pathways i n v o l v e d i n t h e metabolism o f MC. R e l a t i v e tumour response a s s o c i a t e d w i t h these two pathways i s shown i n F i g u r e 4. The two pathways i n v o l v e d i n c l u d e t h e s a t u r a b l e mixed f u n c t i o n o x i d a s e (MFO) pathway and t h e g l u t a t h i o n e - s - t r a n s f e r a s e (GST) pathway. E s t i m a t e s of t h e c o n c e n t r a t i o n o f MC and t h e r a t e s o f each o f t h e two m e t a b o l i c pathways have been examined ( 2 8 ) . The r e s u l t s o f these s t u d i e s a r e g i v e n i n T a b l e V I and have shown t h a t w h i l e t h e r a t e o f the MFO pathway i s comparable i n the two s t u d i e s , the d e l i v e r e d dose by t h e GST pathway and p a r e n t compound c o n c e n t r a t i o n s d i f f e r s u b s t a n t i a l l y . T h i s would tend t o i m p l y t h a t t h e MFO pathway i s not r e s p o n s i b l e f o r t h e tumour i n d u c t i o n seen. F u r t h e r m o r e , i n v i e w o f the f a c t t h a t t h e r a t e o f t h e MFO pathway i s comparable i n b o t h t h e d r i n k i n g water and i n h a l a t i o n s t u d i e s , u t i l i z a t i o n o f t h i s m e t a b o l i c pathway a l o n e f o r t h e purpose o f assessment o f p o t e n t i a l r i s k would l e a d t o erroneous c o n c l u s i o n s ; i t c o u l d not be u t i l i z e d t o e x p l a i n the b i o l o g i c a l response seen i n the i n h a l a t i o n s t u d y but absent i n the d r i n k i n g water s t u d y . C l e a r l y , i n t h i s c a s e , t h e e x a m i n a t i o n o f the GST pathway i s o f paramount importance i n a s s e s s i n g t h e o v e r a l l r i s k a s s o c i a t e d w i t h exposure t o MC. The case o f methylene c h l o r i d e , demonstrates r a t h e r e l e g a n t l y t h e need f o r a thorough u n d e r s t a n d i n g o f m e t a b o l i s m p r i o r t o u t i l i z i n g m e t a b o l i t e l e v e l s as an i n d i c a t i o n o f exposure f o r t h e purpose o f e s t i m a t i n g r i s k . 100 •••

80

Multistage Model Prediction

o

Drinking Water Study

+

Inhalation Study

60 -

40

Saturation of MFO Path

20

0

1 I T 0.005 0.010 0.015

/

/

0.85

GST Activity (g/L/day)

Figure 4. Metabolism of methylene chloride. (Adapted from ref. 28.)


1.80


•adapted from (28)

0 3500 7000

0 60 125 185 250

Drinking water (mg/kg/day)

Inhalation (mg/kg/6 hr day)

Administered Dose

Route of Administration (dose u n i t s )

0.0 3.6 3.7

0.0 1.3 2.8 4.0 5.4

MFO Path (g/L/day)

0.00 0.85 1.80

0 0.003 0.007 0.011 0.016

0 360 770

0 1.3 2.9 4.6 6.4

Delivered Dose GST Path Parent Compound (g/L/day) (mg hr/L)

Table VI. Metabolism of Methylene Chloride i n Female Mice*

366


SUMMARY We b e l i e v e t h a t b i o l o g i c a l m o n i t o r i n g , s p e c i f i c a l l y u r i n a r y m e t a b o l i t e l e v e l s , c a n be used t o e s t i m a t e exposure i f t h e a b s o r p t i o n , d i s t r i b u t i o n , m e t a b o l i s m and e x c r e t i o n a r e known f o r the chemical. The r e l a t i o n s h i p between exposure and u r i n a r y m e t a b o l i t e l e v e l s a r e more e a s i l y u n d e r s t o o d f o r c h e m i c a l s t h a t a r e a b s o r b e d , not s e q u e s t e r e d and e x c r e t e d v i r t u a l l y u n m e t a b o l i z e d . Selection of a few such c h e m i c a l s f o r i n depth e v a l u a t i o n c o u l d l e a d t o a b e t t e r e s t i m a t i o n o f dermal exposure than t h a t p r e s e n t l y o b t a i n a b l e from patches. T h i s i n t u r n would a s s i s t i n t h e e v e n t u a l v a l i d a t i o n o f the concept o f a g e n e r i c approach t o e s t i m a t e s o f e x p o s u r e . I t must be emphasized t h a t measurement o f u r i n a r y m e t a b o l i t e l e v e l s f o l l o w i n g e x p o s u r e , i n t h e absence o f adequate i n f o r m a t i o n on a b s o r p t i o n , d i s t r i b u t i o n , m e t a b o l i s m and e x c r e t i o n , i s u s e l e s s . Under such c i r c u m s t a n c e s , i t c o u l d not be d e t e r m i n e d whether a low c o n c e n t r a t i o n o f m e t a b o l i t e i n u r i n e was due t o poor a b s o r p t i o n (and t h e r e f o r e low r i s k ) , whether i t was w e l l absorbed and s e q u e s t e r e d w i t h i n t h e body o r whether t h e c h e m i c a l was w e l l absorbed and e x c r e t e d as many m e t a b o l i t e s , not a l l o f which were known o r measured. Another p o s s i b i l i t y would be t h a t e x c r e t i o n had taken place v i a other routes. Acknowledgments: The a u t h o r s g r a t e f u l l y m a n u s c r i p t by Wendy M i l k s .

acknowledge t h e t y p i n g o f t h i s

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Use of Biological Monitoring in the Regulatory Process - ACS

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