Biological Monitoring for Pesticide Exposure - American Chemical

Chapter 23

Assessing Risk for Humans on the Basis of Animal Toxicology Data Use of Dermal Absorption Data for Animal Studies

Downloaded by TUFTS UNIV on June 3, 2018 | https://pubs.acs.org Publication Date: December 23, 1988 | doi: 10.1021/bk-1988-0382.ch023

E. J . Hixon Data Evaluation Department, Health, Environment and Safety, Mobay Corporation, Stilwell, KS 66085

A method is presented for predicting dermal absorption of a chemical by man based on data collected in animal studies. The data from dermal absorption studies in animals can be fit to the most appropriate equation based on statistical tests. Once the equation has been fit, the coefficients for the parameters of the equation can be estimated. These parameters can then be used to estimate the amount of applied material that is absorbed. After field exposure studies have determined the amount of material contacting the skin and the time of exposure for the workers, the parameter estimates can be used to estimate the amount of the material that will be absorbed. The absorbed dose can then be compared to available toxicology data for hazard determination. One o f t h e most d i f f i c u l t a s p e c t s o f r i s k assessment i s e s t i m a t i n g the r i s k o f c h e m i c a l exposure f o r humans based on a n i m a l t o x i c i t y data. T h i s e s t i m a t i o n i s even more d i f f i c u l t when the a n i m a l study data a r e c o l l e c t e d u s i n g a d i f f e r e n t r o u t e o f exposure than t h a t expected f o r humans. A case i n p o i n t i s e s t i m a t i n g t h e r i s k f o r p e s t i c i d e a p p l i c a t o r s . The a n i m a l t o x i c i t y database f o r a p e s t i c i d e c o n s i s t s l a r g e l y o f data c o l l e c t e d i n f e e d i n g s t u d i e s . The o n l y s t u d i e s a v a i l a b l e t o address t h e r o u t e s o f exposure a p p r o p r i a t e f o r a p p l i c a t o r s a r e t y p i c a l l y a s i n g l e subacute dermal study and (sometimes) a subacute i n h a l a t i o n s t u d y . These s t u d i e s a r e o f t e n conducted u s i n g treatment f i v e days per week, whereas t h e exposure to t h e a p p l i c a t o r may be d a i l y f o r an extended p e r i o d . Subacute studies rarely last longer than three weeks, whereas t h e applicators exposure may be l o n g e r . These d i s c r e p a n c i e s can make i t d i f f i c u l t t o compare t h e exposure s i t u a t i o n t o t h e a n i m a l d a t a . 1

c

0097-6156/89/0382-0304$06.00/0 1989 American Chemical Society

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


23. HIXON

Assessing Risk for Humans

305

In the p a s t few y e a r s i t has become common t o p e r f o r m a dermal a b s o r p t i o n s t u d y t o determine the e x t e n t t o which a material in c o n t a c t w i t h the s k i n i s absorbed i n t o the g e n e r a l c i r c u l a t i o n . The i n t e n t has been t o use the dermal a b s o r p t i o n s t u d y as a basis for c a l c u l a t i o n o f the dose t o which an i n d i v i d u a l i s exposed. Once the dose " d e l i v e r e d " has been d e t e r m i n e d , a n i m a l s t u d i e s u s i n g any r o u t e of administration could theoretically be used t o e s t i m a t e the l i k e l i h o o d of t o x i c i t y . S e v e r a l p r o t o c o l s have been used t o determine dermal a b s o r p t i o n of a chemical (pesticide). A l l the p r o t o c o l s have a t l e a s t one major d i f f e r e n c e from the way dermal exposure a c t u a l l y o c c u r s i n the field. In the animal studies a measured amount o f m a t e r i a l i s a p p l i e d t o the t r e a t e d s k i n a r e a and l e f t i n c o n t a c t w i t h the skin for a s p e c i f i e d p e r i o d of time. I n c o n t r a s t , an i n d i v i d u a l w o r k i n g i n the f i e l d has a graded exposure to a s l o w l y but steadily increasing amount of m a t e r i a l . The "dose" s t a r t s out r e l a t i v e l y s m a l l and i n c r e a s e s s t e a d i l y throughout the exposure p e r i o d . In s t u d i e s conducted t o measure the exposure o f workers under field conditions, i t i s s t a n d a r d t o measure the t o t a l amount o f m a t e r i a l on the s k i n a t the end o f the exposure p e r i o d and d i v i d e by the number o f hours (or m i n u t e s ) of exposure t o e x p r e s s the exposure as mass of m a t e r i a l d e p o s i t e d per u n i t t i m e . T h i s measure has been referred to i n some c a s e s as the " r a t e " of dermal exposure. In c o n t r a s t , animal studies may determine the amount o f material absorbed (usually as the amount a p p e a r i n g i n the u r i n e ) p e r u n i t t i m e , and r e f e r t o t h i s as the " r a t e " o f dermal a b s o r p t i o n . C l e a r l y these two "rates" do n o t r e f e r t o the same phenomenon, and s h o u l d not be c o n s i d e r e d comparable. D e s p i t e t h i s key d i f f e r e n c e i n the way the d a t a a r e collected, it i s p o s s i b l e to use the a n i m a l dermal a b s o r p t i o n d a t a t o e s t i m a t e the amount o f a p p l i e d m a t e r i a l a b s o r b e d by an exposed individual. The purpose of this paper i s to p r e s e n t a method f o r making t h i s determination. Dermal A b s o r p t i o n P r o c e s s e s S t u d i e s conducted i n a n i m a l s ( 1 ) and w i t h human v o l u n t e e r s ( 2 ) have clearly demonstrated t h a t the amount o f m a t e r i a l absorbed tends t o i n c r e a s e as the amount applied increases. Several studies have demonstrated that the p e r c e n t absorbed d e c r e a s e s w i t h i n c r e a s i n g dose; however the a b s o l u t e mass absorbed tends to increase ( 1 ) . This may not be, and i n fact u s u a l l y i s not, a l i n e a r process. S i m i l a r r e s u l t s have been o b s e r v e d w i t h r e s p e c t t o t i m e . The amount of material absorbed a c r o s s the skin generally increases with i n c r e a s i n g time of c o n t a c t w i t h the s k i n ( 3 - 4 ) . I t i s not uncommon f o r the amount o f a b s o r p t i o n t o p l a t e a u a f t e r a t i m e . Clearly i t i s necessary f o r dermal absorption studies i n animals to take into account both dose and time. I t i s not practical i n the laboratory s e t t i n g t o a p p l y i n c r e a s i n g doses to e x p e r i m e n t a l a n i m a l s , p a r t i c u l a r l y when the s t u d y i s b e i n g done w i t h radio-labeled material. I t i s p r a c t i c a l , however, t o use more than one dose, and t o l o o k a t more than one time p o i n t a f t e r a p p l i c a t i o n . The protocol outlined by R. P. Z e n d z i a n a d d r e s s e s b o t h o f t h e s e needs ( 5 ) . B r i e f l y , groups o f a n i m a l s a r e t r e a t e d w i t h one of at


306

BIOLOGICAL MONITORING FOR PESTICIDE EXPOSURE

least t h r e e doses o f m a t e r i a l w i t h t h e doses spaced a t l o g i n t e r v a l s . The a p p l i c a t i o n a r e a s a r e c o v e r e d and t h e a n i m a l s a r e placed i n metabolism cages f o r c o l l e c t i o n o f u r i n e and f e c e s . A t i n t e r v a l s o f 0.5, 1, 2, 4, 10 and 24 hours a f t e r application subgroups o f a n i m a l s from each t r e a t e d group a r e s a c r i f i c e d f o r d e t e r m i n a t i o n o f r a d i o a c t i v i t y r e m a i n i n g i n s k i n and c a r c a s s . The amount o f m a t e r i a l absorbed i s determined based on t h e amounts o f r a d i o a c t i v i t y e x c r e t e d and t h a t r e m a i n i n g i n t h e c a r c a s s .


M a t h e m a t i c a l Treatment

of Results

A l l a n a l y s e s were done u s i n g s o f t w a r e o f SAS I n s t i t u t e I n c . , Cary, NC. T a b l e I p r e s e n t s d a t a c o l l e c t e d i n a study u s i n g t h e Z e n d z i a n p r o t o c o l w i t h f o u r l o g a r i t h m i c a l l y spaced doses and time p o i n t s up to 24 h o u r s . The d a t a from a dermal a b s o r p t i o n s t u d y conducted according t o the Zendzian p r o t o c o l w i l l c o n t a i n two independent v a r i a b l e s , dose and t i m e , as w e l l as t h e dependent v a r i a b l e , t h e amount absorbed. The f i r s t t e s t t o be done on t h e d a t a i s t o determine whether linear or quadratic r e g r e s s i o n i s most a p p r o p r i a t e . S i n c e we know from s e p a r a t e e x p e r i m e n t s that the amount absorbed i n c r e a s e s w i t h b o t h time o f exposure and dose, we might expect t o f i n d an i n t e r a c t i o n o f these two f a c t o r s when e f f e c t s of both a r e i n v e s t i g a t e d simultaneously. Thus i t i s i m p o r t a n t t h a t t h e d a t a from each experiment be t e s t e d f o r q u a d r a t i c response.

T a b l e I . Dermal A b s o r p t i o n T e s t Data

(Time) 0.5 1.0 2.0 4.0 10 24

0.04

Dose (mg/kg) 4.0

0.4

.00348 .00277 .00378 .00428 .00498 .00519

a

40 4.77 4.56 5.05 4.44 5.20 5.06

.312 .303 .308 .348 .402 .449

.0267 .0319 .0319 .0323 .0452 .0440

Amount absorbed i n mg e q u i v a l e n t s

T h i s t e s t c a n be done e a s i l y u s i n g t h e SAS procedure RSREG. T h i s procedure f i t s t h e parameters o f a q u a d r a t i c response s u r f a c e (6). The e q u a t i o n d e s c r i b i n g t h e response s u r f a c e i s shown h e r e : 2 y = BQ+ n x ]

l

+ B x 2

+ B x

2

3

x

2 + B x 4

2

+ B x x 5

x

2

where x i s t h e dose a p p l i e d , x i s t h e time o f exposure, B Q i s t h e i n t e r c e p t and B ^ , B e t c . a r e t h e c o e f f i c i e n t s o f each term. The RSREG procedure w i l l p e r f o r m a t e s t t o determine how much o f t h e r e s i d u a l e r r o r i s due t o l a c k o f f i t . T h i s f i t t e s t can be used t o determine whether a q u a d r a t i c response b e s t d e s c r i b e s t h e r e s u l t s . 2

2



23. HIXON


307

These d a t a were t e s t e d u s i n g the RSREG p r o c e d u r e , and the r e s u l t s are shown i n T a b l e I I . The procedure^ a p p l i e s f i r s t a l i n e a r r e g r e s s i o n , then adds the q u a d r a t i c terms ( x ^ and x ^ ) , then adds the c r o s s p r o d u c t ( x ^ ) . I n t e s t i n g f o r l a c k of f i t , the procedure RSREG p a r t i t i o n s the t o t a l e r r o r i n t o l a c k of f i t and pure e r r o r . When l a c k of f i t i s s i g n i f i c a n t l y d i f f e r e n t from pure e r r o r , then t h e r e i s v a r i a t i o n i n the model not accounted f o r by random e r r o r . As can be seen from T a b l e I I , l a c k o f f i t i s s i g n i f i c a n t l y d i f f e r e n t from pure e r r o r f o r the t e s t d a t a s e t . T h i s i n d i c a t e s t h a t a q u a d r a t i c response mgdel does not f i t the d a t a , d e s p i t e the apparently favorable R values. Now we a r e f r e e t o p e r f o r m a s i m p l e l i n e a r r e g r e s s i o n on the d a t a . The b e s t way t o approach the d a t a next i s t o determine whether e i t h e r o r b o t h of the independent v a r i a b l e s (dose and time) have an e f f e c t on the dependent v a r i a b l e (amount absorbed). Examining the d a t a i n T a b l e I shows t h a t , w h i l e t h e r e appears t o be a r e a s o n a b l e r e l a t i o n s h i p between dose and amount absorbed, the r e l a t i o n s h i p between time and amount absorbed i s not so c l e a r . We can t e s t t h i s u s i n g the SAS procedure RSQUARE. T h i s procedure f i n d s the subset of independent v a r i a b l e s t h a t tjest p r e d i c t s the amount absorbed based on the optimum v a l u e o f R , the c o e f f i c i e n t of determination (7). The r e s u l t s o b t a i n e d when the d a t a i n Table I were t e s t e d u s i n g the RSQUARE procedure are shown i n T a b l e I I I . C l e a r l y u s i n g time as the s o l e r e g r e s s o r r e s u l t e d i n a poor f i t of the d a t a ; i n o t h e r words, the amount absorbed d i d not c o r r e l a t e v e r y w e l l w i t h time alone. I n c o n t r a s t , a good f i t was a c h i e v e d u s i n g dose as the s o l e r e g r e s s o r . However, the s t a t i s t i c s f o r the r e g r e s s i o n analysis u s i n g b o t h dose and time i s s l i g h t l y b e t t e r t h a n t h a t u s i n g dose a l o n e . T h e r e f o r e , a l t h o u g h the e f f e c t o f time i s s m a l l i t does appear t o improve the f i t o f the c u r v e t o the d a t a , so we are b e t t e r o f f i n c l u d i n g the time f a c t o r i n our a n a l y s i s . Now t h a t we have l e a r n e d t h a t a r e g r e s s i o n u s i n g b o t h dose and time r e s u l t s i n a c u r v e t h a t b e s t f i t s the amount absorbed, we are f r e e t o p e r f o r m a s i m p l e l i n e a r r e g r e s s i o n u s i n g these two independent variables. T h i s was done u s i n g the SAS procedure REG. The REG procedure f i t s l e a s t - s q u a r e s e s t i m a t e s t o l i n e a r regression models (8). For our d a t a w i t h two independent v a r i a b l e s , the e q u a t i o n t h a t i s f i t t e d t o the d a t a i s r e p r e s e n t e d by: y = B

Q

+ B

l X l

+ B x 2

2

The p r o c e d u r e REG w i l l e s t i m a t e the v a l u e s of B^, B^ and B^ and will compare the a c t u a l d a t a t o the responses p r e d i c t e d by the model. By comparing the p r e d i c t e d v a l u e s t o those a c t u a l l y o b t a i n e d we can examine the f i t o f the c u r v e t o the d a t a o b t a i n e d . T h i s comparison i s shown i n Table IV. From examining T a b l e IV i t i s c l e a r t h a t f o r t h i s t e s t d a t a s e t the f i t of the p r e d i c t e d v a l u e s t o the a c t u a l v a l u e s i s not good a t v e r y low d o s e / s h o r t time c o m b i n a t i o n s . At these p o i n t s the p r e d i c t e d v a l u e s are n e g a t i v e numbers, which cannot o c c u r i n the r e a l w o r l d . A c t u a l exposure doses i n mg/kg/day can e a s i l y be i n the range of these low doses, however, so i t i s i m p o r t a n t t o f i n d a way


Wang et al.; Biological Monitoring for Pesticide Exposure ACS Symposium Series; American Chemical Society: Washington, DC, 1988. 0.331 0 0.331

18

0

18

Lack o f F i t

Pure E r r o r

Total Error

SS

DF

100.660

RESIDUAL

T o t a l Regress

0.0184

0

0.0184

MEAN SQUARE

0.9967

0.0007

0.0747

Crossproduct

R-SQUARE 0.9952 0.0008

TYPE I SS 100.506 0.0804

DF

Quadratic

REGRESSION Linear

T a b l e I I . RESULTS OF THE RSREG PROCEDURE


PROB 1.0000

9999.990

0.0001

0.0589

0.1412

PROB 0.0001

F-RATIO

1095.18

4.07

2.19

F-RATIO 2733.72

o

o w w o

NH

o

NH

H

3

O

2

H O

o

r

9

NH

O

5

O

00


0.04 Actual Predicted .00348 -.0814 .00277 -.0784 .00378 -.0722 .00428 -.0599 .00498 -.0230 .00519 .0630 Actual .0267 .0319 .0319 .0323 .0452 .0440

A c t u a l o r p r e d i c t e d amount absorbed i n mg

Time o f Exposure (Hours) 0.5 1.0 2 4 10 24

-0.0894

0.9952

2

A

equivalents

Predicted -.0375 -.0344 -.0282 -.0160 .0209 .107

Actual .312 .303 .308 .348 .402 .449

Dosage A p p l i e d (mg/kg) 4 Predicted .402 .405 .411 .424 .461 .547

Values

0.12

0.12

Actual 4.77 4.56 5.04 4.44 5.20 5.06

PARAMETER ESTIMATES XI

T a b l e I V . Comparison o f A c t u a l v s P r e d i c t e d

-0.0469

INTERCEPT 1.2674

0.9946

R-SQUARE 0.0006

1

NUMBER IN MODEL 1

T a b l e I I I . RESULTS OF THE RSQUARE PROCEDURE


40 Predicted 4.80 4.80 4.81 4.82 4.86 4.94

0.0061

X2 0.0061

310


t o p r e d i c t the amount absorbed a t these low doses. One possibility i s t o do the s t a t i s t i c s on t h e d a t a from j u s t t h e two lower doses. The r e s u l t s o f the RSREG p r o c e d u r e a g a i n showed t h a t the q u a d r a t i c model does n o t f i t the d a t a w e l l ( d a t a not shown). The RSQUARE procedure i n d i c a t e d a g a i n t h a t time a l o n e does n o t f i t the d a t a w e l l but does improve s l i g h t l y the f i t of the d a t a compared t o u s i n g dose as the s o l e r e g r e s s o r ( d a t a n o t shown). I n T a b l e V t h e REG results are shown u s i n g o n l y t h e two l o w e s t dosages of 0.04 and 0.4 mg/kg. T h i s time the p r e d i c t e d v a l u e s agree v e r y w e l l w i t h the a c t u a l values.


T a b l e V.

Comparison o f A c t u a l v s P r e d i c t e d V a l u e s U s i n g the Two Lowest Dosages Dosage A p p l i e d (mg/kg)

Time of Exposure (Hours) 0.5 1.0 2 4 10 24

Actual .00348 .00277 .00378 .00428 .00498 .00519

0.04 Predicted .00162 .00181 .00220 .00296 .00526 .0106

(K4 a

Actual .0267 .0319 .0319 .0323 .0452 .0440

Predicted .0329 .0331 .0335 .0342 .0365 .0419

3

A c t u a l o r p r e d i c t e d amount absorbed i n mg e q u i v a l e n t s REG S t a t i s t i c s Intercept: -0.0020 Bit 0.08 B : 0.0004 R: 0.95 2

2

The same p r o c e d u r e s were done u s i n g the d a t a from o n l y the two m i d d l e dosages o f 0.4 and 4 mg/kg. As e x p e c t e d , the RSREG p r o c e d u r e i n d i c a t e d t h a t the q u a d r a t i c model does n o t f i t the d a t a w e l l ( d a t a not shown). The RSQUARE procedure showed a g a i n t h a t r e g r e s s i o n based on time o f exposure alone does n o t f i t the d a t a w e l l , but t h a t time and dose t o g e t h e r p r o v i d e a s l i g h t l y b e t t e r f i t than u s i n g dose alone ( d a t a n o t shown). The r e s u l t s o f t h e REG p r o c e d u r e a r e shown i n T a b l e V I : a g a i n t h e p r e d i c t e d v a l u e s agree r e a s o n a b l y well with the a c t u a l v a l u e s . F i n a l l y , t h e d a t a from the h i g h e s t two dosages were t e s t e d . The q u a d r a t i c model d i d n o t f i t the d a t a , and i n t h i s case time p r o v i d e d o n l y a m i n i s c u l e e f f e c t on the r e g r e s s i o n r e s u l t s ( d a t a n o t shown). Table V I I presents the r e s u l t s of the REG p r o c e d u r e , and a g a i n i t can be seen t h a t the p r e d i c t e d v a l u e s agree w i t h the a c t u a l v a l u e s . Discussion The s t a t i s t i c s from the t h r e e s e t s of d a t a a r e summarized i n V I I I . S e v e r a l i n t e r e s t i n g o b s e r v a t i o n s can be made from these


Table data.

23. HIXON


311

F i r s t , the i n t e r c e p t (or B ) appears t o be a c o n s t a n t d i s t a n c e from the l o w e s t dosage c o n s i d e r e d i n t h e c a l c u l a t i o n s . Second, the e f f e c t o f time ( B ) appears t o i n c r e a s e w i t h i n c r e a s i n g dosage. ?


Table VI.

Comparison of A c t u a l v s P r e d i c t e d V a l u e s U s i n g the Two M i d d l e Dosages Dosage A p p l i e d (mg/kg)

Time of Exposure (Hours) 0.5 1.0 2 4 10 24

Actual .0267 .0319 .0319 .0323 .0452 .0440

0.4 Predicted .0129 .0146 .0181 .0251 .0461 .0952

4 Predicted .331 .333 .337 .344 .365 .414

Actual .312 .303 .308 .348 .402 .449

A c t u a l or p r e d i c t e d amount absorbed i n mg e q u i v a l e n t s REG S t a t i s t i c s I n t e r c e p t : -0.02 B: 0.09 B: 0.003 R: 0.97 x

2

2

Table V I I .

Comparison of A c t u a l vs P r e d i c t e d V a l u e s U s i n g the Two H i g h e s t Dosages Dosage A p p l i e d (mg/kg)

Time o f Exposure (Hours) 0.5 1.0 2 4 10 24

40

4 Actual .312 .303 .308 .348 .402 .449

Predicted .277 .283 .295 .319 .390 .557

Actual 4.77 4.56 5.05 4.44 5.20 5.06

Predicted 4.77 4.78 4.79 4.81 4.88 5.05

3

A c t u a l or p r e d i c t e d amount absorbed i n mg e q u i v a l e n t s REG S t a t i s t i c s I n t e r c e p t : -0.23 Bj: 0.12 B: 0.012 R: 0.99 2

2



312


T h i r d , the e f f e c t of dose (B-) appears t o be r e l a t i v e l y c o n s t a n t , a l t h o u g h i t may i n c r e a s e v e r y s l i g h t l y w i t h i n c r e a s i n g t i m e . Thus f o r t h i s p a r t i c u l a r d a t a s e t the e f f e c t of time appears t o be e x t r e m e l y s m a l l u n t i l the dosages get f a i r l y l a r g e . A dosage of 4 mg/kg f o r a 60 kg i n d i v i d u a l r e p r e s e n t s a t o t a l exposure of 240 mg, w h i l e a t 40 mg/kg the t o t a l exposure would be 2400 mg. These a r e p r o b a b l y l a r g e r than most of the a c t u a l exposures under normal c o n d i t i o n s o f use. Thus f o r average exposure conditions this a n a l y s i s of these d a t a i n d i c a t e s t h a t we can v i r t u a l l y i g n o r e the d u r a t i o n of exposure and m e r e l y c o n s i d e r the t o t a l dose of m a t e r i a l a p p l i e d t o the s k i n . Under these c i r c u m s t a n c e s i t might be a p p r o p r i a t e t o use the e s t i m a t e d v a l u e o f B^ as a measure of the f r a c t i o n of the a p p l i e d dose t h a t we would expect t o be absorbed. I n o t h e r words, u s i n g the r e s u l t s from the two l o w e s t dosages as an example (Table V I I I ) , we might expect t h a t 0.08, o r 8%, of the a p p l i e d dose would be absorbed r e g a r d l e s s of time o f exposure. T h i s approach can o n l y be used when the e f f e c t o f time i s m i n i s c u l e , as i s the case a t these low dosages f o r t h i s d a t a s e t .

T a b l e V I I I . Summary of S t a t i s t i c s f o r Three Data S e t s Model: Y = B + B. (Dose) + B (Time) n

Intercept

Lowest Dosages -0.002

9

Middle Dosages -0.02

Highest Dosages -0.23

Bi

0.08

0.09

0.12

B

0.0004

0.003

0.012

0.95

0.97

0.99

R

2

G i v e n t h a t these d a t a can be f i t t o a model b e t t e r when not a l l the dosages a r e used a t once, i t c l e a r l y becomes e x t r e m e l y i m p o r t a n t t h a t the dosages used i n the a n i m a l s t u d y b r a c k e t as c l o s e l y as p o s s i b l e the a n t i c i p a t e d range of exposures i n the f i e l d . The data might be e a s i e r t o f i t t o a model i f the dosages used were spaced more c l o s e l y than one l o g a p a r t . For example, dosages spaced at h a l f l o g i n t e r v a l s might g i v e us a b e t t e r f i t , a l t h o u g h the r e s u l t s i n T a b l e V I I I showed o n l y s m a l l d i f f e r e n c e s i n the B ^ and B ^ v a l u e s between the t h r e e s e t s of r e g r e s s i o n d a t a . I t i s o b v i o u s from the r e s u l t s p r e s e n t e d t h a t the p e s t i c i d e used t o produce these d a t a i s not p a r t i c u l a r l y w e l l absorbed r e g a r d l e s s of a p p l i e d dose o r time of exposure. Another compound t h a t i s b e t t e r absorbed might produce a c o m p l e t e l y d i f f e r e n t s e t of statistics. F o r example, one might f i n d t h a t the q u a d r a t i c model f i t a d a t a s e t q u i t e w e l l . I n e i t h e r c a s e , by s u b s t i t u t i n g the e s t i m a t e s o f B Q , B ^ , B « e t c . i n t o the model e q u a t i o n one can determine the a c t u a l amount absorbed u s i n g the amount of dermal exposure measured i n a f i e l d s t u d y as the dose (x^) and the time over w h i c h the exposure was measured as the time ( x ^ ) . I n t h i s way we can take advantage o f the dose and time e f f e c t s noted i n our


23. HIXON

313



a n i m a l s t u d i e s and a p p l y these e f f e c t s t o human exposure. An example o f such c a l c u l a t i o n s i s shown i n Table I X . Here the estimates of and B^ from the r e g r e s s i o n u s i n g t h e two l o w e s t dosages are used because the amount of m a t e r i a l a p p l i e d t o the s k i n i s i n the range o f these dosages. By s u b s t i t u t i n g t h e amount a p p l i e d and the time of exposure i n t o the model e q u a t i o n , the amount absorbed i s p r e d i c t e d t o be 0.009 mg e q u i v a l e n t s of m a t e r i a l . Thus it c a n be easy t o p r e d i c t the amount absorbed once we have the c o r r e c t r e g r e s s i o n parameter e s t i m a t e s . The c a l c u l a t i o n s would be done i n a s i m i l a r f a s h i o n i f the q u a d r a t i c model were found to f i t the d a t a b e s t , a l t h o u g h i t would be s l i g h t l y more c o m p l i c a t e d .

Table IX. E s t i m a t i n g Human Exposure U s i n g A n i m a l Study Data Human Data T o t a l Dermal Exposure: Body Weight o f S u b j e c t : Dosage A p p l i e d : Time of Exposure:

Study Data Intercept:

6 mg 60 k g 0.1 mg/kg 8 hours

-0.002 0.08 0.0004

Bi:

B: 2

Amount Absorbed - (0.8)(0.1) + (.0004)(8) - .002 = .009 mg e q u i v a l e n t s

T h i s p r e s e n t a t i o n has c e n t e r e d around a s i n g l e d a t a s e t , and c e r t a i n procedures were f o l l o w e d based on the c h a r a c t e r i s t i c s o f these d a t a . The i m p o r t a n t t h i n g t o remember i s t h a t each d a t a s e t s h o u l d be c o n s i d e r e d u n i q u e , and the t e s t s s h o u l d be a p p l i e d t o each s e q u e n t i a l l y t o determine how b e s t t o proceed. To summarize these steps: 1.

2.

3.

Because t h e r e w i l l always be two independent v a r i a b l e s , the d a t a s h o u l d always be t e s t e d u s i n g q u a d r a t i c and c r o s s - p r o d u c t models. Simple l i n e a r r e g r e s s i o n s h o u l d not be attempted u n t i l you a r e s a t i s f i e d t h a t a more complex e q u a t i o n w i l l not f i t t h e data. Regardless o f t h e type o f r e g r e s s i o n , whether q u a d r a t i c o r l i n e a r , p r e d i c t e d v a l u e s s h o u l d be compared t o a c t u a l v a l u e s t o be sure the e q u a t i o n works i n the r e a l w o r l d . I t may be n e c e s s a r y t o p e r f o r m r e g r e s s i o n s on o n l y p a r t of your d a t a s e t t o g i v e a good f i t t h a t works i n the r e a l w o r l d . You can o n l y j u s t i f y o m i t t i n g p a r t of your d a t a i f the parameters o f the exposure s i t u a t i o n f i t w i t h i n the range o f the d a t a you use.


314


In c o n c l u s i o n , t h e a v a i l a b i l i t y o f dermal a b s o r p t i o n study d a t a g r e a t l y enhances our a b i l i t y t o p e r f o r m proper and r e a s o n a b l e h a z a r d assessments f o r f i e l d w o r k e r exposure. The flowscheme f o r d a t a a n a l y s i s proposed here i s i n t e n d e d t o s t a n d a r d i z e o u r approach t o these d a t a , t o m i n i m i z e improper use o f t h e d a t a and t o p r o v i d e a more e f f e c t i v e t o o l f o r human h a z a r d assessment.


N o n t e c h n i c a l Summary Dermal a b s o r p t i o n s t u d i e s conducted i n a n i m a l s u s i n g the Z e n d z i a n p r o t o c o l p r o v i d e l a r g e s e t s o f d a t a . These d a t a must be a n a l y z e d c a r e f u l l y f o r p r o p e r use i n p r e d i c t i n g t h e amount o f m a t e r i a l an exposed worker might absorb a c r o s s t h e s k i n . The d a t a must f i r s t be t e s t e d a g a i n s t a q u a d r a t i c model t o determine t h e e f f e c t o f dose, time and dose p l u s t i m e . I f t h e q u a d r a t i c model does n o t f i t , a s i m p l e l i n e a r r e g r e s s i o n can be performed. R e g a r d l e s s o f t h e type of r e g r e s s i o n , the model c a n be used t o e s t i m a t e t h e c o e f f i c i e n t o f dose and t i m e . These c o e f f i c i e n t s can then be used t o c a l c u l a t e the p r e d i c t e d amount o f m a t e r i a l absorbed a f t e r a g i v e n exposure.

Literature Cited 1. 2. 3. 4. 5. 6. 7. 8.

Shah, P. V.; Fisher, H.; Sumler, M.; Monroe, R.; Chernoff, N.; Hall, L. J. Toxicol. Env. Health 1987, 21, 353-366. Wester, R. C.; Maibach, H. J . Toxicol. Env Health 1985, 16, 25-37. Burka, L. T.; Sanders, J . ; Kool, C.; Kim, Y.; Matthews, H. Toxicol. Appl. Pharmacol. 1987, 87, 121-126. Feldmann, R. J.; Maibach, H. Toxicol. Appl. Pharmacol., 1974, 28, 126-132. Zendzian, R. P. Procedure for Studying Dermal Absorption; Third edition revised June 14, 1985; California Modifications, October 9, 1985. SAS Institute Inc. SAS User's Guide: Statistics, Version 5 Edition. SAS Institute Inc.: Cary, 1985; Chapter 33. SAS Institute Inc. SAS User's Guide: Statistics, Version 5 Edition. SAS Institute Inc.: Cary, 1985; Chapter 32. SAS Institute Inc. SAS User's Guide: Statistics, Version 5 Edition. SAS Institute Inc.: Cary, 1985; Chapter 31

RECEIVED March

23, 1988


Biological Monitoring for Pesticide Exposure - American Chemical

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