Percutaneous Absorption in Rhesus Monkeys and Estimation of

Chapter 12

Percutaneous Absorption in Rhesus Monkeys and Estimation of Human Chemical Exposure 1

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Ronald C. Wester , James McMaster , Daniel A. W. Bucks , Eugene M . Bellet , and Howard I. Maibach 2

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Department of Dermatology, University of California School of Medicine, San Francisco, CA 94143 Chemical Consultants International, Overland Park, KS 66204

Downloaded by TUFTS UNIV on June 3, 2018 | https://pubs.acs.org Publication Date: December 23, 1988 | doi: 10.1021/bk-1988-0382.ch012

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Skin absorption estimate is dependent upon animal model for predicting human health hazard for a chemical entering the body through skin. An example is Dinoseb, which, when applied to skin of rats (acetone vehicle; 72 hr exposure) is 90% absorbed. The literature shows absorption through rat skin to be much higher than in man. Dinoseb applied to the skin of rhesus monkeys (Premerge-3; 24 hr exposure) gave absorption of less than 10 percent. Balance in the monkey study accounted for greater than 80 percent of the applied dose, the majority of which was unabsorbed Dinoseb removed from the skin with the post 24 hr soap and water wash. Comparative absorption data for other chemicals show skin absorption in rhesus consistent with man. Central to the determination of human health hazard effects for skin exposure of chemicals is the estimate for percutaneous absorption. This value estimates the rate and extent that a chemical will penetrate the living human epidermis and becomes systemically available for distribution in the human body. Percutaneous absorption is a complex process involving many variables which can affect the estimate for systemic availability (1). However, the objective is crystal clear; an estimate of percutaneous absorption in vivo in man. Therefore, the study design should minimize variables and include aspects most relevant to man. This paper focuses on the variables of the animal model, and on accountability for applied dose. It is hoped that the conclusions derived from the information presented here will aid in producing relevant study designs and continued relevant data. Animal Model The best estimate for human percutaneous absorption would be an in vivo study in man. Factors such as risk, cost, and access to human volunteers necessitate use of an animal model. Cost and access c

0097-6156/89/0382-0152$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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Percutaneous Absorption in Monkeys

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suggest a s m a l l l a b o r a t o r y a n i m a l . The h i s t o r i c a l use o f t h e r a t i n t o x i c o l o g i c a l s t u d i e s s u g g e s t s i t s u s e . What may g e t l o s t i n t h e c h o i c e o f a n i m a l i s t h e p r i o r i t y o f r e l e v a n c e t o man f o r percutaneous absorption. T a b l e I shows t h e percutaneous a b s o r p t i o n o f s e v e r a l c h e m i c a l s by r a t / r a b b i t / p i g and man ( 2 ) . Q u e s t i o n s f o r r e l e v a n c y s h o u l d be i f t h e s k i n a b s o r p t i o n i n t h e a n i m a l i s t h e same a s i n man and/ i f not t h e same, then i s t h e s k i n a b s o r p t i o n c o n s i s t e n t l y p r o p o r t i o n a l l y d i f f e r e n t from man? The answer t o b o t h q u e s t i o n s f o r r a t and r a b b i t i s no. F o r t h e p i g , t h e answer i s a maybe.


T a b l e I . Percutaneous A b s o r p t i o n o f S e v e r a l Compounds by R a t , R a b b i t , P i g and Man ( i n v i v o ) Penetrant rat

Haloprogin Acetylcysteine Cortisone Caffeine Butter yellow Testosterone

95 .8 3 .5 24 .7 53 .1 48 .2 47 .4

rabbit

P e r c e n t Dose Absorbed pig man

113. 0 2.0 30. 3 69. 2 100. 0 69. 6

19 .7 6 .0 4 .1 32 .4 41 .9 29 .4

11..0 2..4 3..4 47,.6 21,.6 13..2

Source: B a r t e k e t a l (2)

I t i s beyond t h i s paper's scope t o p r e s e n t a l l c o m p a r a t i v e d a t a i n v o l v i n g i n v i v o and i n v i t r o s k i n a b s o r p t i o n i n l a b o r a t o r y a n i m a l s and man. D e t a i l s a r e i n r e f e r e n c e s ( 3 - 7 ) . T h i s paper f o c u s e s on t h e use o f t h e r a t and t h e r h e s u s monkey a s r e l e v a n t a n i m a l models. T a b l e I I shows t h e c o m p a r a t i v e i n v i v o percutaneous a b s o r p t i o n of t e s t o s t e r o n e i n s e v e r a l s m a l l s p e c i e s . Absorption i n the l a b o r a t o r y s p e c i e s ( r a t , r a b b i t , g u i n e a p i g ) a r e on t h e upper end o f t h e a b s o r p t i o n s c a l e , w h i l e t h o s e i n t h e p i g , r h e s u s monkey and man a r e on t h e lower end o f t h e s c a l e .

T a b l e I I . Comparative Percutaneous A b s o r p t i o n o f T e s t o s t e r o n e on S e v e r a l S p e c i e s Species Rat Rabbit Guinea p i g Rhesus monkey Man

P e r c e n t o f Dose Absorbed 47.4 69.6 34.9 18.4 13.2


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BIOLOGICAL MONITORING FOR PESTICIDE EXPOSURE

T a b l e I I I summarizes t h e e x i s t i n g c o m p a r a t i v e i n v i v o percutaneous a b s o r p t i o n i n t h e r h e s u s monkey and man. The l i s t i n c l u d e s a v a r i e t y o f c h e m i c a l s and a broad range o f s k i n a b s o r p t i o n e s t i m a t e s . I n a l l c a s e s , t h e percutaneous a b s o r p t i o n i n t h e r h e s u s monkey i s c o n s i s t e n t w i t h t h a t found i n man. Table I I I .

I n V i v o Percutaneous A b s o r p t i o n i n t h e Rhesus Monkey and Man

Chemical

P e r c e n t Dose Absorbed


Rhesus Monkey 2,4-Dinitrochlorobenzene Nitrobenzene Cortisone Testosterone H y d r o c o r t i sone Benzoic a c i d Resorcinol P-Phenylendiamine 2-Nitro-PPD HC-Blue #1

Reference Man

52.5 + 4.3 4.2 + 0.5 5.3 + 3.3 18.4 + 9.5 2.9 + 0.8 59.2 + 7.6 0.18 + 0.03 0.18 + 0.06 0.55 + 0.10 0.13 + 0.03

53.5 + 6.2 1.5 + 0.3 3.4 + 1.6 13.2 + 3.0 1.9 + 1.6 42.6 + 16.4 0.08 + 0.03 0.19 + 0.04 0.1 4+ 0.04 0.15 + 0.12

(8) (8) (9) (10) (10) (10) (11) (11) (11) (11)

B a s i c t o s c i e n t i f i c i n q u i r y i s t h e dose r e s p o n s e . F o r s k i n a b s o r p t i o n i n man, t h e p e r c e n t dose absorbed w i l l be dependent on t h e a p p l i e d dose ( T a b l e IV, r e f e r e n c e s 10,12). The dose response i s s i m i l a r f o r t h e r h e s u s monkey.

T a b l e I V . Percutaneous A b s o r p t i o n o f I n c r e a s e d T o p i c a l Doses o f S e v e r a l Compounds i n t h e Rhesus Monkey and Man ( i n v i v o ) Penetrant

Dose ug/cm2

Percent of Dose Absorbed Man Rhesus

4 40

2.9 2.1

1.9 0.6

Benzoic A c i d

4 40 2,000

59.2 33.6 17.4

42.6 25.7 14.4

Testosterone

4 40 250 400 1,600 4,000

18.4 6.7 2.9 2.2 2.9 1.4

13.2 8.8a

Hydrocortisone

a

2.8

30 ug/cm2.


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WESTER ETAL.

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Dose A c c o u n t a b i l i t y The p r e c e d i n g s e c t i o n on a n i m a l models s u g g e s t s t h e p o s s i b i l i t y o f d i f f e r e n c e s i n s k i n a b s o r p t i o n and subsequent human h e a l t h h a z a r d e f f e c t e s t i m a t e s dependent upon a n i m a l s p e c i e s . The p e r c e n t s k i n p e n e t r a t i o n d a t a from T a b l e V would e s t i m a t e , based on t h e r a t , t h a t a l l o f t h e Dinoseb which g e t s on s k i n i s absorbed. Human h e a l t h h a z a r d e s t i m a t e s would be p r e j u d i c e d i n t h i s d i r e c t i o n . A b s o r p t i o n i n the r h e s u s monkey would suggest t h a t an a b s o r p t i o n o f no more t h a n t e n p e r c e n t would b e t t e r e s t i m a t e human h e a l t h h a z a r d s . The o b v i o u s q u e s t i o n w i t h t h e r h e s u s monkey d a t a i s an a c c o u n t a b i l i t y o f t h e m a j o r i t y o f the dose t o ensure t h a t n o t h i n g p e c u l i a r happened d u r i n g t h e s t u d y . T a b l e VI g i v e s an a c c o u n t a b i l i t y o f t h e a p p l i e d Dinoseb dose. The m a j o r i t y o f the dose appeared i n t h e 24 hour p o s t a p p l i c a t i o n soap and water s k i n wash, and t h u s was not absorbed. Thus, t h e l e s s than t e n p e r c e n t a b s o r p t i o n i s r e a l and i s p r o b a b l y more r e l e v a n t t o man t h a n the complete a b s o r p t i o n observed i n t h e r a t .

T a b l e V.

A p p l i e d Dose ug/cm2

I n V i v o Percutaneous A b s o r p t i o n o f Dinoseb i n Rhesus Monkey and R a t

Percent S k i n P e n e t r a t i o n

a

P e r c e n t Dose Accountabi1ity

RAT 51.5 128.8 643.5

86.4 90.5 93.2

+ + +

1.1 1.1 0.6

87.9 91.5 90.4

+ +

+

86.0 81.2 80.3

+ + +

1.8 0.6 0.7

RHESUS MONKEY 43.6 200.0 3,620.0

5.4 7.2 4.9

+ +

T

2.9 6.4 3.4

4.0 18.1 5.2

Rat = acetone v e h i c l e ; 72 h r a p p l i c a t i o n Monkey = Premerge-3 v e h i c l e ; 24 hour a p p l i c a t i o n Complete Dinoseb d a t a t o be p u b l i s h e d elsewhere R e f e r e n c e 13 f o r r a t d a t a Study D e s i g n O b j e c t i v e A s t u d y d e s i g n s h o u l d r e f l e c t a c l e a r o b j e c t i v e . I n t h e case o f Dinoseb, the r h e s u s monkey s t u d y was d e s i g n e d t o b e s t e s t i m a t e human s k i n a b s o r p t i o n f o r a 24 hour exposure p e r i o d . Dinoseb was a p p l i e d as i t s c o m m e r c i a l l y a v a i l a b l e f o r m u l a t i o n (Premerge-3), and t h e doses


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BIOLOGICAL MONITORING FOR PESTICIDE EXPOSURE

Table VI.

P e r c u t a n e o u s A b s o r p t i o n and A c c o u n t a b i l i t y o f Dinoseb I n V i v o Study i n t h e Rhesus M o n k e y 2

Disposition Parameter

1+3.6

A p p l i e d Dose (ug/cm ) 200.0

P e r c e n t A p p l i e d Dose


Urine Feces Contaminated Pan wash S k i n wash

solids

Total Accountability a

Complete

a

3,620.0

Accountability

3.3 + 1.8 0.8+ 0.5 0.03±0.02 0.04+0.03 81.1+4.0

4.4 + 2.39 3.0 ± 2.1 1.0 + 0.6 3.0 +_ 1.7 0.07± 0.08 0.02+ 0.02 0.4 + 0.3 0.8 + 1.1 75.0 + 22.9 73.8 + 6.8

86.0+4.0

81.2 + 18.1

80.3 + 5.2

Dinoseb d a t a t o be p u b l i s h e d e l s e w h e r e

r e p r e s e n t c o n c e n t r a t i o n s which human s k i n would be exposed t o . The r a t d a t a was t a k e n out o f c o n t e x t , s i n c e i t s o b j e c t i v e was t o compare s k i n a b s o r p t i o n o f young and o l d s k i n f o r a 72 hour exposure o f Dinoseb when a p p l i e d t o s k i n i n a c e t o n e . The comparison o f t h e r a t s t u d y e x t r a p o l a t e d t o a h e a l t h h a z a r d assessment i n humans would be f o r human a p p l i c a t o r s t o use Dinoseb, mixed i n a c e t o n e , c o n t i n u a l l y f o r 72 hours w i t h o u t t h e b e n e f i t o f a shower o r b a t h f o r the 3 day p e r i o d . T h i s c l e a r l y p o i n t s up t h e f a l l a c y o f u s i n g i n a p p r o p r i a t e d a t a from a n i m a l models i n t h e e x t r a p o l a t i o n o f h e a l t h h a z a r d e f f e c t s t o man. The d e s i g n o f a p r o p e r s t u d y complete w i t h w e l l though out o b j e c t i v e s w h i c h a r e t i e d i n a r a t i o n a l s c i e n t i f i c manner t o human h e a l t h exposure i s what i s r e q u i r e d .

A n i m a l Percutaneous A b s o r p t i o n Data t o E s t i m a t e Human Exposure The o b j e c t i v e o f percutaneous a b s o r p t i o n d a t a i s t o e s t i m a t e t h e amount o f c h e m i c a l which w i l l t r a n s f e r from t h e s u r f a c e o f s k i n t h r o u g h t h e e p i d e r m i s i n t o t h e s y s t e m i c c i r c u l a t i o n . That which g e t s i n t o the e p i d e r m i s o r s y s t e m i c c i r c u l a t i o n d e t e r m i n e s t h e e x i s t e n c e or degree o f l o c a l o r s y s t e m i c t o x i c i t y . Thus, s k i n a b s o r p t i o n i s p i v o t a l and i m p o r t a n t i n e s t i m a t i n g p o t e n t i a l h e a l t h h a z a r d s f o r t o p i c a l exposure, and r e l e v a n t i n f o r m a t i o n i s n e c e s s a r y . Data i n a n i m a l models not r e l e v a n t t o man f o r s k i n a b s o r p t i o n c e r t a i n l y cannot g i v e a t r u e e s t i m a t e , and i n f a c t may l e a d t o f u r t h e r confusion. The b e s t a n i m a l model f o r e s t i m a t i n g percutaneous a b s o r p t i o n r e l e v a n t t o man i s man him(her) s e l f . Y e t e s p e c i a l l y w i t h a g r i c u l t u r e chemicals there i s c o n t i n u a l searching f o r "relevant" animal data, when t h e c o r r e c t answers can e a s i l y be o b t a i n e d i n man. Perhaps when r e g u l a t o r y and m a n a g e r i a l p e o p l e r e a l i z e t h i s , t h e emphasis w i l l s h i f t t o t h e p r o p e r human s t u d i e s .


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Literature Cited 1. 2. 3. 4. 5.


6. 7. 8. 9. 10. 11. 12. 13.

Wester, R.C.; Maibach, H.I. Drug Metab. Rev. 1983, 14, 169-205 Bartek, M.J.; La Budde, J.A.; Maibach, H.I. J. Invest. Dermatol.1972, 58, 114-23. Wester, R.C.; Noonan, P.K. Int. J. Pharmaceutics, 1980, 7, 99-110. Wester, R.C.; Maibach, H.I. In Models in Dermatology; H.I. Maibach and N.J. Lowe, Eds.; S. Karger: Basel, 1985, 159-169. Wester, R.C.; Maibach, H.I. In Percutaneous Absorption; R.L. Bronaugh and H.I. Maibach, Eds.; Marcel Dekker: New York, 1985; 251-66. Wester,R.C.,Maibach, H.I. In Progress in Drug Metabolism; J.W. Bridges and L.F. Chasseaud, Eds.; Taylor and Francis: Philadelphia, 1986; Chapter 3. Wester, R.C.; Maibach, H.I. In Dermatotoxicology; F.N. Marzulli and H.I. Maibach, Eds.; Hemisphere: New York, 1987; 135-52. Bronaugh, R.L. In Percutaneous Absorption; R.L. Bronaugh and H.I. Maibach, Eds.; Marcel Dekker: New York; 1985; 267-279. McMaster, J.; Maibach, H.I., Wester, R.C.; Bucks, D.A.W. In Percutaneous Absorption; R. Bronaugh and H. Maibach, Eds.; Marcel Dekker: New York; 1985; 359-61. Wester, R.C.; Maibach, H.I.; Toxicol. Appl. Pharmacol. 1975, 32; 394-98. Wolfram, L.J. In Percutaneous Absorption; R. Bronaugh and H.I. Maibach, Eds; Marcel Dekker: New York, 1985; 409-22. Wester, R.C.; Maibach, H.I. J. Invest. Dermatol. 1976, 67; 518-20. Shah, P.V.; Fisher, H.L.; Sumler, M.R.; Monroe, R.J.; Chernoff, N.;Hall, L.L. J. Toxicol. Environ. Hlth.; 1987, 353-66.

RECEIVED January 25, 1988


Percutaneous Absorption in Rhesus Monkeys and Estimation of

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