Percutaneous Absorption and Inherent Toxicity - ACS Symposium

Chapter 10

Percutaneous Absorption and Inherent Toxicity

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Ronald C. Wester and Howard I. Maibach Department of Dermatology, University of California School of Medicine, San Francisco, CA 94143-0989 The aim of a toxicological study is to determine the inherent activity of some chemical relative to a target tissue. This process requires delivery to the target tissue -- usually described as bioavailability. With topical products, bioavailability is the process of per cutaneous absorption and i t is as important as the inhe rent activity of the chemical. Failure of a patch test system to deliver chemical into skin will produce false negative results. In the skin, the amount of chemical present can correlate with erythema response and epidermal tumors. The skin also has metabolic potential and can alter chemical to more reactive metabolites. Relationship: Percutaneous Absorption and Inherent Toxicity The skin is recognized both as a barrier to absorption and as a primary route to the systemic circulation. The skin's barrier properties are often, but not always, impressive. Fluids and elec trolytes are reasonably well retained within the body, while at the same time many foreign chemicals are partially restricted from entering the systemic circulation. Despite these barrier proper ties, the skin is the route by which many chemicals enter the body. In most instances, the toxicology of the chemical is slight, and/or the bioavailability (rate and amount of absorption) of the chemical is too low to cause an immediate response. However, some chemicals applied to the skin have the potential to produce toxicity. It is now recognized that local and systemic toxicity depend on a chemical penetrating the skin. Table I shows the relationship of percutaneous absorption to toxicologic activity. A local or systemic effect cannot occur unless the chemical has inherent toxicity and the chemical is able to overcome the barrier properties of skin and enter a biologic system (local skin and/or systemic circulation (1). This chapter explores this concept of percutaneous absorption and inherent toxicity. 0097-6156/89/0382-0131$06.00/0 ° 1989 American Chemical Society

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

132

BIOLOGICAL MONITORING FOR PESTICIDE EXPOSURE

T a b l e I . R e l a t i o n s h i p o f Percutaneous Absorption t o Toxicologic A c t i v i t y

Property o f Chemical

Absorption through s k i n

Local o r systemic effect

Inherent toxicity None None None Reaction

+ + +

+

P a t c h T e s t Systems The development o f t o p i c a l drug p r o d u c t s r e q u i r e s t e s t i n g f o r s k i n t o x i c o l o g y r e a c t i o n s . A v a r i e t y o f p a t c h t e s t systems a r e a v a i l a b l e w i t h which c h e m i c a l s a r e a p p l i e d t o s k i n . The purpose o f t h i s s t u d y was t o determine t h e s k i n a b s o r p t i o n o f t h e a l l e r g e n p a r a p h e n y l enediamine (PPDA) from a v a r i e t y o f p a t c h t e s t i n g systems. [14C]PPDA ( 1 % i n petrolatum,USP) was p l a c e d i n a v a r i e t y o f p a t c h t e s t systems a t a c o n c e n t r a t i o n n o r m a l i z e d t o e q u a l s u r f a c e a r e a (2 mg/mm2). S k i n a b s o r p t i o n was d e t e r m i n e d i n t h e g u i n e a p i g by u r i n a r y e x e r t i o n o f 14C. There was a s i x - f o l d d i f f e r e n c e i n t h e range o f s k i n a b s o r p t i o n (p N 0.02) ( F i g u r e 1 ) . In decreasing o r d e r , p e r c e n t s k i n a b s o r p t i o n s from v a r i o u s p a t c h t e s t systems were H i l l Top Chamber (53.4 + 20.6), T e f l o n C o n t r o l P a t c h (48.6 + 9 . 3 ) , S m a l l F i n n Chamber w i t h paper d i s c i n s e r t (34.1 + 19.8), Small Finn Chamber (29.8 + 9.0), L a r g e F i n n Chamber (23.1 + 7.3), AL-Test Chamber (8.0 + 0.8). Thus, t h e c h o i c e o f p a t c h system c o u l d produce a f a l s e n e g a t i v e e r r o r i f t h e system i n h i b i t s s k i n a b s o r p t i o n , and subsequent s k i n t o x i c o l o g y r e a c t i o n ( 2 ) . The h i g h e s t e f f i c i e n c y o f s k i n a b s o r p t i o n was w i t h t h e H i l l - T o p Chamber. P o l i k a n d r i t o u and Conine (3) performed comparative s t u d i e s u s i n g t h e H i l l - T o p chamber system and W e b r i l p a t c h system t o compare d e l a y e d c o n t a c t h y p e r s e n s i t i v i t y . R e a c t i o n s were induced a t s i g n i f i c a n t l y lower c o n c e n t r a t i o n s f o r samples t e s t e d w i t h t h e H i l l - T o p Chamber. The r e a s o n f o r t h i s may have been h i g h e r s k i n absorption. M e t a b o l i c P r o d u c t i o n o f Cutaneous

Carcinogens

Much a t t e n t i o n has been f o c u s e d on p o l y c y c l i c a r o m a t i c hydrocarbons because they produce s k i n carcinomas. Metabolic a c t i v a t i o n o f these compounds i s u s u a l l y t h e f i r s t s t e p toward t h e i n d u c t i o n o f s k i n c a n c e r s . The m e t a b o l i t e s o f benz[a]pyrene (BP) g e n e r a l l y f a l l i n t o t h r e e c l a s s e s : p h e n o l s , quinones, and d i h y d r o d i o l s . I t i s t h e


10.

WESTER AND MAIBACH

Inherent Toxicity

Midpoint (hours) Figure 1. Skin absorption of /7-phenylenediamine, measured by using various patch-testing systems.



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d i h y d r o d i o l s t h a t , when m e t a b o l i z e d t o epoxide d i o l s , become t h e more p o t e n t c a r c i n o g e n s . The e p o x i d e s r e a c t w i t h c e l l u l a r n u c l e o p h i l e s such as DNA, RNA, o r p r o t e i n s . The same i s t r u e f o r o t h e r p o l y c y c l i c a r o m a t i c hydrocarbons such as 3-methylcholanthrene and b e n z [ a ] a n t h r a c e n e d e r i v a t i v e s . These compounds induce s k i n tumors and t h i s p r o b a b l y i s caused by a r e a c t i v e m e t a b o l i t e (an e p o x i d e ) . Knowledge o f the b i n d i n g o f BP m e t a b o l i t e s t o macromolecules has reached a h i g h e r l e v e l o f s o p h i s t i c a t i o n . B i n d i n g o f B P - d i h y d r o d i o l e p o x i d e s was found t o o c c u r w i t h h i g h s t e r e o s e l e c t i v i t y . These i n v e s t i g a t o r s i s o l a t e d the polymer adducts t h a t were formed when [3H]BP was a p p l i e d t o t h e s k i n o f mice. There a r e two s t e r e o c h e m i c a l c o n f i g u r a t i o n s f o r t h e B P - 7 , 8 - d i h y d r o d i o l s , and t h e y may both be m e t a b o l i z e d t o t h e r e s p e c t i v e 9,10-epoxide. The epoxide may then r e a c t w i t h c e l l u l a r n u c l e o p h i l e s such as DNA, RNA, o r p r o t e i n s . For n u c l e i c a c i d s , t h e i n v i v o b i n d i n g o c c u r r e d p r e f e r e n t i a l l y t o guanine a t the 2-amino group ( i n b o t h DNA and RNA). Both s t e r e o i s o m e r s bound c e l l u l a r components, but isomer A formed mostg o f the c o v a l e n t l y bound p r o d u c t s ( 4 ) . Thus, any compound such as benzo[a]pyrene t h a t p e n e t r a t e s t h e s k i n must f i r s t pass i n t o and through t h e e p i d e r m i s and would be s u b j e c t t o an extensive metabolic reaction. Percutaneous

A b s o r p t i o n and E p i d e r m a l Tumors

Wester and co-workers (5) determined t h e e f f e c t o f frequency o f a p p l i c a t i o n on percutaneous a b s o r p t i o n o f h y d r o c o r t i s o n e (Table I I ) . When m a t e r i a l was a p p l i e d once o r t h r e e t i m e s per day t h e r e was a s t a t i s t i c a l d i f f e r e n c e (p 0.05) i n t h e percutaneous a b s o r p t i o n o f h y d r o c o r t i s o n e . One a p p l i c a t i o n per 24-hour exposure gave a h i g h e r percutaneous a b s o r p t i o n than i f t h e m a t e r i a l was a p p l i e d a t a lower c o n c e n t r a t i o n but more f r e q u e n t l y , namely, t h r e e t i m e s per day. T h i s was c o n f i r m e d w i t h a second c h e m i c a l , t e s t o s t e r o n e ( 6 ) .

T a b l e I I . A p p l i c a t i o n Frequency and Percutaneous Absorption of Hydrocortisone

Dose (ug/cm2)

Application (times/day)

T o t a l dose (ug/cm2)

13.3 13.3 40

1 3 1

13.3 40 40

Absorption (ug/cm2) 0.18 0.29 0.84

There i s a c o r r e l a t i o n between f r e q u e n c y o f a p p l i c a t i o n , percutaneous a b s o r p t i o n , and t o x i c i t y o f a p p l i e d c h e m i c a l . Wilson and H o l l a n d (7) determined t h e e f f e c t o f a p p l i c a t i o n f r q u e n c y i n e p i d e r m a l c a r c i n o g e n i c a s s a y s . A p p l i c a t i o n o f a s i n g l e l a r g e dose o f a h i g h l y complex m i x t u r e o f p e t r o l e u m o r s y n t h e t i c f u e l s t o a s k i n s i t e i n c r e a s e d the c a r c i n o g e n i c p o t e n t i a l o f t h e c h e m i c a l compared t o s m a l l e r o r more f r e q u e n t a p p l i c a t i o n s (Table I I I ) .


10.

WESTER AND

MAIBACH

135

Inherent Toxicity

This carcinogenic t o x i c i t y c o r r e l a t e d w e l l with the r e s u l t s of Wester e t a l ( 6 ) / where a s i n g l e a p p l i e d dose i n c r e a s e d t h e percutaneous a b s o r p t i o n o f t h e m a t e r i a l compared t o s m a l l e r o r intermittent applications.

Table I I I .

S h a l e O i l - I n d u c e d I n c i d e n c e o f E p i d e r m a l Tumors

Dose (mg)

Frequency (per week)

T o t a l dose p e r week (mg)

No. o f a n i m a l s with carcinog e n i e tumors

OCSO No. 6

10 10 40

4 x 2 x 1 x

40 40 40

2 4 13

PCSO I I

10 30 40

4 x 4 x 1 x

40 40 40

11 17 19

Shale o i l

Cosmetic C h e m i c a l s and T o x i c i t y T a b l e IV shows t h e r e l a t i o n s h i p between percutaneous a b s o r p t i o n and erythema f o r s e v e r a l o i l s used i n c o s m e t i c s . The a u t h o r s attempted t o c o r r e l a t e a b s o r b a b i l i t y w i t h erythema. The most absorbed o i l / i s o p r o p y l m y r i s t a t e / produced t h e most erythema. The l o w e s t a b s o r b i n g oil, 2 - h e x y l - decanoxyoctane/ produced t h e l e a s t erythema. A b s o r b a b i l i t y and erythema f o r t h e o t h e r o i l s d i d not c o r r e l a t e ( 8 ) . The l e s s o n t o remember w i t h p e r c u t a n e o u s t o x i c i t y i s t h a t a t o x i c response r e q u i r e d b o t h an i n h e r e n t t o x i c i t y i n t h e c h e m i c a l and t h e percutaneous a b s o r p t i o n o f t h e c h e m i c a l . The degree o f t o x i c i t y w i l l depend on t h e c o n t r i b u t i o n o f b o t h c r i t e r i a .

T a b l e IV.

R e l a t i o n s h i p o f Percutaneous A b s o r p t i o n and Erythema f o r S e v e r a l O i l s Used i n C o s m e t i c s

Absorbability (greatest to least) Isopropyl myristate Glycerol tri(oleate) n -Octadecane Decanoxydecane 2-Hexyldecanoxyoctane

Erythema +

+

+; +

Ten S t e p s t o P e r c u t a n e o u s A b s o r p t i o n The p r e c e d i n g examples have shown t h a t two components/ namely i n h e r e n t c h e m i c a l a c t i v i t y and percutaneous a b s o r p t i o n / a r e


136


n e c e s s a r y t o g e t a t o x i c o l o g i c a l r e a c t i o n . I t i s t h e r a t e and extent that a r e a c t i v e chemical i s d e l i v e r e d t o the target t i s s u e t h a t d e t e r m i n e s t h e degree o f t o x i c o l o g i c a l r e s p o n s e . However, percutaneous a b s o r p t i o n i s not a simple a c t o f apply chemical t o s k i n and t h e n " s e e i n g what happens". P e r c u t a n e o u s a b s o r p t i o n i s a complex p r o c e s s c o n s i s t i n g o f many f a c t o r s , any o f w h i c h c a n a f f e c t t h e f i n a l outcome. Wester and Maibach (9) have summarized t h e p r o c e s s i n t e n s t e p s ( o u r c u r r e n t v i e w , b u t presumably many s t e p s remain t o be d i s c o v e r e d ) .

Ten S t e p s t o P e r c u t a n e o u s A b s o r p t i o n 1. 2.

3. 4. 5. 6. 7. 8. 9. 10.

Vehicle release Absorption k i n e t i c s a. S k i n s i t e o f a p p l i c a t i o n b. I n d i v i d u a l v a r i a t i o n c. S k i n c o n d i t i o n d. O c c l u s i o n e. Drug c o n c e n t r a t i o n and s u r f a c e a r e a s f. Multiple-dose application Excretion kinetics E f f e c t i v e c e l l u l a r and t i s s u e d i s t r i b u t i o n S u b s t a n t i v i t y (nonpenetrating surface adsorption) Wash and r u b r e s i s t a n c e Volatility Binding Anatomic pathways Cutaneous m e t a b o l i s m

Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9.

Wester, R.C.; Maibach, H.I. In Environmental Pathology, N.K. Mottet, Ed.; Oxford University Press: New York, 1985;181-194. Kim, O.K.; Wester, R.C.; McMaster, J.A., Bucks, D.A.W.; Maibach, H.I. Contact Dermatitis 1987 17 (in press). Polikandriton, M.; Conine, D.L. J. Soc. Cosmetic Chem. 1985, 36, 159-168. Noonan, P.K.; Wester, R.C. In Dermatotoxicology, F.N. Marzulli and H.I. Maibach, Eds.; Hemisphere Publishing: New York, 1983; pp 71-90. Wester, R.C.; Noonan, P.K.; Maibach, H.I. Arch. Dermatol. Res.,1977 113, 620-622. Wester, R.C.; Noonan, P.K.; Maibach, H.I. Arch. Dermatol. Res.1980 267, 229-235. Wilson, J.S.; Holland, L.M. Toxicology 1982, 24, 45-54. Suzuki, M.; Asaba, K.; Komatsu, H.; Mockizuki, M. J. Soc. Cosmet. Chem. 1978 29, 265-271. Wester, R.C.; Maibach, H.I. Cutaneous Pharmacokinetics: 10 Steps to Percutaneous Absorption. Drug Metab. Disposition, 1983.

RECEIVED January 25, 1988


Percutaneous Absorption and Inherent Toxicity - ACS Symposium

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