Review

Skin Pharmacol Appl Skin Physiol 2000;13:229–234

The Pig as an Experimental Animal Model ofPercutaneous Permeation in Man:Qualitative and Quantitative Observations –An Overview

Gad A. Simon Howard I. Maibach

Department of Dermatology, UCSF Medical School, San Francisco, Calif., USA

Received: Dec. 3, 1999

Accepted: March 30, 2000

Dr. Gad A. SimonDepartment of PharmacologyIsrael Institute for Biological Research, PO Box 19IL–74100 Ness Ziona (Israel)Tel. +972 8 938 1611, Fax +972 8 938 1519, E-Mail simon@iibr.gov.il

ABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com

© 2000 S. Karger AG, Basel1422–2868/00/0135–0229$17.50/0

Accessible online at:www.karger.com/journals/sph

Key WordsSkin permeation W Animal model W Pig

AbstractThe pig has been a well-recognized experi-

mental animal in biomedical research for

many centuries. Physiological and anatomi-

cal similarities between man and pig made

this animal a good model for man in many

research areas. Pharmacological and toxico-

logical research on the skin is often based on

knowledge of skin absorption and percuta-

neous permeation. Anatomical, physiologi-

cal and biochemical similarities are cited and

various uses of the pig as a model for man in

the investigation of skin permeation are re-

viewed. Further, several isolated organ mod-

els are reviewed. The importance of full de-

tails of the experimental animal, namely its

age, sex, breed, size (weight) and body re-

gion, is emphasized.Copyright © 2000 S. Karger AG, Basel

The usefulness of the pig, a well-recognizedexperimental animal in biomedical research,is widely appreciated. Its growing spectrum ofusage as an experimental animal covers awide range of fields. Documentation of its usefor scientific research dates back to the 12thand 14th centuries [1, 2] and to Leonardo daVinci in the 16th century [3]. Several anatom-ical and physiological characteristics, com-mon to pig and man, indicate a likelihood thatthe pig could serve as a model for man. Thepig, like man, is of median body size, largeenough for collection of multiple samples(body fluids, biopsies) over extended periods,while at the same time not too large to be con-veniently handled in standard laboratory ani-mal facilities. The pig, like man, is omnivo-rous and both digestive systems have similari-ties. The skin of pig and man is only sparselycovered with hair and pigmentation is rich insome breeds, while poor in others.

In view of the basic qualities mentionedabove and based on the favorable experiencegained in numerous experiments, the use of

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Simon/Maibach

the pig became popular among the scientificcommunity. In order to comply better withthe needs of the researchers, new breeds ofpigs have been developed, mainly with thegoal of reducing the size of the mature animal,as well as selecting for less hair [4–8].

In the past four decades, reviews and meet-ings were devoted to the pig as an experimen-tal animal, some of general nature [9–20],while others were concerned with specificfields of research [21–25].

Detailed information on skin absorptionand percutaneous permeation is a cornerstoneof skin pharmacological and toxicological re-search. Advance in these fields depends large-ly on the availability of alternative methods tohuman experimentation. In some cases, invitro methods, using human or animal skin,can serve the purpose. However, without areliable in vivo animal model, progress will belimited.

In search of a suitable animal model, con-sider two main options: (1) use of an animalphylogenetically as close as possible to man or(2) use of an animal in which the process underinvestigation is as close as possible to that inman, considering its physiology and biochem-istry, and that the anatomy is similar.

Studies were performed in order to explorethe suitability of experimental animals to serveas model for man in investigations of percuta-neous permeation. In the early sixties Monta-gna pointed out that, although there are simi-larities between porcine and human skin, dis-similarities also do exist [26, 27]. He observedthat the skin of both man and pig is character-ized by a spare hair coat, a thick epidermis thathas a well-differentiated undersculpture, a der-mis that has a well-differentiated papillarybody and a large content of elastic tissue. Dis-similarities are in the vascularization (rich inman, poor in the pig) and in the sebaceousglands. Further, humans have mostly eccrinesweat glands over the body surface, whereas

the pig has only apocrine glands. Similar find-ings were also observed while studying theskin of other domestic mammals [28].

Another report suggests that the histologi-cal appearance of the epidermis, in both manand swine, is similar, except for the stratumcorneum. Swine and human epidermis havebeen found similar when judged by parame-ters of tissue turnover time and the character-ization of keratinous proteins [29]. Swine stra-tum corneum contains protein fractions gross-ly similar to human and animal epidermal tis-sue. Porcine stratum corneum appears similarto humans in respect to variable filament den-sity and areas of cell overlapping [30].

While studying thermal injury in the pig, itwas observed that the number, size, distribu-tion and communications of the dermal bloodvessels of the pig were remarkably similar tothose described in human skin. ‘The similarityof blood vessels in human and porcine skinwas found to be so great that it was with diffi-culty that one could be distinguished from theother’ [31]. Later observations, made during astudy on the vascular supply of the skin andhair in swine, supported the conclusion thatthe cutaneous vascular anatomy, and at leastcertain vascular reactions, was similar in manand in the domestic pig and that each wasunlike that of most other mammals [32]. It wasnoted in yet another study, that the morpholo-gy of the epidermis and upper dermis vascula-ture in the pig was similar to that in man andfunctions of the endothelial cell, such as plas-minogen activator, were also similar [33].

Detailed studies were performed on thecollagen fiber arrangement in the dermis. Inthese studies, both light and scanning electronmicroscopy were used [34, 35].

Results obtained on the architecture of col-lagen fibers and fiber bundles in the dermis ofthe pig generally corresponded to observa-tions from human skin, including the thick-ness of collagen fibrils; however, this was

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found to be the case in the domestic pig (Ger-man Landrace) more than in miniature pigs(Hanford and Göttingen).

The epidermal-dermal junction is detailedin a study, in which the ultrastructure of thepig skin was investigated, using transmissionelectron microscopy [30]: in the pig, the epi-dermal-dermal junction resembled that ofman. It was claimed that the stratum corneumof Hampshire and Yorkshire pigs from 1 to 14weeks resembled that of humans.

Biochemical similarities were recordedwhile studying glycosphingolipids and ceram-ides in human and pig epidermis [36]. Theenzyme patterns of the skin of the domesticpig, as revealed by enzyme histochemical in-vestigations mirror that in man [37].

Percutaneous absorption in man and mostprobably in animals also varies depending onthe area of the body on which the chemicalresides. The first report on regional variationin percutaneous absorption in man was basedon a study with cortisol [38], a review of theknowledge of the past 30 years [39] and theinfluence of anatomical site, age and sex (inhumans) on percutaneous absorption [40]. Al-though some information on regional varia-tion of percutaneous absorption in animal isavailable, little is known about this in the pig.Most of the percutaneous permeation studiesconducted in pigs were performed on theirback [41–48] some others on the ear [49–53]and few on the flank [54, 55] or the abdomen[56]. However, no explanation was given whya certain site was chosen for a given study. Acomparative study on the skin of the back,shoulder and buttock in the pig was restrictedto the distribution of enzymes [37].

In vitro methods are most common anduseful for the study of skin permeation. Theyrequire less laboratory space, have fewer vari-ables than in vivo methods and they can beperformed in both animal and human skinunder identical experimental conditions. Ex-

periments on in vitro permeation of skin todrugs and water revealed that human and por-cine skin were similar with respect to wa-ter permeation [41]. Experiments with otherchemical compounds resulted in the same con-clusion, namely that porcine skin oftenyielded permeation values similar to those ofhuman skin [42, 56]. Comparative studies de-signed to predict skin permeation in man con-cluded that similar permeation values wereobtained between pig and human skin whentested under identical conditions in vitro [43].Permeation of paraquat, carbaryl, aldrin andfluazifop-butyl were also very close in manand pig skin [49]. Investigation of the synthe-sis and turnover of membrane glycoconjugatesin pig and human epidermal cells resulted inthe suggestion that the results for human epi-dermal cells closely matched those for pig epi-dermal cells, indicating that pig cells can beused as a model for human cells [52].

A study on the permeation of hexachloro-phene through the skin indicated that concen-trations of this compound in the blood in manand in the pig were close, but different fromthose in rats and monkeys [57]. Another studyof the percutaneous absorption of hexachloro-phene also concluded that the permeationcharacteristics of the pig skin were compara-ble to man [45]. In vivo studies involving clas-sified chemical warfare agents and agent si-mulants showed that the back skin of wean-ling pigs most closely approximated humanforearm skin with regard to its resistance topermeation [46]. While testing the perme-ation of other compounds it was found thatoverall, skin of miniature swine has the closestpermeability characteristics to that of humanskin with the compounds tested [47]. A signif-icant correlation was obtained when the per-cent percutaneous permeation was comparedin the weanling pig and man [43]. Table 1 listscompounds having permeability resemblancein human and porcine skin.

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Table 1. Compounds having permeation resemblance in human and porcine skin

Compound In vivo In vitro Reference Remarks

Water + 41 hydrated whole skinBenzoic acid + 43 human-skin-grafted athymic nude mouse,

pig-skin-grafted athymic nude mouseAcetylsalicylic acid + 56 dermatomed pig skin, heat-separated human

epidermisHaloprogin + 47Tacrine + 42 dermatomed pig skin, human cadaver whole skinHexachlorophene + 45, 57Warfare agents + 46 compounds not specifiedCortisone + 47Progesterone + 43Fluocinolone acetonide + 43

A combination of some of the advantagesof in vitro methods with those of in vivo canbe achieved by using isolated, perfused skinflaps or isolated perfused whole organs. Theisolated perfused porcine skin flap was devel-oped to overcome some of the shortcomings ofthe classic in vitro methods. It provided ananatomically intact, viable, isolated, perfusedtube-like preparation [58, 59]. The pig wasselected because of its size and because its skinwas found to be functionally and structurallysimilar to that of man. Another model is basedon the isolated pig ear, which can be obtainedat the abattoir and perfused with oxygenatedblood from the same pig [50, 51]. There aretwo major advantages of the perfused pig earmodel over in vitro models. In the pig earmodel, blood is used as the recipient mediuminstead of a buffer containing organic solvents,and the model does not ignore the effect ofchemicals on the dermal vascular system(dose-dependent increase in perfusion pres-sure after noradrenaline and reversal of thesame by isoxsuprine). In table 2, a comparisonis made of the basic characteristics of in vivo,in vitro and infused organ experiments.

The vast amount of documentation accu-mulated substantiates the acknowledged val-

ue of the pig as an animal model for man forskin permeation studies. The articles citedhere were mostly the first and original onesreporting on research conducted on the var-ious aspects of percutaneous permeability inpig and human skin. These articles served asthe base for additional extended researchwork and were cited in many newer papers.Every additional study contributed its sharein this research field, confirmed and support-ed the conclusions on the comparative value.Still, it can be seen that the degree of resem-blance of the permeation of various com-pounds through pig skin and human skin canvary with groups of compounds of differentchemical characteristics. It is therefore essen-tial that in every new study, the degree ofresemblance be checked in the literature or, ifthere is no such data, initial studies be per-formed to establish the similarities of the par-ticular compound under study.

Full details were not always provided onthe race, size (weight) and age of the pigs used.This information is important, since certaincompounds may penetrate faster through theskin of young animals as compared to adult orold animals of the same race [unpubl. data].Several authors used the term ‘weanling pig’

Required laboratory space

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Table 2. Comparison of basiccharacteristics of skin permeabilityexperiments in vivo, with those ofin vitro studies and with experi-ments using infused isolated organmodels

Characteristics In vivo In vitro Infused, isolatedorgan

+++1 + ++2

Variables +++ B +Animal model ++ ++ +Human model + – +

1 Depending on animal species.2 Depending on type of organ.

in describing their experimental animals, notalways indicating the breed, age and/orweight, while others indicated body weightonly. Since strains, in particular the miniaturestrains, have different growth curves, it isimportant to supply detailed information in-cluding breed, sex, age and body weight, and

the body region at which the permeationstudy was performed. Hopefully, the currenttheoretical and practical interest in perme-ability will lead to more comparative quanti-tative data that will aid in setting the bound-ary limits of this model as relates to man.

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