Monteiro-Riviere ,NA. Indirect Immunohistochemistry and immunoelectron microscopy distribution of eight epidermal-dermal junction epitopes in the pig and in isolated perfused skin treated with bis (2-chloroethyl) sulfide. Toxicologic Pathology 23:313-325, 1995.

Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman’s Textbook of Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6th ed., pp.320-349, 2006.

Experimental Model Systems

Animal Models• Practicality• Absorption

• Toxicology - Increased absorption compared to man to assess worse case scenario

• Rats, Mice, Rabbits

• Pharmacology - Similar absorption to man• Pigs, Primates, Hairless Rodents

• Toxicity• Immunological considerations• Rabbits, Guinea Pigs, Rodents

• Species differences for different mechanisms are independent ∴one species is not the best model for all endpoints in humans!

Species Differences

• Anatomical factors such as thickness, adnexial structures, etc.

• Biochemical differences in lipid composition, enzymes, etc.

• Different receptors for immunological or pharmacological agents

• Physiological differences including blood flow, etc.

Body Site Differences• The rate of penetration and absorption differs

across various body sites• Scrotum > Forehead > Axilla > = Scalp > Back =

Abdomen > Palm and Plantar surface• Seen in humans and animals making route to

route extrapolations “interesting.”• The major reasons are due to:

– Differences in anatomy:skin thickness– Differences in physiology: blood flow and distribution

of blood vessels– Stratum corneocyte cell size ?

Pig Skin is Similar to Human Skin

I like pigs. Dogs look up to us. Cats look down on us. Pigs treat us as equals.

• Similar surface characteristics• Body masses and skin to body surface area ratio• Sparse hair coat• Thick epidermis• Hair follicle density• Epidermal turnover kinetics• Lipid composition• Biophysical properties of lipid

Don’t use skin from an abattoir if hide is scalded!

Differences Between Pig and Human Skin

• Pig skin has an additional interfollicular muscle

• Young pigs have hair follicles that occur in a triad

• Pigs have only apocrine sweat glands over most of the body

• Immunological and drug metabolism differences not well characterized

Monteiro-Riviere, NA. Comparative Anatomy, Physiology, and Biochemistry of Mammalian Skin . In Hobson DW (ed) Dermal and Ocular Toxicology: Fundamentals and Methods, Boca Raton, FL, CRC Press, Chpt. 1, 3-71, 1991.

Porcine Skin

Stromberg MW, Huang YC, Monteiro-Riviere NA. Interfollicular smooth muscle in the skin of the domesticated pig. The Anatomical Record 201:455-462, 1981.

Porcine Skin

Human Skin

Monkey Skin

Nude Guinea Pig Skin

Mouse Skin

Nude Mouse

Rat Skin

Rabbit Skin

Cow Skin

Cow Skin

Dog Skin

Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman’s Textbook of Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6th ed., pp.320-349, 2006.

Dog Skin

Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman’s Textbook of Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6th ed., pp.320-349, 2006.

Cat Skin

Cat Skin

Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman’s Textbook of Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6th ed., pp.320-349, 2006.

Cat Foot Pad

Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman’s Textbook of Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6th ed., pp.320-349, 2006.

Comparative Epidermal Thickness and Number of Cell Layers From the Back of Nine Species

Species Epidermis Stratum Corneum Number of Cell Layers(µm) (µm)

Cat 12.97 + 0.93 5.84 + 1.02 1.28 + 0.13 Cow 36.76 + 2.95 8.65 + 1.17 2.22 + 0.11 Dog 21.16 + 2.55 5.56 + 0.85 1.89 + 0.16 Horse 33.59 + 2.16 7.26 + 1.04 2.50 + 0.25 Monkey 26.87 + 3.14 2.05 + 2.30 2.67 + 0.24 Mouse 13.32 + 1.19 2.90 + 0.12 1.75 + 0.08 Pig 51.89 + 1.49 12.28 + 0.72 3.94 + 0.13 Rabbit 10.85 + 1.00 6.56 + 0.37 1.22 + 0.11 Rat 21.66 + 2.23 5.00 + 0.85 1.83 + 0.17

Monteiro-Riviere et al. Interspecies and interegional analysis of the comparative histological thickness and laser Doppler blood flow measurements at five cutaneous sites in nine species. Journal of Investigative Dermatology 95:582-586, 1990.

Blood Flow Measurements of Nine Species at Five Cutaneous Sites

Species BUT EAR HSJ TLJ VAB

Cat 1.82 + 0.59 6.46 + 2.30 1.86 + 0.70 2.39 + 0.35 6.19 + 0.94Cow 6.03 + 1.84 6.98 + 2.19 5.51 + 2.32 5.49 + 1.49 10.49 + 2.13Dog 2.21 + 0.67 5.21 + 1.53 5.52 + 1.31 1.94 + 0.27 8.78 + 1.40Horse 3.16 + 1.22 ----- 6.76 + 1.49 2.99 + 0.86 8.90 + 1.46Monkey 3.12 + 0.58 20.93 + 5.37 8.49 + 3.28 2.40 + 0.82 3.58 + 0.41Mouse 3.88 + 0.92 1.41 + 0.48 10.10 + 3.51 20.56 + 4.69 36.85 + 8.14Pig 3.08 + 0.48 11.70 + 3.02 6.75 + 2.09 2.97 + 0.56 10.68 + 2.14Rabbit 3.55 + 0.93 8.38 + 1.53 5.38 + 1.06 5.46 + 0.94 17.34 + 6.31Rat 4.20 + 1.05 9.13 + 4.97 6.22 + 1.47 9.56 + 2.17 11.35 + 5.53

Units=ml/min/100g (mean + SE)But = buttocks; Ear = pinnae; HSJ = humeroscapular joint; TLJ = thoracolumbar junction; VAB = ventral abdomen.

Monteiro-Riviere et al. Interspecies and interegional analysis of the comparative histological thickness and laser Doppler blood flow measurements at five cutaneous sites in nine species. Journal of Investigative Dermatology 95:582-586, 1990.

Hair Follicle Density

Species Area of Skin Number of Hair Follicles/cm2

Human Abdomen 11 + 1Pig Back 11 + 1Rat Back 289 + 21Mouse Back 658 + 38Hairless Mouse Back 75 + 6

Bronaugh et al. Methods for in vitro percutaneous absorption studies II. Animal models for human skin. Toxicology and Applied Pharmacology 62, 481-488, 1982.