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Comparison of stratum corneum thickness in children and adults
Comparison of stratum corneum thickness in children and adults Janet A. Fairley, M . D . , and James E. Rasmussen, M . D .
Ann Arbor, MI We compared the thickness of the stratnm comeum from abdominal skin in infants less than 3 months of age, children between 3 months and 11 years, and adults. Measurements were made with a filar micrometer eyepiece on histologie sections obtained at autopsy. No significant differences were seen; therefore, a stratum corneum of different thickness cannot be used to explain differences in percutaneous absorption, supporting previous work which suggested that term infants and children have an efficient skin barrier. The greater toxicity from percutaneous absorption of topical compounds sometimes seen in children is more likely due to their increased surface to volume ratio and/or metabolic differences. (J AM ACAD DERMATOL 8:652-654, 1983.)
T h e greater susceptibility o f children to the effects of topically applied medications is well k n o w n . T h e r e are m a n y e p i s o d e s of toxicity f r o m cutaneous absorption of b o r i c acid, m e r c u r y , salicylic acid, phenol, h e x a c h l o r o p h e n e , and corticos t e r o i d s - - m a n y o f these incidents h a v e occurred in children. Several factors m i g h t be responsible for differences in toxicity o f topically applied c o m p o u n d s in children versus adults. These include surface to v o l u m e ratio, stratum c o r n e u m thickness, differences in structural c o m p o n e n t s of the epidermis, or differences in end organ sensitivity, m e t a b o l i s m , or e x c r e t i o n . Since the stratum c o m e u m has been shown to be the m a j o r barrier to percutaneous absorption, I it is often assumed that the stratum c o r n e u m o f children m u s t therefore be thinner. In this study w e have c o m p a r e d the stratum c o r n e u m thickness in children and adults. From the Departmentof Dermatology,Universityof Michigan Medical School. Accepted for publication Sept. 29, 1982. Reprint requests to: Dr. James E. Rasmussen, Department of Dermatology, University of Michigan Hospital, Ann Arbor, MI 48109.
652
MATERIALS AND METHODS Full-thickness skin samples were obtained from the abdomen at autopsy. Thirty samples from children and ten from adults were obtained. The average age was 28 months (children) and 26 years (adult); no preterm infants were studied. Historical evidence of chronic illness, hospitalization more than 48 hours, skin disease, or skin injury was basis for exclusion from the study, as was gross artifact after processing. Causes of death included sudden infant death syndrome, child abuse, automobile accidents, drug ingestion, and suicide (adt~lts only). Samples were fixed in 10% buffered formalin, embedded in paraffin, serially sectioned, and stained with hematoxylin and eosin. Measurements of the stratum corneum thickness were made with a filar micrometer eyepiece (Baush & Lomb Inc.) calibrated for a × 10 microscope. Five measurements were made on each sample from the stratum granulosum to the outermost cell of the stratum corneum. Measurements were made only in areas in which the entire stratum corneum was intact and the normal basket weave appearance maintained. RESULTS Measurements were divided into three groups: adults (n = 10; age range, 17-46 yr), children be-
Volume 8 Number 5 May, 1983
Stratum corneum thickness in children and adults
653
tween the ages of 11 years and 3 months (n = 20, mean age, 3.9 yr), and infants less than 3 months (n = 10, mean age, 17.1 days). Means and standard deviation were calculated for each group (Table I). These means do not represent an absolute value for the stratum comeum thickness, but rather a reproducible artifact that can be used for comparison purposes. A one-way analysis of variance was used to compare the three groups. No statistical difference was seen between any of the groups (p = 0.0746).
Table I. Calculated means and standard deviations
DISCUSSION
late permeability. Similar study of lipid content of the stratum corneum of infants compared to adults has not been done but might prove useful. Once a compound is absorbed, a number of variables may effect its toxicity. The ratio of surface area to body weight in infants is approximately three times that of adults. When equivalent areas of skin are treated with topical salicylic acid, the potential systemic dose is 2.7 times that of adults.'° In addition, the metabolic and excretory pathways are not fully developed in the neonate and may also cause increased systemic effect of a topical medication. '1 We were unable to demonstrate a significant difference in thickness between the stratum corneum of term infants, children, or adults. We conclude that the greater toxicity of some drugs in infants and children is not due to "thinner skin." Differences in surface to volume ratio, metabolism and/or excretion of drugs, and possibly differences in structural components of the stratum corneum are more likely reasons for increased toxicity.
Our data support previous work suggesting that infants and adults have similar rates of percutaneous absorption/era 2. No attempt was made to measure preterm infants, as numerous studies have demonstrated decreased barrier function in this group .2-4 The data suggesting a substantial barrier for infant skin is broad-based and impressive, although by no means conclusive. Using rhesus monkeys as an animal model, Wester et aP showed no difference in percutaneous absorption of testosterone per unit of surface area in the neonatal versus adult monkeys. In vivo measurements of transepidermal water loss and carbon dioxide emission rates have shown no decrease in barrier function in term human infants versus adults. 6"r Rather, transepidermal water loss was slightly decreased in term infants. Nachman and Esterly 2 found the skin of term infants to have normal barrier function when histamine was applied topically. If the barrier is similar, what then might account for the differences in toxicity from topical medications in infants? There is no completely linear relationship between thickness and barrier; other components besides its thickness might play a role in absorption of specific compounds. The fibrous proteins (keratins) and lipids of the epidermis are constituents which may play a role in barrier function. Epidermal keratins from foreskins of neonates and adults have been compared by extraction and polyacrylamide gel electrophoresis, and no differences were seenY Elias et aP recently demonstrated regional differences in the lipid composition of the stratum corneum in adult skin. They hypothesize that the lipid composition may regu-
I Group
N
Mean stratum I Standard corneum thickness(p) deviation
Adult Children
10 20
35.4 28.8
6.4 10.6
(3 mo-11 yr) Infants (<3 mo)
10
35.4
11.3
Drs. John T. Headington and Kent Mancer supplied the skin biopsies. REFERENCES 1. Blank IH, Scheuplein RJ: Transport into and within the skin. Br J Dermatol 81:4-10, 1969. 2. Nachman RL, Esterly NB: Increased skin permeability in preterm infants. J Pediatr 97:628-632, 1971. 3. Rutter N, Hull D: Water loss from the skin of term and preterm babies. Arch Dis Child 54:858-868, 1979. 4. Wilson DR, Maibach HI: Transepidermal water loss in vivo. Biol Neonate 37:180-185, 1980. 5. Wester RC, Noonan PK, Cole MP, Maibach HI: Percutaneous absorption of testosterone in the newborn rhesus monkey: Comparison to the adult. Pediatr Res 11:737-739, 1977. 6. Wildnauer RH, Kennedy R: Transepidermal water loss
654
Fairley and Rasmussen
of human newborns. J Invest Dermatol 54:483-486, 1970. 7. Cunico RL, Maibach HI, Khan H, Bloom E: Skin barrier properties in the newborn. Biol Neonate 32:177-182, 1977. 8. Baden kiP, Lee LD: Fibrous protein of human epidermis. J Invest DermatoI 71: 148-15 l, 1978. 9. Elias PM, Cooper ER, Korc A, Brown BE: Percutaneous transport in relation to stratum corneum structure and
Journal of the American Academy of Dermatology
lipid composition. J Invest Dermatol 76:297-301, 1981. 10. Rasmussen JE: Percutaneous absorption in children. A monograph, in Dobson RL, editor: 1979 Year book of dermatology. Chicago, 1979, Year Book Medical Publishers, Inc., pp. 15-38. 11. West DP, Worobec S, Solomon LM: Pharmacology and toxicology of infant skin. J Invest Dermatol 76:147-150, 1981.
Ann Arbor, MI We compared the thickness of the stratnm comeum from abdominal skin in infants less than 3 months of age, children between 3 months and 11 years, and adults. Measurements were made with a filar micrometer eyepiece on histologie sections obtained at autopsy. No significant differences were seen; therefore, a stratum corneum of different thickness cannot be used to explain differences in percutaneous absorption, supporting previous work which suggested that term infants and children have an efficient skin barrier. The greater toxicity from percutaneous absorption of topical compounds sometimes seen in children is more likely due to their increased surface to volume ratio and/or metabolic differences. (J AM ACAD DERMATOL 8:652-654, 1983.)
T h e greater susceptibility o f children to the effects of topically applied medications is well k n o w n . T h e r e are m a n y e p i s o d e s of toxicity f r o m cutaneous absorption of b o r i c acid, m e r c u r y , salicylic acid, phenol, h e x a c h l o r o p h e n e , and corticos t e r o i d s - - m a n y o f these incidents h a v e occurred in children. Several factors m i g h t be responsible for differences in toxicity o f topically applied c o m p o u n d s in children versus adults. These include surface to v o l u m e ratio, stratum c o r n e u m thickness, differences in structural c o m p o n e n t s of the epidermis, or differences in end organ sensitivity, m e t a b o l i s m , or e x c r e t i o n . Since the stratum c o m e u m has been shown to be the m a j o r barrier to percutaneous absorption, I it is often assumed that the stratum c o r n e u m o f children m u s t therefore be thinner. In this study w e have c o m p a r e d the stratum c o r n e u m thickness in children and adults. From the Departmentof Dermatology,Universityof Michigan Medical School. Accepted for publication Sept. 29, 1982. Reprint requests to: Dr. James E. Rasmussen, Department of Dermatology, University of Michigan Hospital, Ann Arbor, MI 48109.
652
MATERIALS AND METHODS Full-thickness skin samples were obtained from the abdomen at autopsy. Thirty samples from children and ten from adults were obtained. The average age was 28 months (children) and 26 years (adult); no preterm infants were studied. Historical evidence of chronic illness, hospitalization more than 48 hours, skin disease, or skin injury was basis for exclusion from the study, as was gross artifact after processing. Causes of death included sudden infant death syndrome, child abuse, automobile accidents, drug ingestion, and suicide (adt~lts only). Samples were fixed in 10% buffered formalin, embedded in paraffin, serially sectioned, and stained with hematoxylin and eosin. Measurements of the stratum corneum thickness were made with a filar micrometer eyepiece (Baush & Lomb Inc.) calibrated for a × 10 microscope. Five measurements were made on each sample from the stratum granulosum to the outermost cell of the stratum corneum. Measurements were made only in areas in which the entire stratum corneum was intact and the normal basket weave appearance maintained. RESULTS Measurements were divided into three groups: adults (n = 10; age range, 17-46 yr), children be-
Volume 8 Number 5 May, 1983
Stratum corneum thickness in children and adults
653
tween the ages of 11 years and 3 months (n = 20, mean age, 3.9 yr), and infants less than 3 months (n = 10, mean age, 17.1 days). Means and standard deviation were calculated for each group (Table I). These means do not represent an absolute value for the stratum comeum thickness, but rather a reproducible artifact that can be used for comparison purposes. A one-way analysis of variance was used to compare the three groups. No statistical difference was seen between any of the groups (p = 0.0746).
Table I. Calculated means and standard deviations
DISCUSSION
late permeability. Similar study of lipid content of the stratum corneum of infants compared to adults has not been done but might prove useful. Once a compound is absorbed, a number of variables may effect its toxicity. The ratio of surface area to body weight in infants is approximately three times that of adults. When equivalent areas of skin are treated with topical salicylic acid, the potential systemic dose is 2.7 times that of adults.'° In addition, the metabolic and excretory pathways are not fully developed in the neonate and may also cause increased systemic effect of a topical medication. '1 We were unable to demonstrate a significant difference in thickness between the stratum corneum of term infants, children, or adults. We conclude that the greater toxicity of some drugs in infants and children is not due to "thinner skin." Differences in surface to volume ratio, metabolism and/or excretion of drugs, and possibly differences in structural components of the stratum corneum are more likely reasons for increased toxicity.
Our data support previous work suggesting that infants and adults have similar rates of percutaneous absorption/era 2. No attempt was made to measure preterm infants, as numerous studies have demonstrated decreased barrier function in this group .2-4 The data suggesting a substantial barrier for infant skin is broad-based and impressive, although by no means conclusive. Using rhesus monkeys as an animal model, Wester et aP showed no difference in percutaneous absorption of testosterone per unit of surface area in the neonatal versus adult monkeys. In vivo measurements of transepidermal water loss and carbon dioxide emission rates have shown no decrease in barrier function in term human infants versus adults. 6"r Rather, transepidermal water loss was slightly decreased in term infants. Nachman and Esterly 2 found the skin of term infants to have normal barrier function when histamine was applied topically. If the barrier is similar, what then might account for the differences in toxicity from topical medications in infants? There is no completely linear relationship between thickness and barrier; other components besides its thickness might play a role in absorption of specific compounds. The fibrous proteins (keratins) and lipids of the epidermis are constituents which may play a role in barrier function. Epidermal keratins from foreskins of neonates and adults have been compared by extraction and polyacrylamide gel electrophoresis, and no differences were seenY Elias et aP recently demonstrated regional differences in the lipid composition of the stratum corneum in adult skin. They hypothesize that the lipid composition may regu-
I Group
N
Mean stratum I Standard corneum thickness(p) deviation
Adult Children
10 20
35.4 28.8
6.4 10.6
(3 mo-11 yr) Infants (<3 mo)
10
35.4
11.3
Drs. John T. Headington and Kent Mancer supplied the skin biopsies. REFERENCES 1. Blank IH, Scheuplein RJ: Transport into and within the skin. Br J Dermatol 81:4-10, 1969. 2. Nachman RL, Esterly NB: Increased skin permeability in preterm infants. J Pediatr 97:628-632, 1971. 3. Rutter N, Hull D: Water loss from the skin of term and preterm babies. Arch Dis Child 54:858-868, 1979. 4. Wilson DR, Maibach HI: Transepidermal water loss in vivo. Biol Neonate 37:180-185, 1980. 5. Wester RC, Noonan PK, Cole MP, Maibach HI: Percutaneous absorption of testosterone in the newborn rhesus monkey: Comparison to the adult. Pediatr Res 11:737-739, 1977. 6. Wildnauer RH, Kennedy R: Transepidermal water loss
654
Fairley and Rasmussen
of human newborns. J Invest Dermatol 54:483-486, 1970. 7. Cunico RL, Maibach HI, Khan H, Bloom E: Skin barrier properties in the newborn. Biol Neonate 32:177-182, 1977. 8. Baden kiP, Lee LD: Fibrous protein of human epidermis. J Invest DermatoI 71: 148-15 l, 1978. 9. Elias PM, Cooper ER, Korc A, Brown BE: Percutaneous transport in relation to stratum corneum structure and
Journal of the American Academy of Dermatology
lipid composition. J Invest Dermatol 76:297-301, 1981. 10. Rasmussen JE: Percutaneous absorption in children. A monograph, in Dobson RL, editor: 1979 Year book of dermatology. Chicago, 1979, Year Book Medical Publishers, Inc., pp. 15-38. 11. West DP, Worobec S, Solomon LM: Pharmacology and toxicology of infant skin. J Invest Dermatol 76:147-150, 1981.