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Cited by 26Contact Dermatitis and AllergiesImmunotoxicology and immune responsesDermatology and Skin Diseases

Morphological characteristics and notes of the skin in preclinical toxicity assessment

Open access
Moroki, Takayasu·2023·Journal of Toxicologic Pathology
DOI 10.1293/tox.2022-0103PMC PMC10123300
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Abstract

In this review, the histological structures of the skin are summarized for fundamental knowledge for toxicological assessment. The skin is composed of epidermis, dermis, subcutaneous tissue, and associated adnexa. In the epidermis, keratinocytes comprise four layers, and three other cell types, besides keratinocytes, play various roles. Epidermal thickness varies with species and body site. In addition, it can be affected by tissue preparation procedures, which can render toxicity assessments difficult. Bulge stem cells are the origin of sebaceous glands, epidermal basal layer, and hair follicle formation, and they play an important role in the maintenance of the basic structure of the skin. Stem cells and appendages formed from stem cells sometimes become toxic targets, and it is useful to study the origins of the hair follicle/hair cycle to interpret their toxicity. Irritant contact dermatitis and allergic contact dermatitis are the main adverse reactions in topical application studies. The mechanism involves direct chemical irritation of the skin, and histologically, epidermal necrosis and accompanying inflammatory cell infiltration. In allergic contact dermatitis, an inflammatory reaction and intercellular or intracellular edema, histologically represented by lymphocytic infiltration of the epidermis and dermis, are observed. Regional and species differences exist in the dermal absorption of compounds, and differences in the thickness of the stratum corneum substantially contribute to these differences. Learning the basic structures, functions, and possible artifacts will contribute to the evaluation of skin toxicity by topical and systemic applications.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes histological structure, species/site differences, injury mechanisms, and preparation artifacts of skin for preclinical toxicity assessment. It emphasizes that epidermal thickness, hair cycle, adnexa, and stratum corneum barrier properties strongly affect interpretation of dermal toxicity studies.

Key findings

  • The skin comprises epidermis, dermis, subcutaneous tissue, and adnexa; the epidermis has four layers and four cell types (keratinocytes, Langerhans cells, melanocytes, Merkel cells). Epidermal turnover is reported as 30 days in humans, 26–27 days in pigs, 22 days in dogs, 34 days in rats, and only 3–4 days in hairless mice.
  • Epidermal thickness varies by species, body site, sex, age, hair cycle, and tissue preparation; in dorsal skin, rabbits have the thinnest epidermis and minipigs the thickest, with minipig skin closest to human skin. Hair cycle stage (anagen, catagen, telogen) changes skin thickness and carcinogenic/irritation sensitivity; rodents have higher hair follicle density than humans, monkeys, and minipigs.
  • Main adverse reactions in topical studies are irritant contact dermatitis (direct chemical irritation, epidermal necrosis, inflammatory cell infiltration) and allergic contact dermatitis (type IV hypersensitivity, lymphocytic infiltration, intercellular/intracellular edema). Hair follicle stem cells and melanocytes can be toxic targets; chemotherapy-induced alopecia is linked to approximately 80% of scalp follicles being in anagen in humans.
  • Percutaneous absorption depends on stratum corneum integrity/hydration, temperature, carrier solubility, molecular weight, and site; lipophilic compounds absorb into the stratum corneum, while hydrophilic compounds absorb more through adnexa such as hair follicles. Stratum corneum thickness is a major species/site difference, with rodents generally more permeable than humans and pigs/monkeys similar to humans.

Methods

  • Narrative review of histological skin structure for preclinical toxicity assessment, synthesizing published literature and illustrative H&E and electron microscopy figures.
  • Includes comparative skin thickness measurements from male animals (ICR mouse, Sprague-Dawley rat, guinea pig, New Zealand White rabbit, Beagle dog, Göttingen minipig, Cynomolgus monkey) and humans in Table 1; tissues except monkey were prepared by the same technician at the same facility.
  • Main analysis is descriptive: species and site differences, adnexal and hair cycle biology, mechanisms of irritant/allergic contact dermatitis, tissue preparation artifacts, and percutaneous absorption.

Limitations

  • No formal limitations section is stated; the paper notes that epidermal thickness varies by site, sex, age, hair cycle, and preparation conditions, so comparisons should use tissues prepared identically, and the condition of monkey tissues at collection was unknown.
  • Evident: as a narrative review, it lacks systematic search/selection methods and reports no primary experiments or statistical analysis; conclusions depend on cited literature and selected figures/table.
  • Evident: Table 1 values are not reproduced in the provided text, limiting independent verification of the comparative thickness claims.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1293/tox.2022-0103

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

22 of 76 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Bulge stem cells are the origin of sebaceous glands, epidermal basal layer, and hair follicle formation.

    “Bulge stem cells are the origin of sebaceous glands, epidermal basal layer, and hair follicle formation, and they play an important role in the maintenance of the basic structure of the skin.”
    • Also stated in: § Cutaneous Adnexa · plain
      “The bulge provides pluripotent stem cells that differentiate into hair follicles, sebaceous glands, and epidermis2, 32, 33.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [2] 2. Kierszenbaum AL, and Tres LL. Chapter 11: Integumentary system. In: Histology and Cell Biology: An Introduction to Pathology, 5th ed. Elsevier, Philadelphia. 389–416. 2020.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [32] 32. Cotsarelis G. Gene expression profiling gets to the root of human hair follicle stem cells. J Clin Invest. 116: 19–22. 2006. source

      The passage on follicle regeneration says bulge stem cells regenerate the lower hair follicle and produce a new hair; the Identification of stem cells section also says mouse bulge cells generate all follicular lineages. Our copy does not say they give rise to sebaceous glands or the epidermal basal layer. Its reference to the basal layer concerns the follicle’s outer root sheath, not the epidermis. Page numbers are not supplied in the indexed passages. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [33] 33. Yang CC, and Cotsarelis G. Review of hair follicle dermal cells. J Dermatol Sci. 57: 2–11. 2010. source

      The Abstract says bulge stem cells regenerate hair follicles during cycling. Section 5.2 reports that isolated adult hair-follicle stem cells regenerated hair-follicle, sebaceous-gland, and interfollicular-epidermis lineages in a mouse reconstitution assay. It does not specifically identify the epidermal basal layer or establish bulge cells as the origin of all three structures during normal skin development. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Langerhans cells on the inside of the stratum spinosum can extend their dendrites to outside the tight junctions in the stratum granulosum to capture antigens.

    “LCs on the inside of the stratum spinosum can extend their dendrites to outside the TJs in the stratum granulosum to capture antigens17, 19.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [17] 17. Yoshida K, Kubo A, Fujita H, Yokouchi M, Ishii K, Kawasaki H, Nomura T, Shimizu H, Kouyama K, Ebihara T, Nagao K, and Amagai M. Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with a source
    • cites [19] 19. Kubo A, Nagao K, Yokouchi M, Sasaki H, and Amagai M. External antigen uptake by Langerhans cells with reorganization of epidermal tight junction barriers. J Exp Med. 206: 2937–2946. 2009. source

      The Results and Discussion sections report that activated Langerhans cells extend dendrites through tight junctions in the stratum granulosum and take up antigens beyond the barrier. The paper describes LC cell bodies in the deep epidermis, but the passages do not specifically place them in the stratum spinosum. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    Irregular hair spots in rabbits have been reported to appear as raised, thickened islands compared to the surrounding skin.

    “Irregular hair spots in rabbits have been reported to appear as raised, thickened islands compared to the surrounding skin38.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [38] 38. Ishihara T, Yamashita H, Sakurai T, Morita J, Sakamoto K, Ishii A, and Sasaki M. Morphological analysis of patchy thickening and reddish discoloration of active hair growth areas in the skin of New Zealand White rabbits. J Toxicol Pathol. 30: 315–322. 2017. source
  • Premisecitation

    The density of hair follicles varies with species, with higher follicle densities in rodents and lower densities in humans, monkeys, and minipigs.

    “The density of hair follicles varies with species, with higher follicle densities in rodents and lower densities in humans, monkeys, and minipigs7, 9.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [7] 7. Stricker-Krongrad A, Shoemake CR, Pereira ME, Gad SC, Brocksmith D, and Bouchard GF. Miniature swine breeds in toxicology and drug safety assessments: what to expect during clinical and pathology evaluations. Toxicol Pathol. 44: 421–427. 2016. source

      The Conclusion (page unavailable) mentions similarities between miniature swine and humans in the integumentary system, but does not discuss hair-follicle density. Searches of our copy for hair follicles and follicle density found no comparison among rodents, humans, monkeys, and minipigs. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [9] 9. Diegel KL, Danilenko DM, and Wojcinski ZW. Chapter 55: Integument. In: Haschek and Rousseaux’s Handbook of Toxicologic Pathology, 3rd ed. WM Haschek, CG Rousseaux, and MA Wallig (eds). Academic Press, San Diego. 2219–2275. 2013. source
  • Premisecitation

    Erythema and edema have recently been evaluated in repeated dermal administration toxicity studies using minipigs rather than solely in irritation studies.

    “However, erythema and edema have recently been evaluated in repeated dermal administration toxicity studies using minipigs rather than solely in irritation studies7.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] 7. Stricker-Krongrad A, Shoemake CR, Pereira ME, Gad SC, Brocksmith D, and Bouchard GF. Miniature swine breeds in toxicology and drug safety assessments: what to expect during clinical and pathology evaluations. Toxicol Pathol. 44: 421–427. 2016. source

      The Discussion says Hanford minipigs have been used for regulatory dermal toxicity studies, and the Conclusion lists both repeat-dose studies and dermal administration among minipig applications (page numbers unavailable). Neither passage says erythema and edema were evaluated in repeated dermal administration studies or contrasts those studies with irritation studies. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 29
  • May combine two claims. 31

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The mammalian skin consists of two sets of barriers: the stratum corneum and tight junctions in the stratum granulosum.

    “The mammalian skin consists of two sets of barriers: one is the stratum corneum and the other is TJs in the stratum granulosum.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [17] 17. Yoshida K, Kubo A, Fujita H, Yokouchi M, Ishii K, Kawasaki H, Nomura T, Shimizu H, Kouyama K, Ebihara T, Nagao K, and Amagai M. Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with a source
    • cites [19] 19. Kubo A, Nagao K, Yokouchi M, Sasaki H, and Amagai M. External antigen uptake by Langerhans cells with reorganization of epidermal tight junction barriers. J Exp Med. 206: 2937–2946. 2009. source

  • May combine two claims.

    Premisecitation

    Minipig skin most closely resembles human skin, with similar thicknesses of various layers and hair follicle density.

    “In recent years, general toxicity studies and irritation evaluations have been conducted using minipigs, whose skin most closely resembles human skin, with similar thicknesses of various layers and hair follicle density6, 7, 8.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [6] 6. Mahl JA, Vogel BE, Court M, Kolopp M, Roman D, and Nogués V. The minipig in dermatotoxicology: methods and challenges. Exp Toxicol Pathol. 57: 341–345. 2006. source
    • cites [7] 7. Stricker-Krongrad A, Shoemake CR, Pereira ME, Gad SC, Brocksmith D, and Bouchard GF. Miniature swine breeds in toxicology and drug safety assessments: what to expect during clinical and pathology evaluations. Toxicol Pathol. 44: 421–427. 2016. source

      The Conclusion (page unavailable) identifies the integumentary system as a similarity between miniature swine and humans, and the Discussion notes their use in dermal toxicity studies. Our copy does not say minipig skin is the closest match to human skin or give comparisons of skin-layer thickness or hair follicle density. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [8] 8. Diegel K, Andrews-Jones L, Danilenko DM, and Aibo DI. Skin Appendix 3: Mini-atlas of organ system anatomy and histology. Organ system teams. In: The Illustrated Dictionary of Toxicologic Pathology and Safety Science. PS Sahota, RH Spaet, P Bentley, and ZW Wojcinski (eds). 585–618. 2019.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The stratum granulosum contains tight junctions that seal intercellular spaces and control the intercellular transport of water, solutes, and water-soluble molecules.

    “The stratum granulosum contains tight junctions (TJs) that seal intercellular spaces and control the intercellular transport of water, solutes, and water-soluble morecules17.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [17] 17. Yoshida K, Kubo A, Fujita H, Yokouchi M, Ishii K, Kawasaki H, Nomura T, Shimizu H, Kouyama K, Ebihara T, Nagao K, and Amagai M. Distinct behavior of human Langerhans cells and inflammatory dendritic epidermal cells at tight junctions in patients with a source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The stratum corneum is the outermost layer of the epidermis and is the protective barrier of the skin that excludes toxic agents and microbes and prevents dehydration.

    “The stratum corneum is composed of dead deposits of terminally maturing keratinocytes and is the outermost layer of the epidermis, which is the protective barrier of the skin that excludes toxic agents and microbes and prevents dehydration1, 2.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [1] 1. Mecklenburg L, Kusewitt D, Kolly C, Treumann S, Adams ET, Diegel K, Yamate J, Kaufmann W, Müller S, Danilenko D, and Bradley A. Proliferative and non-proliferative lesions of the rat and mouse integument. J Toxicol Pathol. 26(Suppl): 27S–57S. 2013. source

      Normal morphology (page unavailable) describes the stratum corneum as containing terminally differentiated keratinocytes at the desquamating epidermal surface. The Introduction, under “Ontology, anatomy and function of the rodent skin” (page unavailable), says skin protects against chemical and microbiological agents. Our copy does not state that the stratum corneum specifically provides those protections or prevents dehydration. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [2] 2. Kierszenbaum AL, and Tres LL. Chapter 11: Integumentary system. In: Histology and Cell Biology: An Introduction to Pathology, 5th ed. Elsevier, Philadelphia. 389–416. 2020.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The hair cycle consists of three stages: anagen, catagen, and telogen.

    “The hair cycle consists of three stages: an actively growing phase (anagen), transition phase (catagen), and quiescent phase (telogen) (Fig. 6)1, 9, 12.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [1] 1. Mecklenburg L, Kusewitt D, Kolly C, Treumann S, Adams ET, Diegel K, Yamate J, Kaufmann W, Müller S, Danilenko D, and Bradley A. Proliferative and non-proliferative lesions of the rat and mouse integument. J Toxicol Pathol. 26(Suppl): 27S–57S. 2013. source
    • cites [9] 9. Diegel KL, Danilenko DM, and Wojcinski ZW. Chapter 55: Integument. In: Haschek and Rousseaux’s Handbook of Toxicologic Pathology, 3rd ed. WM Haschek, CG Rousseaux, and MA Wallig (eds). Academic Press, San Diego. 2219–2275. 2013. source
    • cites [12] 12. Yamate J. Chapter 19 The skin and subcutis. In: Boorman’s Pathology of the Rat. Reference and Atlas, 2nd ed. AW Suttie (ed). Academic Press, Oxford. 323–345. 2018. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Melanocytes are neural crest-derived cells with melanosomes that produce and secrete melanin to adjacent basal cells and prickle cells.

    “Melanocytes are neural crest-derived cells with organelles called melanosomes that produce and secrete melanin to adjacent basal cells and prickle cells1, 2.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [1] 1. Mecklenburg L, Kusewitt D, Kolly C, Treumann S, Adams ET, Diegel K, Yamate J, Kaufmann W, Müller S, Danilenko D, and Bradley A. Proliferative and non-proliferative lesions of the rat and mouse integument. J Toxicol Pathol. 26(Suppl): 27S–57S. 2013. source

      The Normal morphology section (page not provided) states that mouse melanocytes derive from neural crest cells and become interdigitated between keratinocytes. The paper also mentions melanosomes in its diagnostic discussion, but the retrieved passages do not say that melanocytes produce and secrete melanin to adjacent basal and prickle cells. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [2] 2. Kierszenbaum AL, and Tres LL. Chapter 11: Integumentary system. In: Histology and Cell Biology: An Introduction to Pathology, 5th ed. Elsevier, Philadelphia. 389–416. 2020.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In C57BL6 mice, the epidermis is thinner in males than in females, whereas the dermis is thicker in males.

    “In C57BL6 mice, the epidermis is reported to be thinner in males than that in females, whereas the dermis is thicker in males24, 25.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [24] 24. Calabro K, Curtis A, Galarneau JR, Krucker T, and Bigio IJ. Gender variations in the optical properties of skin in murine animal models. J Biomed Opt. 16: 011008, 011008–8. 2011. source

      Section 3.1 identifies C57Bl/6 as the gray mice, and the Conclusion reports significantly thicker dermal layers in males. The passage headed “Gray” says sex differences in epidermal thickness were not significant for any strain; the available text does not establish that C57Bl/6 males had thinner epidermis than females. Page numbers are unavailable in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [25] 25. Azzi L, El-Alfy M, Martel C, and Labrie F. Gender differences in mouse skin morphology and specific effects of sex steroids and dehydroepiandrosterone. J Invest Dermatol. 124: 22–27. 2005. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hair follicles are formed by differentiation of the stem cells in the follicular bulb, called the bulge, where the arrector pili muscle joins.

    “Hair follicles are formed by differentiation of the stem cells in the follicular bulb, called the bulge, where the arrector pili muscle joins1, 31.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [1] 1. Mecklenburg L, Kusewitt D, Kolly C, Treumann S, Adams ET, Diegel K, Yamate J, Kaufmann W, Müller S, Danilenko D, and Bradley A. Proliferative and non-proliferative lesions of the rat and mouse integument. J Toxicol Pathol. 26(Suppl): 27S–57S. 2013. source

      The Normal morphology section (page not available) says that matrix cells in the hair bulb differentiate to form the hair shaft and inner root sheath. The Neoplastic proliferative lesions section (page not available) mentions stem cells in the hair follicle bulge. Neither passage calls the bulb the bulge or locates the bulge where the arrector pili muscle joins. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [31] 31. Lavker RM, Sun TT, Oshima H, Barrandon Y, Akiyama M, Ferraris C, Chevalier G, Favier B, Jahoda CA, Dhouailly D, Panteleyev AA, and Christiano AM. Hair follicle stem cells. J Investig Dermatol Symp Proc. 8: 28–38. 2003. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The dermis consists of types I, III, V, and VI collagen, elastic and reticulum fibers.

    “The dermis consists of types I, III, V, and VI collagen, elastic and reticulum fibers1, 12.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [1] 1. Mecklenburg L, Kusewitt D, Kolly C, Treumann S, Adams ET, Diegel K, Yamate J, Kaufmann W, Müller S, Danilenko D, and Bradley A. Proliferative and non-proliferative lesions of the rat and mouse integument. J Toxicol Pathol. 26(Suppl): 27S–57S. 2013. source
    • cites [12] 12. Yamate J. Chapter 19 The skin and subcutis. In: Boorman’s Pathology of the Rat. Reference and Atlas, 2nd ed. AW Suttie (ed). Academic Press, Oxford. 323–345. 2018. source

  • May combine two claims.

    Premisecitation

    Dogs differ from the synchronized and mosaic hair-cycle categories, although hair loss associated with hair cycle arrest is seen.

    “Dogs differ from these categories, although hair loss associated with hair cycle arrest is seen33, 36, 37.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [33] 33. Yang CC, and Cotsarelis G. Review of hair follicle dermal cells. J Dermatol Sci. 57: 2–11. 2010. source

      The hair-cycling discussion (section 2.1) describes follicle stages, and the hair-diseases discussion (section 7) concerns androgenetic alopecia. Neither addresses whether dogs differ from synchronized and mosaic hair-cycle categories or whether hair-cycle arrest causes hair loss in dogs. Searches for canine hair-cycle arrest and those categories found no relevant passage in our copy. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [36] 36. Jonson E. Cycles and patterns of hair growth. In: The Physiology and Pathophysiology of the Skin, Vol. 4. The Hair Follicle. A Harrett (ed). Academic Press, New York. 1237–1254. 1977.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [37] 37. Müntener T, Doherr MG, Guscetti F, Suter MM, and Welle MM. The canine hair cycle—a guide for the assessment of morphological and immunohistochemical criteria. Vet Dermatol. 22: 383–395. 2011. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Keratinocytes are often targeted during chemotherapy, and necrosis of keratinocytes has been reported.

    “In addition, keratinocytes are often targeted during chemotherapy, and necrosis of keratinocytes has been reported47.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [47] 47. Hu X, Dong M, Liang X, Liu Z, and Li Q. Reactive oxygen species-mediated inflammation and apoptosis in hand-foot syndrome induced by PEGylated liposomal doxorubicin. Int J Nanomedicine. 16: 471–480. 2021. source

      The Results and Discussion section (page unavailable) reports that doxorubicin and PEGylated liposomal doxorubicin caused keratinocyte apoptosis, supporting chemotherapy-related keratinocyte damage. It does not report keratinocyte necrosis or establish that keratinocytes are often targeted across chemotherapy treatments. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In humans, sweat is produced to regulate body temperature; in rats and mice, it increases friction and strengthens grip.

    “In humans, sweat is produced to regulate body temperature; in rats and mice, it increases friction and strengthens grip43.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [43] 43. Zhang L, Zhang X, Du L, Zhang C, and Li H. Cholinergic- rather than adrenergic-induced sweating play a role in developing and developed rat eccrine sweat glands. Exp Anim. 70: 218–224. 2021. source

  • May combine two claims.

    Premisecitation

    Clipping the dorsal hair of rats synchronizes the hair cycle after a certain period of time, so it may be difficult to compare results with animals that have not undergone this treatment.

    “Clipping the dorsal hair of rats synchronizes the hair cycle after a certain period of time; therefore, it may be difficult to compare the results with those of animals that have not undergone this treatment48.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] 48. Wikramanayake TC, Amini S, Simon J, Mauro LM, Elgart G, Schachner LA, and Jimenez JJ. A novel rat model for chemotherapy-induced alopecia. Clin Exp Dermatol. 37: 284–289. 2012. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Mammary glands were observed in the inguinal region of the skin.

    “The mammary glands were observed in the inguinal region of the skin.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Tentacular hairs larger than body hairs were observed in the nasal area, and the structure of the hair follicles was also characteristic.

    “Tentacular hairs larger than body hairs were observed in the nasal area, and the structure of the hair follicles was also characteristic (Fig. 1D).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    The dermal layer of the plantar skin on the soles of the animal feet contains eccrine glands, with the thickest epidermis of the entire body and few hair follicles.

    “The dermal layer of the plantar skin on the soles of the animal feet contains eccrine glands, with the thickest epidermis of the entire body and few hair follicles (Fig. 1E).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the telogen phase of the rat hair cycle, the hair follicle is smallest and the cells surrounding the hair shaft are few and small.

    “The hair follicle is the smallest, and the cells surrounding the hair shaft are few and small.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In rats, the hair bulb is largest during the anagen phase of the hair cycle, and the papilla surrounded by hair matrix cells can be identified.

    “The hair bulb is the largest in the whole hair cycle, and papilla surrounded by hair matrix cells can be identified.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Comparing the epidermal thickness of the dorsal skin, rabbits have the thinnest epidermis, and minipigs have the thickest epidermis.

    “Comparing the epidermal thickness of the dorsal skin, rabbits have the thinnest epidermis, and minipigs have the thickest epidermis.”
    • Also stated in: § Epidermis · plain
      “The epidermis of minipigs was the thickest compared to that of other animals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The stratum corneum contains lipids, such as cholesterol, free fatty acids, and ceramides, which function as a barrier and are related to moisture retention.

    “The stratum corneum contains lipids, such as cholesterol, free fatty acids, and ceramides, which function as a barrier and are related to moisture retention13.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] 13. van Smeden J, and Bouwstra JA. Stratum corneum lipids: their role for the skin barrier function in healthy subjects and atopic dermatitis patients. Curr Probl Dermatol. 49: 8–26. 2016. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the epidermis, keratinocytes comprise four layers.

    “In the epidermis, keratinocytes comprise four layers, and three other cell types, besides keratinocytes, play various roles.”
    • Also stated in: § Epidermis · plain
      “Keratinocytes are the most abundant and form four layers: the stratum corneum, granulosum, spinosum, and basale (Fig. 2)2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] 2. Kierszenbaum AL, and Tres LL. Chapter 11: Integumentary system. In: Histology and Cell Biology: An Introduction to Pathology, 5th ed. Elsevier, Philadelphia. 389–416. 2020.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The skin is composed of the epidermis, dermis, subcutaneous tissue, and associated adnexa.

    “The skin is composed of epidermis, dermis, subcutaneous tissue, and associated adnexa.”
    • Also stated in: § Introduction · plain
      “It is composed of the epidermis, dermis, subcutaneous tissue, and adnexa, such as hair follicles, sebaceous, apocrine and eccrine glands, and claws2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] 2. Kierszenbaum AL, and Tres LL. Chapter 11: Integumentary system. In: Histology and Cell Biology: An Introduction to Pathology, 5th ed. Elsevier, Philadelphia. 389–416. 2020.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Bulge stem cells play an important role in the maintenance of the basic structure of the skin.

    “Bulge stem cells are the origin of sebaceous glands, epidermal basal layer, and hair follicle formation, and they play an important role in the maintenance of the basic structure of the skin.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Langerhans cells are resident dendritic cells derived from a bone marrow precursor and are responsible for monitoring invading pathogens by taking up foreign antigens and presenting the processed antigens to T cells, resulting in T cell differentiation and activation.

    “LCs are resident dendritic cells derived from a bone marrow precursor and are responsible for monitoring invading pathogens by taking up foreign antigens and presenting the processed antigens to T cells, resulting in T cell differentiation and activation18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] 18. Loser K, and Beissert S. Dendritic cells and T cells in the regulation of cutaneous immunity. Adv Dermatol. 23: 307–333. 2007. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Epidermal turnover is 30 days in humans, 26-27 days in pigs, 22 days in dogs, and 34 days in rats; in hairless mice it is only 3-4 days.

    “Epidermal turnover is 30 days in humans, 26–27 days in pigs, 22 days in dogs, and 34 days in rats. In contrast, the turnover of hairless mice is only 3–4 days10, 11, 12.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] 10. Monteiro-Riviere NA. Comparative anatomy, physiology, and biochemistry of mammalian skin. In: Dermal and Ocular Toxicology: Fundamentals and Methods. DW Hobson (ed). CRC press, Boca Raton. 3–71. 1991. source
    • cites [11] 11. Muller GH, Kirk RW, and Scott DW. Structure and function of the skin. In: Small Animal Dermatology, 4th ed. GH Muller, RW Kirk, and DW Scott (eds). WB Saunders, Philadelphia. 1–48. 1989.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [12] 12. Yamate J. Chapter 19 The skin and subcutis. In: Boorman’s Pathology of the Rat. Reference and Atlas, 2nd ed. AW Suttie (ed). Academic Press, Oxford. 323–345. 2018. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Elastic fibers in the vessel wall can be easily identified, allowing stainability to be confirmed.

    “However, elastic fibers in the vessel wall can be easily identified, allowing stainability to be confirmed in the vessel27.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] 27. Wakayama A, Kudaka W, Matsumoto H, Aoyama H, Ooyama T, Taira Y, Arakaki Y, Shimoji Y, Nakasone T, Nishihira K, Kaneshima I, Tamaki T, Yoshimi N, and Aoki Y. Lymphatic vessel involvement is predictive for lym source

  • May combine two claims.

    Premisecitation

    Carcinogenic sensitivity and skin irritation reactivity differ depending on the hair cycle.

    “Carcinogenic sensitivity and skin irritation reactivity differ depending on the hair cycle35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] 35. Bock FG. Comparative anatomy and function of skin as related to experimental chemical carcinogenesis. Prog Exp Tumor Res. 26: 5–17. 1983. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Melanin consists of black or brown eumelanins and red or yellow pheomelanins, which cover the skin and protect the nuclear DNA from UV radiation.

    “Melanin consists of black or brown eumelanins and red or yellow pheomelanins, which cover the skin and protect the nuclear DNA from UV radiation2, 9.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] 2. Kierszenbaum AL, and Tres LL. Chapter 11: Integumentary system. In: Histology and Cell Biology: An Introduction to Pathology, 5th ed. Elsevier, Philadelphia. 389–416. 2020.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [9] 9. Diegel KL, Danilenko DM, and Wojcinski ZW. Chapter 55: Integument. In: Haschek and Rousseaux’s Handbook of Toxicologic Pathology, 3rd ed. WM Haschek, CG Rousseaux, and MA Wallig (eds). Academic Press, San Diego. 2219–2275. 2013. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Sebaceous lipids consist of free fatty acids, squalene, and triglycerides, which contribute to moisturization and antibacterial activity.

    “Lipids consist of free fatty acids, squalene, and triglycerides, which contribute to moisturization and antibacterial activity42.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] 42. Pappas A. Epidermal surface lipids. Dermatoendocrinol. 1: 72–76. 2009. source

  • May combine two claims.

    Study design and conductreasoning

    The values in Table 1 were prepared by the same technician at the same facility, except for the monkey tissue, and were suitable for comparing skin thickness.

    “The values in Table 1 were prepared by the same technician at the same facility, except for the monkey tissue, and were suitable for comparing skin thickness.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Species differences in epidermal thickness have been reported.

    “Similar to the present results, species differences in the epidermal thickness have also been reported9, 22, 23.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] 9. Diegel KL, Danilenko DM, and Wojcinski ZW. Chapter 55: Integument. In: Haschek and Rousseaux’s Handbook of Toxicologic Pathology, 3rd ed. WM Haschek, CG Rousseaux, and MA Wallig (eds). Academic Press, San Diego. 2219–2275. 2013. source
    • cites [22] 22. Greaves P. Chapter 2. Integumentary system. In: Histopathology of Preclinical Toxicity Studies, 4th ed. Academic Press, San Diego. 11–68. 2012. source
    • cites [23] 23. Sandby-Møller J, Poulsen T, and Wulf HC. Epidermal thickness at different body sites: relationship to age, gender, pigmentation, blood content, skin type and smoking habits. Acta Derm Venereol. 83: 410–413. 2003. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The hair shaft is a hard keratin consisting of three layers: cuticle, hair cortex, and hair medulla, surrounded by an inner root sheath.

    “The hair shaft is a hard keratin consisting of three layers: cuticle, hair cortex, and hair medulla, surrounded by an inner root sheath2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] 2. Kierszenbaum AL, and Tres LL. Chapter 11: Integumentary system. In: Histology and Cell Biology: An Introduction to Pathology, 5th ed. Elsevier, Philadelphia. 389–416. 2020.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Merkel cells are located in the outer root sheath of hair follicles and are receptive to tactile sensation.

    “Merkel cells have been identified in many experimental animals and are located in the outer root sheath of the hair follicles. They are also receptive to tactile sensation9, 20.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] 9. Diegel KL, Danilenko DM, and Wojcinski ZW. Chapter 55: Integument. In: Haschek and Rousseaux’s Handbook of Toxicologic Pathology, 3rd ed. WM Haschek, CG Rousseaux, and MA Wallig (eds). Academic Press, San Diego. 2219–2275. 2013. source
    • cites [20] 20. Ginn PE, Mansell JEKL, and Rakich PM. Chapter 5: Skin and appendages. In: Pathology of Domestic Animals. Volume 1, 5th ed. MG Maxie (ed). Elsevier, Philadelphia. 553–781. 2007.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    Erythema, edema, and histological changes do not always occur in humans, so care should be taken to avoid overestimation.

    “Erythema, edema, and histological changes do not always occur in humans, so care should be taken to avoid overestimation3, 26.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] 3.OECD. OECD guideline for testing of chemicals no. 404: Acute dermal irritation/corrosion. 24. Apr. 2002.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [26] 26. Willard-Mack C, Ramani T, and Auletta C. Dermatotoxicology: safety evaluation of topical products in minipigs: study designs and practical considerations. Toxicol Pathol. 44: 382–390. 2016. source

  • May combine two claims.

    Premisenone given

    Mice, rats, hamsters, chinchillas, and rabbits have a synchronized hair cycle, whereas guinea pigs and humans have an independent hair cycle.

    “Mice, rats, hamsters, chinchillas, and rabbits have a synchronized hair cycle, whereas guinea pigs and humans have an independent hair cycle.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Apocrine glands are considered adrenergic and secrete proteins.

    “They are considered adrenergic and secrete proteins41.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] 41. Farkaš R. Apocrine secretion: new insights into an old phenomenon. Biochim Biophys Acta. 1850: 1740–1750. 2015. source

  • May combine two claims.

    Premiseown data

    The skin of minipigs is the thickest among experimental animals and is the closest to the human skin.

    “These results are consistent with a report that the skin of minipigs is the thickest among experimental animals and is the closest to the human skin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Female macaques are characterized by a reddish, swelling-like appearance of the perineum during estrus, and histologically, they are rich in blood vessels and may appear as hemangiomas.

    “One of the characteristic species differences is that female macaques are characterized by a reddish, swelling-like appearance of the perineum during estrus, and histologically, they are rich in blood vessels and may appear as hemangiomas28.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] 28. Lowenstine LJ. A primer of primate pathology: lesions and nonlesions. Toxicol Pathol. 31(Suppl): 92–102. 2003. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Tissues, except for the monkeys, were collected by placing them on sheets; however, the condition of the monkey tissues at the collection time was unknown.

    “Tissues, except for the monkeys, were collected by placing them on sheets; however, the condition of the monkey tissues at the collection time was unknown.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In humans, dosed substances are absorbed more readily around the face, which is considered to have thinner skin than the trunk and limbs, suggesting that absorption depends on skin thickness.

    “In humans, dosed substances are absorbed more readily around the face, which is considered to have thinner skin than that around the trunk and limbs, suggesting that it depends on the thickness of the skin50, 51.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] 50. Bormann JL, and Maibach HI. Effects of anatomical location on <i>in vivo</i> percutaneous penetration in man. Cutan Ocul Toxicol. 39: 213–222. 2020. source
    • cites [51] 51. Tagami H. Location-related differences in structure and function of the stratum corneum with special emphasis on those of the facial skin. Int J Cosmet Sci. 30: 413–434. 2008. source

  • May combine two claims.

    Premisecitation

    The principal causes of anagen effluvium are systemic cancer chemotherapeutics and heavy metals, where hair follicle cells in the anagen phase are targeted.

    “The principal causes are systemic cancer chemotherapeutics and heavy metals, where hair follicle cells in the anagen phase are targeted45.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] 45. Belsito DV. Chapter 19 Toxic response of the skin. In: Casarett &amp; Doull’s Toxicology: The Basic Science of Poisons, 9th ed. CD Klaassen (ed). McGraw-Hill Education, New York. 953–976. 2019.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Polycyclic aromatic hydrocarbons, such as coal tar and creosote, are known to cause skin cancer in humans and animals.

    “Polycyclic aromatic hydrocarbons, such as coal tar and creosote, are known to cause skin cancer in humans and animals45.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] 45. Belsito DV. Chapter 19 Toxic response of the skin. In: Casarett &amp; Doull’s Toxicology: The Basic Science of Poisons, 9th ed. CD Klaassen (ed). McGraw-Hill Education, New York. 953–976. 2019.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Eccrine glands are localized on the foot pad in mice, rats, and dogs and in the nasal region in pigs.

    “Eccrine glands are localized on the foot pad in mice, rats, and dogs (Fig. 1E) and in the nasal region in pigs”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 8. Diegel K, Andrews-Jones L, Danilenko DM, and Aibo DI. Skin Appendix 3: Mini-atlas of organ system anatomy and histology. Organ system teams. In: The Illustrated Dictionary of Toxicologic Pathology and Safety Science. PS Sahota, RH Spaet, P Bentley, and ZW Wojcinski (eds). 585–618. 2019.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Eccrine glands regulate body temperature by direct secretion of water and salts from the epidermis.

    “and they regulate body temperature by direct secretion of water and salts from the epidermis8.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 8. Diegel K, Andrews-Jones L, Danilenko DM, and Aibo DI. Skin Appendix 3: Mini-atlas of organ system anatomy and histology. Organ system teams. In: The Illustrated Dictionary of Toxicologic Pathology and Safety Science. PS Sahota, RH Spaet, P Bentley, and ZW Wojcinski (eds). 585–618. 2019.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Hair follicle stem cells are susceptible not only topically but also systemically, and lesions in hair follicles are another example of chemically induced skin toxicity.

    “In addition, hair follicle stem cells are susceptible not only topically but also systemically, and lesions in the hair follicles are another example of chemically induced skin toxicity8.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] 8. Diegel K, Andrews-Jones L, Danilenko DM, and Aibo DI. Skin Appendix 3: Mini-atlas of organ system anatomy and histology. Organ system teams. In: The Illustrated Dictionary of Toxicologic Pathology and Safety Science. PS Sahota, RH Spaet, P Bentley, and ZW Wojcinski (eds). 585–618. 2019.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Longitudinal sections are more suitable for evaluating hair follicles.

    “As noted in this review, longitudinal sections are more suitable for evaluating hair follicles.”
    Quote in the paperNot a substantial claim
46 of 46

  • The paper relies on this without support.

    Understanding the basic structure of the skin, including species differences, is important for toxicity assessment.

    “Understanding the basic structure of the skin, including species differences, is important for toxicity assessment.”

  • The paper relies on this without support.

    Learning the basic structures, functions, and possible artifacts will contribute to the evaluation of skin toxicity by topical and systemic applications.

    “Learning the basic structures, functions, and possible artifacts will contribute to the evaluation of skin toxicity by topical and systemic applications.”

  • The paper relies on this without support.

    Appropriate evaluation sites should be selected based on the purpose of the toxicity study.

    “Appropriate evaluation sites should be selected based on the purpose of the toxicity study.”

  • The paper relies on this without support.

    Irritant contact dermatitis and allergic contact dermatitis are the main adverse reactions in topical application studies.

    “Irritant contact dermatitis and allergic contact dermatitis are the main adverse reactions in topical application studies.”

  • The paper relies on this without support.

    The mechanism of irritant contact dermatitis involves direct chemical irritation of the skin, and histologically, epidermal necrosis and accompanying inflammatory cell infiltration.

    “The mechanism involves direct chemical irritation of the skin, and histologically, epidermal necrosis and accompanying inflammatory cell infiltration.”

  • The paper relies on this without support.

    In allergic contact dermatitis, an inflammatory reaction and intercellular or intracellular edema, histologically represented by lymphocytic infiltration of the epidermis and dermis, are observed.

    “In allergic contact dermatitis, an inflammatory reaction and intercellular or intracellular edema, histologically represented by lymphocytic infiltration of the epidermis and dermis, are observed.”

  • The paper relies on this without support.

    Regional and species differences exist in the dermal absorption of compounds.

    “Regional and species differences exist in the dermal absorption of compounds”

  • The paper relies on this without support.

    Differences in the thickness of the stratum corneum substantially contribute to regional and species differences in dermal absorption of compounds.

    “differences in the thickness of the stratum corneum substantially contribute to these differences.”

  • The paper relies on this without support.

    In general, juvenile animals have thinner skin than mature animals.

    “In general, juvenile animals have thinner skin than that of mature animals.”

  • The paper relies on this without support.

    The skin is most sensitive when the mitotic index is low.

    “The skin is most sensitive when the mitotic index is low.”

  • The paper relies on this without support.

    Attention should be paid to studies that evaluate skin reactions in rabbits.

    “Therefore, attention should be paid to studies that evaluate skin reactions in rabbits.”

  • The paper relies on this without support.

    Hair clipping or shaving during the experimental period can affect the hair cycle.

    “Hair clipping or shaving during the experimental period can affect the hair cycle.”

  • The paper relies on this without support.

    The degree of vasodilation of the skin varies depending on whether blood is released during euthanasia or not.

    “The degree of vasodilation of the skin varies depending on whether blood is released during euthanasia or not.”

  • The paper relies on this without support.

    The stratum corneum is detached by physical contact.

    “Because the stratum corneum is detached by physical contact”

  • The paper relies on this without support.

    Excessive extension of the slide during sectioning affects the evaluation of edema and cellular infiltration in the dermal layer.

    “Excessive extension of the slide during sectioning affects the evaluation of edema and cellular infiltration, etc. in the dermal layer.”

  • The paper relies on this without support.

    Percutaneous absorption in laboratory animals varies among species.

    “Percutaneous absorption in laboratory animals has been studied and is known to vary among species.”

  • The paper relies on this without support.

    In general, compounds are absorbed better in rodents than in humans; however, in pigs and monkeys, absorption is similar to that in humans.

    “In general, it is absorbed better in rodents than in humans; however, in pigs and monkeys, it is similar to that in humans.”

  • The paper relies on this without support.

    The thickness of the stratum corneum is thinner in many laboratory animals than in humans and is thus more permeable.

    “the first factor is the thickness of the stratum corneum, which is thinner in many laboratory animals than that in humans and is thus more permeable.”

  • The paper relies on this without support.

    The skin is the only organ that can be daily observed macroscopically and directly touched during the experimental period.

    “The skin is the only organ that can be daily observed (macroscopically) and directly touched during the experimental period.”
19 of 19

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The bulge is placed in both the hair bulb and the isthmus

    Minor

    The first passage places the bulge in the follicular bulb, where the arrector pili muscle joins. The later passage places the muscle junction at the isthmus and the hair bulb below it, in the inferior portion.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 6

  1. 2. Kierszenbaum AL, and Tres LL. Chapter 11: Integumentary system. In: Histology and Cell Biology: An Introduction to Pathology, 5th ed. Elsevier, Philadelphia. 389–416. 2020.
  2. 11. Muller GH, Kirk RW, and Scott DW. Structure and function of the skin. In: Small Animal Dermatology, 4th ed. GH Muller, RW Kirk, and DW Scott (eds). WB Saunders, Philadelphia. 1–48. 1989.
  3. 20. Ginn PE, Mansell JEKL, and Rakich PM. Chapter 5: Skin and appendages. In: Pathology of Domestic Animals. Volume 1, 5th ed. MG Maxie (ed). Elsevier, Philadelphia. 553–781. 2007.
  4. 36. Jonson E. Cycles and patterns of hair growth. In: The Physiology and Pathophysiology of the Skin, Vol. 4. The Hair Follicle. A Harrett (ed). Academic Press, New York. 1237–1254. 1977.
  5. 45. Belsito DV. Chapter 19 Toxic response of the skin. In: Casarett &amp; Doull’s Toxicology: The Basic Science of Poisons, 9th ed. CD Klaassen (ed). McGraw-Hill Education, New York. 953–976. 2019.
  6. 52. Slitt AL. Chapter 5 Absorption, distribution, and excretion of toxicants. In: Casarett &amp; Doull’s Toxicology: The Basic Science of Poisons, 9th ed. CD Klaassen (ed). McGraw-Hill Education, New York. 159–192. 2019.

Cited by

Sorted by citations

Related

Authors
Moroki, T.
Affiliations
Otsuka (Japan) (JP)
Corresponding author
Moroki, Takayasu
Venue
Journal of Toxicologic Pathology
Publisher
Japanese Society of Toxicologic Pathology
Published
2023
Volume
36
Issue
2
Pages
85-94
ISSN
  • 0914-9198 (ISSN-L)
  • 1881-915X
DOI
10.1293/tox.2022-0103
PMC
PMC10123300
OpenAlex
W4313274565
Semantic Scholar
72c6f9caeabc777cab0cb0305420d558459ddff7
Cited by
26
References
41
Citations by year
2026: 10 · 2025: 10 · 2024: 5 · 2023: 1
FWCI
3.23
Type
journal article
Language
en
Open access
Locations
  • Journal of Toxicologic Pathology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Topics
  • Health Sciences › Medicine › Dermatology › Contact Dermatitis and Allergies
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
  • Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
Keywords
skin histology, epidermis, dermis, subcutaneous tissue, skin appendages, keratinocytes, epidermal thickness, bulge stem cells, sebaceous glands, hair follicle, hair cycle, irritant contact dermatitis, allergic contact dermatitis, topical absorption, stratum corneum

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-22.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-22.

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Statistics and arithmetic are recomputed, not judged.

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