The Hardening Phenomenon in Irritant Contact Dermatitis: Cosmetic Implications

Irritant contact dermatitis (ICD) is common and poses a significant problem in high risk populations including hairdressers, health care workers, metal- working professionals and cleaning specialists.1 In fact, as many as 35% of junior hairdressers develop ICD during their first year in training. Most cases of ICD are resolved in spite of continued exposure, allowing individuals to continue with their work. However, some cases develop into chronic ICD, which often manifests on the hands as red, dry, scaly and fissured skin.1

When ICD resolves without intervention, it transitions through a process known as hardening or accommodation. Generally, this self-resolving phenomenon is simply accepted amongst laborers and clinicians but its mechanism remains elusive. While extensive research and a textbook opine on the pathogenesis of irritant contact dermatitis and its related factors, research is sparse pertaining to factors that contribute to non-irritated and non-sensitive skin.2

This is likely because the institution of modern science largely focuses on the mechanisms of active disease rather than those of non-disease and illnesses that self-resolve. Much can be learned, however, by studying these self-healing processes such as the hardening phenomenon. This overview briefly documents the pathogenesis of ICD, focuses on the current understanding of hardening in ICD, and highlights possible productive areas of research. A better understanding of the research to date on the hardening phenomenon, summarized in this paper, will hopefully lead to management advances for the treatment of ICD.

In relation, the authors suspect that the management principles discussed here are equally relevant to cosmetic formulations, including surfactants, steroids and mascaras. Many consumers experience marginal skin irritation after the use of cosmeceutical products. Therefore, a better understanding of the physical and immunologic changes that occur as the skin adapts to irritants could lead to therapies that enable consumers to better tolerate these products as well as the development of less irritating products in the future.

Pathogenesis of ICD
ICD is defined as a multifactorial disease that results from skin exposure to an irritant.3 It is a complex phenomenon that depends on endogenous and exogenous factors such as individual genetics, the nature of the irritants and the physical environment.4 Irritants cause a non-specific reaction upon contact with the skin that disrupts skin barrier function, causes direct cellular damage to the epidermis, and results in the release of pro-inflammatory mediators.4 Different chemicals can target different components of the epidermis and physical properties of the irritant, such as its PKa, as well as contribute to irritancy potential.5 The culmination of these interrelated processes leads to the clinical manifestations of ICD, which are variable.3

Recent evidence suggests that components of the immune system play an integral role in eliciting ICD.3 The skin’s barrier function may also play a role in ICD since patients with altered barrier function, such as those afflicted by atopic dermatitis or challenged by filaggrin null mutations, are more prone to develop ICD.4, 6

Basics of Hardening/Accommodation
As noted, the course of ICD is variable but when chronic ICD is avoided and subsides in spite of continued exposure to the irritant, this condition is referred to as hardening (see Figure 1).

This term, also known as accommodation, has been defined as the adaptation of skin to the cause of irritant contact dermatitis. Its existence has been known for centuries, though its precise mechanisms require elucidation. Some have stated that this process begins with an irritative phase that largely resolves in spite of continued contact with the irritant.2 Following is a summary of theories presented in the literature thus far that attempt to explain the phenomenon of hardening (see Table 1).

Changes in Morphology and Barrier Function
One theory to account for the decreased irritant reactivity of hardened skin is an altered barrier function. This theory holds that morphologic changes in skin structure and composition decrease the irritant’s access to skin. Accommodated skin has a relatively thicker layer of stratum granulosum, compared with normal skin.2, 7 Animal models also have shown a thickened and slightly hyperkeratotic stratum corneum layer with an epidermis 3X thicker and sebaceous glands larger than normal skin.7 Thus, the wider diffusion barrier resulting from these changes could make it more difficult for the irritant to penetrate skin; however, quantitative data is necessary to prove and quantify this theory definitively.

Altered lipid composition of the stratum corneum may also contribute to the decreased irritant response in hardened skin. Heinemann et al. showed that irritant-induced hardening was accompanied by a significant increase of ceramide 1 and therefore proposed that ceramide 1 plays a key protective role against irritation.8

Changes in Permeability and Vascular Reactivity
Another theory to explain the hardening phenomenon is that repetitive irritation induces increased permeability and vascular reactivity, thereby allowing for the faster removal of irritants in hardened skin.2, 7 McOsker et al. showed in an animal model that adapted skin was more permeable to irritants than normal skin, yet with less irritant reaction.7 The researchers resolved this apparent dichotomy by purposing two theories.

The first theory proposes that in hardened skin, the irritant could be reacting less with skin components and is therefore removed more rapidly via blood and lymph. Concentrations of the irritant remaining in the tissues are thus insufficient to induce a reaction. This theory assumes that a certain threshold level of irritant is necessary to induce a reaction, even in accommodated cells.

In a second theory, the resistance of hardened skin to irritants is the result of a reduced permeability in the individual cells. This concept can be reconciled with an overall increase in skin permeability in hardened skin but only if normal skin favors a slower intracellular route of absorption while accommodated skin favors a faster, alternative intercellular route of absorption.2, 7 To date, no known experiments have yet been performed to assess the validity of these theories.

Systemic Changes with Hardening
Evidence also supports that hardening is not locally limited as once thought and that it has global effects, perhaps mediated through cytokines and humoral factors.2, 9 Similarly, exposure to UV light is a more widely known localized skin reaction that has systemic implications. UV exposure can result in systemic immunologic suppression via multiple mechanisms.10 Studies suggest a similar global process may also occur with hardening.

In 1987, Lamintausta et al. showed that repeated SLS applications on the right scapula of human subjects induced a post-irritant hypo-reactive state at a distant site on the left scapula during repeat testing six weeks later.11 In 1990, Wulfhorst et al. provided further support for systemic effects of hardening by again showing that low-dose levels of irritant can induce a globally hyporeactive state.2 While the localized changes observed with hardening are well-documented, more studies are required to explore the possible global effect of this phenomenon, as well as its mechanisms.

Immunologic Changes with Hardening
de Jongh et al. recently showed an altered local expression of multiple cytokines and inflammatory mediators with repeated versus single irritant insults to the skin, and hardening was correlated with these changes in the inflammatory profile of the skin.12 The balance between the cytokines IL-1α and IL1-RA may be an important factor in determining the inflammatory response in hardened skin.

IL1-α is a well-known pro-inflammatory mediator whose effects are counteracted by the anti-inflammatory cytokine IL-1RA. The study by de Jongh et al. showed that IL1-α was increased after a single irritant exposure, while IL-1RA was increased after repeated irritation. The ratio of IL-1RA/IL-1α was increased after repetitive irritation but not after single irritation, suggesting that with repetitive irritation, anti-inflammatory mechanisms come into play to suppress the early pro-inflammatory responses. This altered ratio could be one explanation for the hardening response.12 Granulocyte colony-stimulating factor (G-CSF), which traditionally is considered pro-inflammatory, recently was shown to have anti-inflammatory properties as well,13 and may also play an anti-inflammatory role and contribute to hardening in the skin after repeated irritation.12

Discussion and Conclusions
As mentioned, multiple extrinsic and intrinsic factors influence human irritancy and the mechanisms and predisposing factors determining whether an individual adapts to irritant exposure or develops chronic ICD require investigation. Genetics are an important intrinsic factor. Certain IL1 genotypes have been associated with higher levels of the pro-inflammatory IL-1α and higher IL-1α/IL-1RA ratios, suggesting certain IL1 genotypes may predispose to skin irritation while others may protect against it.14 This suggests that altered cytokine expression may be responsible for differences in the inflammatory response and inter-individual differences in skin hardening.

Another theory to be explored is whether there is irritant cross-reactivity with hardening in irritant contact dermatitis. In 1967, McOsker showed evidence of this when animals that accommodated to 0.25% alkyl benzene sulfonate were also found to resist irritation by other irritants.7 The specificity of hardening in humans, however, remains to be investigated.

Other possibilities for research include further exploration of physical changes of the epidermis with the emergence of hardening. Ceramide 1, an important lipid in SC barrier function, has been shown to up-regulated with hardening.8 It also may be interesting to explore the expression of other stratum corneum molecules such as filaggrin.6 Further characterization of the cytokine profile present in normal versus hardened skin, and an investigation of global changes in the immunologic profile observed with hardening may also prove enlightening.

More data is needed to investigate the mechanisms and variables involved in the phenomenon of hardening. A better understanding could translate into new and improved management options for ICD and chronic ICD—both for occupationally exposed individuals and those who repeatedly utilize marginally irritating cosmetic ingredients such as detergents, mascaras and retinoids.

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1. CM de Jongh et al, Cytokine gene polymorphisms and susceptibility to chronic irritant contact dermatitis, Contact Dermatitis 58 269–277 (2008)
2. B Wulfhorst, Skin hardening in occupational dermatology, in E Kanerva, JE Wahlberg and HI Maibach, eds, Handbook of Occupational Dermatology, Berlin: Springer-Verlag (2000) pp 115–121
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14. CM de Jongh, L Khrenova, S Kezic, T Rustemeyer, MM Verberk and SM John, Polymorphisms in the interleukin-1 gene influence the stratum corneum interleukin-1 alpha concentration in uninvolved skin of patients with chronic irritant contact dermatitis, Contact Dermatitis 58 263–268 (2008)
15. PG van der Valk and HI Maibach, A functional study of the skin barrier to evaporative water loss by means of repeated cellophane-tape stripping, Clin Exp Dermatol 15 180–182 (1990)

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