Tattooing: immediate and long-term adverse reactions and complications

During tattooing, about 14.36 mg of ink is injected into the skin per cm² at a depth of 1–3 mm (23). About one third ink remains in the epidermis (the outer, visible layer of the skin), and about one fourth migrates to the regional lymph nodes through lymph or to other organs through blood (22). While epidermal pigment is eliminated by desquamation, dermal pigment is internalised by neutrophils, fibroblasts and macrophages or dendritic cells.

The injury sustained by needle puncture is followed by inflammation (within 10 days), tissue formation (within three months), and tissue remodelling (within one year). Inflammation involves haemostasis (the process that stops bleeding) and the activity of neutrophils and macrophages. Neutrophils are the first cells that react to skin needle damage, blood loss, and inflammation. These cells are present for about 24 hours, and then they are eliminated. Macrophages, as the main phagocytic cells, ensure the lifelong presence of pigments in the dermis due to continuous successive cycles of pigment release and recapture by newly created macrophages (14). Finally, a small amount of pigment is entrapped and immobilised by connective tissue fibroblasts (11). Over time, 60–90 % of the applied pigment is transported via the lymphatic system or blood to the lymph nodes and other organs, such as the liver, spleen, and lung (Figure 1).

Figure 1

Distribution of tattoo pigments after injection into the skin. HIV – human immunodeficiency virus

Animal research has shown that, besides passive transport with lymph and blood, tattoo pigment is actively transported to the lymph nodes and then to various organs by dendritic cells, neutrophil granulocytes, and macrophages (18).

Research on mouse macrophage cell culture showed that cobalt and zinc pigments have a moderate intrinsic pro-inflammatory effect (11), which permanently affects the immune system by reducing the ability to defend against bacterial skin infections (reduced phagocytosis) and by weakening the ability to recognise cancer cells. Such chronic inflammation is a consequence of increased nitric oxide (NO) and decreased tumour necrosis factor (TNF) levels during infection. The possibility of skin recovery is also reduced due to lower macrophage migration caused by monocyte chemoattractant protein-1 (MCP-1) deficiency (14).

Research on tattoos older than 40 years shows that ink particles remain in the deep dermis and local lymph nodes. According to the WHO data from animal experiments, black and red tattoo ink particles reach the liver, and titanium dioxide (white pigment) reaches the liver, spleen, and lung (4).

Some persons undergoing MRI may experience pain and a subjective sensation of burning at the tattoo site (25). Transient skin irritation followed by inflammation and infection due to skin damage are the main immediate/acute adverse effects of tattooing. Inflammation includes local oedema, pruritus, papules, or nodules at the tattoo ink injection site.

Bacterial, viral, and rare mycotic infections can affect the surface or the deeper layer of the skin. Bacterial infection can appear in the first few days after tattooing, viral infection develops after a few weeks or months, and mycotic infection becomes visible after a few months. The most common bacterial infections are those with the Staphylococcus, Streptococcus, Pseudomonas, and Clostridium species and nontuberculous mycobacteria (26). Primary infections may result from poor hygiene standards during tattooing, and secondary infections may result from poor skin care during healing (27). Also, the tattoo ink itself can be contaminated with various pathogenic microorganisms.

Possible complications of tattooing are acute contact dermatitis, hypersensitivity reactions, chronic inflammatory reactions, or papulo-nodular reactions (28). In the case of poor hygienic conditions during tattooing, there is a risk of infection with bloodborne viruses such as hepatitis B (HBV), hepatitis C (HCV), and human immunodeficiency virus (HIV). The disease can develop within several weeks to several months.

Histological exam of skin inflammation most often shows fibrosis followed by granulomatous reactions, lichenoid reactions, epithelial hyperplasia, psoriasis, pseudolymphomas, and spongiotic reactions (11, 28). It can also show foreign body giant cells (pigment), histiocytes, lymphocytes, granulocytes, and eosinophilic granulocytes, while immunohistochemical analysis can show a subpopulation of cells such as CD³⁺ T cells. It often takes an experienced cytologist to distinguish pigment particles from melanin in the histological preparation.

The most common adverse effects of tattooing are allergic and granulomatous skin reactions. Hypersensitivity reaction most often occurs to red, black, and green pigments and their combinations. According to some reports (29, 30), coloured inks, especially the red ones, are far more often associated with adverse effects than black inks. Before tattooing, it is recommended to test the person for hypersensitivity by applying coloured pigment on a small area of the skin. This will lower the risk of a hypersensitivity reaction (11). Allergic reactions that occur only a few days after tattooing indicate that the patient was already sensitised to some component of the tattoo ink (28). Allergic reactions can also develop during or after the wound has healed, depending on which immune cells have reacted to which tattoo ink ingredients. In sensitised persons this may take four to twenty days after the first exposure (31). Such delayed allergic reactions, usually of type IV, have been reported upon immunohistochemical analysis which demonstrated the presence of CD³⁺ and CD⁸⁺ lymphocytes (28). An allergic reaction can also be caused by a henna tattoo, if some colouring agents (additives) are added to natural henna (32).

However, allergy to tattoo ink cannot be reliably diagnosed with patch tests due to poor penetration of the pigment through the skin and its slow haptenisation (the reaction between antigenic hapten and carrier protein to stimulate immune response). In addition, not all tattoo pigments are available as test allergens in the patch test (16).

Long-term adverse effects depend on pigment colour, i.e., its chemical composition and additives that are an integral part of tattoo inks. Black inks containing iron oxides or carbon can cause chronic inflammation such as granulomatous inflammation or sarcoidosis. Red inks containing mercury, cadmium, or azo compounds can trigger delayed type IV allergy. Blue inks (containing cobalt, nickel, aluminium, or copper compounds or compounds), purple inks (containing cobalt or manganese), or white inks (containing titanium dioxide, zinc, or lead) are also associated with sarcoidosis (10).

Photo-induced reaction has been reported for yellow, red, black, and blue pigments (33, 34) particularly in older tattoos (35). Exposure of tattooed skin to UV radiation or laser light may cause decomposition of tattoo pigment molecules to new, potentially harmful chemical compounds (36).

Long-term effects of tattoo ink include fibrosis and granulomatous changes (formation of nodules and fibrous tissue), which point to a chronic inflammatory response of the skin (37). In addition, tattoo ink can cause systemic inflammation, such as uveitis, arthritis, and enteritis (38).

Another complication can be the development of cutaneous pseudolymphoma. Although its pathogenesis is still unknown, it is believed that through chronic inflammation tattoo pigment triggers polyclonal proliferation of B and T lymphocytes. Fortunately, they seldom become monoclonal and malignant (39, 40). The latest research (41) has shown that cutaneous tumours (squamous cell carcinoma and keratoacanthoma) within tattoos occur most often after red pigment is applied.

Needle or ink-associated infections with HCV and HBV pose a higher risk of developing non-Hodgkin lymphomas and liver cancer, whereas HIV infection has been associated with the development of Hodgkin and non-Hodgkin lymphomas, liver cancer, cervical cancer, and Kaposi sarcoma (7, 11, 42).

Psycho-social complications after tattooing cannot be ignored either. Tattooing is often associated with deviant social behaviour and the consequent negative attitude toward tattooed people (43, 44). Tattooed people sometimes regret having done a tattoo, as they feel in dissonance with their social environment, and some may even experience depression (3).

Tamez and Özlü (45) also refer to isolated systemic complications of tattooing, such as systemic infections (e.g., acquired immunodeficiency syndrome, HBV, HCV, tuberculosis, sepsis, and endocarditis), neoplasms (melanoma, lymphoma, basal cell carcinoma, and squamous cell carcinoma), psychosocial complications (depression, dissatisfaction, internalised stigma), and other rare complications such as vasculitis, uveitis, and burning after magnetic resonance imaging.

The harmful effects of tattoo inks can be determined ex vivo, in vivo, in vitro, and since recently, predicted in silico (Table 3). Ex vivo methods investigate the effects of tattoo inks on human cells, such as lymphocytes and monocytes (46) or on animal tissue maintained under optimal conditions that mimic the natural state (in vivo) (47).

Several ex vivo (histological) and in vitro methods have identified enhanced sensitisation and reduced metabolic potential of certain pigments (49, 50). Some studies test tattoo pigment effects on cell cultures and reconstructed human skin (RHS) models (48–50). According to one such study on RHS (48), some tattoo pigments – red, black, and white in particular – are cytotoxic and cause inflammation and the release of cytokines interleukin-1α (IL-1α), interleukin-8 (IL-8), and interleukin-18 (IL-18).

In vivo research on mice has shown that besides the skin, ingredients of tattoo ink can be found in the liver, spleen, kidney, and the lungs (51).

Human studies mainly refer to case reports of harmful effects in people tattooed with different types of inks. Pigment components in tattooed skin can be identified with skin biopsy, chemical imaging techniques such as micro-X-ray fluorescence (μ-XRF), and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). The last two methods can accurately identify and quantify iron, nickel, copper, titanium, chromium, zirconium, niobium, and chlorine, as reported by van der Bent et al. (52). The main disadvantage of case reports is that they focus on a single patient or a small number of cases. They may highlight rare and atypical conditions, but may not apply to a larger population.

Epidemiological studies of adverse effects and complications of tattooing have the potential to yield useful data for a larger population but are not easy to conduct and therefore scarce. Epidemiological research has so far investigated potential associations between tattoos and cancer (7, 53, 54). Warner et al. (53) found no statistically significant association between tattoos and the risk of non-Hodgkin’s lymphoma or multiple myeloma. As the main limitation of their finding, they noted the lack of data on the chemical composition of tattoo inks (heavy metals or organic dyes). A retrospective study by Serup et al. (29), which covered ten years and was based on medical histories and clinical examinations, showed that about 70 % of 405 tattooed patients had acute skin reactions, 7 % systemic harmful effects, and 6 % persistent complications.

Another potential venue of identification and prediction of adverse effects and complications of tattoing is in silico research (Figure 2), a fast and cost-effective method of screening for toxicological properties of tattoo ink substances that relies on available databases describing relationships between substances, their levels, and activity as well as on data analysis and interpretation tools, machine learning models, and network analysis tools to predict the outcome of specific toxic substances (e.g., drugs, plasticisers)(54). This model can also be a starting point for other tests such as in vitro and ex vivo. Considering the benefits of such research, we expect that it will play an important role in predicting the adverse effects of tattoo inks in the future.

Figure 2

Possible avenues of in silico analysis to predict the adverse effects of tattoo ink components