Tattoo prevalence and public health relevance
Tattooing has become a global trend. The highest prevalence rates (up to 30–40%) are seen in Europe and the USA in adults younger than 40 years, but also increasing numbers of people in low- and middle-income countries are getting tattoos. Exact numbers are sparse, but in Brazil and South Africa the prevalence is estimated to be about 20% in the younger age groups, and rates are growing. Proportionally to this rising prevalence, the relevance of tattoo safety for public health is increasing. This, at least in Europe, is mirrored by the recent inclusion of tattoo and permanent make-up ink ingredients in the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) framework, which defines regulatory limits of chemicals in daily use; these are binding for all European Union (EU) Member States. It remains unclear whether the new inks currently being introduced to the European market do meet all REACH requirements and whether the imposed requirements are sufficient to impede the use of potentially hazardous substances in inks.
Ingredients
Tattoo inks, which consist of colour pigments diluted in a carrier liquid, may contain up to 100 chemicals. In contrast to pharmaceutical drugs and cosmetics, safety testing for the intended use (in this case, intradermal) in humans or animals is not performed before the inks are introduced to the market. About 10–40% of the ink volume – the pigment portion – is insoluble or poorly soluble in water and, depending on the colour, consists of a mixture of inorganic pigments (mostly industrial dyes) and/or organic pigments (e.g. azo pigments), often of nanoparticle size. The remaining 60–90% of the ink volume – the carrier liquid or solvent portion – is readily soluble in water and consists mainly of solvents (e.g. water or alcohol), dispersants, plasticizers, and other auxiliaries, additives, and pollutants. Chemical analyses of tattoo inks consistently identify substances classified by the IARC Monographs programme as carcinogenic (Group 1), probably carcinogenic (Group 2A), or possibly carcinogenic (Group 2B) to humans. The presence of these substances varies according to the colour of the ink. Polycyclic aromatic hydrocarbons (PAHs) are often present in inks with carbon black pigments, and primary aromatic amines (PAAs) are often present in inks with bright-coloured organic pigments. In addition, tattoo inks may contain various metals (e.g. arsenic, chromium, nickel, lead, and cadmium). Apart from PAHs bound to carbon black pigments, all these substances are found in both the solvent portion and the pigment portion of the ink. These agents are associated with a higher risk of various types of cancer, such as cancers of the lung, kidney, liver, and bladder, depending on the substance. However, the IARC Monographs classifications were based mainly on studies investigating oral, dermal, or respiratory exposure routes, as occur in industrial workplaces (e.g. welding or dyeing), through the inhalation of tobacco smoke, or in other consumer products, such as hair dyes. The exposure route of tattoo inks injected directly into the dermis differs significantly from these more traditional uptake routes and remains unexplored in relation to its health effects.
Biodistribution
The systemic absorption of tattoo inks can be divided into two phases, which relate to the solvent portion and the pigment portion of the inks. During the tattooing process, the tattoo ink is directly absorbed by the body through contact with the surrounding damaged blood vessels and lymphatic vessels. The absorption of the solvent portion leads to rapid bioavailability of large amounts of its ingredients (including metals and PAAs) and thus to their immediate metabolization. The duration, bioavailability, and peak concentrations of this process are not known precisely, but the peak exposure is expected to occur in the 24 hours after tattooing, depending on the substance. Although this acute exposure to the solvent portion is a one-time exposure, it may result in long-term damage to the individual being tattooed, because of the direct genotoxicity of many substances in the tattoo inks. For example, acute exposures may give rise to irreversible DNA mutations, and any acute or chronic exposure to these substances may increase the individual’s lifelong risk of developing cancer. A laboratory study investigating this short-term bioavailability in humans was recently conducted, with the involvement of IARC, by the German Federal Institute for Risk Assessment (BfR).
In addition to the acute exposure to chemicals in the solvent portion, a harmful systemic long-term exposure to the pigment portion is likely. Over time and through light-induced fading, 60–90% of the pigment portion is transported from the skin to the lymph nodes and potentially other organs. Clear evidence of the absorption of the pigment portion into the body and its transportation within the body is provided by the macroscopically visible inks in pathological examinations of nearby lymph nodes. The extent to which the pigment portion of tattoo ink is transported to other organs via the lymphatic system or the blood is unexplored in humans. However, the first evidence has come from studies in animals. After the subcutaneous injection of tattoo inks, colour pigments originating from the pigment portion of the ink have been detected in diverse organs. Titanium dioxide was found in the liver, spleen, and lungs, and red and black tattoo ink particles were found in the liver. This slow release could lead to a constant low-dose internal exposure to these substances, which may not be detectable with current measurement techniques.
Tattoos and lymphoma: possible effects on the immune system?
The chronic exposure of the lymphatic tissue and potentially other organs to tattoo inks is very likely. Therefore, tattoo-induced carcinogenesis cannot be ruled out. Because cancer develops in the most exposed organs, lymphomas (Hodgkin lymphoma and non-Hodgkin lymphomas) are of particular concern, even more so than skin cancer, of which most types develop in the epidermal layer of the skin, which has a comparatively low exposure. Lymphomas comprise many heterogeneous neoplasms that develop in the lymphocytes (white blood cells) in the lymphatic system. For example, non-Hodgkin lymphomas may arise in B cells, T cells, or natural killer cells, which all play different important roles in the immune system’s defence against pathogens, toxins, and clonal expansion of cancer cells through complex inflammatory reactions. The consequences of impaired immune function, such as in organ transplant recipients and HIV-positive individuals, in relation to cancer development are well established. Particularly for lymphomas, the link to compromised immunity is important. The main known risk factors for lymphomas are infectious diseases associated with immunodeficiency, such as infection with HIV and Epstein–Barr virus (EBV), which may cause different types of lymphomas mediated by immunosuppression, disruption of normal cellular functions, chronic immune stimulation, abnormal T-cell activity, and oxidative stress. Similar to these mechanisms of action, the formation of reactive oxygen species and chronic inflammatory responses have been demonstrated in animal and cellular studies for the two main tattoo pigments, black (carbon black) and white (titanium dioxide). This observation contributed to the IARC Monographs programme’s classification of carbon black particles as possibly carcinogenic to humans (Group 2B). Independent adverse effects of pigment load and pigment toxicity of zinc and cobalt pigments – metals frequently found in tattoo inks – on different immune and inflammatory markers have been seen in vitro even in a long-term scenario. The subsequent step, a potential carcinogenic effect of these pigment-induced processes, remains largely unexplored. However, development of lung cancer and skin cancer through immunomodulation after exposure to black pigment has been observed in animal studies. It is not known whether a high exposure to tattoo pigment particles in lymph nodes or the skin could trigger similar processes in humans.
What about effects on other organs? Because of the poor solubility of most tattoo pigments, the natural attempts of the immune system to eliminate and wash out the pigment particles may often be unsuccessful and could lead to a constant low-dose inflammatory reaction that overstimulates the immune system. However, very low doses of the pigment-associated substances might be cleared by the intracellular acids of macrophages and could subsequently be transported to other organs. In animal studies, tattoo pigments have been found in the kidney, the liver, and the spleen. Therefore, although this has never been studied in humans, exposure to hazardous ingredients of tattoo inks and even subsequent cancer development should not be ruled out. A further potential hazard is posed by the fact that many tattoo pigments are nanoparticles. Because of their small size, nanoparticles penetrate epithelial layers more easily and can even overcome blood–tissue barriers, including the blood–brain barrier. These properties are useful for medical purposes, such as the delivery of drugs encased in nanoparticles, but they could also increase the toxicological potential of the particles. The long-term health effects of these nanoparticles are still largely unexplored, but because they also have a harmful effect on the immune system, their carcinogenic influence cannot be ruled out.
Tattoo-associated viral infections
In contrast to the unknown potential direct impact of tattoo ink on the risk of certain types of cancer (described above), the increased risk of viral infections through poor hygiene conditions during tattooing is established. As known from needle sharing in intravenous drug users, the piercing, puncturing, and injecting using needles is associated with risks of persistent viral infections, which in turn have associated risks of cancer. Tattooing incurs a risk of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, and tattoo-related HIV and monkeypox infections, although rare, have also been reported. HCV and HBV infections themselves are associated with a higher risk of developing non-Hodgkin lymphomas and liver cancer, and HIV infection is linked with increased risks of the HIV-associated and AIDS-defining malignancies (non-Hodgkin lymphomas, cervical cancer, and Kaposi sarcoma) and other infection-related cancer types (Hodgkin lymphoma, liver cancer, and anal cancer). Although in Europe, improved hygiene standards have drastically reduced tattoo-related infections during recent decades, the rising popularity of tattooing in low- and middle-income countries is worrying, in light of possible poor hygiene conditions, because it may give rise to many new cases of viral infections and associated cancers.