The debate on carcinogenicity of permanent hair dyes: new insights.

Oxidative (permanent) hair dyes contain one or several "primary intermediates" (e.g., p-phenylenediamines, p-aminophenols) and "couplers" (e.g., m-aminophenols, m-hydroxyphenols). In the presence of peroxide, the primary intermediate(s) and the coupler(s) undergo a chemical reaction to form colored oligomers. In the 1970s a number of aromatic amines used in oxidative hair dyes were identified as mutagenic and/or carcinogenic in rodents after lifetime oral administration. In response, regulatory action was taken, and some hair dye ingredients were banned in the European Union. Although recent results suggest that the main "primary intermediate" of oxidative hair dyes, p-phenylenediamine, has a weak genotoxic potential in vitro, it was not mutagenic in a mixture with nonmutagenic couplers, if tested under conditions comparable to those of practical use. Under conditions of use of permanent hair dyes, between 0.1 and 0.5% of the applied p-phenylenediamine may be absorbed through the skin. Acetylation in the skin is a key metabolic step for the primary intermediates p-phenylenediamine and p-aminophenol. Because of the involvement of aromatic amines, the discussion on the carcinogenicity of hair dyes in humans has been focused on urothelial cancer. Numerous epidemiological studies have investigated the risk of bladder cancer associated with the profession as a hairdresser, as well as the risk to consumers of hair dyes. Although some earlier studies suggested an overrepresentation of bladder cancer in male hairdressers, the majority of modern studies do not show an increase in relevant bladder cancer risk for professional or personal use of oxidative hair dyes. Today, there seems to be no relevant bladder cancer risk from the use of oxidative hair dyes. Such a conclusion can be derived from new toxicokinetic and metabolism investigations and is in general accordance with current epidemiological data. Human urothelial cancers, chemically induced by aromatic amines, have typical latency times often longer than 20 years. Since earlier exposures could have an impact decades later, the possibility of bladder cancer in hairdressers having intensively worked with permanent hair dyes during earlier decades (prior to the 1980s) should be taken into account.