Arylamines In The Development of Bladder Cancer

Review of Literature and Status of Arylamines In The Development of Bladder Cancer

Bladder cancer accounts for the 11th most common cancer worldwide. (1) It was the first cancer to be identified as being associated with occupational exposure when in 1895 Dr. Ludwig Rehn reported on bladder cancer in German aniline dye workers. (2) Since that time numerous experimental and epidemiological studies have demonstrated that occupational exposure to arylamines, otherwise referred to as aromatic amines, such as 4-aminobiphenyl (4-ABP), 2-naphthylamine, and benzidine cause bladder cancer. (3) Because of those studies, the amount of those aromatic amines has been strongly regulated and reduced in use in commercial industries. However, aromatic amine exposure remains a concern for the development of bladder cancer.


The carcinogenicity of arylamines was clearly demonstrated in an investigation of British chemical workers. (4) The observed deaths exceeded by far those expected among workers exposed to 2-naphthylamine (Observed/Expected ratio=87) and benzidine (Observed/Expected ratio=14). Since that time other studies have reported increased bladder cancer risk in workers exposed to those two aromatic amines as well as to 4-ABP. (4), (5).


The metabolism of arylamines is what makes it carcinogenic. Arylamines require metabolic activation to transform into fully carcinogenic agents. Arylamines are metabolized in the liver and can have two fates because there are two enzymes available to act on them. The first step in the process in N-oxidation is to form N-hydroxylamines, which leads to the arylamines becoming a pre-carcinogen that are carried to the kidney and bladder where these become carcinogens (6), (7) and (8). Alternatively, arylamines can be catalyzed by ring-oxidation and competing detoxification pathways, which converts them into non-reactive compounds that are safely removed from the body.


The enzymatic reactions that take place in the liver are coded by two distinct genes, NAT1 and NAT2. The NAT2 phenotype, in turn, has been divided into rapid and/or slow acetylators. NAT2 slow acetylators have been found to consistently display a statistically higher level of 3-ABP and 4-ABP hemoglobin adducts relative to NAT2 rapid acetylators. (1) This becomes important with regard to the risk for the development of bladder cancer when there is exposure to occupational and environmental aromatic amines as slow acetylators have been shown to have a higher risk of developing bladder cancer when exposed to aromatic amines than rapid acetylators. (1), (9).


Cigarette smoking has been established as a cause of bladder cancer and accounts for at least 50 percent of the reported bladder cancer cases. (10), (11). Aromatic amines are found in cigarette smoke and account for the increased of bladder cancer development in smokers. The literature linking cigarette smoking to the development of bladder cancer is extensive and generally shows that smokers have up to 2-2.5 fold elevated risk of bladder cancer relative to nonsmokers, with the risk increasing with the number of cigarettes smoked on a regular basis. (1)


Knowing that cigarette smoke contained aromatic amines and that the bladder cancer risk was increased in smokers but only accounted for 50 percent of the bladder cancer cases, researchers sought to determine where other exposure to aromatic amines was possible and if such exposure increased the risk of developing bladder cancer.


Exposure to hair dye was found to represent a substantial source of arylamines exposure. Occupational exposure to hair dyes by hairdressers, barbers, and beauticians showed a moderately increased bladder-cancer risk. (12) Working with hair dye for 10 or more years resulted in a 5-fold (95%CI=1.3-19.2) increased risk compared to individuals not exposed. The establishment of a link between occupational use of hair dye and bladder cancer led to studies to determine whether or not personal use of hair dye was also linked to an increased risk of developing bladder cancer.


There are three major types of hair dyes in use; permanent dyes, semi-permanent dyes, and temporary rinses. (1) Permanent dyes account for roughly three-quarters of all hair dye use. Many commercial brands of hair dyes have been previously described as mutagenic, but few ingredients of the currently commercial hair dyes are known to cause cancer in animals. (12)


One of the largest studies undertaken to determine whether or not there was a causal connection between the personal use of hair dye and bladder cancer took place in Los Angeles County beginning in 1992. (12) The study looked to the use of the three main types of hair dyes in use and the relationship to an increased bladder cancer risk. The premise and subsequent conclusions have been made that the hair dye contained arylamines and that exposure to the arylamines in the hair dye was the source of the development of bladder cancer in some of the case study participants. No association was found between the personal use of either semi-permanent or temporary dyes and bladder cancer. However, there was a statistically significant frequency and duration dependent increase in risk with the personal use of permanent hair dye that was statistically significant. (5), (12).


Among women, there was a consistent relationship between exposure to the use of permanent hair dye and risk regardless of whether exposure was defined by duration of use, frequency of use, or cumulative number of times of use over lifetime. A statistically significant trend in risk was found after adjustment for cigarette smoking. The adjusted odds ratio for the highest categories of duration, frequency, and lifetime use were 3.7 (95% CI 1.2-11.2), 2.1 (95% CI 0.97-4.7), and 2.0 (95% CI 1.04-3.8). (12) The study found the statistically significant associations between permanent hair dye use and bladder cancer risk only among those subjects who exhibited the NAT2 slow acetylators phenotype. (1), (9).


Recent e-mail communications with two of the principal researchers in the area of permanent hair dye and the causal connection with bladder cancer, Mimi Yu and Manuela Gago-Dominguez, have verified that the published results of the connection between slow versus rapid acetylators, as a modifying factor of the hair dye-bladder cancer relationship. It is still supported, and suspected, with the detection of 4-ABP in samples of commercial hair dyes, that these and other contaminants, possibly some carcinogenic anilines, may also be present in hair dye solutions. (14), (15)

As the usage of hair dye increased and retail sales of home hair dyeing kits has approached the $1.6 billion mark (3) the link between use of permanent hair dye and risk of bladder cancer has increasingly been demonstrated. Further research quantified the other aromatic amines, in particular 4-ABP, one of the recognized bladder carcinogens, was present in commercial hair dyes.


Permanent hair dyes and crème developer were purchased and tested, as the prior research was suggestive of carcinogenic arylamines contamination in permanent hair dye products. (3) This study also reported on the presence of 1,4-Phenylenediame (PPD), a key ingredient in the development of color for many hair dyes, and as a plausible source of ABP generation.


Basically, the study found that 4-ABP and PPD were present in the permanent hair dyes examined. The levels detected ranged from not detectable (less than 0.29 ppb) up to 12.8 ppb. 4-ABP was detected in 8 hair dyes tested and was found in black, red, and blonde hair dyes. Some batches of PPD were found to have 4-ABP and was suspected, therefore, of being a source of the ABP contamination in the permanent hair dyes tested. (3). Adducts of both 4-ABP and 3-ABP were higher in the case subjects independent of cigarette smoking history. Active smokers appeared to be exposed to an approximately 3-10 fold higher amount of 4-ABP and 3-ABP than nonsmokers. However, the finding that nonsmokers exhibited higher 4-ABP and 3-ABP hemoglobin adducts compared with control subjects strengthened the hypothesis that exposure to 4-ABP and 3-ABP is linked to bladder cancer risk, that one of those exposures came from use of permanent hair dye. A certain percentage of the bladder cancer cases that are not attributed to cigarette smoking can be attributed to use of permanent hair dye.


There has been some research into determining whether or not use of hair dye has reproductive implications. While it has been reported that aromatic amines in hair dye are mutagenic in vitro and carcinogenic in experimental animals (4), results of reproductive toxicological and epidemiological studies have indicated no or negligible risk to human health. (13) The presence or absence of in vitro genotoxic activity of oxidative hair dye mixtures appeared to depend on the proportion of primary intermediates and couplers, their reaction time and the presence and concentration of hydrogen peroxide and other chemicals. A correct ratio of PPD to couplers and hydrogen peroxide and realistic development times (less than one hour) did not yield genotoxic substances. (13)


A link between exposure to aromatic amines and an increased risk for developing bladder cancer has been clearly established. One source of exposure to aromatic amines is through cigarette smoking, but exposure to aromatic amines from cigarette smoking only accounts for one-half of the reported bladder cancer cases. It is clear that a certain percentage of those exposed to aromatic amines by other environmental factors risk the development of bladder cancer. It is also clear that one of those exposures to aromatic amines other than by cigarette smoking is from exposure through the use of permanent hair dye, which in turn accounts for a certain percentage of bladder cancer cases found in nonsmokers.