BENZIDINE MOLECULESource: http://www.steve.gb.com/images/molecules/amines/benzidine.png
4’4’-diaminobiphenyl, commonly know as Benzidine, is an aromatic amine utilized for the production of fabric, paper and leather dyes. Benzidine is a manufactured chemical that does not occur naturally. In the environment, this chemical may be found as an organic base or as a salt. Production of Benzidine in the US was discontinued in the 1970s. However, larger quantities of the chemical had already been dumped in water sources and soils for a long time. Benzidine attaches easily to soil particles, and when in water sources it sinks to the bottom and found in the silt, mud and soil. The general population is not at great risk of Benzidine exposure, except for residents of contaminated areas (water and soil). Children are at risk of exposure to Benzidine only if they come into contact with contaminated media.
An increased incidence of cancer of the urinary bladder was first associated with human occupational exposure to dyes and dye chemicals manufacturing in 1895. These tumors, initially referred to as aniline cancers because of the extensive use of aniline in dye chemistry, were attributed to exposure to either the starting materials or to the finished dyes. Benzidine was identified as a carcinogen for the human urinary bladder in 1973 (National Toxicology Program 1994). Benzidine exposure effects on human health do not initiate until they have been bioactivated in the body.
Exposure to Benzidine occurs mainly through ingestion and inhalation. Dermal contact to the substance is said to cause allergic eczematous dermatitis, although extensive research of the effects of exposure via this route has not been carried out. Ingestion and inhalation were determined to be the main routes of exposure because most of the dye factory workers that showed severe health effects came into contact with Benzidine in that manner. Once proper industrial hygiene measures were put in place at these factories, harmful health effects diminished. Ingestion effects were identified when Kimono hand painters in Japan who wetted the paintbrushes with saliva by putting them in their mouth, later developed bladder cancer.
Extensive bioassays have been carried out for decades with mice, rats, hamsters and dogs, the results of which vary considerably according to the test species. On mice, rats and hamsters Benzidine exposure indicates liver and mammary malign carcinogenicity. On dogs, same as in humans, urinary bladder cancer was identified. Human exposure conclusions have been derived from actual exposure cases in the US, Europe and Japan.
The IARC identified the following cases of human exposure:
An increased incidence of cancer of the urinary bladder was first associated with human occupational exposure to dyes and dye chemicals manufacturing in 1895. These tumors, initially referred to as aniline cancers because of the extensive use of aniline in dye chemistry, were attributed to exposure to either the starting materials or to the finished dyes. Benzidine was identified as a carcinogen for the human urinary bladder in 1973 (National Toxicology Program 1994). Benzidine exposure effects on human health do not initiate until they have been bioactivated in the body.
Exposure to Benzidine occurs mainly through ingestion and inhalation. Dermal contact to the substance is said to cause allergic eczematous dermatitis, although extensive research of the effects of exposure via this route has not been carried out. Ingestion and inhalation were determined to be the main routes of exposure because most of the dye factory workers that showed severe health effects came into contact with Benzidine in that manner. Once proper industrial hygiene measures were put in place at these factories, harmful health effects diminished. Ingestion effects were identified when Kimono hand painters in Japan who wetted the paintbrushes with saliva by putting them in their mouth, later developed bladder cancer.
Extensive bioassays have been carried out for decades with mice, rats, hamsters and dogs, the results of which vary considerably according to the test species. On mice, rats and hamsters Benzidine exposure indicates liver and mammary malign carcinogenicity. On dogs, same as in humans, urinary bladder cancer was identified. Human exposure conclusions have been derived from actual exposure cases in the US, Europe and Japan.
The IARC identified the following cases of human exposure:
- Dyestuffs factory in Italy, it was possible to distinguish a very high bladder cancer risk (5 deaths observed, 0.06 expected) associated with benzidine production. The study was extended and updated, but the role of exposure to benzidine alone in the dramatically increased bladder cancer risk could not be examined further.
- Of 25 benzidine 'operators' at a plant in the USA, 13 developed bladder cancer; all cases had been exposed for six years or more. Other investigations have shown high incidences of cancer of the bladder and urinary tract after concomitant exposure to benzidine and 2-naphthylamine. Exposure to these two compounds was also associated with an increase in the occurrence of second primary cancers at sites other than the bladder, including the liver.
- Among 1601 workers in the chemical-dye industry in China who were exposed to benzidine, methylnaphthylamine and dianisidine 21 cases of bladder carcinoma were found. All had a history of exposure to benzidine, while no carcinoma was found among workers exposed to methylnaphthylamine or dianisidine. Suggestions of a dose response relationship were provided by analysis according to length of exposure.
The EPA Summary of Risk Estimates explains:
Oral Slope Factor — 2.3E+2 per mg/kg-day
Drinking Water Unit Risk — 6.7E-3 per ug/L
Extrapolation Method: One-hit with time factor, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Drinking Water Unit Risk — 6.7E-3 per ug/L
Extrapolation Method: One-hit with time factor, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
E-4 (1 in 10,000) 2E-2 ug/L
E-5 (1 in 100,000) 2E-3 ug/L
E-6 (1 in 1,000,000) 2E-4 ug/L
E-4 (1 in 10,000) 2E-2 ug/L
E-5 (1 in 100,000) 2E-3 ug/L
E-6 (1 in 1,000,000) 2E-4 ug/L
In summary, Benzidine was established as a known human carcinogen in 1973 after its production had been discontinued. Human cases as well as bioassays have been carried out extensively to provide proof of the human health effects caused by the chemical. Carcinogenicity varies according to species, but in humans urinary bladder cancer occurs after long-term exposure via ingestion or inhalation takes place.
Sources:
-Morgan, Dunnick et al (1994). Summary of the National Toxicology Program Benzidine Dye Initiative. National Institute of Environmental Health Services. North Carolina. Source: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1567082&blobtype=pdf
- Josephy, David (1985). Oxidative Oxidation of Benzidine and its Derivatives by Peroxidiases. Environmental Health Perspectives. Source: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1568598&blobtype=pdf
- US Environmental Protection Agency (1987). Benzidine. Source: http://www.epa.gov/iris/subst/0135.htm
- US Environmental Protection Agency (1987). Benzidine Hazard Summary. Source: http://www.epa.gov/ttn/atw/hlthef/benzidin.html
- Agency for Toxic Substances and Disease Registry (2001). Benzidine ToxFAQs. Source: http://www.atsdr.cdc.gov/tfacts62.pdf
- Agency for Toxic Substances and Disease Registry (2001). Toxicological Profile for Benzidine. Source: http://www.atsdr.cdc.gov/toxprofiles/tp62.pdf
- Vesselinovitch S.D., Rao K., and Mihailovich N. (1975). Factors Modulating Benzidine Carcinogenicity Bioassay. Cancer Research 35, 2814-2819. Source: http://cancerres.aacrjournals.org/cgi/reprint/35/10/2814
- International Agency for Research on Cancer. Benzidine Monograph. Source: http://monographs.iarc.fr/ENG/Monographs/suppl7/Suppl7-25.pdf
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