Benzidine and Aromatic Amines

Benzidine is a manufactured chemical. Its other name is 4,4'-diaminobiphenyl. NCI states plainly that it does not occur in nature.

The NTP Report on Carcinogens profile calls benzidine known to be a human carcinogen. That rests on sufficient evidence from studies in humans. It was listed in the very first Annual Report on Carcinogens, in 1980. Dyes metabolized to benzidine were added later, as a class. That came in the Ninth Report on Carcinogens, in 2000.

That listing history matters. Benzidine was among the earliest chemicals a federal report named as a human carcinogen, and the reason was bladder cancer in workers.

The NTP profile is direct about the strength of the evidence. It cites numerous studies of workers in different parts of the world. They include case reports and cohort studies. All told, they reported a strong link between benzidine at work and urinary bladder cancer.

NCI's substance page reaches the same conclusion. It says work exposure to benzidine results in an increased risk of bladder cancer. Its basis is studies of workers in different geographic locations.

Two qualifications appear in the NTP profile, and both are worth keeping.

Only a few studies evaluated benzidine on its own. In many, workers were also exposed to other chemicals, which makes it harder to attribute the effect to one substance.

And some studies suggest the risk of bladder cancer increases with increasing length of exposure. That dose relationship is part of why the association reads as causal rather than coincidental.

This is the unusual part of the benzidine story, and it is the part that gets left out.

The NTP profile states something worth reading twice. Data suggest urinary bladder cancer rates have decreased since measures to limit benzidine exposure were put in place.

That is a rare thing to be able to say about an occupational carcinogen. The exposure was identified, the controls followed, and the cancer count moved.

NCI describes the same withdrawal from the other direction. Benzidine has not been sold in the United States since the mid-1970s. It is no longer used in medical laboratories, or in the rubber and plastics industries.

The NTP profile lists a century of uses, which explains who was exposed.

Its main role was as a building block for dyes. That covered azo dyes, sulfur dyes, fast color salts, naphthols, and other dyeing compounds. NCI notes those dyes colored cloth, paper, and leather.

The side uses are more surprising. Benzidine was used in clinical laboratories to detect blood. It was a rubber-compounding agent. It went into the manufacture of plastic films. It was used to detect hydrogen peroxide in milk, and to measure nicotine.

NTP says most of those uses stopped, because of concern about cancer. It notes one leftover. Some dyes that may contain benzidine as an impurity are still used as stains for microscopy and similar lab work.

NCI says two routes matter most in the United States today. Breathing in benzidine-based dyes, and swallowing them by accident. It adds that exposure potential declined as those dyes left industrial and consumer markets and were replaced.

The NTP profile explains why release into the environment is expected to be low. Benzidine may be produced only for captive consumption. That means it is made and used inside a closed system, rather than sold on. Accidental releases from those systems could still expose people. The routes are breathing it in, swallowing it, or skin contact.

Benzidine has its own section in the federal workplace safety regulations, but that section is a pointer rather than a rule.

29 CFR 1910.1010 is titled simply "Benzidine." Its entire text points the reader to 29 CFR 1910.1003. That is the standard covering 13 carcinogens. So the working rules for handling benzidine live in that combined standard, not in a benzidine-only one.

Anyone searching for a benzidine exposure limit and finding an apparently empty regulation has not found a gap. They have found a cross-reference.

The NTP profile is careful here in a way that summaries often are not.

Since benzidine was first reviewed for listing, some studies have reported links to cancer at other sites. But not all of them did. The profile names ten sites: liver, kidney, central nervous system, oral cavity, larynx, esophagus, bile duct, gallbladder, stomach, and pancreas. It adds that the evidence for these sites is more limited than for urinary bladder cancer.

"Some but not all" is doing real work in that sentence. Bladder cancer is the established link. The rest are reported findings that have not been consistent.

The mechanism is well characterized, which strengthens the human evidence.

NTP says cytochrome P450 enzymes break benzidine down. The process is called N-oxidation. It yields electrophilic compounds that can bind tightly to DNA. Electrophilic just means electron-seeking. That is what lets these compounds attach where they should not.

The profile lists the genetic damage seen across test systems. Mitotic gene conversion in yeast. Micronucleus formation. DNA strand breaks. Unscheduled DNA synthesis. Cell transformation. Chromosomal aberrations. Sister chromatid exchange. And aneuploidy, meaning the wrong number of chromosomes.

One human observation stands out. Workers exposed to benzidine or benzidine-based dyes had higher levels of chromosomal aberrations in their white blood cells than unexposed workers.

The cancer at the center of this story is described in bladder cancer. Related chemicals in the same family are covered in 2-naphthylamine and cancer. The wider workplace picture is in occupational carcinogens.

• NCI: benzidine
• NTP RoC profile: benzidine and dyes metabolized to benzidine
• govinfo: 29 CFR 1910.1010