How important clinically are nitrosamines?

In my Harvard College biology class in 1972, we discussed Bruce Ames’ Salmonella test which labelled nitrosamines as highly mutagenic. The professor joked that the FDA had over-reacted since the highest levels of nitrosamines were found in grilled meat (hotdogs and hamburgers), and they weren’t banned as carcinogenic.
Fast forward to now, when quinapril production worldwide has been shut down because of excessive nitrosamine levels. Quinapril is the only ACE inhibitor I’ve found so far that can arrest progression of diabetic and hypertensive chronic kidney disease. Just as I’m finally getting to put 1 billion adults worldwide on quinapril, none is available.
It’s time for this joke to stop. It’s gone on for long enough, and now it’s hurting patients, not just chemists. First, mutations don’t cause cancer. Most cancer is age-dependent. Apoptosis, loss of tissue parenchyma, is the hallmark of aging. The physiologic response to apoptosis is for neighboring stem cells to proliferate. The one-third of the population who get cancer don’t all get mutations; they have germline variants that promote tumorigenesis. The FDA is relying on false premises to ban nitrosamines.

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Dear David William,

Your reasoning looks sensible. However, please note in the context of Regulatory toxicology, the exposure through food is different when compared with pharmaceuticals.

To some extent, yeah, it looks like we are dealing with stringent limits, that is burden some. Need not be too conservative in this context. At the same time we should respect decisions from FDA and pharmaceutical industries, because their job is to ensure every chemical entity going into patient body is safe.

Thanks for highlighting about the benefits for Quinapril. Just FYI- Now N-nitroso Quinapril is no more mutagenic!!

As a toxicologist, I agree with the fact that all cancers are not caused by mutations. However our drug discovery and development was based on a central tenet that to remove maximum suspected mutagenic chemical components out of the scope during drug development to ensure maximum safety.


Thank you so much for your thoughts. I would argue, though, that oral ingestion of a pill is no different than oral ingestion of food. There’s only one GI tract with the same absorption mechanisms for both, e.g. dipeptide transporters in the duodenum for ACE inhibitors and dipeptides. The quantities of nitrosamines ingested in grilled foods must be orders of magnitude larger than the tiny amounts ingested in a pill.

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Hi, sadly, and I see it time again, there is a confusion between Hazard and Risk in decision making.
Nitrosamines are a hazard. Just because they exist and we are exposed to them makes the risk. As mentioned, our job is to make sure the risks from exposure to pharmaceuticals are minimised and i agree with that of course. But I find it hard to see how we can do that effectively without benchmarking the from exposure from pharmaceuticals against a lifetime’s exposure to these substances. But then I’m no toxicologist.

Precisely my point, Iain. How can a microgram of nitrosamines possibly amount to a risk comparable to a lifetime of hotdogs and hamburgers? Or for that matter, how can dialysis and death within two years possibly be less serious than the hypothetical risk from nitrosamines? True, Salmonella spp. react poorly to nitrosamines. But no human has ever been diagnosed with cancer caused by excessive intake of grilled meats, not even Wimpy.

Agree @DWMoskowitzMD - But only a point to be added is Nitrosamines in grilled food by normal individuals may not be equivalent with nitrosamines in tablets for compromised patients!