Are added nitrates and nitrites in our diet harmful?

Question

It is widely claimed that meat-curing agents containing nitrates or nitrites are dangerous food additives.

This site puts them in a top ten list of bad food and recommends avoiding cured meats, explaining:

Many foods, especially cured meats such as bacon and hot dogs, use nitrates to preserve color and maintain microbial safety. Nitrate is harmless, but it can convert to nitrite, which can form nitrosamines, a powerful cancer-causing chemical, in your body. Whenever possible, look for nitrate-free preserved meats.

This site also recommends avoiding them:

Teaching your children the importance of eating healthy and staying away from preserved meats may save them from cancer later on in life.

Nitrates do have useful anti-microbial quantities as even critics recognise. But are added nitrates and nitrites a net harm to people who eat food containing them?

2018 update

The story has become topical again (in the UK at least) because a report has called for the elimination of added nitrates and nitrites in cured meat. This Guardian story reports:

The reputation of the meat industry will sink to that of big tobacco unless it removes cancer-causing chemicals from processed products such as bacon and ham, a coalition of experts and politicians warn today.

...the coalition claims there is a “consensus of scientific opinion” that the nitrites used to cure meats produce carcinogens called nitrosamines when ingested.

However there doesn't seem to be any significant new evidence about nitrosamines in the story which repeats worries first raised in the 1970s which petered out as no direct epidemiological link was found. And the recent claims also seem to ignore scientific evidence that cured meat is a small contributor to dietary nitrate/nitrite load in diet.

Has the scientific evidence changed?

Answer 1

First of all, Nitrate and nitrite are considered hazardous, and there are legal limits to their concentration in food and drinking water.

From the Institute of Health Sciences, VU University, Amsterdam, Netherlands:

The World Health Organization (WHO) first set an upper limit for nitrate in food in 1962 (4). It was based on a brief report from the US Food and Drug Administration (5), which stated the following: “sodium nitrate has been fed to rats at levels up to 10% in the diet for their lifetime. Other than some depression on growth at levels above 1% of nitrate, no adverse effects were noted in these animals. Two dogs were fed 2% sodium nitrate in their diet for a period of 105 and 125 days, respectively. No adverse effects were noted” (p 136). The WHO calculated from this that daily intakes of ≤500 mg of sodium nitrate/kg body weight were harmless to rats and dogs. This figure was divided by 100 to yield an Acceptable Daily Intake for humans of 5 mg sodium nitrate or 3.7 mg nitrate per kg body weight, which equals 222 mg for a 60-kg adult. That figure has stood ever since.

Putting a limit on that indicates a form of danger.

Further there's a mention of what can result when consuming nitrates:

It is undisputed that nitrate ingestion widens arteries. Bacteria in the mouth and gut reduce nitrate to nitrite, which is then converted by nitric oxide synthase into the endothelium-derived relaxing factor nitric oxide (2). That is why sublingual nitrate can resolve an episode of angina pectoris.

There are some minor other things discussed in that article, but none are supported very well, but nevertheless good to know.

On Scientific American, the intake of nitrate has positive results:

The story of nitrate's positive side began in 1994, when Jon Lundberg of the Karolinska Institute in Stockholm and Nigel Benjamin of Peninsula Medical School in Exeter, England, independently observed that the human stomach harbors large amounts of the gas nitric oxide (NO). Lundberg and Benjamin immediately suspected that the gas might be killing germs in the stomach, because nitric oxide, when presented to microbes by white blood cells, weakens them.

The question was where the gas was coming from. Nitric oxide performs several vital functions in the body, including dilating blood vessels, and for these activities, a cellular enzyme called nitric oxide synthase extracts the gas molecule from arginine, an amino acid. Chemists have long known another mechanism: at low pH, nitrite (NO2) forms a stew of nitrogen-oxygen compounds, including nitric oxide. Bacteria in the mouth convert nitrate to nitrite, which gets swallowed, so the stomach can naturally produce nitric oxide. If nitric oxide were truly beneficial to the stomach, harmless bacteria feeding on nitrate-rich saliva might have a symbiotic relationship with humans.

Benjamin's group confirmed the antimicrobial effect right away by exposing bacteria responsible for stomach infections to stomach acid both alone and mixed with nitrite. Although acid is often thought to be the stomach's main line of defense against invading bugs, the researchers found that E. coli, Salmonella and other bacteria could survive for hours in it, whereas high normal concentrations of nitrite plus acid killed the bacteria in less than an hour. Next, Lundberg and his co-workers placed saliva from people who had ingested nitrate tablets onto the inside surface of the stomachs of rats. The mucous membranes lining their stomachs thickened and received more blood, both of which are important barriers to infection and ulcers. Rats that received nitrate-poor saliva showed no change. Benjamin has also observed that cavity-causing bacteria self-destruct in a high- nitrite environment, suggesting an experiment to see if a high-nitrate diet prevents cavities.

In the article of the University of Nebraska - Lincoln, They also talk about nitrate danger for infants and cancer related problems.

About the methaemoglobine with infants.

In every one of the instances in which cyanosis (the clinical symptom of methaemoglobinaemia) developed in infants, the wells were situated near barnyards and pit privies.” There was an absence of methaemoglobinaemia when formula milk replacements were made with tap water. Re-evaluation of these original studies indicate that cases of methaemoglobinaemia always occurred when wells were contaminated with human or animal excrement and that the well water contained appreciable numbers of bacteria and high concentrations of nitrate (Avery, 1999). This strongly suggests that Methaemoglobinaemia, induced by well water, resulted from the presence of bacteria in the water rather than nitrate per se. A recent interpretation of these early studies is that gastroenteritis resulting from bacteria in the well water stimulated nitric oxide production in the gut and that this reacted with oxyhaemoglobin in blood, converting it into methaemoglobine.

And secondly, about cancer risks:

About 50 epidemiological studies have been made since 1973 testing the link between nitrate and stomach cancer incidence and mortality in humans, including Forman et al. (1985) and National Academy of Sciences (1981). The Chief Medical Officer in Britain (Acheson, 1985), the Scientific Committee for Food in Europe (European Union, 1995), and the Subcommittee on Nitrate and Nitrite in Drinking Water in the USA (NRC, 1995) all concluded that no convincing link between nitrate and stomach cancer incidence and mortality had been established.

A study reported by Al-Dabbagh et al. (1986) compared incidence of cancers between workers in a factory manufacturing nitrate fertilizer (and exposed to a high intake of nitrate through dust) and workers in the locality with comparable jobs but without the exposure to nitrate. There was no significant difference in cancer incidence between the two groups.

Based on the above findings showing no clear association between nitrate in drinking water and the two main health issues with which it has been linked, some scientists suggest that there is now sufficient evidence for increasing the permitted concentration of nitrate in drinking water without increasing risks to human health.

Answer 2

Yes, in the sense that dose makes poison. Too much is never good.

No. In the sense of nitrates and nitrites in meat products are currently the main culprits this is senseless campaigning based on faulty logic and jumping to conclusions. Fish and vegetables contribute just so much more to all kinds of diets. Nitrite is more poisonous than nitrate and so adding that to by choice to any type of food seems highly questionable. But for the industry it is also quite more effective.

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Nitrate and nitrite in meat and sausages serves primarily three functions:

1. taste (adding more 'zing' than table salt
2. microbial growth control (both substances are poisonous after all; remember the dose, though)
3. a smooth spectrum between aesthetics and outright fraud: it preserves the (by now) expected colours – or simulates a lengthy 'natural ageing' process when in reality the produce was turbo-cured

From a public health perspective "taste" is debatable preference (I do prefer nitrate to be not in it, some want exactly that). The colour of many traditional meat products would be quite dull greys and the avoidance advice of "red meat" very easy to follow if these salts were banned. Only very few meat products keep or attain the red often now expected by traditional curing processes (eg Italian Parma ham is not allowed to contain nitrate.

That leaves the microbial prevention aspect as the only true advantage from a food chemistry and public health standpoint as a real and undeniable plus.

Both chemicals are quite harmful to children and people already having organic problems, like kidney trouble. Both are also used as medical drugs with very useful applications.

The chemistry and food chemistry of these compounds is very complex and thousands of compounds are formed during, growth, harvest, processing, cooking, eating, digestion and even pharmaco-dynamically. We just have a large number of tiny windows into that. Complicated by the fact that humans are coctivores and lab-rats are usually not. Many cancers in rats can be caused by substances that humans effectively control and eliminate without any harm in usual doses.

Using the epidemiological results of "processed meat correlates with cancer" and "nitro-meat is the bogey-man" to "meat is the new tobacco" is unreasonable. Italian ham is red meat and devoid of added nitrate or nitrite. Are there any studies comparing incidence of cancer in American nitro-ham eaters to Italian parma-lovers that manage to control for confounding factors? Of course not. Are there links from compulsive salad eaters to higher risks of cancer, as salad from fertilised fields is usually very high in nitrates? No.
But campaigners just know that "meat is bad".
For a link from the small increase in cancer rates in meat eaters to the nitrates in meat, we find no conclusive evidence.

But the current focus in the debate on cured meat is a crusade of zealots. Deliberatly adding these salts during manufacturing may seem and probably is superfluous. But these substances occur in other foods, even in much higher concentrations, and even contributing more to a typical dietary intake than "processed meat". They are even formed in the human body and also in there are N-nitroso-compounds formed.

Roila R, Branciari R, Staccini B, Ranucci D, Miraglia D, Altissimi MS, Mercuri ML, Haouet NM: "Contribution of vegetables and cured meat to dietary nitrate and nitrite intake in Italian population: Safe level for cured meat and controversial role of vegetables", Ital J Food Saf. 2018 Sep 26; 7(3): 7692. Published online 2018 Nov 7. doi: 10.4081/ijfs.2018.7692 PMCID: PMC6240834 PMID: 30538964

            mean NO3 mg/kg  mean NO2 mg/kg

 Spinach    2036            8
 Radish     3817             –
 Bacon       178            7.7
 Cured ham    21             –

The content of nitrate and nitrite is actually much worse for example in spinach, soy, beets, salads and all kinds of fish. As the physiological fates of nitrates and nitrites forming N-nitroso compounds as the main cancerogenic concern is by far not fully understood. Nitrate from veggies forming nitrosamines is also of significant concern. Even the otherwise often lauded DASH-diet is:

The DASH diet is rich in fruits, vegetables, whole grains, and low-fat dairy foods; includes meat, fish, poultry, nuts, and beans; and is limited in sugar-sweetened foods and beverages, red meat, and added fats.

Any yet, following this diet leads to increased exposure to dietary nitrates and nitrites.

Pietro Santamaria: "Nitrate in vegetables: toxicity, content, intake and EC regulation", Journal of the Science of Food and Agriculture J Sci Food Agric 86:10–17 (2006) DOI: 10.1002/jsfa.2351:
Nevertheless, no official method has been published in EU legislation and nitrate levels in vegetables are generally assayed by modifying the protocols used for other foods. Limits to maximum levels of nitrate for trade in other vegetables are set in some European countries (Table 6). For potato, several countries have put forward the proposal of ‘guidelines’ for nitrate content (in Germany, for instance, only tubers with less than 200 mg kg−1 fresh matter (fm) are accepted), while in Poland there is a maximum limit of 183 mg kg−1 fm.73 Rocket and other Italian export vegetable (e.g. potato) sales contracts include very strict clauses, for instance with Switzerland and Germany. Namely, nitrate content for rocket is required not to exceed 2.5 – 4.0 g kg−1 fm, which is a very strict threshold that is difficult to respect on account of the high accumulation of nitrate in rocket, even when reduced amounts of nitrate are used in its cultivation.

CONCLUSIONS
Although current epidemiological data provide conflicting evidence regarding the potential long-term health risks of nitrate levels encountered in the diet, it is widely accepted that the reduction of dietary nitrate is a desirable preventive measure. The maximum allowable nitrate levels in vegetables should not exceed levels that reflect good agricultural practices.
A reduction in nitrate content can, however, represent added value for vegetable products (already rich in carotenoids, vitamins C and E, selenium, dietary fibre, plant sterols, glucosinolates and indoles, isothiocyanates, flavonoids, phenols, etc.).

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Norman G. Hord & Melissa N. Conley: "Regulation of Dietary Nitrate and Nitrite: Balancing Essential Physiological Roles with Potential Health Risks", p 153–162 (DOI 10.1007/978-3-319-46189-2_12) in: Nathan S. Bryan & Joseph Loscalzo (Eds): "Nitrite and Nitrate in Human Health and Disease", Nutrition and Health, Humana Press: Cham ²2017.

Key Points

• US and European Union regulatory limits on nitrates in drinking water are necessary to limit environmental pollution known as eutrophication.
• Health concerns of excessive nitrate and nitrite consumption have driven regulatory actions due to perceived risk of methemoglobinemia in infants and gastrointestinal cancer risk in adults.
• The World Health Organization’s Acceptable Daily Intake recommendations for nitrate can be exceeded by normal daily intakes of single foods and recommended dietary patterns, such as the DASH diet.
• Inconsistent positions on the health risks and bene ts of foods containing nitrates and nitrites by the International Agency for Research on Cancer (IARC) and the European Food Safety Authority (EFSA) may contribute to confusion for consumers; regulators must take the opportunity to clarify and expand upon these positions in order to provide coherent dietary guidance.
• The established vasoprotective, blood pressure lowering, and antiplatelet aggregation properties of nitrite alone, or of nitrite originating from dietary nitrate, requires a new regulatory paradigm that incorporates the concepts of physiological deficiency, sufficiency, and excess.
• There is a need to engage an independent panel of experts from academia, industry, and governmental and non-governmental sectors to undertake the first comprehensive, systematic review of the potential health risks and bene ts of food sources of nitrates and nitrites.
• U.S. Institute of Medicine’s Dietary Reference Intake paradigm may be a useful guide to the development of coherent dietary nitrate and nitrite intake recommendations.

It may well be that "nitrite" for example reacts differently when added to meat and then further processed or heated and then gets ingested as compared to occurring naturally and very finely dispersed in a vegetable.

Ronald B. Pegg & Fereidoon Shahid: "Nitrite Curing Of Meat. The N-Nitrosamine Problem and Nitrite Alternatives", Food & Nutrition Press: Trumbull, 2000.
Nitrite is a very reactive entity that can act as an oxidizing, reducing and nitrosating agent. It can be converted to various forms such as nitrate, nitric oxide, dinitrogen trioxide and nitrous acid. When added to meat, evidence of its reactiveness comes not only from well-recognized changes in the color, flavor and shelf-life of meat products, as previously discussed, but also because a significant portion of that added disappears. Once processing of cured meat products is complete, less than 50% of the nitrite added can be analyzed chemically (Cassens et al. 1974)
When addressing the fate of nitrite, clarification in terminology is necessary. Research studies have shown that nitrite can react with proteins, lipids, pigments and other constituents of meat, but a portion of it remains unreacted in the free form (i.e.,NO,. and HNO,). This unreacted nitrite is often referred to as free or residual nitrite, whereas nitrite that has reacted with constituents of the meat matrix is termed bound nitrite. Residual nitrite is the quantity of nitrite that can be detected by present analytical methodology, but the accuracy of the assay is questionable (Goutefongea et al. 1977). Conventionally, nitrosyl refers to NO which is liganded to a metal ion such as the ferrous ion of the heme moiety in myoglobin; thus, NOMb is termed as a nitrosylheme complex. Nitroso refers to NO which has reacted with a non-metal constituent (e.g., C - NO, S - NO); a N-nitrosamine is a classic example of N-nitrosation. Nitroso-nitrite derivatives are referred to as nitrosites while nitroso-nitro derivatives are pseudonitrosites.

Despite all of its desirable effects, nitrite can react, under certain conditions, with amines and amino acids in meat producing N-nitrosamines in some thermally processed cured products. N-Nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR) are key examples of such reaction products and have been found to be carcinogenic, mutagenic and teratogenic in experimental animals. Because of their possible link to the incidence of various cancers in man, considerable attention has been focused on the presence of N-nitrosamines in nitrite cured meat products (Magee and Barnes 1967; Gray and Randall 1979; Newberne 1979; Preussmann and Stewart 1984; Preussmann and Eisenbrand 1984; Sen 1986). Greater than 90% of the more than 300 N-nitroso compounds that have been tested in animal species including higher primates caused cancer (Preussmann and Stewart 1984; Tricker and Preussmann 1991), but no known case of human cancer has ever been shown to result from exposure to N-nitroso compounds.

_{For most cured meat products in Canada, nitrite levels have been reduced to a maximum allowable level of 200 mg/kg, except for bacon which was lowered even further to 120 mg/kg, and addition of sodium ascorbate, a N-nitrosamine blocking agent, is required at a minimum level of 500 mg/kg (Canadian Food and Drugs Act and Regulations 1981). Such actions have resulted in a decrease in the concentration of volatile N-nitrosamines (e.g., NDMA and NPYR) detected in thermally processed products, but not their total elimination. However, in the case of fish and seafood, reduced nitrite addition levels do not work as well at curbing N-nitrosamine formation. In order for N-nitrosamines to form, a nitrosating agent and an amine or its precursor, are required. Compared to meat, fish has substantially higher levels of amines and thus the likelihood of N-nitrosamine formation in smoked and cured fish products is greater.}

Current science suggests that adding beer and pure ascorbic acids to a meal of highly processed red meat effectively reduces the amount of nitrates and nitrites absorbed and cancerogenic substances formed compared to an organic spinach salad with 'healthy fish' and no alcohol.

Can that be the basis for scientific nutritional advice? That would seem quite counter-intuitive.

Any call to immediate action for reduction of nitrate in meat – lower than current guidelines – that goes beyond 'give us more money to better research this better' and instead calls for immediate bans and 'eat less meat' looks more like well published hysteria than anything resembling reason. Singling out a single ingredient in an otherwise normal human diet has always been just wrong, it will continue to be that way.