Biologic Fate of Nitrates and Nitrites in the Body

What Is the Biologic Fate of Nitrates and Nitrites in the Body?

Exposure to nitrates and nitrites may come from both internal nitrate production and external sources.

Intake of some amount of nitrates is a normal part of the nitrogen cycle in humans.

The mean intake of nitrate per person in the United States is about 40–100 milligrams per day (mg/day) (in Europe it is about 50–140 mg/day).

Nitrate can be synthesized endogenously from nitric oxide (especially in the case of inflammation), which reacts to form nitrite.

Figure 3 shows ways that nitrate, nitrite and nitric oxide can be produced and utilized from exogenous and endogenous sources.

A schematic diagram of the physiologic disposition of nitrate, nitrite
Figure 1
A schematic diagram of the physiologic disposition of nitrate, nitrite, and nitric oxide (NO) from exogenous (dietary) and endogenous sources. The action of bacterial nitrate reductases on the tongue and mammalian enzymes that have nitrate reductase activity in tissues are noted by the number 1. Bacterial nitrate reductases are noted by the number 2. Mammalian enzymes with nitrite reductase activity are noted by the number 3.

Absorption Nitrates and Nitrites

In the proximal small intestine, nitrate is rapidly and almost completely absorbed (bioavailability at least 92%).

  • Inorganic nitrate/nitrite can be absorbed via inhalation.
  • Inorganic nitrate/nitrite does not undergo first pass metabolism.

Distribution Nitrates and Nitrites

Inorganic nitrates/nitrites are distributed widely through the circulation with approximately 25% of absorbed nitrate concentrating in the salivary glands.

Salivary, plasma, and urinary levels of nitrate and then nitrite rise abruptly after ingestion.

An increase in inorganic nitrite levels peaks around 3 hours post ingestion and can be detected about an hour after ingestion.

Metabolism of Inorganic Nitrates and Nitrites

The two main metabolic pathways for inorganic nitrates / nitrites are

  • The nitrate-nitrite-NO pathway (Figure 1) and
  • Enterosalivary circulation pathway (nitrate reductase activity of bacteria on the tongue generates nitrite and nitrite which is metabolized to NO in the stomach and circulation).

Approximately 5%–10% of the total nitrate intake is converted to nitrite by bacteria in the saliva, stomach, and small intestine.

  • In vivo conversion of nitrates to nitrites significantly enhances nitrates’ toxic potency.
  • This reaction is pH dependent, with no nitrate reduction occurring below pH 4 or above pH 9.
  • The high pH of the infant gastrointestinal system makes them more susceptible to nitrite toxicity from elevated nitrate/nitrite ingestion.

The metabolic pathway of plasma and tissue nitrates depends on local conditions such as tissue oxygenation, and inflammatory state. In the skin, local conditions also include ultraviolet light exposure.

Nitrate can be reduced to nitrite and nitric oxide when needed physiologically or as part of pathological processes (see Figure 1).

Mammalian metalloproteins and enzymes that have nitrate reductase activity include aldehyde oxidase, heme proteins, mitochondria and xanthine reductase.

The reaction of nitrite with endogenous molecules to form N-nitroso compounds may have toxic or carcinogenic effects.

Excretion Nitrates and Nitrites

Approximately 60% to 70% of an ingested nitrate dose is excreted in urine within the first 24 hours.

About 25% is excreted in saliva through an active blood nitrate transport system and potentially is reabsorbed.

Half-lives of parent nitrate compounds are usually less than 1 hour; half-lives of metabolites range from 1 hour to 8 hours.

In the Fourth National Report on Human Exposure to Environmental Chemicals, urinary levels of nitrate were measured in a subsample of the National Health and Nutrition Examination Survey (NHANES) consisting of participants aged 6 years and older during 2007-2008. The geometric mean for urinary nitrate (in mg/g of creatinine) for the US population aged 6 years and older during 2007-2008 was 47.7, with a 95% confidence interval of 45.9-49.7. Note that these measurements are used in population based public health research and not intended for clinical decision making on individual patients.

Key Points the Biologic Fate of Nitrates and Nitrites in the Body

  • Exposure to nitrate and nitrites may come from both internal nitrate production and external sources.
  • Intake of some amount of nitrates is a normal part of the nitrogen cycle in humans.
  • Nitrate can be reduced to nitrite and nitric oxide when needed physiologically or as part of pathological processes depending on local conditions such as inflammation and tissue oxygenation.
  • In vivo conversion of nitrates to nitrites significantly enhances nitrates’ toxic potency.
  • Approximately 5%–10% of the total nitrate intake is converted to nitrite by bacteria in the saliva, stomach, and small intestine.
  • 60-70% of an ingested nitrate dose is excreted in urine within 24 hours.

US Standards for Nitrates and Nitrites Exposure

What are U.S. Standards and Regulations for Nitrates and Nitrites Exposure?

EPA has set an enforceable standard called a maximum contaminant level (MCL) in water for nitrates at 10 parts per million (ppm) (10 mg/L) and for nitrites at 1 ppm (1 mg/L).

  • EPA believes that exposure below this level is not expected to cause significant health problems.
  • All public water supplies must abide by these regulations.
  • Given present technology and resources, this MCL is also a level to which water systems can reasonably be required to remove this contaminant should it occur in drinking water.

Once a water source is contaminated, the costs of protecting consumers from nitrate exposure can be significant. This is because:

  • Nitrate is not removed by conventional drinking water treatment processes.
  • Its removal requires additional, relatively expensive treatment units.

Intake Nitrate Limits

The Joint Expert Committee on Food Additives (JECFA) of the Food and Agriculture Organization of the United Nations / World Health Organization and the European Commission’s Scientific Committee on Food have set an acceptable daily intake (ADI) for nitrate of 0–3.7 milligrams (mg) nitrate ion / kilogram (kg) body weight. This intake appears to be safe for healthy neonates, children, and adults. The same is also true of the EPA reference dose (RfD) for nitrate of 1.6 mg nitrate nitrogen / kg body weight per day (equivalent to about 7.0 mg nitrate ion / kg body weight per day).

JECFA has proposed an ADI for nitrite of 0–0.07 mg nitrite ion/kg body weight. EPA has set an RfD of 0.l mg nitrite nitrogen/kg body weight per day (equivalent to 0.33 mg nitrite ion/kg body weight per day).

Bottled Water and Food Additives Nitrate Limits

The FDA regulates allowable levels of inorganic nitrate and nitrite in bottled water [FDA 2005] as well as levels allowable in foodstuffs.

Bottled Water
Bottled Water

The FDA’s bottled water standard is based on the EPA standards for tap water. The bottled water industry must also follow FDA’s Current Good Manufacturing Practices (CGMPs) for processing and bottling drinking water. If these standards are met, water is considered safe for most healthy individuals. However, although not often reported, bottled water outbreaks do occur.

Allowable nitrite levels in bottled water:

  • Nitrate 10 mg/L (as nitrogen)
  • Nitrite 1 mg/L (as nitrogen)
  • Total nitrates, nitrites 10 mg/L (as nitrogen)

Allowable nitrite levels as an additive to foods:

  • As a preservative and color fixative, with or without sodium nitrite, in Smoked, cured sablefish; Smoked, cured salmon; Smoked, cured shad, so that the level of sodium nitrate does not exceed 500 parts per million (ppm) and the level of sodium nitrite does not exceed 200 ppm in the finished product.
  • As a preservative and color fixative, with or without sodium nitrite, in meat-curing preparations for the home curing of meat and meat products (including poultry and wild game), with directions for use which limit the amount of sodium nitrate to not more than 500 ppm in the finished meat product and the amount of sodium nitrite to not more than 200 ppm in the finished meat product.
  • The food additive potassium nitrate may be safely used as a curing agent in the processing of cod roe, in an amount not to exceed 200 ppm of the finished roe.

The U.S. Department of Agriculture’s (USDA’s) Food Safety and Inspection Service (FSIS) regulates food ingredients approved for use in the production of meat and poultry products. This includes inspection for required labeling of meat products when substances such as sodium nitrate are used in meat packaging.

Environmental Nitrate and Nitrite Standards

The current water standard for nitrate is based on levels considered low enough to protect infants from methemoglobinemia.

  • Some published results suggest a possible association between nitrate exposure during pregnancy and human malformations.
  • However, a review of the toxicology in relation to possible adverse effects on reproduction and development offers no evidence for teratogenic effects attributable to nitrate or nitrite ingestion.
  • The present maximum contaminant level appears to adequately protect even sensitive populations from nitrate-induced toxicity.
  • EPA concludes that the evidence in the literature showing an association between exposures to nitrate or nitrites and cancer in adults and children is conflicting.

Key Points of Nitrate and Nitrite Standards

  • The current water standard for nitrate is based on
    protection of infants from methemoglobinemia.
  • In vivo conversion of nitrates to nitrites significantly
    enhances nitrates’ toxic potency.

Risk from Overexposure to Nitrates and Nitrites

Who is at most Risk of Adverse Health Effects from Overexposure to Nitrates and Nitrites?

Nitrate contaminated water
Nitrate contaminated water

Infants less than 4 months of age are most at risk of adverse health effects from over exposure to nitrates and nitrites through ingestion of formula diluted with nitrate contaminated water.

Although there is no nutritional indication to add complementary foods to the diet of a healthy term infant before 4 to 6 months of age, the American Academy of Pediatrics suggests that home-prepared infant foods from vegetables (i.e. spinach, beets, green beans, squash, carrots) should be avoided until infants are 3 months or older.

Gastroenteritis with vomiting and diarrhea can exacerbate nitrite formation in infants and has been reported to be a major contributor to methemoglobinemia risk in infants independent of nitrate / nitrite ingestion.

In addition, the pregnant woman and her fetus might be more sensitive to toxicity from nitrites or nitrates at or near the 30th week of pregnancy.

Individuals with glucose-6-phsphate dehydrogenase (G6PD) deficiency may have greater susceptibility to the oxidizing effects of methemoglobinemia inducers.

Sleep should be Prescribed

What those Late Nights out could be Costing you

Leading neuroscientist Matthew Walker on why sleep deprivation is increasing our risk of cancer, heart attack and Alzheimer’s – and what you can do about it.

Matthew P. Walker
Matthew P. Walker

Matthew Walker has learned to dread the question “What do you do?” At parties, it signals the end of his evening; thereafter, his new acquaintance will inevitably cling to him like ivy. On an aeroplane, it usually means that while everyone else watches movies or reads a thriller, he will find himself running an hours-long salon for the benefit of passengers and crew alike. “I’ve begun to lie,” he says. “Seriously. I just tell people I’m a dolphin trainer. It’s better for everyone.”

Walker is a sleep scientist. To be specific, he is the director of the Center for Human Sleep Science at the University of California, Berkeley, a research institute whose goal – possibly unachievable – is to understand everything about sleep’s impact on us, from birth to death, in sickness and health. No wonder, then, that people long for his counsel. As the line between work and leisure grows ever more blurred, rare is the person who doesn’t worry about their sleep. But even as we contemplate the shadows beneath our eyes, most of us don’t know the half of it – and perhaps this is the real reason he has stopped telling strangers how he makes his living. When Walker talks about sleep he can’t, in all conscience, limit himself to whispering comforting nothings about camomile tea and warm baths. It’s his conviction that we are in the midst of a “catastrophic sleep-loss epidemic”, the consequences of which are far graver than any of us could imagine. This situation, he believes, is only likely to change if government gets involved.

Why We Sleep - Matthew Walker
Why We Sleep – Matthew Walker

Walker has spent the last four and a half years writing Why We Sleep, a complex but urgent book that examines the effects of this epidemic close up, the idea being that once people know of the powerful links between sleep loss and, among other things, Alzheimer’s disease, cancer, diabetes, obesity and poor mental health, they will try harder to get the recommended eight hours a night (sleep deprivation, amazing as this may sound to Donald Trump types, constitutes anything less than seven hours). But, in the end, the individual can achieve only so much. Walker wants major institutions and law-makers to take up his ideas, too. “No aspect of our biology is left unscathed by sleep deprivation,” he says. “It sinks down into every possible nook and cranny. And yet no one is doing anything about it. Things have to change: in the workplace and our communities, our homes and families. But when did you ever see an NHS poster urging sleep on people? When did a doctor prescribe, not sleeping pills, but sleep itself? It needs to be prioritised, even incentivised. Sleep loss costs the UK economy over £30bn a year in lost revenue, or 2% of GDP. I could double the NHS budget if only they would institute policies to mandate or powerfully encourage sleep.”

Why, exactly, are we so sleep-deprived? What has happened over the course of the last 75 years? In 1942, less than 8% of the population was trying to survive on six hours or less sleep a night; in 2017, almost one in two people is. The reasons are seemingly obvious. “First, we electrified the night,” Walker says. “Light is a profound degrader of our sleep. Second, there is the issue of work: not only the porous borders between when you start and finish, but longer commuter times, too. No one wants to give up time with their family or entertainment, so they give up sleep instead. And anxiety plays a part. We’re a lonelier, more depressed society. Alcohol and caffeine are more widely available. All these are the enemies of sleep.”

But Walker believes, too, that in the developed world sleep is strongly associated with weakness, even shame. “We have stigmatised sleep with the label of laziness. We want to seem busy, and one way we express that is by proclaiming how little sleep we’re getting. It’s a badge of honour. When I give lectures, people will wait behind until there is no one around and then tell me quietly: ‘I seem to be one of those people who need eight or nine hours’ sleep.’ It’s embarrassing to say it in public. They would rather wait 45 minutes for the confessional. They’re convinced that they’re abnormal, and why wouldn’t they be? We chastise people for sleeping what are, after all, only sufficient amounts. We think of them as slothful. No one would look at an infant baby asleep, and say ‘What a lazy baby!’ We know sleeping is non-negotiable for a baby. But that notion is quickly abandoned [as we grow up]. Humans are the only species that deliberately deprive themselves of sleep for no apparent reason.” In case you’re wondering, the number of people who can survive on five hours of sleep or less without any impairment, expressed as a percent of the population and rounded to a whole number, is zero.

The world of sleep science is still relatively small. But it is growing exponentially, thanks both to demand (the multifarious and growing pressures caused by the epidemic) and to new technology (such as electrical and magnetic brain stimulators), which enables researchers to have what Walker describes as “VIP access” to the sleeping brain. Walker, who is 44 and was born in Liverpool, has been in the field for more than 20 years, having published his first research paper at the age of just 21. “I would love to tell you that I was fascinated by conscious states from childhood,” he says. “But in truth, it was accidental.” He started out studying for a medical degree in Nottingham. But having discovered that doctoring wasn’t for him – he was more enthralled by questions than by answers – he switched to neuroscience, and after graduation, began a PhD in neurophysiology supported by the Medical Research Council. It was while working on this that he stumbled into the realm of sleep.

“I was looking at the brainwave patterns of people with different forms of dementia, but I was failing miserably at finding any difference between them,” he recalls now. One night, however, he read a scientific paper that changed everything. It described which parts of the brain were being attacked by these different types of dementia: “Some were attacking parts of the brain that had to do with controlled sleep, while other types left those sleep centres unaffected. I realised my mistake. I had been measuring the brainwave activity of my patients while they were awake, when I should have been doing so while they were asleep.” Over the next six months, Walker taught himself how to set up a sleep laboratory and, sure enough, the recordings he made in it subsequently spoke loudly of a clear difference between patients. Sleep, it seemed, could be a new early diagnostic litmus test for different subtypes of dementia.

After this, sleep became his obsession. “Only then did I ask: what is this thing called sleep, and what does it do? I was always curious, annoyingly so, but when I started to read about sleep, I would look up and hours would have gone by. No one could answer the simple question: why do we sleep? That seemed to me to be the greatest scientific mystery. I was going to attack it, and I was going to do that in two years. But I was naive. I didn’t realise that some of the greatest scientific minds had been trying to do the same thing for their entire careers. That was two decades ago, and I’m still cracking away.” After gaining his doctorate, he moved to the US. Formerly a professor of psychiatry at Harvard Medical School, he is now professor of neuroscience and psychology at the University of California.

Does his obsession extend to the bedroom? Does he take his own advice when it comes to sleep? “Yes. I give myself a non-negotiable eight-hour sleep opportunity every night, and I keep very regular hours: if there is one thing I tell people, it’s to go to bed and to wake up at the same time every day, no matter what. I take my sleep incredibly seriously because I have seen the evidence. Once you know that after just one night of only four or five hours’ sleep, your natural killer cells – the ones that attack the cancer cells that appear in your body every day – drop by 70%, or that a lack of sleep is linked to cancer of the bowel, prostate and breast, or even just that the World Health Organisation has classed any form of night-time shift work as a probable carcinogen, how could you do anything else?”

There is, however, a sting in the tale. Should his eyelids fail to close, Walker admits that he can be a touch “Woody Allen-neurotic”. When, for instance, he came to London over the summer, he found himself jet-lagged and wide awake in his hotel room at two o’clock in the morning. His problem then, as always in these situations, was that he knew too much. His brain began to race. “I thought: my orexin isn’t being turned off, the sensory gate of my thalamus is wedged open, my dorsolateral prefrontal cortex won’t shut down, and my melatonin surge won’t happen for another seven hours.” What did he do? In the end, it seems, even world experts in sleep act just like the rest of us when struck by the curse of insomnia. He turned on a light and read for a while.

Will Why We Sleep have the impact its author hopes? I’m not sure: the science bits, it must be said, require some concentration. But what I can tell you is that it had a powerful effect on me. After reading it, I was absolutely determined to go to bed earlier – a regime to which I am sticking determinedly. In a way, I was prepared for this. I first encountered Walker some months ago, when he spoke at an event at Somerset House in London, and he struck me then as both passionate and convincing (our later interview takes place via Skype from the basement of his “sleep centre”, a spot which, with its bedrooms off a long corridor, apparently resembles the ward of a private hospital). But in another way, it was unexpected. I am mostly immune to health advice. Inside my head, there is always a voice that says “just enjoy life while it lasts”.

The evidence Walker presents, however, is enough to send anyone early to bed. It’s no kind of choice at all. Without sleep, there is low energy and disease. With sleep, there is vitality and health. More than 20 large scale epidemiological studies all report the same clear relationship: the shorter your sleep, the shorter your life. To take just one example, adults aged 45 years or older who sleep less than six hours a night are 200% more likely to have a heart attack or stroke in their lifetime, as compared with those sleeping seven or eight hours a night (part of the reason for this has to do with blood pressure: even just one night of modest sleep reduction will speed the rate of a person’s heart, hour upon hour, and significantly increase their blood pressure).

A lack of sleep also appears to hijack the body’s effective control of blood sugar, the cells of the sleep-deprived appearing, in experiments, to become less responsive to insulin, and thus to cause a prediabetic state of hyperglycaemia. When your sleep becomes short, moreover, you are susceptible to weight gain. Among the reasons for this are the fact that inadequate sleep decreases levels of the satiety-signalling hormone, leptin, and increases levels of the hunger-signalling hormone, ghrelin. “I’m not going to say that the obesity crisis is caused by the sleep-loss epidemic alone,” says Walker. “It’s not. However, processed food and sedentary lifestyles do not adequately explain its rise. Something is missing. It’s now clear that sleep is that third ingredient.” Tiredness, of course, also affects motivation.

Sleep has a powerful effect on the immune system, which is why, when we have flu, our first instinct is to go to bed: our body is trying to sleep itself well. Reduce sleep even for a single night, and your resilience is drastically reduced. If you are tired, you are more likely to catch a cold. The well-rested also respond better to the flu vaccine. As Walker has already said, more gravely, studies show that short sleep can affect our cancer-fighting immune cells. A number of epidemiological studies have reported that night-time shift work and the disruption to circadian sleep and rhythms that it causes increase the odds of developing cancers including breast, prostate, endometrium and colon.

Getting too little sleep across the adult lifespan will significantly raise your risk of developing Alzheimer’s disease. The reasons for this are difficult to summarise, but in essence it has to do with the amyloid deposits (a toxin protein) that accumulate in the brains of those suffering from the disease, killing the surrounding cells. During deep sleep, such deposits are effectively cleaned from the brain. What occurs in an Alzheimer’s patient is a kind of vicious circle. Without sufficient sleep, these plaques build up, especially in the brain’s deep-sleep-generating regions, attacking and degrading them. The loss of deep sleep caused by this assault therefore lessens our ability to remove them from the brain at night. More amyloid, less deep sleep; less deep sleep, more amyloid, and so on. (In his book, Walker notes “unscientifically” that he has always found it curious that Margaret Thatcher and Ronald Reagan, both of whom were vocal about how little sleep they needed, both went on to develop the disease; it is, moreover, a myth that older adults need less sleep.) Away from dementia, sleep aids our ability to make new memories, and restores our capacity for learning.

And then there is sleep’s effect on mental health. When your mother told you that everything would look better in the morning, she was wise. Walker’s book includes a long section on dreams (which, says Walker, contrary to Dr Freud, cannot be analysed). Here he details the various ways in which the dream state connects to creativity. He also suggests that dreaming is a soothing balm. If we sleep to remember (see above), then we also sleep to forget. Deep sleep – the part when we begin to dream – is a therapeutic state during which we cast off the emotional charge of our experiences, making them easier to bear. Sleep, or a lack of it, also affects our mood more generally. Brain scans carried out by Walker revealed a 60% amplification in the reactivity of the amygdala – a key spot for triggering anger and rage – in those who were sleep-deprived. In children, sleeplessness has been linked to aggression and bullying; in adolescents, to suicidal thoughts. Insufficient sleep is also associated with relapse in addiction disorders. A prevailing view in psychiatry is that mental disorders cause sleep disruption. But Walker believes it is, in fact, a two-way street. Regulated sleep can improve the health of, for instance, those with bipolar disorder.

What those late nights out could be costing you
What those late nights out could be costing you

I’ve mentioned deep sleep in this (too brief) summary several times. What is it, exactly? We sleep in 90-minute cycles, and it’s only towards the end of each one of these that we go into deep sleep. Each cycle comprises two kinds of sleep. First, there is NREM sleep (non-rapid eye movement sleep); this is then followed by REM (rapid eye movement) sleep. When Walker talks about these cycles, which still have their mysteries, his voice changes. He sounds bewitched, almost dazed.

REM and NREM sleep
REM and NREM sleep

“During NREM sleep, your brain goes into this incredible synchronised pattern of rhythmic chanting,” he says. “There’s a remarkable unity across the surface of the brain, like a deep, slow mantra. Researchers were once fooled that this state was similar to a coma. But nothing could be further from the truth. Vast amounts of memory processing is going on. To produce these brainwaves, hundreds of thousands of cells all sing together, and then go silent, and on and on. Meanwhile, your body settles into this lovely low state of energy, the best blood-pressure medicine you could ever hope for. REM sleep, on the other hand, is sometimes known as paradoxical sleep, because the brain patterns are identical to when you’re awake. It’s an incredibly active brain state. Your heart and nervous system go through spurts of activity: we’re still not exactly sure why.”

Does the 90-minute cycle mean that so-called power naps are worthless? “They can take the edge off basic sleepiness. But you need 90 minutes to get to deep sleep, and one cycle isn’t enough to do all the work. You need four or five cycles to get all the benefit.” Is it possible to have too much sleep? This is unclear. “There is no good evidence at the moment. But I do think 14 hours is too much. Too much water can kill you, and too much food, and I think ultimately the same will prove to be true for sleep.” How is it possible to tell if a person is sleep-deprived? Walker thinks we should trust our instincts. Those who would sleep on if their alarm clock was turned off are simply not getting enough. Ditto those who need caffeine in the afternoon to stay awake. “I see it all the time,” he says. “I get on a flight at 10am when people should be at peak alert, and I look around, and half of the plane has immediately fallen asleep.”

So what can the individual do? First, they should avoid pulling “all-nighters”, at their desks or on the dancefloor. After being awake for 19 hours, you’re as cognitively impaired as someone who is drunk. Second, they should start thinking about sleep as a kind of work, like going to the gym (with the key difference that it is both free and, if you’re me, enjoyable). “People use alarms to wake up,” Walker says. “So why don’t we have a bedtime alarm to tell us we’ve got half an hour, that we should start cycling down?” We should start thinking of midnight more in terms of its original meaning: as the middle of the night. Schools should consider later starts for students; such delays correlate with improved IQs. Companies should think about rewarding sleep. Productivity will rise, and motivation, creativity and even levels of honesty will be improved. Sleep can be measured using tracking devices, and some far-sighted companies in the US already give employees time off if they clock enough of it. Sleeping pills, by the way, are to be avoided. Among other things, they can have a deleterious effect on memory.

Those who are focused on so-called “clean” sleep are determined to outlaw mobiles and computers from the bedroom – and quite right, too, given the effect of LED-emitting devices on melatonin, the sleep-inducing hormone. Ultimately, though, Walker believes that technology will be sleep’s saviour. “There is going to be a revolution in the quantified self in industrial nations,” he says. “We will know everything about our bodies from one day to the next in high fidelity. That will be a seismic shift, and we will then start to develop methods by which we can amplify different components of human sleep, and do that from the bedside. Sleep will come to be seen as a preventive medicine.”

What questions does Walker still most want to answer? For a while, he is quiet. “It’s so difficult,” he says, with a sigh. “There are so many. I would still like to know where we go, psychologically and physiologically, when we dream. Dreaming is the second state of human consciousness, and we have only scratched the surface so far. But I would also like to find out when sleep emerged. I like to posit a ridiculous theory, which is: perhaps sleep did not evolve. Perhaps it was the thing from which wakefulness emerged.” He laughs. “If I could have some kind of medical Tardis and go back in time to look at that, well, I would sleep better at night.”

Sleep in numbers:

■ Two-thirds of adults in developed nations fail to obtain the nightly eight hours of sleep recommended by the World Health Organisation.

■ An adult sleeping only 6.75 hours a night would be predicted to live only to their early 60s without medical intervention.

■ A 2013 study reported that men who slept too little had a sperm count 29% lower than those who regularly get a full and restful night’s sleep.

■ If you drive a car when you have had less than five hours’ sleep, you are 4.3 times more likely to be involved in a crash. If you drive having had four hours, you are 11.5 times more likely to be involved in an accident.

■ A hot bath aids sleep not because it makes you warm, but because your dilated blood vessels radiate inner heat, and your core body temperature drops. To successfully initiate sleep, your core temperature needs to drop about 1C.

■ The time taken to reach physical exhaustion by athletes who obtain anything less than eight hours of sleep, and especially less than six hours, drops by 10-30%.

■ There are now more than 100 diagnosed sleep disorders, of which insomnia is the most common.

■ Morning types, who prefer to awake at or around dawn, make up about 40% of the population. Evening types, who prefer to go to bed late and wake up late, account for about 30%. The remaining 30% lie somewhere in between.

Things Ruin a Good Night’s Sleep

Which five things ruin a good night’s sleep?

  • Noisy and no comfort;
  • Irregular routines;
  • The wrong temperature;
  • Stimulating food and drink;
  • A busy mind.

Noisy and no comfort

We might feel drowsy as we start to fall asleep, but our brain is still active, and noises or discomfort can disturb us.
As we drift into light sleep, an area of the brain called the hypothalamus starts to block the flow of information from our senses to the rest of the brain. But it will still let through noises, which need to be able to wake us up.
After about half an hour of light sleep, most of us enter a type of deep sleep called slow-wave sleep. Our brains become less responsive and it becomes much harder to be woken up. But some things will always get through – such as our names being called out loudly.
Missing out on parts of our usual sleep cycle reduces the quality and quantity of sleep.

Noisy and no comfort ruin a good night's sleep
Noisy and no comfort ruin a good night’s sleep

Irregular routines

We all have a built-in body clock which tells us when we are tired. It helps synchronise thousands of cells in our body to a 24-hour cycle called the circadian rhythm.
The main synchroniser for our body clock is light. Our eyes react to light and dark, even when our eyelids are closed.
Daylight prompts our brains to reduce the production of the sleep hormone melatonin. This makes us feel more alert.
If we get less sleep during the night, because of going to bed late or waking up early, we’re unlikely to get as much deep sleep as we need.

Irregular routines ruin a good night's sleep
Irregular routines ruin a good night’s sleep

The wrong temperature

Our core body temperature should drop by half a degree when we are asleep. So as sleep approaches, our body clock makes blood vessels in our hands, face and feet open up, in order to lose heat. But if we get too cold, we get restless and find it hard to sleep. Or if our bedrooms or duvets are too warm, our bodies can’t lose heat, which can also cause restlessness.

The wrong temperature ruin a good night's sleep
The wrong temperature ruin a good night’s sleep

Stimulating food and drink

We can have trouble sleeping after we consume food and drink that act as stimulants.

Stimulating food and drink ruin a good night's sleep
Stimulating food and drink ruin a good night’s sleep

Caffeine

Drinks high in caffeine make it harder to fall asleep and can interfere with our deep sleep. Caffeine can stay in our system for many hours, so our sleep quality can be affected by the caffeinated drinks we consume earlier in the day.

Alcohol

In the course of a night we usually have six to seven cycles of REM (rapid eye movement) sleep, during which our brains process the information we’ve absorbed during the day. This leaves us feeling refreshed. But a night of drinking means we’ll typically have only one to two cycles and wake up feeling tired.

Food

Foods containing a chemical called tyramine, such as bacon, cheese, nuts and red wine, can keep us awake at night. This is because tyramine triggers the release of noradrenaline, a brain stimulant.

A busy mind

Stress is the enemy of sleep. In bed, our mind is left free to wander and anxiety concerning sleep will only make it worse.
It’s difficult to keep track of time when you’re lying down in the dark waiting for sleep. People often nod off and wake up again but it feel as if they’re getting no sleep at all. This delivers fragmented sleep with much less time spent in the important deep sleep stages.

A busy mind ruin a good night's sleep
A busy mind ruin a good night’s sleep

Sleep experts recommend that people with this problem get up and do an activity which distracts the mind from worry – such as a puzzle – before trying to sleep again.

What are Routes of Exposure to Nitrates and Nitrites?

The primary routes of exposure to nitrates and nitrites may differ depending on occupational and non­ occupational factors. Non-occupational factors may include:

  • Age,
  • Diet,
  • Medications,
  • Hobbies (such as gardening, arc welding, etc.),
  • History of inhalational drug use,
  • Source of drinking/cooking water and how it is supplied,
  • Outdoor activities, as well as
  • The chemical form of the nitrates and nitrites.

    Routes of Exposure to Nitrates and Nitrites
    Routes of Exposure to Nitrates and Nitrites

Occupational and Paraoccupational Exposures

Occupational exposure occurs primarily through the inhalation and dermal routes. Explosive and fertilizer industry workers may be exposed to nitrate through inhalation of dusts containing nitrate salts. Dusts can also dissolve in sweat exposing skin to concentrated solutions of the salts. Farmers may experience periodic exposures depending on their activities, especially with regard to the handling of fertilizers. Exposure of family members to nitrates from dusts brought home on work clothes has been reported.

Non­-occupational Exposures

The primary route of non-occupational exposure is ingestion of water or foodstuffs that contain high levels of nitrates or nitrites. Inhalation exposures may occur from inhalant drug use and dermal exposures may occur from some topical medications. These would be special instances and not the primary routes of exposure for the general population.

Key Points

  • Primary occupational routes of exposure to nitrates and nitrites include inhalation and dermal routes.
  • The primary route of exposure to nitrates and nitrites for the general population is ingestion.
  • Inhalation and dermal exposures have been reported in non-occupational settings under certain circumstances, but are not the primary routes of exposure for the general population.

Sleep Tips and Advice

Do you like to have a weekend lie-in or a nightcap before going to bed? These habits could actually be harming your sleep.

Relax your mind

  • Simple breathing exercises can help. Breathe, using your abdomen not your chest, through your nose for three seconds, then breathe out for three seconds. Pause for three seconds before breathing in again. Practise this for ten minutes at night (five minutes is better than nothing).
  • Some people find that lavender oil, valerian or other herbs help them to sleep.
  • If you still have problems, you could try massage, aromatherapy, or even acupuncture.
  • If you still find yourself tossing and turning, abandon the bedroom and find something enjoyable and absorbing to do. Jigsaws are perfect. Don’t go back to bed until you begin to feel sleepy.

    Relax your Mind
    Relax your Mind

Exercise regularly

  • Regular exercise is a great way to improve your sleep. Just be careful not to do it close to bed time as exercise produces stimulants that stop the brain from relaxing quickly.
  • This being the case, exercising in the morning is an excellent way to wake up the body. Going for a run or doing some aerobics releases stimulants into the body, which perks you up.
  • If you are injured or disabled, you can still benefit from exercise. Check out disability exercise tips.

    Exercise regularly
    Exercise regularly

Create a calm bedroom environment

  • Your bedroom should be for sleep only. Avoid turning it into an entertainment centre with televisions, computers and stereos.
  • Two thirds of children have a computer, games machine or TV in their bedroom and could be losing out on sleep as a result.

Avoid alcohol

  • It’s fine to have a nightcap, but too much alcohol can make you restless. Alcohol is also a diuretic, which means it encourages you to urinate (never welcomed during the night).
  • Drinking is also more likely to lead to snoring, which can restrict airflow into the lungs. This reduces oxygen in your blood which disturbs your sleep and contributes to your hangover.

Avoid caffeine

  • Caffeine is a stimulant which can stay in your system for many hours. So avoid sources of caffeine such as coffee, chocolate, cola drinks and non-herbal teas.

Watch what you eat

  • Eating a large heavy meal too close to bedtime will interfere with your sleep.
  • Spicy or fatty foods may cause heartburn, which leads to difficulty in falling asleep and discomfort throughout the night.
  • Foods containing tyramine (bacon, cheese, ham, aubergines, pepperoni, raspberries, avocado, nuts, soy sauce, red wine) might keep you awake at night. Tyramine causes the release of norepinephrine, a brain stimulant.
  • If you get the munchies close to bedtime, eat something that triggers the hormone serotonin, which makes you sleepy. Carbohydrates such as bread or grain, cereal will do the trick.

    Cereals - Watch what you eat
    Cereals – Watch what you eat

Set a regular bedtime and wake up time

  • Create a habit of going to bed and waking up at the same time each day, even on weekends. This helps anchor your body clock to these times. Resisting the urge for a lie-in can pay dividends in alertness.
  • If you feel you haven’t slept well, resist the urge to sleep in longer than normal; getting up on schedule keeps your body in its normal wake-up routine.
  • Remember, even after only four hours, the brain has gained many of the important benefits of sleep.

It’s only natural

  • Most of us have a natural dip in alertness between 2 – 4pm.
  • A 15 minute nap when you’re tired can be a very effective way of staying alert throughout the day. Avoid napping for longer than 20 minutes, after which you will enter deep sleep and feel even worse when you wake up.

See a doctor if your problem continues

Ask us about FREE screening
Ask us about FREE screening:

If you have trouble falling asleep night after night, or if you always feel tired the next day, snore, or stop breathing during sleep you might have a sleep disorder. It is advisable to seek more advice from your doctor. Most sleep disorders can be treated effectively.

Where are Nitrates and Nitrites found?

Understanding the environmental fate of nitrates and nitrites may help pinpoint potential sources of exposure. This would be important in assessment of patient exposure risk, prevention and mitigation of nitrate / nitrite overexposure and in the prevention of adverse health effects from exposure.

Environmental Nitrogen Cycle

In general, the following describes the activity of nitrates and nitrites in the environment. Microbial action in soil or water decomposes wastes containing organic nitrogen into ammonia, which is then oxidized to nitrite and nitrate.

Environmental Nitrogen Cycle
Environmental Nitrogen Cycle
  • Because nitrite is easily oxidized to nitrate, nitrate is the compound predominantly found in groundwater and surface waters.
  • Contamination with nitrogen-containing fertilizers (e.g. potassium nitrate and ammonium nitrate), or animal or human organic wastes, can raise the concentration of nitrate in water.
  • Nitrate-containing compounds in the soil are generally water soluble and readily migrate with groundwater.

Water Contamination

Shallow, rural domestic wells are those most likely to be contaminated with nitrates, especially in areas where nitrogen-based fertilizers are widely used.

Water Contamination
Water Contamination
  • Approximately 15 percent of Americans rely on their own private drinking water supplies which are not subject to U.S. Environmental Protection Agency (EPA) standards, although some state and local governments do set guidelines to protect users of these wells.
  • In agricultural areas, nitrogen-based fertilizers are a major source of contamination for shallow groundwater aquifers that provide drinking water.
  • A recent United States Geological Survey study showed that 7 percent of 2,388 domestic wells and about 3 percent of 384 public-supply wells nationwide were contaminated with nitrate levels above the EPA drinking water standard of 10 parts per million (ppm) or 10 mg/L.
  • Elevated concentrations were most common in domestic wells that were shallow (less than 100 feet deep) and located in agricultural areas because of relatively large nitrogen sources, including septic systems, fertilizer use, and livestock.
  • Although suppliers of public water sources are required to monitor nitrate concentrations regularly, few private rural wells are routinely tested for nitrates.
  • During spring melt or drought conditions, both domestic wells and public water systems using surface water can show increased nitrate levels.
  • Drinking water contaminated by boiler fluid additives may also contain increased levels of nitrites.
  • Mixtures of nitrates / nitrites with other well contaminants such as pesticides and VOCs have been reported.

Food Contamination

Nitrate and nitrite overexposure has been reported via
ingestion of foods containing high levels of nitrates and nitrites. Inorganic nitrates and nitrites present in contaminated soil and water can be taken up by plants, especially green leafy vegetables and beet root.

Food Contamination Nitrate in Vegetables
Food Contamination Nitrate in Vegetables
  • Contaminated foodstuffs, prepared baby foods, and sausage / meats preserved with nitrates and nitrites have caused overexposure in children.
  • Although vegetables are seldom a source of acute toxicity in adults, they account for about 80% of the nitrates in a typical human diet.
  • Celery, spinach lettuce, red beetroot and other vegetables have naturally greater nitrate content than other plant foods do.
  • The remainder of the nitrate in a typical diet comes from drinking water (about 21%) and from meat and meat products (about 6%) in which sodium nitrate is used as a preservative and color- enhancing agent.
  • For infants who are bottle-fed, however, the major source of nitrate exposure is from contaminated drinking water used to dilute formula.
  • Bottled water is regulated by the U.S. Food and Drug Administration (FDA) as a food. It is monitored for nitrates, nitrites and total nitrates / nitrites.

Nitrate Content of Selected Vegetables

Vegetable Nitrate contentmg / 100g fresh weight
Celery, lettuce, red beetroot, spinach Very High (> 2500)
Parsley, leek, endive, Chinese cabbage, fennel High (100-250)
Cabbage, dill, turnip Medium (50-100)
Broccoli, carrot, cauliflower, cucumber, pumpkin Low (20-50)
Artichoke, asparagus, eggplant, garlic, onion, green bean, mushroom, pea, pepper, potato, summer squash, sweet potato, tomato, watermelon Very Low (<20)

Other Sources of Exposure

Nitrate or nitrite exposure can occur from certain medications and volatile nitrite inhalants.

Nitrate or nitrite exposure from certain medications
Nitrate or nitrite exposure from certain medications

Accidental and inadvertent exposures to nitrites as well as ingestion in suicide attempts have been reported.

Deliberate abuse of volatile nitrites (amyl, butyl, and isobutyl nitrites) frequently occurs. Amyl nitrite (nicknamed by some as “poppers”) is used commercially as a vasodilator and butyl / isobutyl nitrites can be found in products such as room air fresheners.

Fatalities have been reported in adults exposed to nitrates in burn therapy; however infants and children are especially susceptible to adverse health effects from exposure to topical silver nitrate used in burn therapy.

Other medications implicated in methemoglobinemia include:

  • Quinone derivatives (antimalarials),
  • Nitroglycerine,
  • Bismuth subnitrite (antidiarrheal),
  • Ammonium nitrate (diuretic),
  • Amyl and sodium nitrites (antidotes for cyanide and hydrogen sulfide poisoning),
  • Isosorbide dinitrate/tetranitrates (vasodilators used in coronary artery disease therapy),
  • Benzocaine (local anesthetic), and
  • Dapsone (antibiotic).

Other possible sources of exposure include ammonium nitrate found in cold packs and nitrous gases used in arc welding.

An ethyl nitrite folk remedy called “sweet spirits of nitre” has caused fatalities.

Key Points

  • Shallow, rural domestic wells are those most likely to be contaminated with nitrates, especially in areas where nitrogen based fertilizers are in widespread use.
  • Other nitrate sources in well water include seepage from septic sewer systems and animal wastes.
  • Foodstuffs high in nitrates, home prepared baby foods, and sausage/meats preserved with nitrates and nitrites have caused overexposure in children.
  • Nitrate or nitrite exposure can occur from certain medications and volatile nitrite inhalants.

About Sleep

Why do we sleep?

Sleep is a normal, indeed essential part of our lives. But if you think about it, it is such an odd thing to do.
At the end of each day we become unconscious and paralysed. Sleep made our ancestors vulnerable to attack from wild animals. So the potential risks of this process, which is universal among mammals and many other groups, must offer some sort of evolutionary advantage.
Research in this area was slow to take off. But recently there has been a series of intriguing results that are giving researchers a new insight into why we sleep and what happens when we do it.

Why do we sleep?
Why do we sleep?

Why do I sleep?

Scientists simply don’t know for sure. In broad terms researchers believe it is to enable our bodies and especially our brains to recover. Recently researchers have been able to find out some of the detailed processes involved.
During the day brain cells build connections with other parts of the brain as a result of new experiences. During sleep it seems that important connections are strengthened and unimportant ones are pruned. Experiments with sleep-deprived rats have shown that this process of strengthening and pruning happens mostly while they sleep.
And sleep is also an opportunity for the brain to be cleared of waste.
A group led by Prof Maiken Nedergaard at the University of Rochester Medical Centre in New York discovered a network of microscopic fluid-filled channels in rats that clears waste chemicals from the brain. Prof Nedergaard told us when her research was first published in 2013 that this process occurs mostly when the brain is shut off.
“You can think of it like having a house party. You can either entertain the guests or clean up the house, but you can’t really do both at the same time.”

Why do I sleep?
Why do I sleep?

What happens when I don’t get enough sleep?

It seems that a lack of sleep alters the way in which the genes in the body’s cells behave.
Researchers at Surrey University in Guildford have found that genes involved in inflammation seem to increase their activity. Dr Malcolm von Schantz, who is involved with the Surrey research, believes that the genes are responding to lack of sleep as if the body is under stress.
He speculates that in the distant past in times of stress our ancestors’ bodies would prepare themselves for injury by activating these inflammation genes which would cushion the effects of attacks by wild animals or human enemies.
“It puts the body on alert for a wound but no wound happens,” he told Sleep Advice.
“This could easily help explain the links between sleep deprivation and negative health outcomes such as heart disease and stroke.”
In modern times though preparing for an injury that never happens has no beneficial effect – in fact the consequent activation of the immune system might increase the risk of heart disease and stroke.

What happens when I don't get enough sleep?
What happens when I don’t get enough sleep?

Why is it hard to think when I am tired?

The expression “half asleep” might be an accurate description of what is going on in the brain when you are feeling slow-witted.
Research suggests that parts of the human brain may well be asleep when it is sleep-deprived. Studies on whales and dolphins show that when asleep they continue to use half of their brain to swim and come up to the surface for air.
A study on human patients showed that something similar goes on in our brains. As they became more sleep-deprived, parts of their brain became inactive while they were still awake.
What’s more the local sleep areas move around the brain. So although when we go to bed we think one moment we are awake and then there is an abrupt change to sleep – it may well be more of a continuous process.

Why is it hard to think when I am tired?
Why is it hard to think when I am tired?

What is the role of dreaming?

That’s a question that psychiatrists, notably Carl Jung and Sigmund Freud, have tried to answer but with limited success. More recently a team at the ATR Computational Neuroscience Laboratories in Kyoto in Japan has begun trying to answer some of these questions by building the beginnings of a dream-reading machine.
They asked volunteers to doze off in an MRI scanner and recorded their brain patterns. The volunteers were then woken up and asked to tell researchers what they were dreaming about.
The team then listed 20 separate categories of dream content from these accounts such as dwelling, street, male, female, building or computer screen. The researchers then compared the accounts with the pattern of activity in the area of the brain responsible for processing visual information – and to their amazement they found that there was a correlation. So much so that they could predict which of the 20 different categories they had listed the patient had dreamt of with 80% accuracy.
The device is a very rough tool but it may well be a first step to something that can see in more detail what happens in our dreams and so help researchers learn more about why we dream.

What is the role of dreaming?
What is the role of dreaming?

How is modern life affecting our sleep patterns?

Several studies show that the light bulb has led people shifting their day and getting less sleep. On average we go to bed and wake up two hours later than a generation ago.
The US Centres for Disease Control reported in 2008 that around a third of working adults in the US get less than six hours sleep a night, which is 10 times more than it was 50 years ago. In a later study it was also reported that nearly half of all the country’s shift workers were getting less than six hours sleep.
And a study led by Prof Charles Czeisler of Harvard Medical School found that those who read electronic books before they went to bed took longer to get to sleep, had reduced levels of melatonin (the hormone that regulates the body’s internal body clock) and were less alert in the morning.
At the time of publication he said: “In the past 50 years, there has been a decline in average sleep duration and quality.
“Since more people are choosing electronic devices for reading, communication and entertainment, particularly children and adolescents who already experience significant sleep loss, epidemiological research evaluating the long-term consequences of these devices on health and safety is urgently needed.”

How is modern life affecting our sleep patterns?
How is modern life affecting our sleep patterns?

What’s stopping you sleeping?

– One in eight of us keep our mobile phones switched on in our bedroom at night, increasing the risk our sleep will be disturbed.

Mobile Phones - stopping you sleeping
Mobile Phones – stopping you sleeping

– Foods such as bacon, cheese, nuts and red wine, can also keep us awake at night.

Bacon, Cheese, Nuts, Red Wine - stopping you sleeping
Bacon, Cheese, Nuts, Red Wine – stopping you sleeping

Many studies report that there is evidence that sleep loss is associated with obesity, diabetes, depression and lower life expectancy – while others, such as Prof James Horne, a sleep researcher at Loughborough University believes that such talk amounts to “scaremongering”.
“Despite being ‘statistically significant’, the actual changes are probably too small to be of real clinical interest,” he told Sleep Advice. “Most healthy adults sleep fewer than that notional ‘eight hours’ and the same went for our grandparents.
“Our average sleep has fallen by less than 10 minutes over the last 50 years. Any obesity and its health consequences attributable to short sleep are only seen in those few people sleeping around five hours, where weight gain is small – around 1.5kg per year – which is more easily rectified by a better diet and 15 minutes of daily brisk walking, rather than by an hour or so of extra daily sleep.”
A team from the universities of Surrey and Sao Paulo in Brazil have spent the past 10 years tracking the health of the inhabitants of Bapendi, a small town in Brazil where modern day lifestyles haven’t yet taken hold.
Many of the inhabitants of this town get up and go to bed early. The investigators hope to find out soon whether the old adage “early to bed and early to rise” really does make us, if not “wealthy and wise”, at least “healthy and wise”.

What are Nitrates and Nitrites?

Nitrates and nitrites can be categorized into inorganic and organic forms based on their chemical structure.
There are similarities and differences between these two chemical forms that affect their pharmacokinetic and pharmacodynamic properties and their subsequent biologic effects in humans. This artical  will focus on inorganic nitrates.

Inorganic Nitrates and Nitrites

Inorganic nitrate (NO3–) and nitrite (NO2–) are water soluble (as a result of their interaction with the positively charged portions of polar water molecules)

Structures of Nitrate and Nitrite Ions
Structures of Nitrate and Nitrite Ions

and commonly exist as salts of nitric acid and nitrous acid, respectively. They are often bound to a metal cation such as Na+ or K+ and occur naturally through the fixation of atmospheric nitrogen and oxygen as part of the environmental nitrogen cycle (the cyclic movement of nitrogen in different chemical forms from the environment, to organisms, and then back to the environment as illustrated).

Environmental Nitrogen Cycle
Environmental Nitrogen Cycle

Inorganic nitrites are also produced endogenously through oxidation of nitrous oxide (NO) formed from the enzymatic degradation of L-arginine and through the reduction of nitrate with xanthine oxidoreductase.

Organic Nitrates and Nitrites

The organic forms of nitrates and nitrites are more complex and most are synthesized medicinal products (except ethyl nitrite). Organic nitrates are small non-polar hydrocarbon chains attached to a nitrooxy-radical (-ONO2; -ONO for amyl and ethyl nitrite). The addition of aliphatic or aromatic groups of variable length and volume affect the lipophilic properties of these molecules. It has been suggested that for some molecules, the greater the number of –ONO2 groups, the greater its potency; (the potency being dependent on the molecule’s lipophilicity).

Key Points

  • Nitrates and Nitrites exist in organic and inorganic
    forms.
  • The chemical form affects the pharmacokinetic and
    pharmacodynamic properties of nitrates and
    nitrates.
  • Inorganic nitrates and nitrites are generally more
    water soluble than organic nitrates and nitrates.
  • Inorganic nitrates and nitrites are produced
    endogenously and exogenously.
  • Organic nitrates and nitrites are mostly synthesized
    medicinal products.
  • Organic nitrates and nitrites are generally more
    complex and lipophilic than inorganic nitrates and nitrites.