Kroger Vitamin C Chewable

Kroger Vitamin C Chewable

Photo Courtesy: Dougal Waters/DigitalVision/Getty Images

Vitamin E is a compound that plays many important roles in your body and provides multiple health benefits. In order to maintain healthy levels of vitamin E, you need to ingest it through food or consume it as an oral supplement. Read on to find out which foods are recommended sources of this essential nutrient, along with other basics to know about vitamin E.

Vitamin E is classified as an antioxidant. This means that vitamin E helps to destroy harmful compounds called free radicals that can build up in your body. Free radicals cause damage to cells through oxidative stress, and they've been linked to aging and health problems such as cancer and heart disease. Getting enough vitamin E on a daily basis may help to combat these conditions by protecting the outer membranes of your cells from free radical damage.

Photo Courtesy: Leren Lu/Photodisc/Getty Images

Vitamin E also plays an important role in your immune system and your body's ability to fight infection. At certain doses, vitamin E has been shown to stimulate the function of T cells — a type of cell that responds to pathogens that cause disease. Recent studies have shown that increasing your vitamin E intake may correlate with a stronger immune response and greater resistance to infection.

Vitamin E is present in the following whole foods:

  • Wheat germ
  • Almonds
  • Plant oils (vegetable, sunflower, grapeseed, etc.)
  • Sunflower seeds
  • Peanut butter
  • Spinach
  • Broccoli
  • Kiwi
  • Mango

Daily Dosage Recommendations

As people age, their daily dosage recommendation for vitamin E increases. For these standard recommended daily doses, a healthy balanced diet is usually sufficient for getting the required amount of vitamin E:

Photo Courtesy: skynesher/E+/Getty Images
  • Birth to 6 months: 4 milligrams (mg)/day
  • 1 to 12 months: 5 mg/day
  • 1 to 3 years: 6mg/day
  • 4 to 8 years: 7mg/day
  • 9 to 13 years: 11mg/day
  • 14+ years, including adults and seniors: 15mg/day

A person's age, gender and health conditions can help determine their recommended daily dose of vitamin E. Always consult a healthcare professional before altering your intake of vitamin E from the recommended daily dosage.

Taking Vitamin E Supplements

If it becomes necessary, such as if you become deficient in vitamin E, your doctor may advise you to start taking vitamin E supplements. Vitamin E supplements may come with some minor side effects if you take more than the recommended daily amount or if you combine these supplements with certain medications.

Photo Courtesy: Moyo Studio/E+/Getty Images

For example, vitamin E may increase the risk of bleeding if you take it with anticoagulants (also called blood thinners) like warfarin. Other medications, like chemotherapy drugs and cholesterol-lowering drugs, have potential harmful interactions when combined with vitamin E supplements. Talk to a healthcare professional before introducing daily vitamin E supplements, and be sure to discuss current medications you're taking.

Signs of a Vitamin E Deficiency

Because most people are able to get a sufficient amount of vitamin E through their normal daily diet, vitamin E deficiency is rare and typically related to an underlying health issue. For example, because vitamin E is a fat-soluble nutrient, there's a risk for vitamin E deficiency in people whose bodies are unable to absorb fat properly. Premature infants may also become deficient in vitamin E.

Photo Courtesy: LaylaBird/E+/Getty Images

When vitamin E deficiency does occur, these are some of its common symptoms:

  • Muscle weakness
  • Unsteady gait
  • Nerve pain or numbness
  • Impaired vision

Vitamin E deficiency can be detected with a blood test. It typically resolves with minor changes in your diet or the addition of vitamin E supplements. It's important to address any out-of-range vitamin E levels with your doctor. Chronic deficiencies may prevent your immune system from functioning normally.

Resource Links:

https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/

https://medlineplus.gov/vitamine.html

https://reader.elsevier.com/reader/sd/pii/S0032579119309897?token=FECB039E3D3637A000648C32AE675FBC7DC9866130E4593853DCEBEFE0BEDCF4C0CA144BFF3E8EB55E81DF3922EB0743

https://www.mdpi.com/2072-6643/10/11/1614/htm

https://iubmb.onlinelibrary.wiley.com/doi/epdf/10.1002/iub.1976

MORE FROM SYMPTOMFIND.COM

Kroger Vitamin C Chewable

Source: https://www.symptomfind.com/health/vitamin-e-nutrition-basics?utm_content=params%3Ao%3D740013%26ad%3DdirN%26qo%3DserpIndex

Share:

Is Taking Vitamin C Bad For You

Is Taking Vitamin C Bad For You

  • Vitamin C Benefits
    • What is vitamin C and what is its role in your body?
  • Foods Containing Vitamin C
    • Which foods contain vitamin C?
  • Vitamin C Deficiency Symptoms
    • What happens if you have low levels of vitamin C in your body?
  • Center
    • Why Is Too Much Vitamin C Bad for You? Center

too much of vitamin c

Side effects of taking too much vitamin C can include diarrhea, nausea, heartburn, and stomach cramps.

Too much vitamin C is bad for you because it can cause side effects and symptoms such as diarrhea, nausea, heartburn, and stomach cramps. If you have a medical condition in which iron gets deposited in various organs of your body (hemochromatosis), taking too much vitamin C can complicate the condition.

Other conditions in which excessive amounts of vitamin C can result in negative side effects include:

  • Chronic kidney disease: Excessive levels of oxalate in the urine due to consumption of vitamin C supplements may be a problem for people with kidney disease due to an increased risk of kidney failure.
  • Kidney stones: If you develop kidney stones, it is better to avoid taking vitamin C supplements unless advised by your doctor. High levels of vitamin C can increase the risk of kidney stones.
  • Glucose-6-phosphate dehydrogenase deficiency (a metabolic deficiency): People with this condition may develop broken red blood cells when they consume a large amount of vitamin C.

It is unlikely that you will consume too much vitamin C from your diet. Doctors recommend that adults should get 65 to 90 mg of vitamin C per day. Excess vitamin C is removed from your body through urination. However, you still need to make sure you do not consume more than the tolerable upper limit, which is 2,000 mg in a day.

Problems of taking too much vitamin C are more likely to occur from consuming too many vitamin C supplements.

What is vitamin C and what is its role in your body?

Vitamin C, also known as ascorbic acid, is a water-soluble vitamin that naturally occurs in foods.

It serves the following functions in the body:

  • Produces collagen: Collagen is a protein that plays a vital role in the healing of wounds.
  • Enhances iron absorption: Having an adequate amount of vitamin C in your diet ensures that iron from plant-based foods is absorbed well into the body.
  • Antioxidant: Antioxidants are substances that protect cells from damage caused by free radicals and improve immunity. Free radicals are compounds that are formed out of the oxidation process, which causes various diseases including diabetes, heart disease, and cancer.

Which foods contain vitamin C?

Vitamin C is found in abundance in fruits and vegetables, such as:

  • Citrus fruits
    • Oranges
    • Grapefruit
    • Limes
  • Red and green pepper
  • Kiwifruit
  • Strawberries
  • Broccoli
  • Cantaloupe
  • Tomatoes
  • Baked potatoes

Moreover, you will also find foods and drinks that have been fortified with vitamin C, which you can verify by checking food labels.

Most people will get the required amount of vitamin C from an orange or a cup of strawberries, chopped red pepper, or broccoli.

What happens if you have low levels of vitamin C in your body?

Low levels of vitamin C in the body (vitamin C deficiency) are rare in the United States. However, you should remember to consume foods that contain vitamin C daily because the vitamin does not get stored in the body and is excreted daily through urine. A condition known as scurvy can result only when you intake little or no vitamin C for many weeks.

Signs and symptoms of scurvy include:

  • Swollen and red gums
  • Bleeding from the gums
  • Fatigue
  • Poor wound healing
  • Muscle pain
  • Joint pain
  • Petechiae (small red or purple spots on the skin)
  • Joint pain
  • Anemia
  • Corkscrew hair
  • Loss of teeth
  • Depression

Conditions that can lower vitamin C levels in your body include:

  • Tobacco intake: Smoking and chewing tobacco lower the vitamin C level in your body.
  • Alcohol use disorder: People who drink alcohol frequently and in excessive amounts and have alcohol addiction often have a vitamin C deficiency.
  • Chronic kidney disease: Chronic kidney disease might increase your odds of developing vitamin C deficiency.

SLIDESHOW

Vitamin D Deficiency: How Much Vitamin D Is Enough? See Slideshow

Medically Reviewed on 9/20/2021

References

Vitamin Toxicity Clinical Presentation. https://emedicine.medscape.com/article/819426-clinical#b1

Is it possible to take too much vitamin C? https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/expert-answers/vitamin-c/faq-20058030

Is Taking Vitamin C Bad For You

Source: https://www.medicinenet.com/why_is_too_much_vitamin_c_bad_for_you/article.htm

Share:

How Many Vitamin C Can I Take In A Day

How Many Vitamin C Can I Take In A Day

9ed95495-7055-46a9-b3e4-57cef5c1dd2b

Q.  I'm 79 years old and have been taking 3,000 mg of vitamin C a day for years. I'm now uneasy about taking this amount and plan to cut back to 1,000 mg daily. Is this the right vitamin c dose? Will my body be startled by the abrupt change?

A.  Cutting back on daily vitamin C is a wise decision. You've been taking much more vitamin C than you need.

Vitamin C, or ascorbic acid, plays a role in many vital functions, including metabolism and immunity. We can't make vitamin C in the body, so we need to get it from dietary sources. It's found in high concentrations in many fresh fruits and vegetables (see the chart); it's also available in most multivitamins and as a single-ingredient supplement.

Food sources of vitamin C

Food (serving size)

Vitamin C (mg)

Guava (1 medium)

165

Strawberries (1 cup)

98

Cantaloupe (¼ medium)

95

Papaya (1 medium)

95

Bell pepper, red, raw (½ cup)

95

Orange juice (¾ cup)

60

Kale (1 cup, cooked)

53

Broccoli (½ cup, cooked)

50

Bell pepper, green, raw (½ cup)

45

Tomato juice (1 cup)

45

Mango (1 medium)

30

Lemon juice (½ cup)

30

In large population studies, people who eat lots of fruits and vegetables high in vitamin C appear to have a reduced risk for various types of cancer, including cancers of the mouth, esophagus, stomach, colon, and lung. But it's not clear that these benefits come specifically from vitamin C. The Age-Related Eye Disease Study found that a daily supplement containing 500 milligrams (mg) of vitamin C, 400 international units (IU) of vitamin E, 15 mg of beta carotene, 80 mg of zinc, and 2 mg of copper can help slow the progression of macular degeneration, an age-related eye disease that causes vision loss. But we don't know what benefits, if any, are conferred by vitamin C in particular.

Many people take vitamin C supplements in unnecessarily high doses to prevent or treat various conditions for which its effectiveness is unproved. The vitamin C supplements have variously been touted for preventing cardiovascular disease and osteoarthritis, staving off sunburn, and improving the appearance of wrinkles. None of these purported benefits have been verified in scientific studies.

Perhaps the best-known and most widely promoted use of high-dose vitamin C is to prevent or treat the common cold. The bulk of the evidence shows that high-dose vitamin C will, at most, shorten a cold by one day. In ordinary circumstances, vitamin C appears to have no preventive value, although a few studies have reported a 50% reduced risk of developing colds among people taking vitamin C in extreme circumstances — for example, skiers, marathon runners, and soldiers working in sub-Arctic conditions.

The recommended vitamin C dosage per day for healthy women is 75 mg per day (120 mg per day for women who are pregnant or breastfeeding). For adults, the tolerable upper intake level (UL) — the highest daily intake likely to pose no risks — is 2,000 mg per day.

Vitamin C is water-soluble, so any excess is usually excreted in the urine rather than stored in the body. It's safe in almost any amount from foods, and supplements in recommended amounts are also regarded as safe for most people. In some people, high doses — more than, say, 2,000 or 3,000 mg per day — can cause symptoms such as diarrhea, nausea, heartburn, gastritis, fatigue, flushing, headache, and insomnia. People with chronic liver or kidney conditions, gout, or a history of calcium-oxalate kidney stones should take no more than 1,000 mg a day.

Image: czekma13/Getty Images

As a service to our readers, Harvard Health Publishing provides access to our library of archived content. Please note the date of last review or update on all articles. No content on this site, regardless of date, should ever be used as a substitute for direct medical advice from your doctor or other qualified clinician.

How Many Vitamin C Can I Take In A Day

Source: https://www.health.harvard.edu/staying-healthy/by-the-way-doctor-whats-the-right-amount-of-vitamin-c-for-me

Share:

Grapefruit And Vitamin C

Grapefruit And Vitamin C

White, yellow, pink, or red, grapefruits have a variety of health benefits that make them not quite like any other fruit.

Why choose grapefruit?

Grapefruits_AdobeStock_87991432

Grapefruit can seem like an acquired taste. Their bulbous size, bitter pith (the white stuff that surrounds the fruit), and tart taste can be off-putting to those who are more accustomed to their sweeter citrus cousins.

But it might do your health some good if you consider adding this superfood to your regular rotation of healthy foods. It's among the 20 best foods to eat for breakfast. And you don't have to limit your intake to the early morning hours: Grapefruit are supremely portable and make a great snack (with very few calories) that fills you up while also relieving thirst due to its high water content.

Here, experts weigh in on why you should start buying more of the tangy citrus fruit, due to its health benefits.

RELATED: Raw Kale, Grapefruit, and Toasted Hazelnut Salad

Advertisement

Advertisement

Grapefruit contains a lot of water

They're hydrating

Credit: Getty Images

At about 92% water, grapefruit has one of the highest water contents of any fruit. That makes it good for overall health.

"All of our body systems and process . . . require water," Wesley Delbridge, RD, a Phoenix-based dietitian, tells Health. "Proper hydration makes your body more efficient in everything you're doing."

About 20% of your daily fluid intake actually comes from food. So add some grapefruit to get closer to your daily H2O goal and choose the heavier of two fruits of equal size: It has more juice.

RELATED: Grapefruit and Avocado Salad With Seared Salmon

Grapefruit may speed weight loss

grapefruit-weight-loss-speedy

Credit: Getty Images

Several studies have shown that people who eat half a fresh grapefruit or drink grapefruit juice before each meal lose more weight than people who do not.

Not all studies have shown the same weight-loss benefit and scientists don't know if the effect seen in the studies was specifically due to grapefruit—or filling up on a low-calorie food in general—but fruits and vegetables should always be part of your strategy to lose or maintain weight.

What is 100% ironclad fact: Grapefruit delivers a lot of nutrition and water for very few calories: there are just 39 calories in one half of a grapefruit. So it's a great choice if you want to boost your intake of high nutrient, low calorie foods.

RELATED:Can Grapefruit Really Make You Slim?

Advertisement

Even the pith is good for you

grapefruit-pith-good

Credit: Getty Images

When you peel away the outer layer of a grapefruit, you may be tempted to pick off the white flesh that is between you and the juicy fruit, and throw it away. This stuff is called pith. Don't do it.

"That [pith] is very rich in antioxidants and nutrients and also soluble fiber which is going to help you feel fuller and impact your glucose reactions," says Delbridge.

While the pith of grapefruit can have more of a bitter taste than say, oranges, it's worth eating along with the fruit (if you can). Fiber is a good thing, and can help lower blood sugar, cholesterol, and possibly even colon cancer risk.

RELATED: The Grapefruit Diet

Grapefruit can help lower "bad" cholesterol

grapefruit-low-cholesterol

Credit: Getty Images

A grapefruit a day may help lower "bad" LDL cholesterol levels by as much as 15.5%, according to a 2006 study in theJournal of Agricultural and Food Chemistry. In the study, researchers looked at 57 patients ages 39 to 72 who had high cholesterol and had undergone bypass surgery for heart trouble. For one month, some ate a grapefruit daily (either red or white) while others, the control group, did not. Grapefruit eaters, particularly those eating red, had a drop in bad cholesterol, while the control group did not.

This is great news for your heart. LDL cholesterol is a type of fat that can build up in your arteries and raise the risk for heart attack and stroke. But if you are taking a cholesterol-lowering drug, don't add a grapefruit for extra effect—the FDA issued a warning in 2012 about interactions with such medications.

RELATED: Beyond Guacamole: Vitamin-Rich Grapefruit-Avocado Salad

Grapefruit may help pump up your immune system

grapefruit-immune-system

Credit: Getty Images

That's because of the hefty dose of vitamins A and C in each serving. "Vitamin C and A are huge as far as immune boosting," says Delbridge.

Some research indicates that not having enough vitamin C (and other micronutrients) may actually hurt your immune system, especially if you're elderly.

Grapefruit may not prevent a cold but the vitamins inside may reduce your suffering or possibly the duration of a cold.

"There's nothing else you can do for a cold so why not?" says Ann Marie Chiasson, MD, assistant director of the Fellowship in Integrative Medicine at the University of Arizona College of Medicine in Tucson.

RELATED: 6 Foods to Eat to Help Prevent the Flu

Advertisement

Advertisement

Grapefruit can lower triglyceride levels

grapefruit-triglycerides

Credit: Getty Images

There's another reason grapefruit can be good for your heart: It reduces levels of triglycerides, another type of fat—like "bad" LDL cholesterol—which can quickly clog up your arteries.

The same study that found that adding one grapefruit a day lowered cholesterol levels also found that this simple daily regimen lowered triglycerides—by as much as 27%. This was in patients who already had coronary artery disease and so were at high risk for heart attacks and other complications.

Red grapefruit, in particular, surpassed its "blond" cousins in lowering triglycerides.

RELATED: Eat This to Lower Cancer Risks

Grapefruit can lower blood pressure

grapefruit-blood-pressure

Credit: Getty Images

"Grapefruit has got some data that it decreases systolic blood pressure, not by a lot—it's usually about five points—but there's definitely good data," says Chiasson. And for the 70 million Americans who have hypertension, any drop in blood pressure is a good drop.

The effect on blood pressure may be due to grapefruit's high potassium levels. Potassium neutralizes the negative effects of sodium.  (Here are 15 foods that are high in potassium.)

But again, don't eat grapefruit if you are already taking a blood-pressure lowering drug. Certain ones, such as Procardia and Adalat CC (both are from the generic nifedipine), can be dangerous when combined with grapefruit, according to the FDA.

RELATED: Risks and Symptoms of High Blood Pressure

The redder, the better

grapefruit-color-matters

Credit: Getty Images

All the grapefruit colors are packed with goodness, vitamins, and nutrients but the red and pink ones come with a little extra.

"They have a higher antioxidant level, specifically beta carotene," says Delbridge. "They also have lycopene, another antioxidant."

Lycopene is one of a group of carotenoids or pigments that gives hued grapefruit (and other fruits and vegetables) their color. Eating diets rich in carotenoids may lower the risk of heart disease and some cancers.

Antioxidants in general may play a key role in preventing cancer.

RELATED: 12 Ways to Eat More Colorful Fruits and Vegetables

Advertisement

Grapefruit may help control blood sugar

grapefruit-blood-sugar

Credit: Getty Images

Grapefruit also has a low glycemic index (GI), around 25, which means it doesn't raise blood sugar as quickly or as much as high-GI foods like white bagel (72) or even a banana (48) or watermelon (72).  (The highest GI score is 100.)

A 2006 study published in the Journal of Medicinal Food, found that people who ate grapefruit (juice or half a fruit) before a meal had a lower spike in insulin two hours later than those taking a placebo, and fresh grapefruit was associated with less insulin resistance.  All 91 patients in the 12-week study were obese, but they did not necessarily have type 2 diabetes.

While the results are promising in those without diabetes, blood-sugar reactions to food can vary widely, so if you have been diagnosed with type 2 diabetes, test your blood sugar after eating grapefruit to make sure it can be part of your healthy eating plan.

RELATED: 7 Ways to Make Blood-Sugar Testing Less Painful

The fruit is better than the juice

grapefruit-juice-good-fruit-better

Credit: Getty Images

Grapefruit juice has plenty of benefits, but the traditional fruit itself is going to give you more bang for your buck when it comes to nutrition and health benefits.

"When you take juice, you're getting some of the nutrients but you're losing all the fiber," says Delbridge. "Grapefruit juice is great but at the end of the day, the entire fruit has pectin and rind and all the parts of it."

Grapefruit juice can also spike your blood sugar more than the fruit itself. If you opt for juice of any kind, Delbridge recommends not drinking more than 6 ounces a day and going only for 100% juice products that don't have added sugar.

RELATED: Bethenny's Pink Grapefruit Spritzer

Grapefruit may speed wound healing

grapefruit-speedy-healing

Credit: Getty Images

Vitamin C helps form healthy scar tissue and new blood vessels, both of which help return your body to a healthy state. A grapefruit contains about 72 mg of vitamin C, which is 120% of the daily value.

"Vitamin C speeds up wound healing post surgically," says Chiasson. "I tell people to take 500 milligrams of vitamin C before they go into surgery."

Always ask your doctor before adding vitamins, minerals, or any herbal supplements to your daily regimen, especially if you're about to have surgery.  In this case, that goes for grapefruit too, given its ability to affect the metabolism of certain drugs.

RELATED: The Healing Power of Tea

Advertisement

Grapefruit may even help prevent cancer

grapefruit-prevents-cancer

Credit: Getty Images

A large study conducted in Japan found that people who ate citrus (including grapefruit) throughout the week had a lower risk of developing cancer, especially prostate and pancreatic, compared with the total group of participants.

The effect was amplified among those who also drank a lot green tea.

The authors speculate that compounds in citrus fruits reduce inflammation and stop cancer cells from multiplying. They may also help repair damaged DNA, which contributes to the development of tumors.

The fiber in grapefruit may also help prevent colorectal cancer while fruits high in vitamin C and beta-carotene, which is in pink and red grapefruit, may lower the risk of esophageal cancer.

RELATED: 6 Foods to Eat to Help Prevent the Flu

They can be stored in your fridge, or on the shelf

grapefruit-room-temperature

Credit: Getty Images

Grapefruit can be stored in your fridge for as long as three weeks but they release their best flavor when kept at room temperature. If you plan to eat them within a week, leave them on a counter or table.

There's an added advantage to keeping them in plain view.

"The increased visibility helps you remind yourself that you need to eat them," says Delbridge. "Studies show that when you put fruits and vegetables out in a bowl or common area of the house, you will eat more."

If you don't think you will eat the grapefruit for 2 or 3 weeks, tuck them in the fridge but make sure they're at room temperature before you actually dig in. This will give you maximum flavor.

RELATED: Pink Grapefruit Cupcakes

You can make a meal out of grapefruit

grapefruit-main-course

Credit: Getty Images

Grapefruit is most often associated with breakfast, but don't let that limit your imagination.

Grapefruit is also super in salads and with fish or chicken. In fact, it's best when paired with protein and a little fat, like a handful of walnuts.

"If it's paired with proteins and fats, it will delay your gastric emptying so you'll feel full longer," says Delbridge. The fiber, too, keeps you feeling fuller longer.

RELATED: Grapefruit Elderflower Cooler

Advertisement

Grapefruit may have more vitamin A than an orange

They're good for your heart

Credit: Getty Images

One-half of one grapefruit contains 28% of your daily value of vitamin A (based on a 2000-calorie daily intake), or far more than the 4% in oranges, says Delbridge. This first vitamin in the alphabet is good for your eyes, not to mention your heart, lungs, kidneys and other organs.

What's more, you also get 64% of your vitamin C, 8% of your fiber, a bit of calcium (3%) and iron (1%), and you start to understand why it's called a superfood. (For more comparisons, read "12 Foods That Have More Vitamin C Than an Orange.") Why eat a half a grapefruit when you can eat a whole one?

RELATED: 9 Healthy Salad Dressing Recipes

You can drink it in beer form

grapefruit-beer

Credit: Getty Images

If you find the fruit itself to be too tart, try a grapefruit-flavored beverage: There are a bevy of products—including grapefruit-flavored beer—that might be more palatable to you.

Because citrus pairs well with beer, there are plenty of orange and lemon flavored beers, but grapefruit is the a newer flavor in the brewing world: A few examples include Pink Fuzz, Grapefruit Shandy, and Turtle Power Grapefruit Pale Ale.

RELATED: How to Make an Immune Booster Juice

The scent alone can give you a boost

They're packed with potassium

Credit: Getty Images

Citrus scents are becoming more popular in aromatherapy for a reason. "Citrus is really amazing for increased energy and vitality," says Chiasson. "It will wake people up."

Not all aromatherapy is inhaled. You can also rub an essential oil on your skin, which allows you to feel it and inhale it at the same time. Grapefruit aromatherapy may even act as a natural skin toner, says Chiasson.

To get our top stories delivered to your inbox, sign up for the Healthy Living  newsletter

Advertisement

Up Next

Grapefruit And Vitamin C

Source: https://www.health.com/food/grapefruit-facts

Share:

Fat Soluble Vitamin C Foods

Fat Soluble Vitamin C Foods

Foods high in vitamin C have long been hailed as immunity-boosting powerhouses and essential for inclusion in your day-to-day diet. According to the Office of Dietary Supplements, vitamin C is vital to protect against illness and disease as, in the body, it acts as an antioxidant helping to protect cells from the damage caused by free radicals.

What is vitamin C?

Also known as ascorbic acid or nicknamed 'the immunity vitamin', the water-soluble nutrient is most commonly found in fruit and veg.

What does vitamin C do?

Vitamin C has a number of purposes in the body, explains nutritional therapist Paula Werrett. 'It acts as an antioxidant, helping to protect cells from free radicals created through normal energy production and ingested through foods and from sunlight and pollution in the environment.'

And that's not all. 'The body also requires vitamin C to produce collagen, a protein needed for the maintenance of health for bones, cartilage, gums, teeth and skin to help wounds heal. Finally, vitamin C is also extremely important to help with the absorption of iron-rich foods and helps the immune system to manage the disease', she shares. Not bad.

Ensuring you absorb enough iron from your diet is especially important if you exercise regularly. Working on the reg although good for you can actually contribute to iron deficiency, so giving your body a helping hand if you're a fan of a good sweat sesh definitely won't do any harm.

What else is vitamin C good for?

Vitamin C is also needed to prevent deficiency diseases such as scurvy, and is helpful for the maintenance of good energy and metabolism and for healthy skin, cartilage, bones and teeth, she expands.

But it is also relevant to coronavirus . 'Vitamin C has been shown to help shorten the length and severity of respiratory infections, such as colds.' This means, in short, that eating enough regularly can can help you bounce back from common cold and flu symptoms more quickly, she explains.

So what's the link between vitamin C and Coronavirus?

Doctor Aragona Giuseppe, GP and medical advisor at Prescription Doctor, says it's important to clarify the vit C's role in dealing with COVID-19: 'There is no medical or scientific evidence to suggest that a certain food or supplement can help prevent a person catching COVID-19'.

vitamin c foods vegetables

yulkapopkova

Dr Giuseppe explains that because vitamin C is well-known as an immunity boosting vitamin many people assume that it can help fight off coronavirus. 'While vitamin C could help to reduce or get rid of any symptoms, there is no evidence to suggest that vitamin C alone will fight off the virus. Every body is different and is being affected by the virus differently', he continues.

There is no evidence to suggest that vitamin C alone will fight off the virus

However, Heather Rosa (@IONHRosa), the Dean of the Institute for Optimum Nutrition, disagrees, sharing that a study suggests early and high intravenous doses of Vitamin C could help to fight the coronavirus disease. 'A recent Medicine in Drug Discovery study led by Virginia Commonwealth University found that patients who received intravenous vitamin C spent significantly fewer days in intensive care and hospital overall. On average, the vitamin C group spent three fewer days in the ICU and a week less in the hospital overall.'

vitamin c foods closeup of a cheerful young couple picking some fruit and veggies from the fridge to make some healthy breakfast on sunday morning shot from inside the working fridge

gilaxia

Plus, she shares that a group of hospitals in New York are treating their most critical COVID-19 patients with high doses of vitamin C.

Only time will tell the true impact vitamin C can have on the virus as scientists, doctors and experts continue to work towards a vaccine and potential counters. Whatever the effect of the vitamin, Giuseppe advises listening to government guidelines, staying at home and making a few small lifestyle tweaks, if you don't already do these things, to ensure you keep yourself (and your immune system) in tip top shape.

  • Eat plenty of nutrient dense foods (Giuseppe advises fruit, fish, healthy oils, protein and vegetables)
  • Stay hydrated with eight glasses of water a day
  • Get moving and use your hour a day outside wisely
  • Be mindful of your alcohol intake
  • Maximise your sleep and aim for eight hours a night (if you're struggling with this, read our guide to clean sleeping).

    However, experts do maintain that eating a diet high in antioxidants and whole, non-processed foods generally will support bodily functioning and, in turn, potentially assist your immune system in fighting off viruses.

    How much vitamin C do I need per day?

    'The NHS recommends we get 40 mg a day', says Rosa. 'Anything more than 1,000 mg a day and you may experience stomach pain and diarrhoea', she warns.

    The World Health Organisation guidelines state similar, recommending 45mg of vitamin C per day or 300mg per week from your diet.

    To put that into context, a small orange contains around 51g of vitamin C. You know what they say—an orange a day…

    However, Werrett believes that the sky is the limit with vitamin C consumption—within reason. 'The RDA of 40mg is the minimum amount you need to consume to prevent deficiency disease, such as scurvy. Much higher levels, however, may be optimal, with the Department of Health and Social Care suggesting up to 1,000mg daily for adults is unlikely to cause harm. Recent research trials show that still larger doses of 3,000 to 5,000mg a day (or even higher) may be needed for optimal effects in protection against viruses.'

    What are the best vitamin C foods?

    As mentioned, vitamin C is found predominantly in plants, with oranges the most well known natural source.

    • Acerola cherries
    • Blackcurrants
    • Broccoli
    • Brussel Sprouts
    • Chilli peppers
    • Guavas
    • Kale
    • Kiwis
    • Kakadu plum
    • Lemons
    • Lychees
    • Mustard
    • Oranges
    • Papayas
    • Parsley
    • Red peppers
    • Spinach
    • Strawberries
    • Sweet yellow peppers
    • Thyme

      As you can see while oranges are high in vit C, they're not the only fruit or veg.

      What is the best source of vitamin C?

      Fun fact: 100g of red pepper has 4.5 times the amount of vitamin C than an orange and a certain type of plum has over ten times. Scroll to see how 100g of orange stacks up against 100g of its rivals, in order from the highest:

      • Kakadu plum - 7000 mg per 100g veg
      • Red Peppers - 242.5 mg per 100g veg
      • Kale - 120 mg per 100g veg
      • Kiwi - 92.7 mg per 100g veg
      • Broccoli - 89.2 mg per 100g veg
      • Brussels Sprouts - 85 mg per 100g veg
      • Strawberries - 58.8 mg per 100g veg
      • Orange - 53.2 mg1 per 100g veg.

        Can you overdose on Vitamin C?

        Generally speaking, no, although if you consume too much, the majority will be excreted in your urine, shares nutritionist Lily Soutter (@lily_soutter_nutrition). 'You may also experience symptoms such as stomach pain, diarrhoea and flatulence if you ingest 1g per day or more.'

        Plus, Rosa stressed that high doses of ascorbic acid (vitamin C) can wear away tooth enamel. She recommends washing your mouth out with a little water after consumption.

        If you have type 1 diabetes, G6DP deficiency or hyperoxaluria, Rosa also advises that consuming too much vitamin C could be damaging or detrimental for reasons independent to each condition.

        Keen to read up on vitamin C skincare and how it could perk up your skin? You're in the right place—read the WH guide to learn more about that.

        Should I take a vitamin C supplement?

        'Eating a healthy diet including plenty of Vitamin C rich foods is important for overall health. Extra vitamin C from supplements, however, may be needed to support the immune system further at times of stress or to further optimise the immune system,' shares Werrett. Essentially, you should consider your exercise levels, exposure to pollution and general diet.

        This content is imported from {embed-name}. You may be able to find the same content in another format, or you may be able to find more information, at their web site.

        If you are worried about deficiencies, turning to vitamin C supplements can be an easy and effective way of ensuring you're meeting your RDA.

        Vitamin C Supplements

        Boots VITAMIN C 1000 mg Effervescent tablets

        Boots VITAMIN C 1000 mg Effervescent tablets

        boots pharmaceuticals boots.com

        £4.00

        Solgar Natural Cranberry with Vitamin C Vegi Capsules

        Solgar Natural Cranberry with Vitamin C Vegi Capsules

        Solgar hollandandbarrett.com

        £14.99

        Holland & Barrett Iron & Vitamin C 100 Tablets

        Holland & Barrett Iron & Vitamin C 100 Tablets

        hollandandbarrett.com

        £3.29

        Boots Vitamin C 30 Gummies

        Boots Vitamin C 30 Gummies

        boots pharmaceuticals boots.com

        £4.00


        Disclaimer: The information in this story is accurate as of the publication date. While we are attempting to keep our content as up-to-date as possible, the situation surrounding the coronavirus pandemic continues to develop rapidly, so it's possible that some information and recommendations may have changed since publishing. For any concerns and latest advice, visit the World Health Organisation . If you're in the UK, the National Health Service can also provide useful information and support, while US users can contact the Center for Disease Control and Prevention .

        Cut through the noise and g et practical, expert advice, home workouts, easy nutrition and more direct to your inbox. Sign up to t he WOMEN'S HEALTH NEWSLETTER .

        This content is created and maintained by a third party, and imported onto this page to help users provide their email addresses. You may be able to find more information about this and similar content at piano.io

        Fat Soluble Vitamin C Foods

        Source: https://www.womenshealthmag.com/uk/food/healthy-eating/a32223259/vitamin-c-foods/

        Share:

        Dr Eve_Ryouth Vitamin C

        Dr Eve_Ryouth Vitamin C

        Researchers in the United Kingdom say a study on eyesight shows diet and environmental factors are more important than genetics in lowering risk of cataracts.

        Eating an apple a day may keep the doctor away, but eating oranges might do the same for cataracts.

        In a study published today in the journal Ophthalmology, researchers in the United Kingdom said a higher dietary intake of vitamin C might significantly reduce the risk of developing cataracts.

        The study, led by scientists at King's College London, is the first to conclude that dietary and environmental factors play a larger role than genetics in the development of cataracts.

        "The findings of this study could have significant impact, particularly for the aging population globally by suggesting that simple dietary changes such as increased intake of fruits and vegetables as part of a healthier diet could help protect them from cataracts," Dr. Chris Hammond, professor of ophthalmology at King's College, consultant eye surgeon and lead author of the study, said in a statement.

        Read More: What Is a Cataract? »

        The researchers estimated genetic factors account for 35 percent of the difference in cataract progression. Environment and lifestyle account for 65 percent.

        To study the impact diet has on cataracts, the researchers tracked the progression of the eye condition in 324 pairs of female twins from the United Kingdom.

        The scientists examined digital images of the women's eye lenses when they were about 60 years old. They then studied the same type of images 10 years later.

        They kept track of the women's intake of vitamins A, B, C, D, and E. They also tracked their intake of copper, manganese, and zinc using a food questionnaire.

        The researchers said the women who ingested more vitamin C initially had a 20 percent reduced risk of developing cataracts. After 10 years, that risk had decreased by 33 percent.

        The researchers noted that there was little risk reduction in the women who took vitamin supplements. Instead the preventative effects appeared to be obtained only by eating foods rich in vitamin C.

        Dr. Ravi D. Goel, an ophthalmologist from New Jersey who is also a clinical instructor at Wills Eye Hospital in Pennsylvania, said the study provides helpful information for patients and doctors.

        "These are novel findings for patients going forward," Goel, a spokesperson for the American Academy of Ophthalmology, told Healthline. "This is a helpful tool for patient education."

        Read More: Americans Spend Billions on Vitamins and Supplements That Don't Work »

        Cataracts occur when the lens of the eye becomes cloudy due to oxidation over a long period of time.

        The researchers said the fluids that bathe the eye are rich in vitamin C, which helps stop the lens from oxidizing.

        The dietary intake of vitamin C helps prevent cataracts by increasing the amount of this vitamin in the eye fluid.

        The researchers added that smoking and diabetes also are risk factors for certain kinds of cataracts, so a balanced diet and healthy lifestyle are important.

        "Healthy diets are always an advantage for patients," added Goel.

        Goel also said vitamin C has already been shown to help slow the progression of age-related macular degeneration.

        This latest information on cataracts adds to vitamin C's attributes. "It helps overall eye health," he said.

        The researchers did note that their observational study has its limitations as it only involved women who were aged 60 years and older.

        However, the researchers believe the information could also be relevant for male patients.

        Cataracts are the leading cause of blindness in the world, affecting about 20 million people, according to statistics from the World Health Organization (WHO). Cataracts also affect 24 million Americans over the age of 40.

        The condition can cause blurry vision, glare, poor night vision, and sensitivity to light.

        Initially, better lighting and glasses may help ease some of the symptoms, but as cataracts progress surgery is sometimes needed.

        Read More: Diabetes and Blurry Vision: What You Need to Know »

        Dr Eve_Ryouth Vitamin C

        Source: https://www.healthline.com/health-news/vitamin-c-may-reduce-risk-of-cataracts

        Share:

        Does Pineapple Has Vitamin C

        Does Pineapple Has Vitamin C

        A Guide to Vitamin C Serums

        leonori/Shutterstock

        For 70 years Vitamin C has been one of the biggest weapons in the skin care industry. It's used to make cleansers, moisturizers, lotions, masks, and serums. So what is this powerful vitamin? How can it benefit you? Why should you use serums that contain Vitamin C? We're here to answer all of those burning questions in this complete guide and reveal the many benefits Vitamin C serums offer for your skin.

        What Are Vitamin C Serums?

        There are many variations of Vitamin C, but the most popular is ascorbic acid, a common ingredient in skincare products. However, all the variations of Vitamin C have anti-inflammatory benefits.

        Vitamin C Serums are products that contain a high level of Vitamin C. They're used to treat wrinkles, sagging skin, lighten dark or red spots, prevent breakouts and even your skin tone. Basically, they battle all of those annoying skin issues. There are loads of products out there that claim they'll save your skin, but some can cause damage. Vitamin C is one of the most revered ingredients and conclusive research has shown how effective it can be.

        How Are Vitamin C Serums Made?

        Well so far we've talked about how incredible Vitamin C is and it sounds like a dream come true doesn't it? It's not all good. In fact, the mighty vitamin is unstable when it's exposed to air and light. Other ingredients need to be used to stabilize it and allow it to deliver amazing results. The serums are combined with ferulic acid and Vitamin E. According to researchers the perfect mixture is 15% Vitamin C with 1% Vitamin E and 0.5% ferulic acid. This makes Vitamin C perform to the best of its abilities, without damaging your skin.

        What Does Vitamin C Serum Do for Your Face?

        Boosts Collagen Production: Collagen keeps your skin firm and prevents sagging. Environmental factors such as lifestyle choices and pollution can increase the elasticity of your skin, so it's important you try to increase your collagen production.

        Hydrates Your Skin: Dry skin is a common issue, but Vitamin C can help to give your skin that much-needed moisture boost. Remember, it doesn't work immediately so you need to keep applying the serum to see results.

        Brightens Your Complexion: Dark spots on your skin are caused by the overproduction of melanin. Vitamin C decreases the production and lightens the dark spots to even out your complexion.

        Reduces Redness and Inflammation: Conditions such as Rosacea leave many people searching for a magic cure. Vitamin C helps facial redness and inflammation by reducing the appearance of broken capillaries.

        Why Should You Be Using Vitamin C Serum?

        Don't think Vitamin C serums are just beneficial for your face. They can also shield you from sun damage and reduce stretch marks.

        Saves You From The Sun: Prolonged exposure to UV rays can cause long-term damage to your skin. Luckily, Vitamin C is a powerful antioxidant that reduces red sports and prevents sunburn from spreading.

        Fades Acne Scars: Acne plagues most of us at some point and we look forward to being free. Most of us get stuck with some scars but Vitamin C helps to fade scars and even out any discoloration.

        Reduces Stretch Marks: Yes, Vitamin C serum can even help prevent those unsightly stretch marks by tightening your skin.

        Are you ready to change your skin? Add a Vitamin C serum to your beauty regimen and enjoy a glowing complexion.

        Does Pineapple Has Vitamin C

        Source: https://www.bloglines.com/article/a-guide-to-vitamin-c-serums?utm_content=params%3Ao%3D740010%26ad%3DdirN%26qo%3DserpIndex

        Share:

        Current Rda For Vitamin C

        Current Rda For Vitamin C

        SUMMARY

        Vitamin C functions physiologically as a water-soluble antioxidant by virtue of its high reducing power. It is a cofactor for enzymes involved in the biosynthesis of collagen, carnitine, and neurotransmitters in vitro, and it can quench a variety of reactive oxygen species and reactive nitrogen species in aqueous environments. Evidence for in vivo antioxidant functions of ascorbate include the scavenging of reactive oxidants in activated leukocytes, lung, and gastric mucosa, and diminished lipid peroxidation as measured by urinary isoprostane excretion. To provide antioxidant protection, a Recommended Dietary Allowance (RDA) of 90 mg/day for adult men and 75 mg/day for adult women is set based on the vitamin C intake to maintain near-maximal neutrophil concentration with minimal urinary excretion of ascorbate. Because smoking increases oxidative stress and metabolic turnover of vitamin C, the requirement for smokers is increased by 35 mg/day. Estimates of median dietary intakes of vitamin C for adults are 102 mg/day and 72 mg/day in the United States and Canada, respectively. The Tolerable Upper Intake Level (UL) for adults is set at 2 g/day; the adverse effects upon which the UL is based are osmotic diarrhea and gastrointestinal disturbances.

        BACKGROUND INFORMATION

        Vitamin C is a water-soluble vitamin that is essential for all humans and a few other mammals that lack the ability to biosynthesize the compound from glucose because they lack the enzyme gulonolactone oxidase. The term vitamin C refers to both ascorbic acid and dehydroascorbic acid (DHA), since both exhibit anti-scorbutic activity. Ascorbic acid, the functional and primary in vivo form of the vitamin, is the enolic form of an α-ketolactone (2,3-didehydr L -threo-hexano-1,4-lactone). The two enolic hydrogen atoms give the compound its acidic character and provide electrons for its function as a reductant and antioxidant. Its one-electron oxidation product, the ascorbyl radical, readily dismutates to ascorbate and DHA, the two-electron oxidation products. Both the ascorbyl radical and DHA are readily reduced back to ascorbic acid in vivo. However, DHA can be hydrolyzed irreversibly to 2,3-diketogulonic acid. The molecular structure of ascorbic acid contains an asymmetric carbon atom that allows two enantiomeric forms, of which the L form is naturally occurring (the D -form, isoascorbic or erythorbic acid, provides antioxidant but little or no anti-scorbutic activity), as shown in Figure 5-1.

        FIGURE 5-1. Chemical structure of ascorbic acid.

        Function

        The biological functions of ascorbic acid are based on its ability to provide reducing equivalents for a variety of biochemical reactions. Because of its reducing power, the vitamin can reduce most physiologically relevant reactive oxygen species (Buettner, 1993). As such, the vitamin functions primarily as a cofactor for reactions requiring a reduced iron or copper metalloenzyme and as a protective antioxidant that operates in the aqueous phase both intra- and extracellularly (Englard and Seifter, 1986; Halliwell and Whiteman, 1997; Tsao, 1997). Both the one- and the two-electron oxidation products of the vitamin are readily regenerated in vivo—chemically and enzymatically—by glutathione, nicotinamide adenine dinucleotide (NADH), and nicotinamide adenine dinucleotide phosphate (NAD-PH) dependent reductases (May et al., 1998; Park and Levine, 1996).

        Vitamin C is known to be an electron donor for eight human enzymes. Three participate in collagen hydroxylation; two in carnitine biosynthesis; and three in hormone and amino acid biosynthesis. The three enzymes that participate in hormone and amino acid biosynthesis are dopamine-β-hydroxylase, necessary for the biosynthesis of the catecholamines norepinephrine and epinephrine; peptidyl-glycine monooxygenase, necessary for amidation of peptide hormones; and 4-hydroxyphenylpyruvatedioxygenase, involved in tyrosine metabolism. Ascorbate's action with these enzymes involves either monooxygenase or dioxygenase activities (Levine et al., 1996b).

        As a cofactor for hydroxylase and oxygenase metalloenzymes, ascorbic acid is believed to work by reducing the active metal site, resulting in reactivation of the metal-enzyme complex, or by acting as a co-substrate involved in the reduction of molecular oxygen. The best known of these reactions is the posttranslational hydroxylation of peptide-bound proline and lysine residues during formation of mature collagen. In these reactions, ascorbate is believed to reactivate the enzymes by reducing the metal sites of prolyl (iron) and lysyl (copper) hydroxylases (Englard and Seifter, 1986; Tsao, 1997).

        Evidence also suggests that ascorbate plays a role in or influences collagen gene expression, cellular procollagen secretion, and the biosynthesis of other connective tissue components besides collagen, including elastin, fibronectin, proteoglycans, bone matrix, and elastin-associated fibrillin (Ronchetti et al., 1996). The primary physical symptoms of ascorbic acid's clinical deficiency disease, scurvy, which involves deterioration of elastic tissue, illustrate the important role of ascorbate in connective tissue synthesis.

        Ascorbic acid is involved in the synthesis and modulation of some hormonal components of the nervous system. The vitamin is a co-factor for dopamine-β-hydroxylase, which catalyzes hydroxylation of the side chain of dopamine to form norepinephrine, and α-amidating monooxygenase enzymes, involved in the biosynthesis of neuropeptides. Other nervous system components modulated by ascorbate concentrations include neurotransmitter receptors, the function of glutamatergic and dopaminergic neurons, and synthesis of glial cells and myelin (Englard and Seifter, 1986; Katsuki, 1996).

        Because of its ability to donate electrons, ascorbic acid is an effective antioxidant. The vitamin readily scavenges reactive oxygen species (ROS) and reactive nitrogen species (RNS) (e.g., hydroxyl, peroxyl, superoxide, peroxynitrite, and nitroxide radicals) as well as singlet oxygen and hypochlorite (Frei et al., 1989; Halliwell and Whiteman, 1997; Sies and Stahl, 1995). The one- and two-electron oxidation products of ascorbate are relatively nontoxic and easily regenerated by the ubiquitous reductants glutathione and NADH or NAD-PH. The relatively high tissue levels of ascorbate provide substantial antioxidant protection: in the eye, against photolytically generated free-radical damage; in neutrophils, against ROS produced during phagocytosis; and in semen, against oxidative damage to sperm deoxyribonucleic acid (DNA) (Delamere, 1996; Fraga et al., 1991; Levine et al., 1994). Ascorbic acid protects against plasma and low-density lipoprotein (LDL) oxidation by scavenging ROS in the aqueous phase before they initiate lipid peroxidation (Frei et al., 1988; Jialal et al., 1990) and possibly by sparing or regenerating vitamin E (Halpner et al., 1998). Evidence suggests that ascorbate also provides antioxidant protection indirectly by regenerating other biological antioxidants such as glutathione and α-tocopherol back to their active state (Jacob, 1995).

        Ascorbic acid functions as a reducing agent for mixed-function oxidases in the microsomal drug-metabolizing system that inactivates a wide variety of substrates, such as endogenous hormones or xenobiotics (i.e., other chemical compounds such as drugs, pesticides, or carcinogens that are foreign to humans) (Tsao, 1997). The activity of both microsomal drug-metabolizing enzymes and cytochrome P-450 electron transport is lowered by ascorbate deficiency. The vitamin is involved in the biosynthesis of corticosteroids and aldosterone and in the microsomal hydroxylation of cholesterol in the conversion of cholesterol to bile acids. In reactions similar to the hydroxylation of proline for collagen synthesis, ascorbate is required along with iron at two steps in the pathway of carnitine biosynthesis. Ascorbic acid modulates iron absorption, transport, and storage (Gosiewska et al., 1996). Limited data suggest that ascorbate modulates prostaglandin synthesis and thus exerts bronchodilatory and vasodilatory as well as anticlotting effects (Horrobin, 1996).

        Physiology of Absorption, Metabolism, and Excretion

        Absorption and Transport

        Intestinal absorption of ascorbic acid occurs through a sodium-dependent active transport process that is saturable and dose dependent (Rumsey and Levine, 1998; Tsao, 1997). At low gastrointestinal ascorbate concentrations, active transport predominates, while simple diffusion occurs at high concentrations. Some 70 to 90 percent of usual dietary intakes of ascorbic acid (30 to 180 mg/day) are absorbed; however, absorption falls to about 50 percent or less with increasing doses above 1 g/day (Kallner et al., 1979). The bioavailabilities of the vitamin from foods and supplements are not significantly different (Johnston and Luo, 1994; Mangels et al., 1993).

        Cellular transport of ascorbic acid and DHA is mediated by transporters that vary by cell type (Jacob, 1999; Tsao, 1997). DHA is the form of the vitamin that primarily crosses the membranes of blood and intestinal cells, after which it is reduced intracellularly to ascorbic acid. Accumulation of ascorbate into neutrophils and lymphocytes is mediated by both high- and low-affinity transporters, and the vitamin is localized mostly in the cytosol. Intracellularly and in plasma, vitamin C exists predominately in the free reduced form as ascorbate monoanion, as shown in Figure 5-1 (Levine et al., 1994).

        Metabolism and Excretion

        Since the immediate oxidized forms of vitamin C are readily reduced back to ascorbic acid, relatively small amounts of the vitamin are lost through catabolism. The primary products of oxidation beyond DHA include oxalic and threonic acids, L -xylose, and ascorbate 2-sulfate (Jacob, 1999). With large intakes of the vitamin, unabsorbed ascorbate is degraded in the intestine, a process that may account for the diarrhea and intestinal discomfort sometimes reported by persons ingesting large doses (see section on "Adverse Effects").

        Besides dose-dependent absorption, a second primary mechanism for regulation of body ascorbate content is renal action to conserve or excrete unmetabolized ascorbate. Recent studies have shown that little unmetabolized ascorbate is excreted with dietary intakes up to about 80 mg/day and that renal excretion of ascorbate increases proportionately with higher intakes (Blanchard et al., 1997; Melethil et al., 1986).

        Body Stores

        Dose-dependent absorption and renal regulation of ascorbate allow conservation of the vitamin by the body during low intakes and limitation of plasma levels at high intakes. Tissue-specific cellular transport systems allow for wide variation of tissue ascorbate concentrations. High levels are maintained in the pituitary and adrenal glands, leukocytes, eye tissues and humors, and the brain, while low levels are found in plasma and saliva (Hornig, 1975). Due to homeostatic regulation, the biological half-life of ascorbate varies widely from 8 to 40 days and is inversely related to the ascorbate body pool (Kallner et al., 1979). Similarly, catabolic turnover varies widely, about 10 to 45 mg/day, over a wide range of dietary intakes due to body pool size. A total body pool of less than 300 mg is associated with scurvy symptoms (Baker et al., 1971), while maximum body pools are limited to about 2 g (Kallner et al., 1979). At very low ascorbate intakes, essentially no ascorbate is excreted unchanged and a minimal loss occurs.

        Clinical Effects of Inadequate Intake

        Scurvy, the classic disease of severe vitamin C deficiency, is characterized by symptoms related to connective tissue defects. Scurvy usually occurs at a plasma concentration of less than 11 µmol/L (0.2 mg/dL). Clinical features of scurvy include follicular hyperkeratosis, petechiae, ecchymoses, coiled hairs, inflamed and bleeding gums, perifollicular hemorrhages, joint effusions, arthralgia, and impaired wound healing (Baker et al., 1971; Chazan and Mistilis, 1963; Levine et al., 1996b). Other symptoms include dyspnea, edema, Sjögren's syndrome (dry eyes and mouth), weakness, fatigue, and depression. In experimental subjects made vitamin C deficient but not frankly scorbutic, gingival inflammation (Leggott et al., 1986) and fatigue (Levine et al., 1996a) were among the most sensitive markers of deficiency. Vitamin C deficiency in infants may result in bone abnormalities such as impaired bone growth and disturbed ossification, hemorrhagic symptoms, and resultant anemia (Jacob, 1999).

        Lack of ascorbate-related hydroxyproline and hydroxylysine formation needed for collagen cross-linking may explain many of the connective tissue and hemorrhagic manifestations of scurvy, however, the specific histologic defects have not been identified. Oxidative degradation of some blood coagulation factors due to low plasma ascorbate concentrations may contribute to hemorrhagic symptoms (Parkkinen et al., 1996).

        Scurvy is rare in developed countries but is occasionally seen in individuals who consume few fruits and vegetables, peculiar or restricted diets, or in those who abuse alcohol or drugs. In the United States, low blood ascorbate concentrations are more prevalent in men, especially elderly men, than in women and are more prevalent in populations of lower socioeconomic status (LSRO/FASEB, 1989). Infantile scurvy is rarely seen, because human milk provides an adequate supply of vitamin C and infant formulas are fortified with the vitamin.

        SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR VITAMIN C

        Antioxidant Functions

        There is much support for the role of increased oxidative stress in the pathogenesis of cardiovascular disease (Jialal and Devaraj, 1996; Witztum and Steinberg, 1991). The most plausible and biologically relevant hypothesis is that the oxidative modification of low-density lipoprotein (LDL) and other lipoproteins promote atherogenesis (Berliner and Heinecke, 1996; Devaraj and Jialal, 1996; Witztum and Steinberg, 1991). Several lines of evidence suggest that oxidized LDL (oxLDL) is pro-atherogenic. Furthermore, data support the in vivo existence of oxLDL (Berliner and Heinecke, 1996; Witztum and Steinberg, 1991). In vitro studies have clearly shown that vitamin C at concentrations greater than 40 µmol/L (0.8 mg/dL) inhibits the oxidation of isolated LDL induced by transition metals, free-radical initiators, and activated human neutrophils and macrophages (Jialal and Grundy, 1991; Jialal et al., 1990; Scaccini and Jialal, 1994). This is because vitamin C effectively scavenges aqueous reactive oxygen species (ROS) and reactive nitrogen species (RNS), which prevents them from attacking LDL. Thus, in vitro vitamin C clearly functions as an antioxidant.

        Studies shown in Table 5-1 examined the effect of vitamin C supplementation alone on biomarkers of lipid peroxidation. Of the 13 studies, 7 showed that vitamin C supplementation resulted in a significant decrease in lipid oxidation products in plasma, LDL, or urine. The vitamin C supplements that resulted in positive effects ranged from 500 to 2,000 mg/day. The most convincing evidence that vitamin C functions as an antioxidant in vivo is the study by Reilly et al. (1996) showing that supplementation of smokers with 2.0 g vitamin C for 5 days was associated with a significant reduction in urinary isoprostanes, an indicator of oxidative stress. In the remaining six studies in which vitamin C was supplemented in amounts ranging from 500 to 6,000 mg/day, there was no significant effect of vitamin C supplementation on lipid oxidation products in plasma, urine, or plasma LDL.

        TABLE 5-1. Effect of Vitamin C Supplementation on Biomarkers of Lipid Oxidation in Humans.

        TABLE 5-1

        Effect of Vitamin C Supplementation on Biomarkers of Lipid Oxidation in Humans.

        Carr and Frei (1999) examined the effect on LDL oxidation of supplementation with vitamin C in combination with vitamin E and β-carotene. Although these investigators have clearly shown that the supplements decrease LDL oxidation, it is difficult to assess the contribution of vitamin C alone.

        Vitamin C supplementation (2,000 mg/day for 4 to 12 months) in 41 patients with non-atrophic gastritis decreased gastric mucosal nitrotyrosine, a measure of RNS activity (Table 5-2) (Mannick et al., 1996). Thus, from this study and the study by Reilly et al. (1996), it can be concluded that supplementation with vitamin C results in an antioxidant effect in vivo because it significantly reduces nitrotyrosine and urinary isoprostanes.

        TABLE 5-2. Vitamin C Intake and Biomarkers of Gastric and Bladder Cancer.

        TABLE 5-2

        Vitamin C Intake and Biomarkers of Gastric and Bladder Cancer.

        However, with respect to the effect of vitamin C on LDL oxidation, the data are inconclusive. This could be explained by the fact that, because vitamin C is water soluble, it does not partition into the LDL particle. Also, it must be pointed out that in one of the 13 studies summarized in Table 5-1, there was an increase in plasma thiobarbituric acid reactive substances (TBARS), an indicator of oxidative stress, with a 500-mg dose of ascorbic acid (Nyyssonen et al., 1997b).

        Adhesion of mononuclear cells to endothelium is an early event in atherogenesis and may be triggered by oxidative stress. Smokers have low levels of vitamin C and increased oxidative stress. A recent study showed that monocytes of smokers display greater adhesion to endothelial cells than those of nonsmokers (Weber et al., 1996). When supplemented with 2,000 mg/day of vitamin C, the plasma ascorbate level of smokers increased, and adhesion of their monocytes to endothelium decreased to that seen in nonsmokers.

        Impaired vascular function is crucial to the clinical manifestation of atherosclerosis. As depicted in Table 5-3, numerous investigators have reported a beneficial effect of high dose vitamin C administration, either orally or intraarterially, on vasodilation. This beneficial effect of vitamin C is most likely related to its antioxidant effect. Endothelium-derived relaxing factor, nitric oxide (NO), promotes vasodilation but is rapidly inactivated by superoxide. Vitamin C improves endothelial function and vasodilation, possibly by scavenging superoxide radicals, conserving intracellular glutathione, or potentiating intracellular NO synthesis. In human endothelial cells in culture, extracellular vitamin C at physiological concentrations increased cellular NO synthesis up to threefold, and the increase in NO synthesis followed a time course similar to ascorbate uptake into the cells (Heller et al., 1999).

        TABLE 5-3. Vitamin C and Endothelium-Dependent Vasodilation in Humans.

        TABLE 5-3

        Vitamin C and Endothelium-Dependent Vasodilation in Humans.

        Antioxidant Functions in Leukocytes

        The content of vitamin C in leukocytes is especially important because the ROS generated during phagocytosis and neutrophil activation are associated with infectious and inflammatory stresses (Jariwalla and Harakeh, 1996; Levine et al., 1994). Along with pituitary and adrenal glands and eye lens, leukocytes contain the highest vitamin C concentrations of all body tissues (Moser, 1987). Studies with guinea pigs and monkeys show that the concentration of ascorbate in the leukocytes more accurately reflects liver and body pool ascorbate than does the concentration in plasma or erythrocytes (Omaye et al., 1987). The vitamin is transported into leukocytes by an energy-dependent transport system that concentrates the vitamin some twenty-five-, forty-, and eightyfold over plasma levels in neutrphils, platelets, and lymphocytes, respectively (Evans et al., 1982; Jacob et al., 1992; Levine et al., 1996a). Metabolic priority for maintenance of intracellular lymphocyte ascorbate levels was demonstrated by its lower depletion rates compared to plasma and semen ascorbate levels during controlled vitamin C deficiency (intake of 5 mg/day) and faster recovery during vitamin repletion at 60 mg/day (Jacob et al., 1992). Intracellular ascorbate recycling (the intracellular regeneration of oxidized extracellular ascorbate) provides a cellular reservoir of reducing capacity (electrons) that can be transmitted both into and across the cell membrane (May et al., 1999).

        The high intracellular concentration of ascorbate in leukocytes provides cellular protection against oxidant damage associated with the respiratory burst. In isolated neutrophils, ascorbate recycling is increased up to thirtyfold upon exposure of the cells to microbial pathogens (Wang et al., 1997b). Ascorbate effectively neutralizes phagocyte-derived oxidants without inhibiting the bactericidal activity of the phagosome (Anderson and Lukey, 1987). Evidence that ascorbate modulates leukocyte phagocytic action, blastogenesis, immunoglobulin production, chemotaxis, and adhesiveness has been reported in vitro, although evidence for the latter two functions has been mixed (Evans et al., 1982; Jariwalla and Harakeh, 1996).

        Concentrations of ascorbate normally found in plasma (22 to 85 µmol/L [0.4 to 1.7 mg/dL]) were shown to neutralize hypochlorous acid (HOCl), one of many powerful oxidants generated by myeloperoxidase in activated neutrophils and monocytes (Halliwell et al., 1987; Heinecke, 1997). This action was hypothesized to protect α-1-antiprotease against inactivation by HOCl and thereby prevent proteolytic damage at inflamed sites such as the rheumatoid joint (Halliwell et al., 1987). Indeed, the ratio of oxidized to reduced ascorbate was found to be increased in the knee synovial fluid of active rheumatoid arthritis patients, which suggests that ascorbate is acting to scavenge phagocyte-derived oxidants in this locally inflamed area (Lunec and Blake, 1985). Similarly, increased ascorbate oxidation in the plasma of patients with adult respiratory distress syndrome (Cross et al., 1990) and in smokers (Lykkesfeldt et al., 1997) indicates protection against oxidant damage from activated neutrophils and other sources in the lung. Exposure of nine apparently healthy adults to 2,000 parts per billion (ppb) of ozone, an environmental pollutant, for 2 hours resulted in increased myeloperoxidase and decreased ascorbate concentrations in bronchoalveolar lavage fluid. These results imply that ascorbate protects against inflammatory oxidative stress induced by ozone (Mudway et al., 1999).

        Ascorbate scavenging of myeloperoxidase-derived oxidants from phagocytic white cells may also be protective against in vivo LDL oxidation because HOCl-oxidized proteins have been identified in human atherosclerotic lesions (Hazell et al., 1996). In an in vitro system, ascorbate at a physiologically relevant concentration of 50 µmol/L (0.9 mg/dL) was the most effective antioxidant for preventing LDL oxidation due to myeloperoxidase-derived RNS (Byun et al., 1999).

        Oxidative Deoxyribonucleic Acid and Chromosome Damage

        Cellular Deoxyribonucleic Acid (DNA) Damage

        Table 5-4 summarizes the results of five experimental human studies in which cellular markers of DNA damage were measured after various vitamin C intakes. Three of the studies varied vitamin C alone, while the other two studies varied vitamin C and other micronutrients.

        Of the three studies that varied only vitamin C intake, one showed that 60 or 250 mg/day decreased sperm 8-hydroxy-7, 8-dihydro-2′-deoxyguanosine (8-oxodG), a measure of oxidative stress, but did not affect lymphocyte or urine 8-oxodG or DNA strand breaks (Fraga et al., 1991). In contrast, the second study showed no effect of either 60 or 6,000 mg/day vitamin C on lymphocyte DNA or chromosome damage as measured by comet assay (Anderson et al., 1997). The third study showed both decreases and increases in measures of lymphocyte DNA oxidative damage after vitamin C supplementation of 500 mg/day (Podmore et al., 1998). In a subsequent report of results from the study of Podmore et al. (1998), the investigators hypothesized that increases in serum and urine 8-oxodG following the decreases of lymphocyte 8-oxoguanine and 8-oxodG suggest a role for vitamin C in the repair of oxidant-damaged DNA (Cooke et al., 1998).

        The two studies that co-supplemented with vitamin E and β-carotene (Duthie et al., 1996) or iron (Rehman et al., 1998) demonstrated mixed results in that both decreases and increases in lymphocyte DNA oxidant damage measures. Since the contribution of vitamin C alone to the results of these studies cannot be determined, these studies cannot be used to estimate a vitamin C requirement. Results of the latter study involving supplementation of apparently healthy individuals with both vitamin C and iron are discussed in the section "Tolerable Upper Intake Levels."

        Inverse correlations of lymphocyte ascorbate and glutathione concentrations with oxidized DNA bases in another study of 105 apparently healthy adults suggest that these two intracellular antioxidants protect human lymphocytes against oxidative damage (Lenton et al., 1999). In sum, the results of studies testing the effects of vitamin C on cellular DNA damage are mixed and cannot be used for estimating the vitamin C requirement.

        TABLE 5-4. Vitamin C Intake and Biomarkers of Cellular Oxidative DNA Damage in Humans.

        TABLE 5-4

        Vitamin C Intake and Biomarkers of Cellular Oxidative DNA Damage in Humans.

        Urinary Markers of DNA Damage

        Urinary excretion of DNA oxidant damage products, which is thought to represent the balance of total body DNA damage and repair has been measured in the studies shown in Table 5-5. This is a nonspecific measure used to assess changes due to micronutrient status. Except for the study by Cooke et al. (1998), no relationships between vitamin C intake and urinary markers of DNA damage were found. Thus, urinary markers of DNA damage cannot be used to determine vitamin C requirements.

        TABLE 5-5. Vitamin C Intake and Urinary Excretion of Oxidative DNA Damage Products in Humans.

        TABLE 5-5

        Vitamin C Intake and Urinary Excretion of Oxidative DNA Damage Products in Humans.

        Ex Vivo Damage

        The five studies in Table 5-6 measured DNA and chromosome damage ex vivo after supplementing the subjects with vitamin C. Single large doses of vitamin C (1 g/day or more) provided protection against lymphocyte DNA strand break damage induced ex vivo by radiation or hydrogen peroxide (H2O2) as measured by the comet assay (Green et al., 1994; Panayiotidis and Collins, 1997). In contrast, Crott and Fenech (1999) reported that a single 2-g dose of vitamin C neither caused DNA damage nor protected cells against hydrogen peroxide-induced toxicity. The two other studies measured DNA chromosome damage after treatment of lymphocytes with bleomycin, a test for genetic instability. Following vitamin C supplementation for two weeks, Pohl and Reidy (1989) found decreased chromosome breaks and Anderson et al. (1997) reported no effects on DNA damage but increased chromosome aberrations. Since the findings of these studies were inconsistent, ex vivo damage cannot be used to estimate a vitamin C requirement.

        TABLE 5-6. Vitamin C Intake and Ex Vivo Measures of Oxidative DNA Damage in Humans.

        TABLE 5-6

        Vitamin C Intake and Ex Vivo Measures of Oxidative DNA Damage in Humans.

        Cancer Biomarkers

        Effects of vitamin C intakes on surrogate markers and biomarkers of colorectal, gastric, and bladder cancer are shown in Table 5-2 and Table 5-7. Of six studies of patients with precancerous colon polyps, vitamin C treatment for 1 month to 3 years demonstrated variable results with regard to effect on polyp growth and cell proliferation (Table 5-7).

        TABLE 5-7. Vitamin C Intake and Colorectal Polyps.

        TABLE 5-7

        Vitamin C Intake and Colorectal Polyps.

        Biomarkers of gastric cancer after vitamin C treatment of patients with the precancerous conditions, gastritis, or Helicobacter pylori infections were measured in four studies (Table 5-2). Three studies showed positive results of vitamin C supplementation in vivo: Mannick et al. (1996) reported decreased gastric mucosal nitrotyrosine (a measure of RNS activity); Dyke et al. (1994a) reported decreased mucosal DNA damage in one group of gastric cancer patients and subsequently found increased mucosal O 6 -alkyltransferase, a DNA repair enzyme in a second group of patients with gastric cancer (Dyke et al. 1994b). Leaf et al. (1987) found decreased nitrosation in men after vitamin C supplementation. Drake et al. (1996) used electron paramagnetic resonance to demonstrate the presence of the ascorbyl radical in 82 unsupplemented patients with dyspepsia and showed that ascorbyl radical concentrations correlated with ROS activity. Gastric muscosal concentrations of ascorbyl radical, ROS, and malondialdehyde (a measure of lipid peroxidation) were higher in patients with gastritis and Helicobacter pylori infections compared to patients with normal mucosal histology. Young et al. (1990) found decreased β-glucuronidase activity (linked to bladder cancer) after in vivo supplementation of apparently healthy men with 1,500 mg/day of vitamin C for 1 week.

        Summary

        For the three studies shown in Table 5-4 in which only vitamin C intake was varied, some markers of cellular DNA damage showed no change with increased vitamin C intake, two markers decreased, and one increased. Urinary measures of oxidized DNA products showed no change attributable to vitamin C intake (Table 5-5). Two of three studies of ex vivo DNA damage showed a benefit of vitamin C supplementation (Table 5-6); however, the relation of these results to the in vivo situation is uncertain. Studies of surrogate markers and biomarkers in precancerous colonic and gastric patients show beneficial or no effects of vitamin C supplementation. However, the interpretation of these endpoints and the relevance of the results to apparently healthy individuals are questionable. The study of dyspepsia patients indicates that vitamin C acts as an antioxidant in the gastric mucosa and prevents oxidative damage by scavenging ROS (Drake et al., 1996). This is consistent with previous findings that substantial amounts of ascorbic acid are secreted into the digestive tract (Dabrowski, 1990; Waring et al., 1996) and that vitamin C supplementation decreases gastric mucosal DNA adduct formation (Dyke et al., 1994a).

        Overall, the results do not provide compelling evidence that vitamin C intakes of 60 to 6,000 mg/day reduce in vivo DNA oxidative damage in apparently healthy individuals. Hence, present data cannot be used to estimate a vitamin C requirement using the end-point of reduction of oxidative damage to DNA and chromosomes.

        Immune Function

        As summarized in Table 5-8, vitamin C has been shown to affect various components of the human immune response, including antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis, and delayed dermal sensitivity (DDS). Except for the metabolic unit study of Jacob et al. (1991) and the study of patients with furunculosis (Levy et al., 1996), the studies involved apparently healthy free-living populations supplemented with from 200 mg/day to 6 g/day of vitamin C in addition to dietary vitamin intake. Hence, the results relate largely to the pharmacological range of vitamin C intakes rather than the nutritional range of intakes usually provided from food alone.

        TABLE 5-8. Vitamin C Intake and Measures of Immune Function in Humans.

        TABLE 5-8

        Vitamin C Intake and Measures of Immune Function in Humans.

        As seen from analysis of Table 5-8, vitamin C supplementation resulted about equally in improved or little change in frequently used measures of immune function: lymphocyte proliferation, chemotaxis, and DDS response. The decrease in DDS during vitamin C depletion of men in a metabolic unit cannot be ascribed solely to changes in ascorbate status because the DDS did not increase again upon repletion for 4 weeks with 60 to 250 mg/day of the vitamin (Jacob et al., 1991). The only negative effect of intakes in the range of 600 to 10,000 mg/day was the decrease in ex vivo bactericidal activity found after apparently healthy men received 2,000 (but not 200) mg/day of the vitamin for 4 weeks (Shilotri and Bhat, 1977).

        Few controlled studies of the effect of vitamin C intake on infectious episodes in humans have been reported, except for studies of the common cold (covered later under "Common Cold" in the section "Relationship of Vitamin C Intake to Chronic Disease"). Peters et al. (1993) reported a significantly decreased incidence of post-race upper respiratory infections in marathon runners receiving 600 mg/day of vitamin C compared to control runners taking a placebo.

        Results from some studies show improvement in indices of immune function due to increased vitamin C intake, whereas other studies show no effect. The lack of effect may be due to the use of subject populations whose baseline vitamin C status is already adequate, because leukocytes saturate with vitamin C at a lower intake than is required to saturate plasma, about 100 mg/day (Levine et al., 1996a). Nevertheless, the existing data do not provide convincing evidence that supplemental vitamin C has a significant effect on immune functions in humans. Therefore, data from currently available immune function studies cannot be used to estimate the vitamin C requirement.

        Other Indicators

        Collagen Metabolism

        Ascorbic acid is required along with iron as a cofactor for the post-translational hydroxylation of proline and lysine to effect crosslinking of mature collagen (Englard and Seifter, 1986). Lack of this function due to ascorbate deficiency results in defective collagen formation and the physical symptoms of scurvy. However, serum or urinary levels of proline or lysine, their hydroxylated forms, or other measures of collagen metabolism have not been shown to be reliable markers of ascorbate status (Hevia et al., 1990). Therefore, despite the important role of the vitamin in collagen formation, no collagen-related measures are available to use as a functional indicator for the dietary vitamin C requirement.

        Carnitine Biosynthesis

        Ascorbate is required along with iron at two steps in the pathway of carnitine biosynthesis in reactions similar to the hydroxylation of proline during collagen formation. Muscle carnitine is significantly depleted in scorbutic guinea pigs, suggesting that loss of energy derived from carnitine-related β-oxidation of fatty acids may explain the fatigue and muscle weakness observed in human scurvy (Jacob and Pianalto, 1997; Rebouche, 1995). However, neither guinea pig nor human studies show a consistent relationship between vitamin C status and carnitine levels (Davies et al., 1987; Jacob and Pianalto, 1997; Johnston et al., 1996). Although vitamin C deficiency appears to alter carnitine metabolism, the specific interactions and their relevance to functional carnitine status in humans are unclear. Therefore, measures of carnitine status cannot be used as an indicator for estimating the vitamin C dietary requirement.

        Periodontal Health

        The gingival and dental pathology that accompanies scurvy has prompted numerous investigations of the relationship between ascorbic acid and periodontal health. Epidemiological studies have failed to demonstrate an association between vitamin C intake and periodontal disease (Alvares, 1997; Russell, 1967). Controlled experimental studies of patients with gingivitis and apparently healthy adults with vitamin C intakes of 5 to 1,500 mg/day have shown mixed results with regard to the influence of vitamin C status on periodontal integrity (Leggott et al., 1986, 1991; Vogel et al., 1986; Woolfe et al., 1984). Other studies, with animals and humans, have shown that vitamin C intake can affect the structural integrity of gingival tissue, including permeability of the gingival sulcular epithelium (Alvares, 1997).

        Overall, while evidence suggests that vitamin C deficiency is linked to some aspects of periodontal disease, the relationship of vitamin C intake to periodontal health in the population at large is unclear. Beyond the amount needed to prevent scorbutic gingivitis (less than 10 mg/day) (Baker et al., 1971), the results from current studies are not sufficient to reliably estimate the vitamin C requirement for apparently healthy individuals based on oral health endpoints.

        Relationship of Vitamin C Intake to Chronic Disease

        Cardiovascular Disease

        As suggested earlier, there is reason to expect that the antioxidant vitamins should decrease the risk of cardiovascular disease (Gey, 1995; Jha et al., 1995; Simon, 1992). Several studies have considered the association between vitamin C concentrations in blood and the risk of cardiovascular disease. Singh et al. (1995) found that the risk of coronary artery disease was approximately two times less among the top compared to the bottom quintile of plasma vitamin C concentrations in Indian subjects. A prospective study of 1,605 Finnish men showed that those with increased plasma vitamin C (greater than 11.4 µmol/L [0.2 mg/dL]) had a 60 percent decreased risk of coronary heart disease (Nyyssonen et al., 1997a). The Basel Prospective Study of 2,974 Swiss men reported that plasma vitamin C concentrations greater than 23 µmol/L (0.4 mg/dL) were associated with nonsignificant reductions in the risk of coronary artery disease (Eichholzer et al., 1992) and stroke (Gey et al., 1993). In a 20-year follow-up of 730 elderly adults in Britain, plasma vitamin C concentrations greater than 28 µmol/L (0.5 mg/dL) were associated with a 30 percent decreased risk of death from stroke compared with concentrations less than 12 µmol/L (0.2 mg/dL) (Gale et al., 1995). In a similar study, cross-sectional in design, in 6,624 men and women in the Second National Health and Nutrition Examination Survey, the relative risk of coronary heart disease and stroke was decreased about 26 percent with serum vitamin C concentrations of 63 to 153 µmol/L (1.1 to 2.7 mg/dL) compared with concentrations of 6 to 23 µmol/L (0.1 to 0.4 mg/dL) (Simon et al., 1998).

        In addition, several prospective cohort studies have shown that vitamin C intakes between 45 and at least 113 mg/day are associated with reduced risk of cardiovascular disease (Gale et al., 1995; Knekt et al., 1994; Pandey et al., 1995). Gale et al. (1995) reported that in 730 elderly British men and women, vitamin C intakes greater than 45 mg/day were associated with a 50 percent lower risk of stroke than were intakes less than 28 mg/day. There was a nonsignificant 20 percent decrease in the risk of coronary artery disease in this study. Knekt et al. (1994) studied more than 5,000 Finnish men and women and found that women consuming more than 91 mg/day vitamin C had a lower risk of coronary artery disease than those consuming less than 61 mg/day. However, a similar association was not found in the men. In the Western Electric study in Chicago, a cohort of 1,556 middle-aged men consuming greater than 113 mg/day of vitamin C had a 25 percent lower risk of coronary artery disease than those consuming less than 82 mg/day (Pandey et al., 1995).

        Other prospective studies have looked at higher levels of vitamin C intake and have reported similar findings. The First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study cohort of more than 11,000 adults showed a reduction in cardiovascular disease of 45 percent in men and 25 percent in women whose vitamin C intakes were approximately 300 mg/day from food and supplements (Enstrom et al., 1992). Sahyoun et al. (1996) studied 725 elderly Massachusetts adults and reported a 62 percent lower risk of cardiovascular disease in those whose vitamin C intakes were more than 388 mg/day compared to those whose intakes were less than 90 mg/day. Kritchevsky et al. (1995) reported a negative association between vitamin C intake and carotid artery wall thickness in men and women more than 55 years of age in the Atherosclerosis Risk in Communities Study. Women consuming more than 728 mg/day and men consuming at least 982 mg/day of vitamin C had decreased intima thickness compared to women with intakes of less than 64 mg/day and men with intakes of less than 56 mg/day vitamin C.

        In contrast to the above studies, several studies have reported no association between vitamin C intake and risk of cardiovascular disease. In a cohort composed of 3,119 residents of Alameda County, California, vitamin C intakes were not associated with a reduction in risk for cardiovascular disease (Enstrom et al., 1986). In the Established Populations for Epidemiologic Studies of the Elderly with more than 11,000 adults 65 years of age and older (Losonczy et al., 1996) and in the Iowa Women's Heath Study of 34,486 postmenopausal women (Kushi et al., 1996b), vitamin C intake was not associated with an alteration in risk of coronary heart disease mortality in these older age groups. Similarly, the U.S. Health Professionals Follow-up Study of nearly 40,000 male health professionals found that increased intakes of vitamin C (ranging from 92 to 1,162 mg/day) were not associated with a lower risk of coronary heart disease (Rimm et al., 1993).

        Although many of the above studies suggest a protective effect of vitamin C against cardiovascular disease, the data are not consistent or specific enough to estimate a vitamin C requirement based on any of these specific biomarkers for cardiovascular disease.

        Cancer

        As a possible protectant against cancer, vitamin C has engendered a great deal of interest. Block (1991) has reported that the epidemiologic evidence is strongly suggestive of a protective effect, especially for the non-hormone-dependent cancers. However, Ames et al. (1995) have cautioned that the evidence to date of a protective effect for any of the antioxidants is far from complete. Available studies assessing the role of vitamin C in specific cancers by site are evaluated in the following section.

        Breast Cancer. A combined meta-analysis, based upon data from 12 case-control studies, found vitamin C to be the micronutrient most strongly associated with breast cancer risk (Howe et al., 1990). According to Howe and colleagues's statistical analyses, each 300-mg increase in vitamin C intake was associated with a 37 percent decrease in the risk of postmenopausal, but not premenopausal, breast cancer. The Iowa Women's Health Study (Kushi et al., 1996a) found a 20 percent decrease in breast cancer risk with greater than 500 mg/day of vitamin C intake from supplements; in contrast, the Nurses Health Study, which used the same dietary assessment instrument, found no decreased risk of breast cancer at intakes greater than 359 mg/day (Hunter et al., 1993). Similarly, a Finnish cohort study (Jarvinen et al., 1997) of 4,697 women aged 15 years and older and the New York State Cohort Study (Graham et al., 1992) of more than 18,000 postmenopausal women with vitamin C intakes up to 498 mg/day found no association between vitamin C intake and breast cancer risk.

        Cervical Cancer. In a case-control study, Wassertheil-Smoller et al. (1981) found high plasma vitamin C concentrations to be associated with decreased cervical cancer risk. Similarly Romney et al. (1985) reported a case-control study showing a negative association between increasing plasma vitamin C concentrations and cervical dysplasia.

        Colorectal Cancer. In a large case-control study, Freudenheim et al. (1990) reported that increased intakes of vitamin C from food and supplements were associated with decreased risk of rectal cancer. In contrast, the Iowa Women's Cohort Study found no association between vitamin C intake and colon cancer risk at intakes from food and supplements of approximately 300 mg/day vitamin C (Bostick et al., 1993). However, in the women consuming more than 60 mg/day vitamin C from supplements compared with no supplements, the risk was decreased by 30 percent.

        Pancreatic Cancer. Two separate case-control studies in Poland (Zatonski et al., 1991) and in Canada (Ghadirian et al., 1991) found that an elevated intake of vitamin C was associated with a decreased risk of pancreatic cancer. A study in the Netherlands, using a similar design, found a protective effect of vitamin C on pancreatic cancer in women but not in men (Bueno de Mesquita et al., 1991). A collaborative pooling of these and other case-control studies in 1992 found evidence overall of an inverse relationship between vitamin C and pancreatic cancer (Howe et al., 1992).

        Lung Cancer. Several studies have considered whether vitamin C might be protective against lung cancer. The results of two large case-control studies in Hawaii found no association between dietary vitamin C intake and lung cancer (Hinds et al., 1984; Le Marchand et al., 1989). In contrast, Fontham et al. (1988) reported that vitamin C intake of approximately 140 mg/day was associated with protection for lung cancer among men and women in Louisiana who were non- or light smokers. Similarly, data from the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study of more than 10,000 men and women indicated that dietary vitamin C intakes greater than 133 mg/day were inversely associated with lung cancer risk (Yong et al., 1997). There was no additional protective effect of vitamin C supplements. This association between vitamin C intake and risk of lung cancer was weaker but still in a protective direction in several studies: a Finnish cohort study of 4,538 men (Knekt et al., 1991); a Dutch cohort study of 561 men (Ocke et al., 1997); a United States prospective study of 3,102 men (Shekelle et al., 1981); and the New York State Cohort Study of 27,544 men (Bandera et al., 1997).

        Gastric Cancer. Epidemiological and experimental evidence has suggested that vitamin C may protect against the development of gastric cancer by inhibiting formation of carcinogenic N -nitroso compounds or by scavenging ROS/RNS in the gastric mucosa (Fontham, 1994; Mirvish, 1994; O'Toole and Lombard, 1996). As noted earlier and summarized in Table 5-2, several experimental studies have linked increased vitamin C status to decreased ROS/RNS activity and oxidant damage products in the gastric mucosa of patients with gastritis and Helicobacter pylori infection (Drake et al., 1996; Dyke et al., 1994a; Mannick et al., 1996). Gastric juice ascorbate concentrations of patients with H. pylori infection and chronic gastritis, risk factors for gastric cancer, are low compared to those of apparently healthy individuals and are increased by eradication of the H. pylori infection or by vitamin C supplementation (Rokkas et al., 1995; Waring et al., 1996). However, H. pylori infection and accompanying inflammation do not alter vitamin C levels or antioxidant potential in the gastroduodenal mucosa (Phull et al., 1999). Despite the epidemiological associations and the evidence that gastric juice vitamin C is protective against nitrosation and oxidant damage, the two vitamin C supplementation studies conducted to date have not shown a subsequent decrease in gastric cancer incidence (Blot et al., 1993; O'Toole and Lombard, 1996).

        Although many of the above studies suggest a protective effect of vitamin C against specific cancers by site, the data are not consistent or specific enough to estimate a vitamin C requirement based on cancer.

        Cataract

        Ocular tissue concentrates vitamin C, which might suggest, teleologically, that the tissue needs this vitamin (Rose et al., 1998). It is reasonable to expect, therefore, that oxidative damage to ocular tissue is an important source of degenerative eye disease and that supplementation by vitamin C would be an effective means of lessening the risk of diseases such as cataract.

        In a case-control comparison of 77 subjects with cataract and 35 control subjects with clear lenses, vitamin C intakes of greater than 490 mg/day were associated with a 75 percent decreased risk of cataracts compared with intakes of less than 125 mg/day (Jacques and Chylack, 1991). Similarly, vitamin C intakes greater than 300 mg/day were associated with a 70 percent reduced risk of cataracts (Robertson et al., 1989). In a second case-control comparison with 1,380 cataract patients and 435 control subjects, similar results were found: although intake numbers were not reported, above-median vitamin C intake was associated with a 20 percent decrease in the risks of cataracts (Leske et al., 1991). In contrast, an analysis of data derived from the Baltimore Longitudinal Study on Aging found no increased association between 260 mg/day of vitamin C and risk of cataracts compared to 115 mg/day (Vitale et al., 1993).

        In an 8-year prospective study, Hankinson et al. (1992) evaluated the experience of more than 50,000 nurses in the Nurses Health Study. Dietary vitamin C intakes were not associated with a decreased risk of cataract, but cataract risk was 45 percent lower among the nurses who consumed vitamin C supplements for 10 or more years. With a cohort of 247 nurses from the above study, vitamin C supplement use, in amounts ranging from less than 400 mg/day to greater than 700 mg/day for 10 years or more, was associated with a statistically significant protective effect on lens opacities (Jacques et al., 1997). Women who consumed vitamin C supplements for less than 10 years were not protected.

        Although many of the above studies suggest a protective effect of vitamin C against cataracts, the data are not consistent or specific enough to estimate the vitamin C requirement based on cataracts.

        Asthma and Obstructive Pulmonary Disease

        It is suspected that vitamin C may decrease the risk of asthma and other related pulmonary conditions (Hatch, 1995). Two cross-sectional studies suggest that high plasma vitamin C concentrations or intakes protect or perhaps enhance respiratory function in men but not in women (Ness et al., 1996) and in both men and women (Britton et al., 1995). Similarly, dietary vitamin C intake was positively associated with enhanced pulmonary function in 2526 adult men and women participants in the First National Health and Nutrition Survey Epidemiological Follow-up Study (Schwartz and Weiss, 1994). In another study, 20 middle-aged men and women patients with mild asthma had decreased ascorbate and α-tocopherol concentrations in lung lining fluid, while blood levels were normal (Kelly et al., 1999). These findings and the presence of increased oxidized glutathione in the airways indicate an increased oxidative stress in asthma patients.

        A series of small, clinical experiments reported that vitamin C supplementation of 2 g/day may be protective against airway responsiveness to viral infections, allergens, and irritants (Bucca et al., 1992). In contrast, a clinical experiment testing the blocking effect of 2 g/day vitamin C against exercise-induced asthma found little evidence of such an effect (Cohen et al., 1997).

        Although many of the above studies suggest a protective effect of vitamin C against asthma and obstructive pulmonary disease, the data are not consistent or specific enough to estimate the vitamin C requirement based on asthma or pulmonary disease.

        Common Cold

        There has been a great deal of interest in the use of vitamin C to protect against the common cold, much of this research stimulated by the views put forth by the late Linus Pauling (Hemila and Herman, 1995). Reviews of numerous studies generally conclude that vitamin C megadoses have no significant effect on incidence of the common cold, but do provide a moderate benefit in terms of the duration and severity of episodes in some groups (Chalmers, 1975; Jariwalla and Harakeh, 1996; Ludvigsson et al., 1977). The often-reported improvement in severity of colds after vitamin C ingestion may be due to the antihistaminic action of the vitamin at pharmacological doses (Johnston et al., 1992). One early study comparing 44 school-aged twins in vulnerability to colds found no significant overall treatment effect of vitamin C intakes at doses of 500 to 1,000 mg/day (Miller et al., 1977). Other trials came to similar conclusions (Coulehan et al., 1976; Ludvigsson et al., 1977). Some reviews have stated that any impact of vitamin C is slight or that it is protective only among some subgroups of people (Hemila, 1996, 1997). Others view the accumulated results as so incomplete and flawed as to offer no evidence of protective effects (Herbert, 1995). Thus, the data are not consistent or specific enough to estimate the vitamin C requirement based on the common cold.

        Cognitive Function and Memory

        Although vitamin C's role as an antioxidant and cofactor for catecholamine biosynthesis might suggest that it protects cognitive function, there is little valid evidence that it does. One study found no association between cognitive function and vitamin C intake (range 84 to 147 mg/day) in 5,182 Dutch residents aged 55 to 95 years (Jama et al., 1996). Another study of 442 men and women, aged 65 to 94 years, reported that higher plasma ascorbate levels were associated with better memory performance (Perrig et al., 1997).

        Summary

        Although several studies have reported an inverse correlation between vitamin C intake and cardiovascular disease, some types of cancer, and cataracts, others have failed to do so. Very little variation in risk is seen based on the intake of vitamin C for chronic obstructive pulmonary disease, cold or infectious disease, or cognitive function and memory. Also it is important that, for all their power, human-based observational or epidemiological studies imply but do not prove cause and effect. Such studies do not rule out the impact of unidentified factors. In a recent review of epidemiological studies, Gey (1998) suggested that plasma vitamin C concentrations as low as 50 µmol/L (1.0 mg/dL) provide the optimal benefits with regard to cardiovascular disease and cancer. This plasma vitamin C concentration is achieved at a dietary intake of approximately 90 mg/day vitamin C (Levine et al., 1996a). Thus, in the United States or Canada, it may be difficult to do a large-scale trial that demonstrates a health benefit for vitamin C unless the subjects are prescreened to have dietary intakes less than 90 mg/day and plasma levels less than than 50 µmol/L (1.0 mg/dL) of vitamin C.

        FACTORS AFFECTING THE VITAMIN C REQUIREMENT

        Bioavailability

        Some 70 to 90 percent of usual dietary intakes of ascorbic acid (30 to 180 mg/day) are absorbed, although absorption decreases to about 50 percent and less with single doses above 1 g (Kallner et al., 1979; Levine et al., 1996b). The type of food consumed has not been shown to have a significant effect on absorption of either intrinsic or supplemental vitamin C. The bioavailability of the vitamin naturally found in foods or in the form of a supplement has not been shown to be significantly different from that of pure synthetic ascorbic acid (Johnston and Luo, 1994; Mangels et al., 1993).

        Nutrient-Nutrient Interactions

        Vitamin C participates in redox reactions with many other dietary and physiological compounds, including glutathione, tocopherol, flavonoids, and the trace metals iron and copper (Jacob, 1995).

        Glutathione

        Interactions of ascorbate with the endogenous antioxidant glutathione have been shown in both rodents and humans. In apparently healthy men fed a low-ascorbate diet of 5 to 20 mg/day, plasma total glutathione (reduced [GSH] and oxidized [GSSG] forms) and the ratio of GSH/GSSG, both indicators of oxidative stress, were significantly decreased (Henning et al., 1991). In apparently healthy adults supplemented with 500 mg/day of ascorbic acid, erythrocyte glutathione rose significantly (Johnston et al., 1993). The results indicate that ascorbate may contribute to antioxidant protection by maintaining reduced glutathione.

        Tocopherol and Flavonoids

        Evidence from in vitro and animal studies has shown that vitamin C can regenerate or spare α-tocopherol (Halpner et al., 1998), but studies in guinea pigs and humans have not confirmed that this interaction occurs to a significant extent in vivo (Jacob et al., 1996). Calculation of redox potentials indicates that ascorbate can recycle the flavonoid radical (Bors et al., 1995), and Skaper et al. (1997) showed that ascorbic acid acts synergistically with the flavonoid quercetin, to protect cutaneous tissue cells in culture against oxidative damage induced by glutathione deficiency.

        Iron and Copper

        A variety of interactions of ascorbate with the redox-active trace metals iron and copper have been reported (the potential pro-oxidant effects are discussed later in the section "Pro-oxidant Effects"). Ascorbic acid is involved in the regulation of iron metabolism at a number of points. Ascorbate-related reduction of iron to the ferrous state is involved in iron transfer and storage pathways. Ascorbic acid added to meals facilitates intestinal absorption of nonheme iron, possibly due to lowering of gastrointestinal iron to the more absorbable ferrous state or amelioration of the effect of dietary iron absorption inhibitors (Hallberg, 1985). However, studies in which the vitamin is added to meals over long periods have not shown significant improvement of body iron status, indicating that ascorbic acid has less effect on iron bioavailability than has been predicted from tests with single meals (Hunt et al., 1994).

        Some evidence indicates that excess ascorbic acid intake may affect copper metabolism in a variety of ways, including inhibition of intestinal absorption and ceruloplasmin oxidase activity and labilization of ceruloplasmin-bound copper for cellular transport (Harris and Percival, 1991). High concentrations of plasma ascorbate in premature infants has been suggested to decrease ceruloplasmin ferroxidase activity and thereby compromise antioxidant protection (Powers et al., 1995). However, the significance of these effects in humans is questionable, because high ascorbate intakes among men on a metabolic unit did not inhibit copper absorption (Jacob et al., 1987b). In addition, the findings of decreased ceruloplasmin ferroxidase activity due to high physiologic ascorbate concentrations have been attributed to an artifact of nonphysiological assay pH (Løvstad, 1997).

        Smoking

        Nearly all studies show that smokers have decreased plasma and leukocyte ascorbate levels compared to nonsmokers. Part of this difference may be attributable to a lower intake of fruits and vegetables among smokers than among nonsmokers (Dallongeville et al., 1998; Marangon et al., 1998). However, studies that have adjusted for differences in vitamin C intake (Marangon et al., 1998) and those which have assessed populations with similar fruit and vegetable intakes (Lykkesfeldt et al., 2000) still find that smokers have lower plasma vitamin C concentrations than nonsmokers. This indicates that smoking per se predisposes to lower vitamin C status.

        Vitamin C Turnover

        The mechanism by which smoking compromises vitamin C status has not been well established. A radioisotope-labeled ascorbic acid dilution study showed that the metabolic turnover of the vitamin in smokers averaged about double that of nonsmokers: 70.0 versus 35.7 mg/day (Kallner et al., 1981). Increased ascorbate turnover in smokers is likely due to the increased oxidative stress from substances in smoke that are directly oxidizing or that stimulate oxidizing inflammatory responses (Elneihoum et al., 1997; Lehr et al., 1997; Pryor, 1997). This hypothesis is supported by the finding that the ratio of dehydroascorbic acid (DHA) to ascorbate in plasma of smokers is increased compared to that in nonsmokers (Lykkesfeldt et al., 1997).

        Most studies have found that smokers suffer increased in vivo oxidation of susceptible biological molecules, including lipids (Morrow et al., 1995; Reilly et al., 1996), lipoproteins (Sasaki et al., 1997), and deoxyribonucleic acid (DNA) (Asami et al., 1997; Panayiotidis and Collins, 1997). In many but not all of these studies, intervention with administration of vitamin C or cessation of smoking decreased the oxidant damage measured. Supplementation of smokers with vitamin C (2 g/day) reduced elevated levels of urinary isoprostanes, a measure of in vivo lipid peroxidation (Reilly et al., 1996). This is consistent with earlier findings that either endogenous or in vitro added ascorbic acid uniquely protected plasma lipids against oxidative damage caused by cigarette smoke (Frei et al., 1991). Large doses of vitamin C (1 g/day or more) provided protection against lymphocyte DNA strand break damage induced ex vivo by radiation with H2O2 (hydrogen peroxide) (Green et al., 1994; Panayiotidis and Collins, 1997). Endogenous DNA strand breaks (in the absence of added H2O2) were not different between smokers and nonsmokers; however, DNA damage due to ex vivo H2O2 addition was significantly greater in smokers than in nonsmokers. Vitamin C at 1 g/day decreased ex vivo DNA damage by about 20 percent in both groups (Panayiotidis and Collins, 1997).

        A few studies have shown no effect of smoking or vitamin C supplementation on oxidizable biomolecules (Marangon et al., 1997, 1998). Supplementation of 21 male smokers with 500 mg/day of vitamin C for 2 months had no effect on urinary excretion of 8-hydroxy-7, 8-dihydro-2′-deoxyguanosine (8-oxodG), a product of oxidative DNA damage (Prieme et al., 1997).

        Endothelial and Hemostatic Dysfunction

        Smokers also suffer from endothelial and hemostatic dysfunctions that are reported to be ameliorated by vitamin C. Some evidence suggests that ascorbate in neurons modulates synthesis of the vasodilator nitric oxide (NO) (Millar, 1995). Since endothelium-dependent, but not endothelium-independent, vasodilation was improved by vitamin C administration in smokers, Heitzer et al. (1996) concluded that vitamin C acts to decrease oxidative stress within the vasculature of smokers by directly scavenging reactive oxygen species (ROS), thereby protecting the endogenous vasodilator NO, among other hypothesized effects. Vitamin C in physiological amounts has been shown to increase by threefold the synthesis of NO by human endothelial cells in culture (Heller et al., 1999). Motoyama et al. (1997) reported that vitamin C infusion improved impaired endothelium-dependent vasodilation in the brachial arteries of smokers, along with a decrease in plasma thiobarbitutic acid reactive substances (TBARS), a nonspecific measure of lipid peroxidation. Smokers with low levels of plasma vitamin C compared to nonsmokers also had increased monocyte adhesion to endothelial cells, which was normalized to that of nonsmokers after oral supplementation with 2 g/day of vitamin C (Weber et al., 1996). A mechanism for the effect of vitamin C on diminishing leukocyte or platelet adhesion and aggregation in smokers is suggested by findings in hamsters, in which the vitamin decreases formation of oxidized phospholipids that induce intravascular adhesion, aggregation, and inflammation (Lehr et al., 1997).

        Pregnancy

        Cigarette smoking also promotes oxidant damage and disturbs vitamin C nutriture in pregnant women. Although vitamin C intakes and serum concentrations were not different between third trimester smokers compared to nonsmokers; breath ethane, a measure of lipid peroxidation, was increased in the smokers and correlated inversely with serum vitamin C in the smokers but not the nonsmokers (Schwarz et al., 1995). There are more than 1015 organic free radicals per puff in gas-phase cigarette smoke (Pryor, 1992). Given the time elapsed between the last cigarette smoked and the breath collection as well as the absence of correlation between breath ethane values and hours since the last cigarette smoked, the breath ethane in pregnant smokers was thought to originate from peroxidation of the smoker's body lipids rather than the smoke itself. In Spanish women in their third trimester, serum vitamin C levels were not different between smokers and nonsmokers, but vitamin C levels were lower in the smokers' milk after parturition (Ortega et al., 1998).

        Environmental Tobacco Smoke

        Increased oxidative stress and ascorbate turnover have also been shown in nonsmoking individuals who are regularly exposed to tobacco smoke in their environment. Environmental or sidestream tobacco smoke provokes oxidant damage similar to mainstream cigarette smoke (Bermudez et al., 1994; Pryor et al., 1983). Plasma ascorbate concentrations of passive smokers were intermediate between those of active smokers and nonsmokers who were not exposed to environmental tobacco smoke, despite similar vitamin C intakes (Tribble et al., 1993). Hypovitaminosis C (plasma ascorbate concentrations less than 23 µmol/L [0.5 mg/dL]) was found in 24 percent of the active smokers and 12 percent of passive smokers and indicated that both passive and active smoke exposure lowered body ascorbate pools. Exposure of nonsmokers to secondhand smoke for 30 minutes in a smoke-filled room resulted in a significant decline in serum ascorbate, increased lipid peroxidation, and oxidatively modified low-density lipoprotein (LDL) (Valkonen and Kuusi, 1998). Although the above data are insufficient to estimate a special requirement for nonsmokers regularly exposed to tobacco smoke, these individuals are urged to ensure that they meet the Recommended Dietary Allowance (RDA) for vitamin C.

        Gender

        In both observational and intervention studies, human plasma or serum ascorbate levels are usually found to be higher in females than in males of the same population. Serum ascorbate concentrations of adult females aged 19 and older were greater than those of males in the same age category as reported in the Third National Health and Nutrition Examination Survey (NHANES III) (Appendix Table F-1). A minority of studies has reported no gender difference in plasma vitamin C levels (Johnston and Thompson, 1998). Although the reported gender differences in blood vitamin C concentrations may be attributed in part to differences in vitamin C intake, studies of elderly populations show that the difference exists over a wide range of vitamin C intakes and remains significant when males and females consuming similar amounts of the vitamin are compared (Garry et al., 1982; Itoh et al., 1989; Jacob et al., 1988; VanderJagt et al., 1987). In a population of elderly English adults (75 years and older), higher fruit consumption by women contributed to but did not entirely account for their higher plasma and leukocyte ascorbate levels compared to men (Burr et al., 1974). However, the latter finding of higher leukocyte ascorbate in women compared to men was not confirmed in a subsequent study, which found no gender differences in leukocyte ascorbate concentrations (Evans et al., 1982).

        Part of the gender difference could be attributed to the larger body and fat-free mass of men compared to women (Baker et al., 1962; Blanchard, 1991a,b; Jacob et al., 1987a). However, since differences in fat-free mass accounted for only 10 to 31 percent of the variation in plasma vitamin C parameters, other unknown genderrelated variables such as hormonal or metabolic effects are needed to explain fully the observed gender differences in vitamin C metabolism (Blanchard, 1991a). The differences are not explained by renal handling of ascorbic acid, since renal clearance parameters of ascorbic acid for both young and elderly adults showed no genderrelated differences (Oreopoulos et al., 1993).

        Overall, the data indicate that women maintain higher plasma ascorbate levels than men at a given vitamin C intake. Although studies were not found that directly compare the vitamin C requirements for men and women, a difference in average vitamin C requirements of men and women is assumed based on mean differences in body size, total body water, and lean body mass.

        FINDINGS BY LIFE STAGE AND GENDER GROUP

        Infants Ages 0 through 12 Months

        Method Used to Set the Adequate Intake

        No functional criteria of vitamin C status have been demonstrated that reflect response to dietary intake in infants. Thus, recommended intakes of vitamin C are based on an Adequate Intake (AI) that reflects the observed mean vitamin C intake of infants fed principally with human milk.

        Human Milk. Human milk is recognized as the optimal milk source for infants throughout at least the first year of life; it is recommended as the sole nutritional milk source for infants during the first 4 to 6 months of life (IOM, 1991). Therefore determination of the AI for vitamin C for infants is based on data from infants fed human milk as the principal fluid during the periods 0 through 6 months and 7 through 12 months of age. The AI is set at the mean value for observed intakes as determined from studies in which the intake of human milk was measured by test weighing volume and the intake of food was determined by dietary records.

        A number of reports of vitamin C content of human milk are available (Table 5-9). In mothers not taking vitamin C supplements, vitamin C in human milk in the first 6 months of lactation varied from 34 mg/L (Bates et al., 1982) to 83 mg/L (Byerley and Kirksey, 1985). In mothers taking vitamin C supplements ranging from 45 to greater than 1,000 mg/day, vitamin C content of human milk varied from 45 to 115 mg/L (Byerley and Kirksey, 1985; Udipi et al., 1985). Thus, the influence of maternal vitamin C intake and its effect on the vitamin C content of human milk are inconclusive (Byerley and Kirksey, 1985; Sneed et al., 1981; Thomas et al., 1979, 1980). The vitamin C content of human milk appears to decline during the first year of life so that by the twelfth month of lactation the vitamin C content is about 8 to 12 percent lower (Karra et al., 1986; Salmenpera, 1984).

        TABLE 5-9. Vitamin C Content in Human Milk.

        In a study of infantile vitamin C intake during prolonged lactation, mean human milk vitamin C concentration decreased from 49.7 ± 10.6 mg/L (SD) at at 4 months of lactation to 44.6 ± 5.6 mg/L (SD) at 9 months of lactation (Salmenpera, 1984). Calculated from the milk concentrations and volumes, the average daily vitamin C intake by these infants was 36 mg/day at 4 and 6 months, and 42 mg/day at 9 months. The plasma concentrations of vitamin C of all infants studied were in the normal range, greater than 34 µmol L (0.6 mg/dL) indicating that exclusively human milk-fed infants are well protected against vitamin C deficiency.

        Ages 0 through 6 Months. The AI for infants 0 through 6 months is based on the average volume of milk intake of 0.78 L/day (Allen et al., 1991; Butte et al., 1984; Heinig et al., 1993), and an average concentration of vitamin C in human milk of 50 mg/L. This is the average vitamin C content of mature milk as assessed by Salmenpera (1984), Sneed et al. (1981), and George and De Francesca (1989) and is in the range of vitamin C content measured in the other studies (Table 5-9). Multiplying this amount by the average intake of human milk at 0 through 6 months, the AI would be 50 mg/L × 0.78 L/day = 39 mg/day vitamin C. Therefore the AI for vitamin C for infants 0 through 6 months of age is 40 mg/day, after rounding.

        This amount is lower than the median intake of 75 mg/day of vitamin C for infants 1 through 6 months as reported in the U.S. Department of Agriculture 1994–1996 Continuing Survey of Food Intake by Individuals (CSFII) where intake data ranged from 4 to 273 mg, (Appendix Table D-1). The latter figure is probably higher than that calculated for an infant fed human milk because the data in CSFII are based on consumption of infant formula plus solid food, and the vitamin C content of proprietary infant formulas is approximately 50 mg/L (FDA, 1985). However, the proposed AI is comparable to vitamin C intakes from human milk-fed German infants whose median intakes were 41 mg/day at 6 months of age (Alexy et al., 1999). These figures are much higher than the amount of vitamin C shown to protect infants from scurvy (7 mg/day) in early studies determining amounts necessary to prevent deficiencies (Goldsmith, 1961; Rajalakshmi et al., 1965; Van Eekelen, 1953).

        Ages 7 through 12 Months. During the second 6 months of life, solid foods become a more important part of the infant diet and add a significant but poorly defined amount of vitamin C to the diet. Although limited data are available for typical vitamin C intakes from foods by infants fed human milk, mean vitamin C intakes from solid foods are 22 mg/day for formula-fed infants (Montalto et al., 1985). For purposes of developing an AI for this age group, it is assumed that infants who are fed human milk have intakes of solid food similar to formula-fed infants of the same age group (Specker et al., 1997). Based on data of Dewey et al. (1984), mean human milk intake during the second 6 months of life would be 0.6 L/day. Thus, vitamin C intake from human milk with a vitamin C concentration of about 45 mg/L at 9 months (the midpoint of this age group) of lactation (Salmenpera, 1984) would be approximately 27 mg/day. Adding the intake from milk (27 mg/day) and food (22 mg/day), the total AI for vitamin C is rounded to 50 mg/day.

        An alternative method to calculate vitamin C intake is to use the method described in Chapter 3 to extrapolate from the AI for infants ages 0 through 6 months who receive human milk. Utilizing this method, the AI for the older infants is rounded up to 50 mg/day of vitamin C. This is comparable to the value calculated above utilizing human milk and solid food.

        The 1994 to 1996 CSFII data for infants 7 through 12 months of age ranged from 21 to 293 mg/day, with median 106 mg/day of vitamin C (Appendix Table D-1).

        Vitamin C AI Summary, Ages 0 through 12 Months

        View in own window

        AI for Infants
        0–6 months 40 mg (227 µmol)/day of vitamin C ≈6 mg/kg
        7–12 months 50 mg (256 µmol)/day of vitamin C ≈6 mg/kg

        Children and Adolescents Ages 1 through 18 Years

        Evidence Considered in Estimating the Average Requirement

        No direct data were found on which to base an Estimated Average Requirement (EAR) for vitamin C for children ages 1 through 18 years. In the absence of additional information, and because vitamin C is a water-soluble vitamin and males have a larger lean body mass and total body water than women, EARs for children and adolescents have been estimated on the basis of relative body weight as described in Chapter 3 using reference weights from Chapter 1 (Table 1-1).

        The Recommended Dietary Allowances (RDAs) estimated below for children 1 through 13 years of age are lower than the AIs calculated above for infants 0 through 12 months of age. The reason an AI may be higher than an RDA lies in the way they are determined (see "Differences Between the AI and the RDA" in Chapter 1). The AI is based on data on milk composition and volume of milk consumed to calculate an adequate intake of infants. The vitamin C RDA, in the case of 1- through 13-year-old children, is based on assumed differences in body weight from adults for whom there are some data. Thus, the data that are utilized to estimate the AI and RDA are different and cannot be compared.

        Vitamin C EAR and RDA Summary, Ages 1 through 18 Years

        View in own window

        EAR for Children
        1–3 years 13 mg (74 µmol)/day of vitamin C
        4–8 years 22 mg (125 µmol)/day of vitamin C
        EAR for Boys
        9–13 years 39 mg (222 µmol)/day of vitamin C
        14–18 years 63 mg (358 µmol)/day of vitamin C
        EAR for Girls
        9–13 years 39 mg (222 µmol)/day of vitamin C
        14–18 years 56 mg (318 µmol)/day of vitamin C

        The RDA for vitamin C is set by assuming a coefficient of variation (CV) of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement for vitamin C; the RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for vitamin C the RDA is 120 percent of the EAR). The calculated values for RDAs have been rounded to the nearest 5 mg.

        View in own window

        RDA for Children
        1–3 years 15 mg (85 µmol)/day of vitamin C
        4–8 years 25 mg (142 µmol)/day of vitamin C
        RDA for Boys
        9–13 years 45 mg (256 µmol)/day of vitamin C
        14–18 years 75 mg (426 µmol)/day of vitamin C
        RDA for Girls
        9–13 years 45 mg (256 µmol)/day of vitamin C
        14–18 years 65 mg (370 µmol)/day of vitamin C

        Adults Ages 19 through 50 Years

        Evidence Considered in Estimating the Average Requirement

        Although it is known that the classic disease of severe vitamin C deficiency, scurvy, is rare in the United States and Canada, other human experimental data that can be utilized to set a vitamin C requirement, based on a biomarker other than scurvy, are limited. Values recommended here are based on an amount of vitamin C that is thought to provide antioxidant protection as derived from the correlation of such protection with neutrophil ascorbate concentrations.

        It is recognized that there are no human data to quantify directly the dose-response relationship between vitamin C intake and in vivo antioxidant protection. In addition, only one study (Levine et al., 1996a) with seven apparently healthy males reported plasma, neutrophil, and urinary ascorbate concentrations during vitamin C depletion and repletion to steady state. Thus, there are wide uncertainties in the data utilized to estimate the vitamin C requirements. However, in the absence of other data, maximal neutrophil concentration with minimal urinary loss appears to be the best biomarker at the present time. It must be emphasized that research is urgently needed to explore the use of other biomarkers to assess vitamin C requirements.

        Antioxidant Protection

        The evidence summarized in the preceding sections indicates that vitamin C functions in vivo to scavenge reactive oxidants in activated leukocytes, lung, and gastric mucosa, and to protect against lipid peroxidation. Therefore, the determination of an EAR for vitamin C is based on an amount estimated to provide antioxidant protection. Evidence summarized in the earlier section "Antioxidant Functions in Leukocytes" indicates that the vitamin's antioxidant function in leukocytes, which includes neutrophils, lymphocytes, and monocytes, is especially important. In addition, studies with guinea pigs and monkeys show that the concentration of ascorbate in the leukocytes more accurately reflects liver and body pool ascorbate than does the concentration in plasma or erythrocytes (Omaye et al., 1987). The vitamin is transported into leukocytes by an energy-dependent transport system that concentrates the vitamin some 25, 40, and 80 times higher than plasma levels in neutrophils, platelets, and lymphocytes, respectively (Evans et al., 1982; Jacob et al., 1992; Levine et al., 1996a).

        The cells actively concentrate the vitamin, which serves as a cellular reservoir of reducing capacity and scavenges damaging phagocyte-derived oxidants such as superoxide and myeloperoxidase-derived hypochlorus acid (HOCl) and reactive nitrogen species (RNS). In both the cell-free and the activated neutrophil systems described earlier, the protection of α-1-antiprotease against inactivation by HOCl (Halliwell et al., 1987) and the inhibition of super-oxide production (Anderson and Lukey, 1987) were directly proportional to ascorbate concentrations within the normal range of plasma ascorbate concentrations (22 to 85 µmol/L [0.4 to 1.5 mg/dL]). Data plotted in Figure 5-2 show that superoxide production by activated neutrophils was inhibited 29, 44, 52, and 55 percent by extracellular ascorbate concentrations of 28, 57, 114, and 284 µmol/L (0.5, 1.1, 2.2, and 5.0 mg/dL), respectively, without any effect on intracellular bacterial killing (Anderson and Lukey, 1987). This indicates that antioxidant protection is increasingly provided as ascorbate concentrations increase, with the greatest change in protection seen for ascorbate concentrations between 28 and 57 µmol/L (0.5 and 1.0 mg/dL).

        FIGURE 5-2. The effect of varying extracellular ascorbate concentrations on inhibition of superoxide produced by activated neutrophils.

        FIGURE 5-2

        The effect of varying extracellular ascorbate concentrations on inhibition of superoxide produced by activated neutrophils. The range of normal human plasma ascorbate concentrations is shown within the arrows. SOURCE: Adapted from Anderson and Lukey (1987). (more...)

        Although similar dose-response data for leukocyte ascorbate levels are not available, the limited data from Levine et al. (1996a), seen in Figure 5-3 and Figure 5-4, show that plasma and neutrophil ascorbate concentrations are both directly related to vitamin intake between about 50 and 90 mg/day. The concentrations were measured by a sensitive high-pressure liquid chromatography assay with electrochemical detection. Therefore, increasing neutrophil ascorbate concentrations within this range should provide for increased protection against phagocyte-derived oxidant damage.

        FIGURE 5-3. Steady-state plateau ascorbic acid concentrations (µmol/L) in plasma as a function of daily dose.

        FIGURE 5-3

        Steady-state plateau ascorbic acid concentrations (µmol/L) in plasma as a function of daily dose. Values are the means of plateau ascorbic acid concentrations from up to seven volunteers. SOURCE: Adapted from Levine et al. (1996a).

        FIGURE 5-4. Neutrophil ascorbic acid concentrations (mmol/L) as a function of dose.

        FIGURE 5-4

        Neutrophil ascorbic acid concentrations (mmol/L) as a function of dose. SOURCE: Adapted from Levine et al. (1996a).

        There are no data to quantify directly the dose-response relation between vitamin C intake and in vivo antioxidant protection. Therefore, the criterion chosen for the EAR is the vitamin C intake that maintains near-maximal neutrophil vitamin C concentrations with minimal urinary loss. Since leukocyte ascorbate, which includes neutrophil ascorbate, correlates well with liver and body pool ascorbate (Omaye et al., 1987), this criterion should provide for adequate in vivo antioxidant protection to body tissues while minimizing excess urinary vitamin excretion. Vitamin C intakes greater than the urinary excretion threshold provide little or no increase in the ascorbate body pool (Baker et al., 1969; Kallner et al., 1979). A vitamin C intake that meets the above criteria is estimated from a controlled vitamin C dose-response study described below.

        Depletion-Repletion Study

        The requirement for vitamin C based on the above criteria can be estimated from the data reported by Levine et al. (1996a) in which plasma, neutrophil, and urinary ascorbate concentrations were determined during vitamin C depletion and repletion to steady-state. The rigorous criteria for achieving steady-state plasma concentrations (five daily samples that varied less than or equal to 10 percent) make the Levine et al. (1996a) data unique among depletion-repletion studies.

        Seven apparently healthy male volunteers, aged 20 to 26 years, were studied as in-patients for 4 to 6 months. Subjects were depleted by being fed a diet containing less than 5 mg/day vitamin C. Depletion was defined as completed when plasma vitamin C concentrations ranged from 5 to 10 µmol/L (0.1 to 0.2 mg/dL) without signs or symptoms of scurvy. For repletion, seven consecutive doses of vitamin C (30, 60, 100, 200, 400, 1,000, and 2,500 mg/day) were given sequentially until steady-state plasma and leukocyte (neutrophils, monocytes, and lymphocytes) vitamin C concentrations were achieved at each dosage. The results for plasma and neutrophil concentrations can be seen in Figure 5-3 and Figure 5-4, and Table 5-10.

        TABLE 5-10. Intracellular Ascorbic Acid Concentration in Neutrophils of Depleted Subjects Given Increasing Doses of Vitamin C (mmol/L).

        TABLE 5-10

        Intracellular Ascorbic Acid Concentration in Neutrophils of Depleted Subjects Given Increasing Doses of Vitamin C (mmol/L).

        As seen in Figure 5-4 and Table 5-10, the ascorbate saturation concentration in neutrophils was approximately 1.3 mmol/L. This was attained by four of the seven subjects at a vitamin C intake of 100 mg/day. Monocytes and lymphocytes also reached maximum concentrations at 100 mg/day (Levine et al., 1996a). However, at neutrophil saturation, about 25 percent of the doses were excreted in the urine, whereas at 60 percent of maximum ascorbate (dose of 60 mg/day), essentially no ascorbate was excreted.

        No data from the Levine at al. (1996a) study are available for vitamin C intakes between 60 and 100 mg/day. However, because 60 percent of maximal ascorbate concentration in neutrophils would provide less antioxidant protection than 80 or 100 percent (Figure 5-2) (Anderson and Lukey, 1987), and since 25 percent of the dose is excreted at 100 percent of maximum neutrophil ascorbate concention, the midpoint 80 percent of maximum (1.0 mmol/L) was chosen. This is assuming that antioxidant protection in this range is linear. This point should better estimate an approximate neutrophil target concentration that fulfills the criteria of adequate in vivo antioxidant protection with little or no urinary loss. From the equation of Figure 5-4, 80 percent of maximal neutrophil concentration (1.0 mmol/L) is equivalent to a vitamin C intake of about 75 mg/day. This represents an EAR, because 80 percent (1.0 mmol/L) neutrophil concentration is an average value, estimated by regression analysis, for the men consuming 75 mg/day of vitamin C as shown in Table 5-10.

        Relevancy of Above EAR to Other Possible Vitamin C Biomarkers

        Scurvy. As discussed earlier, scurvy occurs at plasma concentrations of less than 10 µmol/L. At an EAR of 75 mg/day, scurvy would be prevented for more than a month if vitamin C ingestion were to cease suddenly (Levine et al., 1996b).

        Body Pool Saturation. Kallner et al. (1979) previously reported that the body pool of vitamin C was saturated at an intake of 100 mg/day in healthy non-smoking men; thus, an average intake at the EAR of 75 mg/day would not provide body pool saturation of vitamin C.

        Antioxidant Role. At a vitamin C intake of 90 mg/day, the plasma ascorbate concentration reaches 50 µmol/L which has been shown to inhibit LDL oxidation in vitro in both cellular and cell free systems (Jialal et al., 1990). Although it is not known whether vitamin C prevents LDL oxidation in vivo, if it does this might be relevant in the prevention of heart disease (Jialal et al., 1990). Also, as discussed earlier, since neutrophils are at 80 percent saturation at an EAR of 75 mg/day, this should potentially protect intracellular proteins from oxidative injury when these cells are activated during infectious and inflammatory processes (Anderson and Lukey, 1987; Halliwell et al., 1987).

        Plasma Vitamin C Concentrations. Based on data from the Third National Health and Nutrition Examination Survey (NHANES III), although more than 75 percent of adult men have dietary vitamin C intakes higher than the EAR of 75 mg/day (Appendix Table C-1), only 50 percent have plasma vitamin C concentrations greater than 38 µmol/L (0.67 mg/dL) (Appendix Table F-1). This plasma concentration is estimated from the data of Levine et al. (1996a) to correspond to an intake of 75 mg/day of vitamin C (Figure 5-3). This finding is not surprising since the NHANES III vitamin C plasma concentrations are for both smokers and nonsmokers, and it is known that plasma vitamin C concentrations are reduced by about 40 percent in male smokers (Pelletier, 1977; Weber et al., 1996). In addition, as discussed in the earlier section "Environmental Tobacco Smoke," exposure of nonsmokers to environmental tobacco smoke can result in a decline in plasma ascorbate concentrations (Tribble et al., 1993; Valkonen and Kuusi, 1998). Findings from the first three years (1988 to 1991) of NHANES III indicate that 38 percent of the participants were smokers and an additional 23 percent were nonsmokers exposed to environmental tobacco smoke at home or work (Pirkle et al., 1996).

        Vitamin C EAR and RDA Summary, Ages 19 through 50 Years

        Based on vitamin C intakes sufficient to maintain near-maximal neutrophil concentrations with minimal urinary loss, the data of Levine et al. (1996a) support an EAR of 75 mg/day of vitamin C for men. Since the data were based on men and no similar data are available for women at the present time, it is assumed that women will have a lower requirement due to their smaller lean body mass, total body water, and body size. This assumption is supported by the findings previously discussed that women maintain higher plasma ascorbate concentrations than men at a given vitamin C intake. Thus, the requirement for women is extrapolated based on body weight differences from those established for men (see Table 1-1).

        View in own window

        EAR for Men
        19–30 years 75 mg (426 µmol)/day of vitamin C
        31–50 years 75 mg (426 µmol)/day of vitamin C
        EAR for Women
        19–30 years 60 mg (341 µmol)/day of vitamin C
        31–50 years 60 mg (341 µmol)/day of vitamin C

        The RDA for vitamin C is set by assuming a coefficient of variation (CV) of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement for vitamin C; the RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for vitamin C the RDA is 120 percent of the EAR). Due to the many assumptions and approximations involved, the RDA for women is rounded up to 75 mg from its calculated value of 72 mg/day.

        View in own window

        RDA for Men
        19–30 years 90 mg (511 µmol)/day of vitamin C
        31–50 years 90 mg (511 µmol)/day of vitamin C
        RDA for Women
        19–30 years 75 mg (426 µmol)/day of vitamin C
        31–50 years 75 mg (426 µmol)/day of vitamin C

        Adults Ages 51 Years and Older

        Evidence Considered in Estimating the Average Requirement

        Some cross-sectional studies have shown that vitamin C status, as measured by plasma and leukocyte ascorbate concentrations, is lower in the elderly, especially institutionalized elderly, than in young adults (Burr et al., 1974; Cheng et al., 1985). Low blood vitamin C concentrations in institutionalized and chronically ill elderly were normalized to those of active elderly and young adults by increasing their dietary vitamin C intake, suggesting that the low levels were primarily due to poor intake (Newton et al., 1985). However, Davies et al. (1984) found that intestinal absorption of a 500-mg oral dose of ascorbic acid, as measured by urinary ascorbate excretion, was significantly less in elderly (mean age 83 years) than in younger subjects (mean age 22 years). Although this dose (500 mg/day) was about 5 times higher than the vitamin C intake of many elderly individuals, it prompted the suggestion that impaired intestinal absorption may be an important causative factor in low blood concentrations of vitamin C in the elderly.

        However, other studies, both cross-sectional and longitudinal, of apparently healthy, well-nourished elderly populations in the United States have not found evidence of a greater incidence of vitamin C deficiency among the elderly compared to young adults and no decrease in plasma ascorbate with advancing age (Garry et al., 1982, 1987; Jacob et al., 1988). Measurement of plasma, leukocyte, and urine ascorbate concentrations in a series of studies in elderly and young men and women showed no differences due to age (Blanchard, 1991a; Blanchard et al., 1989, 1990a,b). These studies included pharmacokinetic measures related to vitamin C absorption, depletion, repletion, and renal clearance. Consistent with these findings, a later study that measured maximal renal tubular reabsorption and excretion thresholds of ascorbic acid in apparently healthy elderly and young adults found no differences in renal handling of the vitamin between the two groups (Oreopoulos et al., 1993).

        Older age groups, both men and women, have decreased lean body mass compared to younger individuals and thus, potentially a lower requirement for vitamin C. However, the vitamin C requirement of the elderly may be increased due to the oxidative stress of inflammatory and infectious conditions often found in this population (Cheng et al., 1985). As previously discussed, older adults have similar or lower plasma ascorbate concentrations than young adults. Therefore, the estimated requirement for vitamin C for individuals 51 years and older will remain the same as that of the younger adult.

        Vitamin C EAR and RDA Summary, Ages 51 Years and Older

        In summary, no consistent differences in the absorption or metabolism of ascorbic acid due to aging have been demonstrated at median vitamin C intakes. This suggests that the reports of low blood vitamin C concentrations in elderly populations may be due to poor dietary intakes, chronic disease or debilitation, or other factors, rather than an effect of aging per se. Therefore, for the older adults, no additional vitamin C allowance beyond that of younger adults is warranted.

        View in own window

        EAR for Men
        51–70 years 75 mg (426 µmol)/day of vitamin C
        >70 years 75 mg (426 µmol)/day of vitamin C
        EAR for Women
        51–70 years 60 mg (341 µmol)/day of vitamin C
        >70 years 60 mg (341 µmol)/day of vitamin C

        The RDA for vitamin C is set by assuming a coefficient of variation (CV) of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement for vitamin C; the RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for vitamin C the RDA is 120 percent of the EAR). As with the RDA for younger women, the calculated RDA of 72 mg has been rounded up to 75 mg/day.

        View in own window

        RDA for Men
        51–70 years 90 mg (511 µmol)/day of vitamin C
        >70 years 90 mg (511 µmol)/day of vitamin C
        RDA for Women
        51–70 years 75 mg (426 µmol)/day of vitamin C
        >70 years 75 mg (426 µmol)/day of vitamin C

        Pregnancy

        Evidence Considered in Estimating the Average Requirement

        Plasma vitamin C concentration decreases with the progression of pregnancy, probably secondary to hemodilution (Morse et al., 1975) as well as active transfer to the fetus (Choi and Rose, 1989). This decrease in plasma concentration has not been shown to be associated with poor pregnancy outcomes. The placenta apparently clears oxidized ascorbic acid from the maternal circulation and delivers it in the reduced form to the fetus (Choi and Rose, 1989). Ascorbic acid deficiency during pregnancy is associated with increased risk of infections, premature rupture of the membranes (Casanueva et al., 1993; Pfeffer et al., 1996), premature birth (Casanueva et al., 1993; Tlaskal and Novakova, 1990), and eclampsia (Jendryczko and Tomala, 1995). In addition, both serum and amniotic fluid concentrations of ascorbic acid are decreased in pregnant smokers compared to nonsmokers (Barrett et al., 1991).

        Vitamin C EAR and RDA Summary, Pregnancy

        Although the amount of vitamin C required by the growing fetus is unknown, it is known that maternal plasma vitamin C concentration decreases with the progression of pregnancy due to hemodilution as well as active transfer to the fetus. Therefore, in order to transfer adequate vitamin C to the fetus, additional vitamin C is needed during pregnancy. In the absence of data on near maximal neutrophil saturation during pregnancy, the method of determining the EAR for pregnancy is based on adding the EAR for near-maximal neutrophil concentration of the nonpregnant woman to the amount of vitamin C necessary to transfer adequate vitamin C to the fetus. In the absence of precise data regarding transfer of maternal vitamin C to the fetus, and with the knowledge that intakes of 7 mg/day of vitamin C will prevent young infants from developing scurvy (Goldsmith, 1961; Rajalakshmi et al., 1965; van Eekelen, 1953), the EAR for pregnancy was estimated to increase 10 mg/day over the vitamin C requirement for the nonpregnant woman.

        View in own window

        EAR for Pregnancy
        14–18 years 66 mg (375 µmol)/day of vitamin C
        19–30 years 70 mg (398 µmol)/day of vitamin C
        31–50 years 70 mg (398 µmol)/day of vitamin C

        The RDA for vitamin C is set by assuming a coefficient of variation (CV) of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement for vitamin C; the RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for vitamin C the RDA is 120 percent of the EAR). The calculated values for the pregnancy RDA have been rounded up to the nearest 5 mg.

        View in own window

        RDA for Pregnancy
        14–18 years 80 mg (454 µmol)/day of vitamin C
        19–30 years 85 mg (483 µmol)/day of vitamin C
        31–50 years 85 mg (483 µmol)/day of vitamin C

        Special Considerations

        Certain subpopulations of pregnant women may have increased requirements for vitamin C. This group includes users of street drugs and cigarettes, heavy users of alcohol, and regular users of aspirin (Flodin, 1988). Women who smoke more than 20 cigarettes per day may require twice as much vitamin C as nonsmokers to maintain a replete body pool of vitamin C (Kallner et al., 1981). It has been reported that plasma vitamin C in pregnant smokers exhibited an indirect correlation with the breath content of ethane, a volatile marker of lipid peroxidation, even though the pregnant women were receiving supplements with 320 mg/day of vitamin C (Schwarz et al., 1995). Thus, pregnant women in these special sub-populations should consume additional vitamin C.

        Lactation

        Evidence Considered in Estimating the Average Requirement

        As indicated earlier, infants fed human milk are estimated to consume on average 40 mg/day vitamin C during the first 6 months of life. Salmenpera (1984) reported that the vitamin C intake of 47 mothers during prolonged lactation ranged from 48 to 277 mg/day, mean 138 mg/day. Three mothers in this study who consumed less than 100 mg/day of vitamin C demonstrated plasma ascorbate values below the lower limit of normal [less than 10 µmol/L (0.2 mg/dL)]. Women who consumed 100 to 199 mg/day of vitamin C produced milk with 100 mg/L of vitamin C (Byerley and Kirksey, 1985). Maternal vitamin C intake in excess of 200 mg/day resulted in increased urinary excretion of vitamin C but did not increase the content of the vitamin in human milk (Byerley and Kirksey, 1985). It is thought that a regulatory mechanism in the mammary gland prevents the elevation of milk vitamin C concentrations beyond that level seen when urinary execretion increases representing blood saturation (Byerley and Kirksey, 1985).

        Vitamin C EAR and RDA Summary, Lactation

        To estimate the EAR for lactation, the average vitamin C produced in milk, 40 mg/day during the first 6 months of lactation, is added to the EAR for the nonlactating women. Although the vitamin C content of human milk declines with length of lactation and milk volume declines with the addition of solid foods, the EAR is not decreased for longer periods of lactation.

        View in own window

        EAR for Lactation
        14–18 years 96 mg (545 µmol)/day of vitamin C
        19–30 years 100 mg (568 µmol)/day of vitamin C
        31–50 years 100 mg (568 µmol)/day of vitamin C

        The RDA for vitamin C is set by assuming a coefficient of variation (CV) of 10 percent (see Chapter 1) because information is not available on the standard deviation of the requirement for vitamin C; the RDA is defined as equal to the EAR plus twice the CV to cover the needs of 97 to 98 percent of the individuals in the group (therefore, for vitamin C the RDA is 120 percent of the EAR).

        View in own window

        RDA for Lactation
        14–18 years 115 mg (653 µmol)/day of vitamin C
        19–30 years 120 mg (682 µmol)/day of vitamin C
        31–50 years 120 mg (682 µmol)/day of vitamin C

        Special Considerations

        Smokers

        Evidence that smokers have lower vitamin C status than nonsmokers, even with comparable vitamin C intakes, is summarized in the preceding section "Factors Affecting the Vitamin C Requirement." The data also show that the metabolic turnover of ascorbate in smokers is about 35 mg/day greater than in nonsmokers (Kallner et al., 1981), apparently due to increased oxidative stress and other metabolic differences. These findings indicate that smokers need additional vitamin C to provide comparable nutriture to nonsmokers.

        From analysis of NHANES II data on vitamin C intakes and serum concentrations, Schectman et al. (1991) estimated that the average intake of smokers needed to be at least 200 mg/day of vitamin C in order to attain serum ascorbate concentrations equivalent to those of nonsmokers who meet the 1989 RDA of 60 mg/day (NRC, 1989). Use of population survey data to estimate an increased ascorbate requirement for smokers is questionable, because the cause and significance of the observed differences in serum ascorbate concentrations between smokers and nonsmokers are largely unknown.

        From in vitro data on the loss of ascorbate in plasma exposed to cigarette smoke, it was estimated that one cigarette may consume about 0.8 mg of ascorbate, or about 32 mg/day for a two-pack-a-day smoker (Cross and Halliwell, 1993). More precise data were obtained from an experimental study of 17 apparently healthy male smokers who were administered radiolabeled tracer ascorbic acid at steady-state intakes of 30 to 180 mg/day to allow kinetic calculations of ascorbate metabolism and body pools. Results were compared with a similar protocol for nonsmokers (Kallner et al., 1979, 1981). Metabolic turnover of the vitamin was about 35 mg/day greater in smokers than in nonsmokers. Thus, to obtain a near maximal steady-state ascorbate body pool equivalent to that of nonsmokers, smokers would require an additional 35 mg/day of vitamin C over that needed by nonsmokers.

        Passive Smokers

        Environmental or sidestream tobacco smoke provokes oxidant damage similar to mainstream cigarette smoke (Bermudez et al., 1994; Pryor et al., 1983). Hypovitaminosis C (plasma ascorbate concentrations less than 23 µmol/L [0.5 mg/dL]) was found in 24 percent of the active smokers and 12 percent of passive smokers and indicated that both passive and active smoke exposure lowered body ascorbate pools (Tribble et al., 1993). Exposure of nonsmokers to secondhand smoke for 30 minutes in a smoke-filled room resulted in a significant decline in serum ascorbate, increased lipid peroxidation, and oxidatively modified low-density lipoprotein (LDL) (Valkonen and Kuusi, 1998). Although the above data are insufficient to estimate a special requirement for nonsmokers regularly exposed to tobacco smoke, these individuals are urged to ensure that they meet the Recommended Dietary Allowance (RDA) for vitamin C.

        Exercise and Stress

        The role of ascorbate as a cofactor for biosynthesis of carnitine, steroid hormones, and neurotransmitters provides a theoretical basis for increased requirements of the vitamin in persons under excessive physical and emotional stress. Studies of vitamin C status and physical activity in humans have shown mixed results, such that no definitive conclusion regarding vitamin C and exercise can be derived (Keith, 1994). For example, Fishbaine and Butterfield (1984) reported that blood vitamin C was higher in runners compared to sedentary control subjects, while a later study found that the vitamin C status of highly trained athletes was not significantly different from control subjects (Rokitzki et al., 1994). A cross-sectional study of physical activity, fitness, and serum ascorbate in 1,600 apparently healthy Irish adults provided no evidence that active people had different ascorbate status than inactive, and thus no justification for supplementation of exercisers (Sharpe et al., 1994). No substantial evidence that mental or emotional stress increases vitamin C turnover or requirement in apparently healthy persons has been reported. In sum, none of the above types of stress has been demonstrated to affect the human requirement for vitamin C.

        INTAKE OF VITAMIN C

        Food Sources

        Almost 90 percent of vitamin C in the typical diet comes from fruits and vegetables, with citrus fruits, tomatoes and tomato juice, and potatoes being major contributors (Sinha et al., 1993). Other sources include brussel sprouts, cauliflower, broccoli, strawberries, cabbage, and spinach. Vitamin C is also added to some processed foods as an antioxidant. Values for the vitamin C content of foods can vary depending on the growing conditions, season of the year, stage of maturity, location, cooking practices, and storage time prior to consumption (Erdman and Klein, 1982).

        Dietary Intake

        Data from nationally representative U.S. and Canadian surveys are available to estimate vitamin C intakes (Appendix Table C-1, Table D-1, and Table E-1). In the United States, the median dietary intake of vitamin C by adult men from 1988 to 1994 was about 105 mg (596 µmol)/day and median total intake (including supplements, see Appendix Table C-2) is about 120 mg (682 µmol)/day. For women, the median intake was estimated to be 90 mg (511 µmol)/day and median total intake (including supplements) is about 108 mg (613 µmol)/day. (See Chapter 9 for vitamin C intake of men and women who smoke.) In Canada, the median dietary intake of vitamin C for adult men and woman was lower than in the United States with intake estimated to be about 70 mg (397 µmol)/day (Appendix Table E-1). Although most Americans consume fewer than the minimum of five daily servings of fruits and vegetables recommended by the U.S. Department of Agriculture and the National Cancer Institute, estimated median daily vitamin C consumption is above the Estmated Average Requirement (EAR). Five servings of most fruits and vegetables provide more than 200 mg (1,136 µmol)/day of vitamin C per day.

        The Boston Nutritional Status Survey of the Elderly estimated that among this relatively advantaged group of people over aged 60, those who were not taking supplements had a median vitamin C intake of 132 mg/day for males and 128 mg/day for females (Hartz et al., 1992).

        Intake from Supplements

        Information from the Boston Nutritional Status Survey of the Elderly estimated that 35 and 44 percent of the males and females, respectively, took some form of vitamin C supplements; while 19 percent of males and 15 percent of females surveyed who took supplements had intakes greater than 1,000 mg (5,680 µmol)/day. Approximately 31 percent of all adults in one 1986 survey reported taking a vitamin C supplement (Moss et al., 1989). Total vitamin C intakes from food plus supplements from the Third National Health and Nutrition Examination Survey (NHANES III) are found in Appendix Table C-2.

        TOLERABLE UPPER INTAKE LEVELS

        The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects in almost all individuals. Although members of the general population should be advised not to exceed the UL routinely, intake above the UL may be appropriate for investigation within well-controlled clinical trials. In light of evaluating possible benefits to health, clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxicity and as long as these trials employ appropriate safety monitoring of trial subjects. Also, the UL is not meant to apply to individuals who are receiving vitamin C under medical supervision.

        Hazard Identification

        Adverse Effects

        Many people believe vitamin C to be nontoxic and beneficial to health; therefore, the vitamin is often taken in large amounts. There is no evidence suggesting that vitamin C is carcinogenic or teratogenic or that it causes adverse reproductive effects. Reviews of high vitamin C intakes have indicated low toxicity (Johnston, 1999); adverse effects have been reported primarily after very large doses (greater than 3 g/day). Data show little increase in plasma steady-state concentrations at intakes above 200 mg/day (Figure 5-3), and saturable intestinal absorption and renal tubular reabsorption data suggest that overload of ascorbic acid is unlikely in humans (Blanchard et al., 1997; Levine et al., 1996a). Possible adverse effects associated with very high intakes have been reviewed and include:diarrhea and other gastrointestinal disturbances, increased oxalate excretion and kidney stone formation, increased uric acid excretion, pro-oxidant effects, systemic conditioning ("rebound scurvy"), increased iron absorption leading to iron overload, reduced vitamin B12 and copper status, increased oxygen demand, and erosion of dental enamel (Hornig and Moser, 1981; Rivers, 1987). The data on these adverse effects are reviewed below. The UL for vitamin C applies to intake from both food and supplements.

        Gastrointestinal Effects. Gastrointestinal disturbances such as nausea, abdominal cramps, and diarrhea are the most common adverse effects of high vitamin C intake (Hoffer, 1971). These effects are attributed to the osmotic effect of unabsorbed vitamin C passing through the intestine. Intestinal absorption of ascorbic acid occurs by a saturable process (Rumsey and Levine, 1998; Tsao, 1997). The remainder is not absorbed and is eliminated in the stool. The evidence of gastrointestinal disturbances following high vitamin C intakes is primarily from uncontrolled case reports (Hoffer, 1971; Hoyt, 1980). However, some studies have been conducted to evaluate gastrointestinal effects. Cameron and Campbell (1974) reported diarrhea, transient colic, and flatulent distension in normal healthy volunteers at doses of 3 to 4 g/day. Another study, which evaluated the adverse effects of 1-, 5-, and 10-g/day supplemental ascorbate for 5 days in apparently healthy adults, reported diarrhea in 2 of 15 subjects at 10 g/day (Wandzilak et al., 1994). Stein et al. (1976) reported mild diarrhea in one of three subjects following ingestion of 4 g of ascorbic acid.

        Increased Oxalate Excretion and Kidney Stone Formation. Controversy exists as to whether increased intake of vitamin C can significantly increase urinary excretion of oxalate and, therefore, lead to an increase in the potential for renal calcium oxalate stone formation. The findings from studies evaluating the effect of vitamin C intake (0.03 to 10 g/day) on urinary oxalate excretion in apparently healthy individuals are conflicting (Hughes et al., 1981; Lamden and Chrystowski, 1954; Levine et al., 1996a; Mitch et al., 1981; Schmidt et al., 1981; Tiselius and Almgard, 1977; Tsao and Salimi, 1984; Wandzilak et al., 1994). An intervention study by Hughes et al. (1981) reported significant increases in mean urinary oxalate excretion in 39 apparently healthy adults consuming 1, 3, 6, and 9 g/day of ascorbic acid. However, Tsao and Salimi (1984) reported normal plasma oxalate concentrations in healthy subjects ingesting 3–10 g/day of ascorbic acid for at least two years, and no significant change in urinary oxalate excretion in five of six subjects who consumed 10 g/day of vitamin C over 1 day. Levine et al. (1996a) showed increased urinary oxalate excretion in apparently healthy male volunteers consuming 1 g/day of ascorbic acid; however, mean oxalate concentrations remained within the reference range. None of these studies showed oxalate excretion above normal.

        Reports of kidney stone formation associated with excess ascorbic acid intake are limited to individuals with renal disease (see Sauberlich, 1994 for a review). Data from epidemiological studies do not support an association between excess ascorbic acid intake and kidney stone formation in apparently healthy individuals (Curhan et al., 1996, 1999; Fellstrom et al., 1989). A prospective cohort study by Curhan et al. (1996) of 45,000 men aged 40 to 70 years with no history of renal calculi showed that vitamin C intake was not significantly associated with the risk of stone formation. In fact, the age-adjusted relative risk for men consuming 1,500 mg/day or more compared to less than 250 mg/day was 0.78. In addition, vitamin C intake was not associated with kidney stone formation in women (Curhan et al., 1999). The lack of findings on oxalate excretion and kidney stone formation may be explained by the limited absorption of vitamin C at doses greater than 200 mg/day (Levine et al., 1996a). Because of the limited intestinal absorption, limited amounts of vitamin C are metabolized to oxalate in the urine. In addition, the large majority of excess absorbed vitamin C is excreted in the urine as ascorbic acid rather than its degradation products.

        Increased Uric Acid Excretion. Similarly, the effect of high ascorbic acid intake on urate excretion has been studied (Berger et al., 1977; Fituri et al., 1983; Hatch et al., 1980; Herbert, 1978; Levine et al., 1996a; Mitch et al., 1981; Schmidt et al., 1981; Stein et al., 1976). Theoretically, increased uric acid excretion could be an important factor in the formation of uric acid stones especially in subjects who normally excrete large amounts of uric acid. The findings are conflicting. Levine et al. (1996a) reported significantly increased uric acid excretion above the normal range following ascorbic acid intakes of 1 g/day or more in 7 apparently healthy male subjects. Another study reported a 70 to 90 percent increase in the fractional clearance of uric acid following a single 4-g dose in nine subjects (Stein et al., 1976). Other studies have shown no significant effect of ascorbic acid intakes up to 12 g/day on uric acid excretion in apparently healthy subjects (Fituri et al., 1983; Hatch et al., 1980; Herbert, 1978; Mitch et al., 1981; Schmidt et al., 1981).

        Excess Iron Absorption. Another possible adverse effect of high vitamin C intake is enhanced iron absorption leading to iron overload. Bendich and Cohen (1990) evaluated 24 studies to determine whether daily ascorbic acid intakes (ranging from 1 to 1,000 mg, with most in the 10- to 100-mg range) could increase iron stores above recommended levels in apparently healthy individuals. They found that vitamin C intakes did not increase the number of high iron absorbers, and limited data involving ascorbic acid intakes above 100 mg/day showed no change in iron absorption values. Another study by Cook et al. (1984) showed no increase in iron stores following vitamin C intakes up to 2 g/day (taken with meals for 20 months) in iron-replete subjects who consumed foods that contain iron. This suggests that vitamin C does not induce excess iron absorption in apparently healthy individuals. However, it is unknown if individuals with hereditary hemochromatosis, which affects between 1 in 200 and 1 in 400 persons of northern European descent (Bacon et al., 1999), could be adversely affected by long-term ingestion of large doses of vitamin C (McLaran et al., 1982).

        Lowered Vitamin B 12 Levels. An in vitro study showed that increasing destruction of vitamin B12 was associated with increasing vitamin C levels (Herbert and Jacob, 1974). However, when this study was performed using different analytical procedures, no loss of vitamin B12 was observed (Newmark et al., 1976). In a review of the stability of cobalamins under varying conditions, Hogenkamp (1980) found that only aquocobalamin was decreased and destroyed by ascorbic acid. Aquocobalamin is not a major cobalamin in biological tissues. Furthermore, results of in vivo studies in human subjects have shown that vitamin C intakes up to 4 g/day did not induce vitamin B12 deficiency (Afroz et al., 1975; Ekvall et al., 1981).

        Systemic Conditioning. Evidence of systemic conditioning (the accelerated metabolism or excretion of ascorbic acid) exists from uncontrolled observations in humans following abrupt discontinuation of prolonged, high-dose vitamin C supplementation (Rhead and Schrauzer, 1971; Siegel et al., 1982). Omaye et al. (1986) showed increased turnover of plasma ascorbic acid in apparently healthy human adults who abruptly decreased their vitamin C intake from 605 to 5 mg/day. Two other studies showed that high intakes resulted in increased clearance but did not result in blood levels lower than normal (Schrauzer and Rhead, 1973; Tsao and Leung, 1988). Other studies have reported no rebound scurvy or excessive lowering of ascorbate blood levels after cessation of high intakes (Hoffer, 1973; Ludvigsson et al., 1979). Evidence that rebound scurvy may appear in infants whose mothers ingested large doses of vitamin C during pregnancy is limited to one anecdotal report of 2 infants (Cochrane, 1965). Overall, the evidence is inconsistent and does not suggest that systemic conditioning occurs to any significant extent in infants and adults.

        Pro-oxidant Effects. Under certain conditions, ascorbate can act as a pro-oxidant by reducing iron and copper ions, which catalyze production of the hydroxyl radical via Fenton chemistry (Buettner and Jurkiewicz, 1996). The combination of ascorbic acid and redoxactive (non-protein-bound) iron can promote lipid peroxidation in vitro (Laudicina and Marnett, 1990). In vivo however, iron is bound to proteins such as transferrin and ferritin and therefore is not normally available for such catalytic functions. Nevertheless, the strong pro-oxidant nature of the iron-ascorbate complex in vitro raises concern that consumption of vitamin C supplements by individuals with high iron stores may contribute to oxidative damage in vivo. In addition, dietary ascorbic acid can enhance the intestinal absorption of nonheme iron (Hallberg, 1985).

        Concerns for a possible in vivo pro-oxidant effect of the iron-ascorbate couple were heightened by the report of a fatal cardiomyopathy in a patient with hemochromatosis who ingested excessive vitamin C (McLaran et al., 1982). Also, an association between myocardial infarctions and serum ferritin levels has been reported in a Finnish population (Salonen et al., 1992). Other studies have not supported the latter finding that high iron stores were associated with increased risk of heart disease (Baer et al., 1994) and have not indicated that excess vitamin C intakes have contributed significantly to iron overload or oxidant damage in normal healthy people. Controlled human studies in which supplemental vitamin C was added to the meals of apparently healthy adults for periods of up to 2 years showed little or no change in iron status measures including serum ferritin (Cook et al., 1984; Hunt et al., 1994). Data on iron-ascorbate combinations in the plasma of normal healthy adults and preterm infants with high plasma ascorbate levels showed that high plasma ascorbate concentrations in the presence of redox-active iron did not cause either lipid or protein oxidation. In addition, the endogenous ascorbate prevented rather than promoted lipid peroxidation in iron-overloaded plasma (Berger et al., 1997).

        Similarly, concern for an in vivo pro-oxidant action of vitamin C in concert with copper has been suggested but not substantiated. Possible increased oxidant damage in premature infants had been attributed to the effect of high serum ascorbate levels inhibiting ceruloplasmin ferroxidase activity, thereby creating an excess of reactive ferrous ions (Powers et al., 1995). This result and other reports of ascorbate inhibition of ceruloplasmin ferroxidase activity (Gutteridge, 1991) have subsequently been attributed to an artifact of using a nonphysiological pH buffer in the ceruloplasmin ferroxidase assay (Løvstad, 1997).

        Results of studies testing the effects of supplemental vitamin C intake on markers of oxidant damage to deoxyribonucleic acid (DNA) and chromosomes are discussed in an earlier section and are summarized in Table 5-4, Table 5-5, and Table 5-6. The results are mixed, with studies showing a decrease, increase, or no change in oxidant damage measures. A study of 30 apparently healthy adults supplemented with 500 mg/day of vitamin C for 6 weeks reported an increase in 8-oxoadenine, but a decrease in the more mutagenic DNA lesion, 8-oxoguanine (Podmore et al., 1998). Supplementation of apparently healthy volunteers with vitamin C and iron resulted in increases in some DNA damage markers, decreases in others, and a rise in total DNA base damage at 6 weeks, which disappeared at 12 weeks (Rehman et al., 1998). Other evidence from in vitro and in vivo data as well as epidemiological studies have not shown increased oxidative DNA damage or increased cancer risk associated with high intakes of vitamin C (Block, 1991; Fontham, 1994; Fraga et al., 1991; Rifici and Khachadurian, 1993).

        Other Adverse Effects. Other adverse effects observed following high vitamin C intakes include diminished high-altitude resistance (Schrauzer et al., 1975), delayed-type allergic response (Metz et al., 1980), and erosion of dental enamel (Giunta, 1983). Additional studies confirming these findings were not found.

        Identification of Distinct and Highly Sensitive Subpopulations. Data show that individuals with hemochromatosis, glucose-6-phosphate dehydrogenase deficiency, and renal disorders may be susceptible to adverse effects from excess vitamin C intake. Vitamin C may enhance iron absorption and exacerbate iron-induced tissue damage in individuals with hemochromatosis (McLaran et al., 1982). Individuals with renal disorders may have increased risk of oxalate kidney stone formation from excess vitamin C intake (Auer et al., 1998; Ono, 1986; Urivetzky et al., 1992). Hemolysis has been associated with ascorbic acid administration in newborns with glucose-6-phosphate dehydrogenase deficiency and in normal premature infants (Ballin et al., 1988; Mentzer and Collier, 1975). There is also anecdotal evidence of hemolysis following ascorbic acid intake in adults with glucose-6-phosphate dehydrogenase deficiency (Campbell et al., 1975; Rees et al., 1993). However, a clinical study does not support the association (Beutler, 1991).

        Summary

        Based on considerations of causality, relevance, and the quality and completeness of the database, osmotic diarrhea and related gastrointestinal disturbances were selected as the critical endpoints on which to base a UL. The in vivo data do not clearly show a causal relationship between excess vitamin C intake by apparently healthy individuals and other adverse effects (i.e., kidney stone formation, excess iron absorption, reduced vitamin B12 and copper levels, increased oxygen demand, systemic conditioning, pro-oxidant effects, dental enamel erosion, or allergic response) in adults and children.

        The data regarding possible vitamin C deficiency in two newborns resulting from abrupt withdrawal from mothers consuming high levels of vitamin C during pregnancy were considered too anecdotal and uncertain to warrant derivation of a separate UL for pregnant women.

        Dose-Response Assessment

        Adults

        Data Selection. The data on osmotic diarrhea and gastrointestinal disturbances were selected as most relevant on which to base a UL for apparently healthy adults. The effects are generally not serious and are self-limiting; individuals experiencing them may easily eliminate them by reducing supplemental vitamin C intakes.

        Identification of a No-Observed-Adverse-Effect Level (NOAEL) and Lowest-Observed-Adverse-Effect Level (LOAEL). A LOAEL of 3 g/day can be identified based on the data of Cameron and Campbell (1974). These investigators reported symptoms of flatulent distension, transient colic, and diarrhea at doses of 3 to 4 g/day in normal healthy volunteers (number of volunteers not stated). The volunteers increased oral ascorbic acid intake by increments of 1g/day in successive weeks. Supporting evidence is provided by case reports (Hoffer, 1971; Hoyt, 1980), a graded dose study by Stein et al. (1976), and a multiple crossover study by Wandzilak et al. (1994). Stein et al. (1976) gave three patients 8 g/day in four divided doses of 2 g for 3 to 7 days. This study reported mild diarrhea in one of three subjects following ingestion of 4 g/day of ascorbic acid. Wandzilak et al. (1994) investigated the effect of high-dose ascorbic acid intake on 15 apparently healthy volunteers. Subjects ingested 1, 5, and 10 g/day supplemental ascorbate at mealtime for 5 days, separated by 5 days of no supplementation. This study reported diarrhea in 2 of the 15 subjects taking 10 g/day. These subjects were unable to continue at this dose

        The above human data suggest that an intake of vitamin C greater than 3 g/day is likely to cause osmotic diarrhea in many individuals, although some reports involving a few individuals suggest this may occur at 3 g/day. Thus, the 3-g/day intake is considered a LOAEL.

        Uncertainty Assessment. There is little uncertainty regarding the range of vitamin C intakes that are likely to induce osmotic diarrhea. An uncertainty factor (UF) of 1.5 was selected to extrapolate the LOAEL to a NOAEL. Thus, the 3 g/day intake is considered a LOAEL, and a NOAEL of 2 g/day is estimated for adult humans. Because the database has no other significant sources of uncertainty and because of the mild, reversible nature of osmotic diarrhea caused by high vitamin C intakes, no further uncertainty factors are necessary.

        Derivation of a UL. The LOAEL of 3 g/day was divided by the UF of 1.5 to obtain a NOAEL and UL value of 2 g/day.

        Image p20003381g162001.jpg

        Vitamin C UL Summary, Ages 19 Years and Older

        Other Life Stage Groups

        Infants. For infants, the UL was judged not determinable because of insufficient data on adverse effects in this age group and concern about the infant's ability to handle excess amounts. Potential concerns for high vitamin C concentrations in infants stem from isolated reports of anecdotal rebound scurvy, oxidative damage, and hemolysis (Ballin et al., 1988; Cochrane, 1965; Powers et al., 1995). To prevent high levels of intake, the only source of intake for infants should be that available from food and formula.

        Children and Adolescents. Limited data exist on vitamin C toxicity in toddlers, children, and adolescents. Ludvigsson et al. (1977) conducted a double-blind, 7-week pilot study and a 3-month main study evaluating the prophylactic effect of 1,000 mg/day of vitamin C on colds in 172 and 642 children, respectively, ages 8 to 9 years. Reported side effects, including stomach pains, skin rash, headache, diarrhea, and nausea, were observed in about 3 percent of the children, which was no different from the control group and was not dose related. Therefore, this study could be used to support a NOAEL of 1,000 mg/day.

        Another study tested the effectiveness of a megavitamin regimen including 3 g/day of ascorbic acid for 3 months on attention deficit disorder (ADD) in 41 children ages approximately 7 to 11 years (Haslam et al., 1984). Forty-two percent of the children developed elevation of serum aminotransferases, and it was concluded that the regimen (which was ineffective) should not be used to treat ADD. It is unlikely that the increases in serum aminotransferases were due to the high acsorbic acid intake since no such effects of high vitamin C intakes have been reported by other investigators. Nevertheless, this study appears consistent with the adult data indicating a LOEAL at intakes of 3 g/day. However, this study cannot be utilized to establish a UL for children as the vitamin C was part of a mega-vitamin and the contribution of vitamin C to the results cannot be determined.

        Because the results of these studies (particularly the study by Ludvigsson et al., 1977) are consistent with the data on adverse effects in adults on a body weight basis, the UL values for toddlers, children, and adolescents are extrapolated based on body weight differences from those established for adults as described in Chapter 4 using reference weights from Chapter 1 (Table 1-1). The calculated UL is rounded to the nearest 50 mg.

        Pregnancy. No evidence of maternal toxicity of excess vitamin C intakes was found. However, because vitamin C is actively transported from maternal to fetal blood, there could be a potential for maternal intake of megadoses of vitamin C during pregnancy to lead to markedly elevated concentrations of vitamin C in the fetus. There is one anecdotal report (Cochrane, 1965) of possible fetal vitamin C dependence induced in utero in two infants, whose mothers consumed 400 mg/day of vitamin C during pregnancy. Although the infants developed scurvy during the first few weeks of life, the observation was complicated by the relatively high incidence of scurvy in the region of Canada in which the infants were born. Other concerns for high vitamin C concentrations in infants stem from reports of hemolysis (Ballin et al., 1988) and possible increased oxidative damage (Powers et al., 1995) in premature infants. However, these effects are not well documented, and do not warrant a separate UL for pregnant females.

        Lactation. Byerley and Kirksey (1985) noted that the vitamin C composition of human milk was not affected by maternal vitamin C intake ranging from 156 to 1,123 mg/day and that urinary excretion increased as intake increased over 200 mg/day, suggesting that mammary tissue becomes saturated with vitamin C. One woman ingested 4,000 mg/day of vitamin C as a supplement; no toxic effects of the excess vitamin intake were noted in the mother. Her milk content of vitamin C was 100.5 mg/L, which was on the high end of values reported for human milk, but not reflective of the high intake (Anderson and Pittard, 1985). Based on these findings, the ULs for lactating adolescents and women are not different from those of nonlactating females.

        Vitamin C UL Summary, Ages 1 through 18 Years, Pregnancy, Lactation

        View in own window

        UL for Infants
        012 months Not possible to establish; source of intake should be formula and food only
        UL for Children
        13 years 400 mg (2,272 µmol)/day of vitamin C
        48 years 650 mg (3,692 µmol)/day of vitamin C
        9–13 years 1,200 mg (6,816 µmol)/day of vitamin C
        UL for Adolescents
        14–18 years 1,800 mg (10,224 µmol)/day of vitamin C
        UL for Pregnancy
        14–18 years 1,800 mg (10,224 µmol)/day of vitamin C
        19 years and older 2,000 mg (11,360 µmol)/day of vitamin C
        UL for Lactation
        14–18 years 1,800 mg (10,224 µmol)/day of vitamin C
        19 years and older 2,000 mg (11,360 µmol)/day of vitamin C

        Special Considerations

        Individuals with hemochromatosis, glucose-6-phosphate dehydrogenase deficiency, and renal disorders may be especially susceptible to adverse effects of excess vitamin C intake and therefore should be cautious about ingesting more vitamin C than the Recommended Dietary Allowance (RDA). Vitamin C intakes of 250 mg/day or higher have been associated with false-negative results for detecting stool and gastric occult blood (Gogel et al., 1989; Jaffe et al., 1975). Therefore, high-dose vitamin C supplements should be discontinued at least 2 weeks before physical exams because they may interfere with blood and urine tests.

        Intake Assessment

        Based on data from the Third National Health and Nutrition Examination Survey (NHANES III), the highest mean intake of vitamin C from diet and supplements for any gender and lifestage group was estimated to be about 200 mg (1,136 µmol)/day (Appendix Table C-2). This was the intake of males aged 51 through 70 years and females aged 51 years and older. The highest reported intake at the ninety-ninth percentile was greater than 1,200 mg (6,816 µmol)/day in males aged 31 through 70 years and in females aged 51 through 70 years (Appendix Table C-2).

        Risk Characterization

        The risk of adverse effects resulting from excess intake of vitamin C from food and supplements appears to be very low at the highest intakes noted above. Although members of the general population should be advised not to exceed the UL routinely, intake greater than the UL may be appropriate for investigation within well-controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxicity and as long as these trials employ appropriate safety monitoring of trial subjects. In addition, the UL is not meant to apply to individuals who are receiving vitamin C under medical supervision.

        RESEARCH RECOMMENDATIONS FOR VITAMIN C

        • Despite the many known biochemical roles of ascorbic acid, no reliable biochemical or physiologically based functional measures of vitamin C nutriture have been established. As a result, vitamin C intake requirements in adults have been based on estimates of body pool or tissue ascorbate deemed adequate to provide anti-oxidant protection. Knowledge of vitamin C intakes needed to fulfill specific functional roles of ascorbate will allow more accurate and precise determinations of the individual and average population requirements of the vitamin. Some current candidates that could be used as functional measures include pathways related to collagen and carnitine metabolism, oxidative damage, and oral health indices; however, research on new functions of the vitamin is also needed. Determination of vitamin C requirements based on antioxidant functions will require development of more reliable tests for in vivo oxidative damage and further understanding of the interactions of ascorbate with other physiological antioxidants. Additionally, a practical method for measuring the vitamin C body pool is needed as a standard of comparison against proposed functional measures and measures of health or disease endpoints.

        • Since the requirements for children ages 1 through 18 years are extrapolated from the adult Estimated Average Requirements (EARs), it is critically important to conduct large-scale studies with children using state-of-the-art biomarkers to assess their vitamin C requirement.

        • Many studies that provided vitamin C supplements to apparently healthy well-nourished populations were investigating pharmacological (at or above the point where body tissues are saturated) rather than nutritional effects of the vitamin. This may obscure possible relationships between vitamin C intake and disease risk in the range of dietary intakes. Therefore, population studies on the relationship of vitamin C nutriture and chronic disease should focus more on individuals or populations who eat few fruits and vegetables and are marginally deficient in vitamin C. Attention also has to be given to methods for sorting out the effects of vitamin C intake from those of other dietary and life-style factors that may also affect disease risk.

        • While the evidence of adverse effects due to intakes of vitamin C supplements is at this time limited to osmotic diarrhea and gastrointestinal disturbances which are self-limiting, the frequency of high intakes of the vitamin in the North American population warrants further investigation. The well known pro-oxidant effects of the iron-ascorbate couple in vitro suggest that further research be done on possible related in vivo reactions—for example, during simultaneous supplement ingestion, iron overload, and inflammation or tissue trauma where non-protein-bound iron may be released.

        • A small number of isolated reports raise concern that high vitamin C intakes during pregnancy may expose the fetus or neonate to risks of withdrawal symptoms, hemolysis, or oxidant damage. Further research is needed to confirm or refute these concerns.

        REFERENCES

        • Afroz M, Bhothinard B, Etzkorn JR, Horenstein S, McGarry JD. 1975. Vitamins C and B12 . J Am Med Assoc 232:246. [PubMed: 1173112]

        • Alexy U, Kersting M, Sichert-Hellert W, Manz F, Schöch G. 1999. Vitamin intake of 3- to 36-month-old German infants and children—Results of the DONALD study. Int J Vitam Nutr Res 69:285–291. [PubMed: 10450535]

        • Allen JC, Keller RP, Archer P, Neville MC. 1991. Studies in human lactation: Milk composition and daily secretion rates of macronutrients in the first year of lactation. Am J Clin Nutr 54:69–80. [PubMed: 2058590]

        • Alvares O. 1997. Ascorbic acid and periodontal disease. In: Packer L, Fuchs J, eds. Vitamin C in Health and Disease . New York: Marcel Dekker. Pp.505–516.

        • Anderson D, Phillips BJ, Yu T, Edwards AJ, Ayesh R, Butterworth KR. 1997. The effects of vitamin C supplementation on biomarkers of oxygen radical generated damage in human volunteers with "low" or "high" cholesterol levels. Environ Mol Mutagen 30:161–174. [PubMed: 9329641]

        • Anderson DM, Pittard WB. 1985. Vitamin E and C concentrations in human milk with maternal megadosing. A case report. J Am Diet Assoc 85:715–717. [PubMed: 3998344]

        • Anderson R, Lukey, PT. 1987. A biological role for ascorbate in the selective neutralization of extracellular phagocyte-derived oxidants. Ann NY Acad Sci 498:229–247. [PubMed: 3304062]

        • Anderson R, Oosthuizen R, Maritz R, Theron A, Van Rensburg AJ. 1980. The effects of increasing weekly doses of ascorbate on certain cellular and humoral immune function in normal volunteers. Am J Clin Nutr 33:71–76. [PubMed: 7355784]

        • Asami S, Manabe H, Miyake J, Tsurudome Y, Hirano T, Yamaguchi R, Itoh H, Kasai H. 1997. Cigarette smoking induces an increase in oxidative DNA damage, 8-hydroxydeoxyguanosine, in a central site in the human lung. Carcinogenesis 18:1763–1766. [PubMed: 9328173]

        • Auer BL, Auer D, Rodgers AL. 1998. Relative hyperoxaluria, crystalluria and haematuria after megadose ingestion of vitamin C. Eur J Clin Invest 28:695–700. [PubMed: 9767367]

        • Bacon BR, Olynyk JK, Brunt EM, Britton RS, Wolff RK. 1999. HFE genotype in patients with hemochromatosis and other liver diseases. Ann Int Med 130:953–962. [PubMed: 10383365]

        • Baer DM, Tekawa IS, Hurley LB. 1994. Iron stores are not associated with acute myocardial infarction. Circulation 89:2915–2918. [PubMed: 8205708]

        • Baker EM, Sauberlich HE, Wolfskill SJ, Wallace WT, Dean EE. 1962. Tracer studies of vitamin C utilization in men: Metabolism of D -glucuronolactone-6-C14, D -glucuronic-6-C14 acid and L -ascorbic-1-C14 acid . Proc Soc Exp Biol Med 109:737–741.

        • Baker EM, Hodges RE, Hood J, Sauberlich HE, March SC. 1969. Metabolism of ascorbic-1-C14 acid in experimental human scurvy . Am J Clin Nutr 22:549–558. [PubMed: 4891320]

        • Baker EM, Hodges RE, Hood J, Sauberlich HE, March SC, Canham JE. 1971. Metabolism of 14C- and 3H-labeled L -ascorbic acid in human scurvy. Am J Clin Nutr 24:444–454. [PubMed: 5090632]

        • Ballin A, Brown EJ, Koren G, Zipursky A. 1988. Vitamin C-induced erythrocyte damage in premature infants. J Pediatr 113:114–120. [PubMed: 3385519]

        • Bandera EV, Freudenheim JL, Marshall JR, Zielezny M, Priore RL, Brasure J, Baptiste M, Graham S. 1997. Diet and alcohol consumption and lung cancer risk in the New York State Cohort. Cancer Causes Control 8:828–840. [PubMed: 9427425]

        • Barrett B, Gunter E, Jenkins J, Wang M. 1991. Ascorbic acid concentration in amniotic fluid in late pregnancy. Biol Neonate 60:333–335. [PubMed: 1790258]

        • Bates CJ, Prentice AM, Prentice A, Paul AA, Whitehead RG. 1982. Seasonal variations in ascorbic acid status and breast milk ascorbic acid levels in rural Gambian women in relation to dietary intake. Trans Royal Soc Trop Med Hyg 76:341–347. [PubMed: 7112656]

        • Belcher JD, Balla J, Balla G, Jacobs DR Jr, Gross M, Jacob HS, Vercellotti GM. 1993. Vitamin E, LDL, and endothelium. Brief oral vitamin supplementation prevents oxidized LDL-mediated vascular injury in vitro. Arterioscler Thromb 13:1779–1789. [PubMed: 8241098]

        • Bendich A, Cohen M. 1990. Ascorbic acid safety: Analysis of factors affecting iron absorption. Toxicol Lett 51:189–201. [PubMed: 2184546]

        • Berger L, Gerson CD, Yu TF. 1977. The effect of ascorbic acid on uric acid excretion with a commentary on the renal handling of ascorbic acid. Am J Med 62:71–76. [PubMed: 835593]

        • Berger TM, Polidori MC, Dabbagh A, Evans PJ, Halliwell B, Morrow JD, Roberts LJ II, Frei B. 1997. Antioxidant activity of vitamin C in iron-overloaded human plasma. J Biol Chem 272:15656–15660. [PubMed: 9188455]

        • Berliner JA, Heinecke JW. 1996. The role of oxidized lipoproteins in atherogenesis. Free Radic Biol Med 20:707–727. [PubMed: 8721615]

        • Bermudez E, Stone K, Carter KM, Pryor WA. 1994. Environmental tobacco smoke is just as damaging to DNA as mainstream smoke. Environ Hlth Perspect 102:870–874. [PMC free article: PMC1567343] [PubMed: 9644196]

        • Beutler E. 1991. Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 324:169–174. [PubMed: 1984194]

        • Blanchard J. 1991. a. Depletion and repletion kinetics of vitamin C in humans. J Nutr 121:170–176. [PubMed: 1995787]

        • Blanchard J. 1991. b. Effects of gender on vitamin C pharmacokinetics in man. J Am Coll Nutr 10:453–459. [PubMed: 1955621]

        • Blanchard J, Conrad KA, Watson RR, Garry PJ, Crawley JD. 1989. Comparison of plasma, mononuclear and polymorphonuclear leucocyte vitamin C levels in young and elderly women during depletion and supplementation. Eur J Clin Nutr 43:97–106. [PubMed: 2707219]

        • Blanchard J, Conrad KA, Garry PJ. 1990. a. Effects of age and intake on vitamin C disposition in females. Eur J Clin Nutr 44:447–460. [PubMed: 2387280]

        • Blanchard J, Conrad KA, Mead RA, Garry PJ. 1990. b. Vitamin C disposition in young and elderly men. Am J Clin Nutr 51:837–845. [PubMed: 2333842]

        • Blanchard J, Tozer TN, Rowland M. 1997. Pharmacokinetic perspectives on megadoses of ascorbic acid. Am J Clin Nutr 66:1165–1171. [PubMed: 9356534]

        • Block G. 1991. Vitamin C and cancer prevention: The epidemiologic evidence. Am J Clin Nutr 53:270S–282S. [PubMed: 1985398]

        • Blot WJ, Li J-Y, Taylor PR, Guo W, Dawsey S, Wang G-Q, Yang CS, Zheng S-F, Gail M, Li G-Y, Yu Y, Liu B-Q, Tangrea J, Sun Y-H, Liu F, Fraumeni JF Jr, Zhang Y-H, Li B. 1993. Nutrition intervention trials in Linxian, China: Supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 85:1483–1492. [PubMed: 8360931]

        • Bors W, Michel C, Schikora S. 1995. Interaction of flavonoids with ascorbate and determination of their univalent redox potentials: A pulse radiolysis study. Free Radic Biol Med 19:45–52. [PubMed: 7635358]

        • Bostick RM, Potter JD, McKenzie DR, Sellers TA, Kushi LH, Steinmetz KA, Folsom AR. 1993. Reduced risk of colon cancer with high intake of vitamin E: The Iowa Women's Health Study. Cancer Res 53:4230–4237. [PubMed: 8364919]

        • Britton JR, Pavord ID, Richards KA, Knox AJ, Wisniewski AF, Lewis SA, Tattersfield AE, Weiss ST. 1995. Dietary antioxidant vitamin intake and lung function in the general population. Am J Respir Crit Care Med 151:1383–1387. [PubMed: 7735589]

        • Bucca C, Rolla G, Farina JC. 1992. Effect of vitamin C on transient increase of bronchial responsiveness in conditions affecting the airways. Ann NY Acad Sci 669:175–187. [PubMed: 1444023]

        • Bueno de Mesquita HB, Maisonneuve P, Runia S, Moerman CJ. 1991. Intake of foods and nutrients and cancer of the exocrine pancreas: A population-based case-control study in The Netherlands. Int J Cancer 48:540–549. [PubMed: 1646177]

        • Buettner GR. 1993. The pecking order of free radicals and antioxidants: Lipid peroxidation, alpha-tocopherol, and ascorbate. Arch Biochem Biophys 300:535–543. [PubMed: 8434935]

        • Buettner GR, Jurkiewicz BA. 1996. Catalytic metals, ascorbate and free radicals: Combinations to avoid. Radiat Res 145:532–541. [PubMed: 8619018]

        • Burr ML, Elwood PC, Hole DJ, Hurley RJ, Hughes RE. 1974. Plasma and leukocyte ascorbic acid levels in the elderly. Am J Clin Nutr 27:144–151. [PubMed: 4204847]

        • Bussey HJ, DeCosse JJ, Deschner EE, Eyers AA, Lesser ML, Morson BC, Ritchie SM, Thomson JP, Wadsworth J. 1982. A randomized trial of ascorbic acid in polyposis coli. Cancer 50:1434–1439. [PubMed: 7049351]

        • Butte NF, Garza C, Smith EO, Nichols BL. 1984. Human milk intake and growth in exclusively breast-fed infants. J Pediatr 104:187–195. [PubMed: 6694010]

        • Byerley LO, Kirksey A. 1985. Effects of different levels of vitamin C intake on the vitamin C concentration in human milk and the vitamin C intakes of breastfed infants. Am J Clin Nutr 41:665–671. [PubMed: 3984919]

        • Byun J, Mueller DM, Fabjan JS, Heinecke JW. 1999. Nitrogen dioxide radical generated by the myeloperoxidase-hydrogen peroxide-nitrite system promotes lipid peroxidation of low density lipoprotein. FEBS Lett 455:243–246. [PubMed: 10437781]

        • Cadenas S, Rojas C, Méndez J, Herrero A, Barja G. 1996. Vitamin E decreases urine lipid peroxidation products in young healthy human volunteers under normal conditions. Pharmacol Toxicol 79:247–253. [PubMed: 8936558]

        • Cahill RJ, O'Sullivan KR, Mathias PM, Beattie S, Hamilton H, O'Morain C. 1993. Effects of vitamin antioxidant supplementation on cell kinetics of patients with adenomatous polyps. Gut 34:963–967. [PMC free article: PMC1374235] [PubMed: 8344584]

        • Cameron E, Campbell A. 1974. The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem Biol Interact 9:285–315. [PubMed: 4430016]

        • Campbell GD Jr, Steinberg MH, Bower JD. 1975. Ascorbic acid-induced hemolysis in G-6-PD deficiency. Ann Intern Med 82:810. [PubMed: 1138591]

        • Carr AC, Frei B. 1999. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr 69:1086–1087. [PubMed: 10357726]

        • Casanueva E, Polo E, Tejero E, Meza C. 1993. Premature rupture of amniotic membranes as functional assessment of vitamin C status during pregnancy. Ann NY Acad Sci 678:369–370. [PubMed: 8494290]

        • Chalmers TC. 1975. Effects of ascorbic acid on the common cold. An evaluation of the evidence. Am J Med 58:532–536. [PubMed: 1092164]

        • Chazan JA, Mistilis SP. 1963. The pathophysiology of scurvy. Am J Med 34:350–358. [PubMed: 14041584]

        • Cheng L, Cohen M, Bhagavan HN. 1985. Vitamin C and the elderly. In: Watson RR, ed. CRC Handbook of Nutrition in the Aged . Boca Raton, FL: CRC Press. Pp.157–185.

        • Choi JL, Rose RC. 1989. Transport and metabolism of ascorbic acid in human placenta. Am J Physiol 257:C110–C113. [PubMed: 2750883]

        • Cohen HA, Neuman I, Nahum H. 1997. Blocking effect of vitamin C in exercise-induced asthma. Arch Pediatr Adolesc Med 151:367–370. [PubMed: 9111435]

        • Cook JD, Watson SS, Simpson KM, Lipschitz DA, Skikne BS. 1984. The effect of high ascorbic acid supplementation on body iron stores. Blood 64:721–726. [PubMed: 6466873]

        • Cooke MS, Evans MD, Podmore ID, Herbert KE, Mistry N, Mistry P, Hickenbotham PT, Hussieni A, Griffiths HR, Lunec J. 1998. Novel repair action of vitamin C upon in vivo oxidative DNA damage. FEBS Lett 439:363–367. [PubMed: 9845354]

        • Coulehan JL, Eberhard S, Kapner L, Taylor F, Rogers K, Garry P. 1976. Vitamin C and acute illness in Navajo school children. N Engl J Med 295:973–977. [PubMed: 787788]

        • Cross CE, Halliwell B. 1993. Nutrition and human disease: How much extra vitamin C might smokers need? Lancet 341:1091. [PubMed: 8096979]

        • Cross CE, Forte T, Stocker R, Louie S, Yamamoto Y, Ames BN, Frei B. 1990. Oxidative stress and abnormal cholesterol metabolism in patients with adult respiratory distress syndrome. J Lab Clin Med 115:396–404. [PubMed: 2324609]

        • Crott JW, Fenech M. 1999. Effect of vitamin C supplementation on chromosome damage, apoptosis and necrosis ex vivo. Carcinogenesis 20:1035–1041. [PubMed: 10357785]

        • Curhan GC, Willett WC, Rimm EB, Stampfer MJ. 1996. A prospective study of the intake of vitamins C and B6, and the risk of kidney stones in men. J Urol 155:1847–1851. [PubMed: 8618271]

        • Curhan GC, Willett WC, Speizer FE, Stampfer MJ. 1999. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol 10:840–845. [PubMed: 10203369]

        • Dabrowski K. 1990. Gastro-intestinal circulation of ascorbic acid. Comp Biochem Physiol 95A:481–486.

        • Dallongeville J, Marécaux N, Fruchart J-C, Amouyel P. 1998. Cigarette smoking is associated with unhealthy patterns of nutrient intake: A meta-analysis. J Nutr 128:1450–1457. [PubMed: 9732304]

        • Davies HE, Davies JE, Hughes RE, Jones E. 1984. Studies on the absorption of L xyloascorbic acid (vitamin C) in young and elderly subjects. Hum Nutr Clin Nutr 38C:463–471. [PubMed: 6542908]

        • Davies HE, Gruffudd S, Hughes RE, Jones E. 1987. Ascorbic acid and carnitine in man. Nutr Report Int 36:941–948.

        • DeCosse JJ, Adams MB, Kuzma JF, LoGerfo P, Condon RE. 1975. Effect of ascorbic acid on rectal polyps of patients with familial polyposis. Surgery 78:608–612. [PubMed: 1188603]

        • Delafuente JC, Prendergast JM, Modigh A. 1986. Immunologic modulation by vitamin C in the elderly. Int J Immunopharmacol 8:205–211. [PubMed: 3710663]

        • Delamere NA. 1996. Ascorbic acid and the eye. Subcell Biochem 25:313–329. [PubMed: 8821981]

        • Devaraj S, Jialal I. 1996. Oxidized low-density lipoprotein and atherosclerosis. Int J Clin Lab Res 26:178–184. [PubMed: 8905449]

        • Dewey KG, Finley DA, Lonnerdal B. 1984. Breast milk volume and composition during late lactation (7–20 months). J Pediatr Gastroenterol Nutr 3:713–720. [PubMed: 6502372]

        • Drake IM, Davies MJ, Mapstone NP, Dixon MF, Schorah CJ, White KLM, Chalmers DM, Axon ATR. 1996. Ascorbic acid may protect against human gastric cancer by scavenging mucosal oxygen radicals. Carcinogenesis 17:559–562. [PubMed: 8631145]

        • Duthie SJ, Ma A, Ross MA, Collins AR. 1996. Antioxidant supplementation decreases oxidative DNA damage in human lymphocytes. Cancer Res 56:1291–1295. [PubMed: 8640816]

        • Dyke GW, Craven JL, Hall R, Garner RC. 1994. a. Effect of vitamin C supplementation on gastric mucosal DNA damage. Carcinogenesis 15:291–295. [PubMed: 8313520]

        • Dyke GW, Craven JL, Hall R, Garner RC. 1994. b. Effect of vitamin C upon gastric mucosal O 6 -alkyltransferase activity and on gastric vitamin C levels. Cancer Lett 86:159–165. [PubMed: 7982203]

        • Eichholzer M, Stahelin HB, Gey KF. 1992. Inverse correlation between essential antioxidants in plasma and subsequent risk to develop cancer, ischemic heart disease and stroke respectively: 12-year follow-up of the Prospective Basel Study. Exp Suppl 62:398–410. [PubMed: 1450600]

        • Ekvall S, Chen IW, Bozian R. 1981. The effect of supplemental ascorbic acid on serum vitamin B12 levels in myelomenigocele patients. Am J Clin Nutr 34:1356–1361. [PubMed: 7258126]

        • Elneihoum AM, Falke P, Hedblad B, Lindgarde F, Ohlsson K. 1997. Leukocyte activation in atherosclerosis: Correlation with risk factors. Atherosclerosis 131:79–84. [PubMed: 9180248]

        • Englard S, Seifter S. 1986. The biochemical functions of ascorbic acid. Annu Rev Nutr 6:365–406. [PubMed: 3015170]

        • Enstrom JE, Kanim LE, Breslow L. 1986. The relationship between vitamin C intake, general health practices, and mortality in Alameda County, California. Am J Pub Hlth 76:1124–1130. [PMC free article: PMC1646565] [PubMed: 3740338]

        • Enstrom JE, Kanim LE, Klein MA. 1992. Vitamin C intake and mortality among a sample of the United States population. Epidemiology 3:194–202. [PubMed: 1591317]

        • Erdman JW Jr, Klein BP. 1982. The influence of harvesting, processing, and cooking on vitamin C in foods. In: Seib PA, Tolbert BM, eds. Ascorbic Acid: Chemistry, Metabolism and Uses . Washington, DC: American Chemical Society. Pp.499–532.

        • Evans RM, Currie L, Campbell A. 1982. The distribution of ascorbic acid between various cellular components of blood in normal individuals, and its relation to the plasma concentration. Br J Nutr 47:473–482. [PubMed: 7082619]

        • FDA (Food and Drug Adminstration). 1985. Nutrient requirements for infant formulas. Fed Regis 50:45106–45108.

        • Fellstrom B, Danielson BG, Karlstrom B, Lithell H, Ljunghall S, Vessby B. 1989. Dietary habits in renal stone patients compared with healthy subjects. Br J Urol 63:575–580. [PubMed: 2752249]

        • Fishbaine B, Butterfield G. 1984. Ascorbic acid status of running and sedentary men. Int J Vitam Nutr Res 54:273. [PubMed: 6500857]

        • Fituri N, Allawi N, Bentley M, Costello J. 1983. Urinary and plasma oxalate during ingestion of pure ascorbic acid: A re-evaluation. Eur Urol 9:312–315. [PubMed: 6628476]

        • Flodin NW. 1988. Pharmacology of Micronutrients . New York: Alan R. Liss. Pp.201–244.

        • Fontham ET. 1994. Vitamin C, vitamin C-rich foods, and cancer: Epidemiologic studies. In: Frei B, ed. Natural Antioxidants in Human Health and Disease . San Diego: Academic Press. Pp.157–197.

        • Fontham ET, Pickle LW, Haenszel W, Correa P, Lin YP, Falk RT. 1988. Dietary vitamins A and C and lung cancer risk in Louisiana. Cancer 62:2267–2273. [PubMed: 3179940]

        • Fraga CG, Motchnik PA, Shigenaga MK, Helbock HJ, Jacob RA, Ames BN. 1991. Ascorbic acid protects against endogenous oxidative DNA damage in human sperm. Proc Natl Acad Sci USA 88:11003–11006. [PMC free article: PMC53061] [PubMed: 1763015]

        • Frei B, Stocker R, Ames BN. 1988. Antioxidant defenses and lipid peroxidation in human blood plasma. Proc Natl Acad Sci USA 85:9748–9752. [PMC free article: PMC282858] [PubMed: 3200852]

        • Frei B, England L, Ames BN. 1989. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci USA 86:6377–6381. [PMC free article: PMC297842] [PubMed: 2762330]

        • Frei B, Forte TM, Ames BN, Cross CE. 1991. Gas phase oxidants of cigarette smoke induce lipid peroxidation and changes in lipoprotein properties in human blood plasma. Protective effects of ascorbic acid. Biochem J 277:133–138. [PMC free article: PMC1151201] [PubMed: 1854329]

        • Freudenheim JL, Graham S, Marshall JR, Haughey BP, Wilkinson G. 1990. A casecontrol study of diet and rectal cancer in western New York. Am J Epidemiol 131:612–624. [PubMed: 2156419]

        • Fuller CJ, Grundy SM, Norkus EP, Jialal I. 1996. Effect of ascorbate supplementation on low density lipoprotein oxidation in smokers. Atherosclerosis 119:139–150. [PubMed: 8808491]

        • Gale CR, Martyn CN, Winter PD, Cooper C. 1995. Vitamin C and risk of death from stroke and coronary heart disease in cohort of elderly people. Br Med J 310:1563–1566. [PMC free article: PMC2549941] [PubMed: 7787644]

        • Garry PJ, Goodwin JS, Hunt WC, Gilbert BA. 1982. Nutritional status in a healthy elderly population: Vitamin C. Am J Clin Nutr 36:332–339. [PubMed: 7102589]

        • Garry PJ, Vanderjagt DJ, Hunt WC. 1987. Ascorbic acid intakes and plasma levels in healthy elderly. Ann NY Acad Sci 498:90–99. [PubMed: 3476004]

        • George DR, De Francesca BA. 1989. Human milk in comparison to cow milk. In: Lebenthal E, editor. , ed. Textbook of Gastroenterology and Nutrition in Infancy and Childhood, 2nd edition. New York: Raven Press. Pp.242–243.

        • Gey KF. 1995. Ten-year retrospective on the antioxidant hypothesis of arterioscl rosis: Threshold plasma levels of antioxidant micronutrients related to minimum cardiovascular risk. Nutr Biochem 6:206–236.

        • Gey KF. 1998. Vitamins E plus C and interacting conutrients required for optimal health. A critical and constructive review of epidemiology and supplementation data regarding cardiovascular disease and cancer. Biofactors 7:113–174. [PubMed: 9523035]

        • Gey KF, Stahelin HB, Eichholzer M. 1993. Poor plasma status of carotene and vitamin C is associated with higher mortality from ischemic heart disease and stroke: Basel Prospective Study. Clin Invest 71:3–6. [PubMed: 8453256]

        • Ghadirian P, Boyle P, Simard A, Baillargeon J, Maisonneuve P, Perret C. 1991. Reported family aggregation of pancratic cancer within a population-based case-control study in the francophone community in Montreal, Canada. Int J Pancreatol 10:183–196. [PubMed: 1787333]

        • Giunta JL. 1983. Dental erosion resulting from chewable vitamin C tablets. J Am Dent Assoc 107:253–256. [PubMed: 6578267]

        • Gogel HK, Tandberg D, Strickland RG. 1989. Substances that interfere with guaiac card tests: Implications for gastric aspirate testing. Am J Emerg Med 7:474–480. [PubMed: 2787993]

        • Goldsmith GA. 1961. Human requirements for vitamin C and its use in clinical medicine. Ann NY Acad Sci 92:230–245. [PubMed: 13706612]

        • Gosiewska A, Mahmoodian F, Peterkofsky B. 1996. Gene expression of iron-related proteins during iron deficiency caused by scurvy in guinea pigs. Arch Biochem Biophys 325:295–303. [PubMed: 8561510]

        • Graham S, Zielezny M, Marshall J, Priore R, Freudenheim J, Brasure J, Haughey B, Nasca P, Zdeb M. 1992. Diet in the epidemiology of postmenopausal breast cancer in the New York State Cohort. Am J Epidemiol 136:1327–1337. [PubMed: 1336931]

        • Green MHL, Lowe JE, Waugh APW, Aldridge KE, Cole J, Arlett CF. 1994. Effect of diet and vitamin C on DNA strand breakage in freshly-isolated human white blood cells. Mutat Res 316:91–102. [PubMed: 7521006]

        • Greenberg ER, Baron JA, Tosteson TD, Freeman DH, Beck GJ, Bond JH, Colacchio TA, Coller JA, Frankl HD, Haile RW, Mandel JS, Nierenberg DW, Rothstein R, Snover DC, Stevens MM, Summers RW, van Stolk RU. 1994. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N Engl J Med 331:141–147. [PubMed: 8008027]

        • Gutteridge JMC. 1991. Plasma ascorbate levels and inhibition of the antioxidant activity of caeruloplasmin. Clin Sci 81:413–417. [PubMed: 1717196]

        • Hallberg L. 1985. The role of vitamin C in improving the critical iron balance situation in women. Int J Vitam Nutr Res 27:177–187. [PubMed: 3926692]

        • Halliwell B. 1998. Can oxidative DNA damage be used as a biomarker of cancer risk in humans? Free Radic Res 29:469–486. [PubMed: 10098453]

        • Halliwell B, Whiteman M. 1997. Antioxidant and prooxidant properties of vitamin C. In: Packer L, editor; , Fuchs J, editor. , eds. Vitamin C in Health and Disease . New York: Marcel Dekker. Pp.59–73.

        • Halliwell B, Wasil M, Grootveld M. 1987. Biologically significant scavenging of the myeloperoxidase-derived oxidant hypochlorous acid by ascorbic acid. FEBS Lett 213:15–17. [PubMed: 3030805]

        • Halpner AD, Handelman GJ, Belmont CA, Harris JM, Blumberg JB. 1998. Protection by vitamin C of oxidant-induced loss of vitamin E in rat hepatocytes. J Nutr Biochem 9:355–359.

        • Hankinson SE, Stampfer MJ, Seddon JM, Colditz GA, Rosner B, Speizer FE, Willett WC. 1992. Nutrient intake and cataract extraction in women: A prospective study. Br Med J 305:335–339. [PMC free article: PMC1882980] [PubMed: 1392884]

        • Harats D, Ben-Naim M, Dabach Y, Hollander G, Havivi E, Stein O, Stein Y. 1990. Effect of vitamin C and E supplementation on susceptibility of plasma lipopr teins to peroxidation induced by acute smoking. Atherosclerosis 85:47–54. [PubMed: 2282108]

        • Harats D, Chevion S, Nahir M, Norman Y, Sagee O, Berry EM. 1998. Citrus fruit supplementation reduces lipoprotein oxidation in young men ingesting a diet high in saturated fat: Presumptive evidence for an interaction between vitamins C and E in vivo. Am J Clin Nutr 67:240–245. [PubMed: 9459371]

        • Harris ED, Percival SS. 1991. A role for ascorbic acid in copper transport. Am J Clin Nutr 54:1193S–1197S. [PubMed: 1962569]

        • Hartz SC, Russell RM, Rosenberg IH. 1992. Nutrition in the Elderly. The Boston Nutr tional Status Survey . London: SmithGordon. P. 38.

        • Haslam RH, Dalby JT, Rademaker AW. 1984. Effects of megavitamin therapy on children with attention deficit disorders. Pediatrics 74:103–111. [PubMed: 6234505]

        • Hatch GE. 1995. Asthma, inhaled oxidants, and dietary antioxidants. Am J Clin Nutr 61:625S–630S. [PubMed: 7879729]

        • Hatch M, Mulgrew S, Bourke E, Keogh B, Costello J. 1980. Effect of megadoses of ascorbic acid on serum and urinary oxalate. Eur Urol 6:166–169. [PubMed: 7371664]

        • Hazell LJ, Arnold L, Flowers D, Waeg G, Malle E, Stocker R. 1996. Presence of hypochlorite-modified proteins in human atherosclerotic lesions. J Clin Invest 97:1535–1544. [PMC free article: PMC507214] [PubMed: 8617887]

        • Heinecke JW. 1997. Pathways for oxidation of low density lipoprotein by myelope oxidase: Tyrosyl radical, reactive aldehydes, hypochlorous acid and molecular chlorine. BioFactors 6:145–155. [PubMed: 9259996]

        • Heinig MJ, Nommsen LA, Peerson JM, Lonnerdal B, Dewey KG. 1993. Energy and protein intakes of breast-fed and formula-fed infants during the first year of life and their association with growth velocity: The DARLING Study. Am J Clin Nutr 58:152–161. [PubMed: 8338041]

        • Heitzer T, Just H, Munzel T. 1996. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation 94:6–9. [PubMed: 8964118]

        • Heller R, Munscher-Paulig F, Grabner R, Till U. 1999. L -Ascorbic acid potentiates nitric oxide synthesis in endothelial cells. J Biol Chem 274:8254–8260. [PubMed: 10075731]

        • Hemila H. 1996. Vitamin C, the placebo effect, and the common cold: A case study of how preconceptions influence the analysis of results. J Clin Epidemiol 49:1079–1084. [PubMed: 8826986]

        • Hemila H. 1997. Vitamin C intake and susceptibility to the common cold. Br J Nutr 77:59–72. [PubMed: 9059230]

        • Hemila H, Herman ZS. 1995. Vitamin C and the common cold: A retrospective analysis of Chalmers' review. J Am Coll Nutr 14:116–123. [PubMed: 7790685]

        • Henning SM, Zhang JZ, McKee RW, Swendseid ME, Jacob RA. 1991. Glutathione blood levels and other oxidant defense indices in men fed diets low in vitamin C. J Nutr 121:1969–1975. [PubMed: 1941261]

        • Herbert V. 1978. Risk of oxalate stones from large doses of vitamin C. N Engl J Med 298:856. [PubMed: 634328]

        • Herbert V. 1995. Vitamin C supplements and disease—Counterpoint. J Am Coll Nutr 14:112–113. [PubMed: 7790683]

        • Herbert V, Jacob E. 1974. Destruction of vitamin B12 by ascorbic acid. J Am Med Assoc 230:241–242. [PubMed: 4479087]

        • Hevia P, Omaye ST, Jacob RA. 1990. Urinary hydroxyproline excretion and vitamin C status in healthy young men. Am J Clin Nutr 51:644–648. [PubMed: 2321570]

        • Hinds MW, Kolonel LN, Hankin JH, Lee J. 1984. Dietary vitamin A, carotene, vitamin C and risk of lung cancer in Hawaii. Am J Epidemiol 119:227–237. [PubMed: 6695902]

        • Hoffer A. 1971. Ascorbic acid and toxicity. N Engl J Med 285:635–636. [PubMed: 5563968]

        • Hoffer A. 1973. Vitamin C and infertility. Lancet 2:1146. [PubMed: 4128030]

        • Hofstad B, Almendingen K, Vatn M, Andersen S, Owen R, Larsen S, Osnes M. 1998. Growth and recurrence of colorectal polyps: A double-blind 3-year intervention with calcium and antioxidants. Digestion 59:148–156. [PubMed: 9586828]

        • Hogenkamp HP. 1980. The interaction between vitamin B12 and vitamin C. Am J Clin Nutr 33:1–3. [PubMed: 7355772]

        • Hornig B, Arakawa N, Kohler C, Drexler H. 1998. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation 97:363–368. [PubMed: 9468210]

        • Hornig D. 1975. Distribution of ascorbic acid, metabolites and analogues in man and animals. Ann NY Acad Sci 258:103–118. [PubMed: 1106295]

        • Hornig DH, Moser U. 1981. The safety of high vitamin C intakes in man. In: Counsell JN, editor; , Hornig DH, editor. , eds. Vitamin C (Ascorbic Acid). London: Applied Science. Pp.225–248.

        • Horrobin DF. 1996. Ascorbic acid and prostaglandin synthesis. Subcell Biochem 25:109–115. [PubMed: 8821971]

        • Howe GR, Hirohata T, Hislop TG, Iscovich JM, Yuan JM, Katsouyanni K, Lubin F, Marubini E, Modan B, Rohan T. 1990. Dietary factors and risk of breast cancer: Combined analysis of 12 case-control studies. J Natl Cancer Inst 82:561–. [PubMed: 2156081]

        • Howe GR, Ghadirian P, Bueno de Mesquita HB, Zatonski WA, Baghurst PA, Miller AB, Simard A, Baillargeon J, de Waard F, Przewozniak K. 1992. A collaborative case-control study of nutrient intake and pancreatic cancer within the search programme. Int J Cancer 51:365–372. [PubMed: 1317361]

        • Hoyt CJ. 1980. Diarrhea from vitamin C. J Am Med Assoc 244:1674. [PubMed: 7411820]

        • Hughes C, Dutton S, Truswell AS. 1981. High intakes of ascorbic acid and urinary oxalate. J Hum Nutr 35:274–280. [PubMed: 7276555]

        • Hunt JR, Gallagher SK, Johnson LK. 1994. Effect of ascorbic acid on apparent iron absorption by women with low iron stores. Am J Clin Nutr 59:1381–1385. [PubMed: 8198064]

        • Hunter DJ, Manson JE, Colditz GA, Stampfer MJ, Rosner B, Hennekens CH, Speizer FE, Willett WC. 1993. A prospective study of the intake of vitamins C, E, and A and the risk of breast cancer. N Engl J Med 329:234–240. [PubMed: 8292129]

        • IOM (Institute of Medicine). 1991. Nutrition During Lactation . Washington, DC: National Academy Press. P. 179. [PubMed: 25144080]

        • Itoh R, Yamada K, Oka J, Echizen H, Murakami K. 1989. Sex as a factor in levels of serum ascorbic acid in a healthy elderly population. Int J Vitam Nutr Res 59:365–372. [PubMed: 2634043]

        • Jacob RA. 1995. The integrated antioxidant system. Nutr Res 15:755–766.

        • Jacob RA. 1999. Vitamin C. In: Shils ME, editor; , Olson JA, editor; , Shike M, editor; , Ross AC, editor. , eds. Modern Nutrition in Health and Disease, 9th edition. Baltimore, MD: Williams & Wilkins. Pp.467–483.

        • Jacob RA, Pianalto FS. 1997. Urinary carnitine excretion increases during experimental vitamin C depletion of healthy men. J Nutr Biochem 8:265–269.

        • Jacob RA, Skala JH, Omaye ST. 1987. a. Biochemical indices of human vitamin C status. Am J Clin Nutr 46:818–826. [PubMed: 3673928]

        • Jacob RA, Skala JH, Omaye ST, Turnlund JR. 1987. b. Effect of varying ascorbic acid intakes on copper absorption and ceruloplasmin levels of young men. J Nutr 117:2109–2115. [PubMed: 3694287]

        • Jacob RA, Otradovec CL, Russell RM, Munro HN, Hartz SC, McGandy RB, Morrow FD, Sadowski JA. 1988. Vitamin C status and nutrient interactions in a healthy elderly population. Am J Clin Nutr 48:1436–1442. [PubMed: 3202092]

        • Jacob RA, Kelley DS, Pianalto FS, Swendseid ME, Henning SM, Zhang Jz, Ames BN, Fraga CG, Peters JH. 1991. Immunocompetence and oxidant defense during ascorbate depletion of healthy men. Am J Clin Nutr 54:1302S–1309S. [PubMed: 1962587]

        • Jacob RA, Pianalto FS, Agee RE. 1992. Cellular ascorbate depletion in healthy men. J Nutr 122:1111–1118. [PubMed: 1564563]

        • Jacob RA, Kutnink MA, Csallany AS, Daroszewska M, Burton GW. 1996. Vitamin C nutriture has little short-term effect on vitamin E concentrations in healthy women. J Nutr 126:2268–2277. [PubMed: 8814216]

        • Jacques PF, Chylack LT Jr. 1991. Epidemiologic evidence of a role for the antioxidant vitamins and carotenoids in cataract prevention. Am J Clin Nutr 53:352S–355S. [PubMed: 1985409]

        • Jacques PF, Taylor A, Hankinson SE, Willett WC, Mahnken B, Lee Y, Vaid K, Lahav M. 1997. Long-term vitamin C supplement use and prevalence of early age related lens opacities. Am J Clin Nutr 66:911–916. [PubMed: 9322567]

        • Jaffe RM, Kasten B, Young DS, MacLowry JD. 1975. False-negative stool occult blood tests caused by ingestion of ascorbic acid (vitamin C). Ann Intern Med 83:824–826. [PubMed: 1200528]

        • Jama JW, Launer LJ, Witteman JC, den Breeijen JH, Breteler MM, Grobbee DE, Hofman A. 1996. Dietary antioxidants and cognitive function in a population based sample of older persons. The Rotterdam Study. Am J Epidemiol 144:275–280. [PubMed: 8686696]

        • Jariwalla RJ, Harakeh S. 1996. Antiviral and immunomodulatory activities of asco bic acid. Subcell Biochem 25:213–231. [PubMed: 8821976]

        • Jarvinen R, Knekt P, Seppanen R, Teppo L. 1997. Diet and breast cancer risk in a cohort of Finnish women. Cancer Lett 114:251–253. [PubMed: 9103304]

        • Jendryczko A, Tomala J. 1995. The total free radical trapping ability of blood pla ma in eclampsia. Zentralbl Gynakol 117:126–129. [PubMed: 7740845]

        • Jha P, Flather M, Lonn E, Farkouh M, Yusuf S. 1995. The antioxidant vitamins and cardiovascular disease. A critical review of epidemiologic and clinical trial data. Ann Intern Med 123:860–872. [PubMed: 7486470]

        • Jialal I, Devaraj S. 1996. The role of oxidized low density lipoprotein in atherogenesis. J Nutr 126:1053S–1057S. [PubMed: 8642431]

        • Jialal I, Grundy SM. 1991. Preservation of the endogenous antioxidants in low density lipoprotein by ascorbate but not probucol during oxidative modification. J Clin Invest 87:597–601. [PMC free article: PMC296348] [PubMed: 1991843]

        • Jialal I, Vega GL, Grundy SM. 1990. Physiologic levels of ascorbate inhibit the oxidative modification of low density lipoprotein. Atherosclerosis 82:185–191. [PubMed: 2375783]

        • Johnston CS. 1991. Complement component Clq unaltered by ascorbate supplementation in healthy men and women. J Nutr Biochem 2:499–501.

        • Johnston CS. 1999. Biomarkers for establishing a tolerable upper intake level for vitamin C. Nutr Rev 57:71–77. [PubMed: 10101920]

        • Johnston CS, Luo B. 1994. Comparison of the absorption and excretion of three commercially available sources of vitamin C. J Am Diet Assoc 94:779–781. [PubMed: 8021423]

        • Johnston CS, Thompson LL. 1998. Vitamin C status of an outpatient population. J Am Coll Nutr 17:366–370. [PubMed: 9710847]

        • Johnston CS, Martin LJ, Cai X. 1992. Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis. J Am Coll Nutr 11:172–176. [PubMed: 1578094]

        • Johnston CS, Meyer CG, Srilakshmi JC. 1993. Vitamin C elevates red blood cell glutathione in healthy adults. Am J Clin Nutr 58:103–105. [PubMed: 8317379]

        • Johnston CS, Solomon E, Corte C. 1996. Vitamin C depletion is associated with alterations in blood histamine and plasma free carnitine in adults. J Am Coll Nutr 15:586–591. [PubMed: 8951736]

        • Kallner A, Hartmann D, Hornig D. 1979. Steady-state turnover and body pool of ascorbic acid in man. Am J Clin Nutr 32:530–539. [PubMed: 420145]

        • Kallner AB, Hartmann D, Hornig DH. 1981. On the requirements of ascorbic acid in man: Steady-state turnover and body pool in smokers. Am J Clin Nutr 34:1347–1355. [PubMed: 7258125]

        • Karra MV, Udipi SA, Kirksey A, Roepke JL. 1986. Changes in specific nutrients in breast milk during extended lactation. Am J Clin Nutr 43:495–503. [PubMed: 3962902]

        • Katsuki H. 1996. Vitamin C and nervous tissue: In vivo and in vitro aspects. Subcell Biochem 25:293–311. [PubMed: 8821980]

        • Keith RE. 1994. Vitamins and physical activity. In: Wolinsky I, editor; , Hickson JF, editor. , eds. Nutrition in Exercise and Sport, 2nd edition. Boca Raton, FL: CRC Press. Pp.159–183.

        • Kelly FJ, Mudway I, Blomberg A, Frew A, Sandstrom T. 1999. Altered lung antioxidant status in patients with mild asthma. Lancet 354:482–483. [PubMed: 10465176]

        • Kennes B, Dumont I, Brohee D, Hubert C, Neve P. 1983. Effect of vitamin C supplements on cell-mediated immunity in old people. Gerontology 29:305–310. [PubMed: 6604680]

        • Knekt P, Jarvinen R, Seppanen R, Rissanen A, Aromaa A, Heinonen OP, Albanes D, Heinonen M, Pukkala E, Teppo L. 1991. Dietary antioxidants and the risk of lung cancer. Am J Epidemiol 134:471–479. [PubMed: 1897503]

        • Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromaa A. 1994. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol 139:1180–1189. [PubMed: 8209876]

        • Kritchevsky SB, Shimakawa T, Tell G, Dennis B, Carpenter M, Eckfeldt JH, Peacher-Ryan H, Heiss G. 1995. Dietary antioxidants and carotid artery wall thickness. The ARIC Study. Circulation 92:2142–2150. [PubMed: 7554194]

        • Kushi LH, Fee RM, Sellers TA, Zheng W, Folsom AR. 1996. a. Intake of vitamins A, C, and E and postmenopausal breast cancer. The Iowa Women's Health Study. Am J Epidemiol 144:165–174. [PubMed: 8678048]

        • Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM. 1996. b. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med 334:1156–1162. [PubMed: 8602181]

        • Lamden MP, Chrystowski GA. 1954. Urinary oxalate excretion by man following ascorbic acid ingestion. Proc Soc Exp Biol Med 85:190–192. [PubMed: 13134331]

        • Laudicina DC, Marnett LJ. 1990. Enhancement of hydroperoxide-dependent lipid peroxidation in rat liver microsomes by ascorbic acid. Arch Biochem Biophys 278:73–80. [PubMed: 2108607]

        • Leaf CD, Vecchio AJ, Roe DA, Hotchkiss JH. 1987. Influence of ascorbic acid dose on N-nitrosoproline formation in humans. Carcinogenesis 8:791–795. [PubMed: 3608076]

        • Leggott PJ, Robertson PB, Rothman DL, Murray PA, Jacob RA. 1986. The effect of controlled ascorbic acid depletion and supplementation on periodontal health. J Periodontol 57:480–485. [PubMed: 3462381]

        • Leggott PJ, Robertson PB, Jacob RA, Zambon JJ, Walsh M, Armitage GC. 1991. Effects of ascorbic acid depletion and supplementation on periodontal health and subgingival microflora in humans. J Dent Res 70:1531–1536. [PubMed: 1663525]

        • Lehr HA, Weyrich AS, Saetzler RK, Jurek A, Arfors KE, Zimmerman GA, Prescott SM, McIntyre TM. 1997. Vitamin C blocks inflammatory platelet-activating factor mimetics created by cigarette smoking. J Clin Invest 99:2358–2364. [PMC free article: PMC508074] [PubMed: 9153277]

        • Le Marchand L, Yoshizawa CN, Kolonel LN, Hankin JH, Goodman MT. 1989. Vegetable consumption and lung cancer risk: A population-based case-control study in Hawaii. J Natl Cancer Inst 81:1158–1164. [PubMed: 2545891]

        • Lenton KJ, Therriault H, Fulop T, Payette H, Wagner JR. 1999. Glutathione and ascorbate are negatively correlated with oxidative DNA damage in human lymphocytes. Carcinogenesis 20:607–613. [PubMed: 10223188]

        • Leske MC, Chylack LT Jr, Wu SY. 1991. The Lens Opacities Case-Control Study. Risk factors for cataract. Arch Ophthalmol 109:244–251. [PubMed: 1993036]

        • Levine GN, Frei B, Koulouris SN, Gerhard MD, Keaney JF Jr, Vita JA. 1996. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 93:1107–1113. [PubMed: 8653830]

        • Levine M, Dhariwal KR, Wang Y, Park JB, Welch RW. 1994. Ascorbic acid in neutrophils. In: Frei B, editor. , ed. Natural Antioxidants in Health and Disease . San Diego: Academic Press. Pp.469–488.

        • Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, Park JB, Lazarev A, Graumlich JF, King J, Cantilena LR. 1996. a. Vitamin C pharmacokinetics in healthy volunteers: Evidence for a recommended dietary allowance. Proc Natl Acad Sci USA 93:3704–3709. [PMC free article: PMC39676] [PubMed: 8623000]

        • Levine M, Rumsey S, Wang Y, Park J, Kwon O, Xu W, Amano N. 1996. b. Vitamin C.In: Ziegler EE, editor; , Filer LJ Jr, editor. , eds. Present Knowledge in Nutrition, 7th edition. Washington, DC: ILSI Press. Pp.146–159.

        • Levy R, Shriker O, Porath A, Riesenberg K, Schlaeffer F. 1996. Vitamin C for the treatment of recurrent furunculosis in patients with impaired neutrophil functions. J lnfect Dis 173:1502–1505. [PubMed: 8648230]

        • Loft S, Vistisen K, Ewertz M, Tjonneland A, Overvad K, Poulsen HE. 1992. Oxidative DNA damage estimated by 8-hydroxydeoxyguanosine excretion in humans: Influence of smoking, gender and body mass index. Carcinogenesis 13:2241–2247. [PubMed: 1473230]

        • Losonczy KG, Harris TB, Havlik RJ. 1996. Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: The Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr 64:190–196. [PubMed: 8694019]

        • Løvstad RA. 1997. A study on ascorbate inhibition of ceruloplasmin ferroxidase activity. BioMetals 10:123–126. [PubMed: 9210294]

        • LSRO/FASEB (Life Sciences Research Office/Federation of American Societies for Experimental Biology). 1989. Nutrition Monitoring in the United States: An Update Report on Nutrition Monitoring . Prepared for the U.S. Department of Agriculture and the U.S. Department of Health and Human Services. DHHS Publication No. (PHS) 89-1255. Washington, DC: U.S. Government Printing Office.

        • Ludvigsson J, Hansson LO, Tibbling G. 1977. Vitamin C as a preventive medicine against common colds in children. Scand J Infect Dis 9:91–98. [PubMed: 897573]

        • Ludvigsson J, Hansson LO, Stendahl O. 1979. The effect of large doses of vitamin C on leukocyte function and some laboratory parameters. Int J Vitam Nutr Res 49:160–165. [PubMed: 381229]

        • Lunec J, Blake DR. 1985. The determination of dehydroascorbic acid and ascorbic acid in the serum and synovial fluid of patients with rheumatoid arthritis. Free Radic Res Commun 1:31–39. [PubMed: 3880014]

        • Lykkesfeldt J, Loft S, Nielsen JB, Poulsen HE. 1997. Ascorbic acid and dehydroascorbic acid as biomarkers of oxidative stress caused by smoking. Am J Clin Nutr 65:959–963. [PubMed: 9094879]

        • Lykkesfeldt J, Christen S, Wallock LM, Change HH, Jacob RA, Ames BN. 2000. Ascorbate is depleted by smoking and repleted by moderate supplementation: A study in male smokers and nonsmokers with matched dietary antioxidant intakes. Am J Clin Nutr 71:530–536. [PubMed: 10648268]

        • Mangels AR, Block G, Frey CM, Patterson BH, Taylor PR, Norkus EP, Levander OA. 1993. The bioavailability to humans of ascorbic acid from oranges, o ange juice and cooked broccoli is similar to that of synthetic ascorbic acid. J Nutr 123:1054–1061. [PubMed: 8505665]

        • Mannick EE, Bravo LE, Zarama G, Realpe JL, Zhang XJ, Ruiz B, Fontham ETH, Mera R, Miller MJS, Correa P. 1996. Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: Effect of antibiotics and antioxidants. Cancer Res 56:3238–3243. [PubMed: 8764115]

        • Marangon K, Herbeth B, Artur Y, Esterbauer H, Siest G. 1997. Low and very low density lipoprotein composition and resistance to copper-induced oxidation are not notably modified in smokers. Clin Chim Acta 265:1–12. [PubMed: 9352124]

        • Marangon K, Herbeth B, Lecomte E, Paul-Dauphin A, Grolier P, Chancerelle Y, Artur Y. 1998. Diet, antioxidant status, and smoking habits in French men. Am J Clin Nutr 67:231–239. [PubMed: 9459370]

        • May JM, Cobb CE, Mendiratta S, Hill KE, Burk RF. 1998. Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. J Biol Chem 273:23039–23045. [PubMed: 9722529]

        • May JM, Mendiratta S, Qu ZC, Loggins E. 1999. Vitamin C recycling and function in human monocytic U-937 cells. Free Radic Biol Med 26:1513–1523. [PubMed: 10401617]

        • McKeown-Eyssen G, Holloway C, Jazmaji V, Bright-See E, Dion P, Bruce WR. 1988. A randomized trial of vitamins C and E in the prevention of recurrence of colorectal polyps. Cancer Res 48:4701–4705. [PubMed: 3293777]

        • McLaran CJ, Bett JHN, Nye JA, Halliday JW. 1982. Congestive cardiomyopathy and haemochromatosis—Rapid progression possibly accelerated by excessive ingestion of ascorbic acid. Aust NZ J Med 12:187–188. [PubMed: 6953962]

        • Melethil S, Mason WD, Chang C-J. 1986. Dose-dependent absorption and excretion of vitamin C in humans. Int J Pharmaceut 31:83–89.

        • Mentzer WC, Collier E. 1975. Hydrops fetalis associated with erythrocyte G-6-PD deficiency and maternal ingestion of fava beans and ascorbic acid. J Pediatr 86:565–567. [PubMed: 1127504]

        • Metz J, Hundertmark U, Pevny I. 1980. Vitamin C allergy of the delayed type. Contact Dermatitis 6:172–174. [PubMed: 7389324]

        • Millar J. 1995. The nitric oxide/ascorbate cycle: How neurones may control their own oxygen supply. Med Hypoth 45:21–26. [PubMed: 8524171]

        • Miller JZ, Nance WE, Norton JA, Wolen RL, Griffith RS, Rose RJ. 1977. Therapeutic effect of vitamin C. A co-twin control study. J Am Med Assoc 237:248–251. [PubMed: 318715]

        • Mirvish SS. 1994. Experimental evidence for inhibition of N-nitroso compound formation as a factor in the negative correlation between vitamin C consumption and the incidence of certain cancers. Cancer Res 54:1948S–1951S. [PubMed: 8137317]

        • Mitch WE, Johnson MW, Kirshenbaum JM, Lopez RE. 1981. Effect of large oral doses of ascorbic acid on uric acid excretion by normal subjects. Clin Pharmcol Ther 29:318–321. [PubMed: 7471601]

        • Montalto MB, Benson JD, Martinez GA. 1985. Nutrient intakes of formula-fed infants and infants fed cow's milk. Pediatrics 75:343–351. [PubMed: 3969338]

        • Morrow JD, Frei B, Longmire AW, Gaziano JM, Lynch SM, Shyr Y, Strauss WE, Oates JA, Roberts LJ II. 1995. Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. N Engl J Med 332:1198–1203. [PubMed: 7700313]

        • Morse EH, Clark RP, Keyser DE, Merrow SB, Bee DE. 1975. Comparison of the nutritional status of pregnant adolescents with adult pregnant women. I. Biochemical findings. Am J Clin Nutr 28:1000–1013. [PubMed: 1163467]

        • Moser U. 1987. Uptake of ascorbic acid by leukocytes. Ann NY Acad Sci 498:200–215. [PubMed: 3475998]

        • Moss AJ, Levy AS, Kim I, Park YK. 1989. Use of Vitamin and Mineral Supplements in the United States: Current Users, Types of Products, and Nutrients . Advance Data, Vital and Health Statistics of the National Center for Health Statistics. Number 174. Hyattsville, MD: National Center for Health Statistics. Pp.1–19.

        • Motoyama T, Kawano H, Kugiyama K, Hirashima O, Ohgushi M, Yoshimura M, Ogawa H, Yasue H. 1997. Endothelium-dependent vasodilation in the brachial artery is impaired in smokers: Effect of vitamin C. Am J Physiol 273:H1644–H1650. [PubMed: 9362226]

        • Mudway IS, Krishna MT, Frew AJ, MacLeod D, Sandstrom T, Holgate ST, Kelly FJ. 1999. Compromised concentrations of ascorbate in fluid lining the respiratory tract in human subjects after exposure to ozone. Occup Environ Med 56:473–481. [PMC free article: PMC1757764] [PubMed: 10472319]

        • Mulholland CW, Strain JJ, Trinick TR. 1996. Serum antioxidant potential, and lipoprotein oxidation in female smokers following vitamin C supplementation. Int J Food Sci Nutr 47:227–231. [PubMed: 8735778]

        • Naidoo D, Lux O. 1998. The effect of vitamin C and E supplementation on lipid and urate oxidation products in plasma. Nutr Res 18:953–961.

        • Ness AR, Khaw KT, Bingham S, Day NE. 1996. Vitamin C status and respiratory function. Eur J Clin Nutr 50:573–579. [PubMed: 8880036]

        • Newmark HL, Scheiner MS, Marcus M, Prabhudesai M. 1976. Stability of vitamin B12 in the presence of ascorbic acid. Am J Clin Nutr 29:645–649. [PubMed: 1274888]

        • Newton HM, Schorah CJ, Habibzadeh N, Morgan DB, Hullin RP. 1985. The cause and correction of low blood vitamin C concentrations in the elderly. Am J Clin Nutr 42:656–659. [PubMed: 4050725]

        • NRC (National Research Council). 1989. Recommended Dietary Allowances , 10th edition. Washington, DC: National Academy Press. [PubMed: 25144070]

        • Nyyssonen K, Parviainen MT, Salonen R, Tuomilehto J, Salonen JT. 1997. a. Vitamin C deficiency and risk of myocardial infarction: Prospective population study of men from eastern Finland. Br Med J 314:634–638. [PMC free article: PMC2126082] [PubMed: 9066474]

        • Nyyssonen K, Poulsen HE, Hayn M, Agerbo P, Porkkala-Sarataho E, Kaikkonen J, Salonen R, Salonen JT. 1997. b. Effect of supplementation of smoking men with plain or slow release ascorbic acid on lipoprotein oxidation. Eur J Clin Nutr 51:154–163. [PubMed: 9076405]

        • Ocke MC, Bueno-de-Mesquita HB, Feskens EJ, van Staveren WA, Kromhout D. 1997. Repeated measurements of vegetables, fruits, beta-carotene, and vit mins C and E in relation to lung cancer. Am J Epidemiol 145:358–365. [PubMed: 9054240]

        • Omaye ST, Skala JH, Jacob RA. 1986. Plasma ascorbic acid in adult males: Effects of depletion and supplementation. Am J Clin Nutr 44:257–264. [PubMed: 3728363]

        • Omaye ST, Schaus EE, Kutnink MA, Hawkes WC. 1987. Measurement of vitamin C in blood components by high-performance liquid chromatography. Implication in assessing vitamin C status. Ann NY Acad Sci 498:389–401. [PubMed: 3304068]

        • Ono K. 1986. Secondary hyperoxalemia caused by vitamin C supplementation in regular hemodialysis patients. Clin Nephrol 26:239–243. [PubMed: 3802587]

        • Oreopoulos DG, Lindeman RD, VanderJagt DJ, Tzamaloukas AH, Bhagavan HN, Garry PJ. 1993. Renal excretion of ascorbic acid: Effect of age and sex. J Am Coll Nutr 12:537–542. [PubMed: 8263270]

        • Ortega RM, Lopez-Sobaler AM, Quintas ME, Martinez RM, Andres P. 1998. The influence of smoking on vitamin C status during the third trimester of pregnancy and on vitamin C levels in maternal milk. J Am Coll Nutr 17:379–384. [PubMed: 9710849]

        • Panayiotidis M, Collins AR. 1997. Ex vivo assessment of lymphocyte antioxidant status using the comet assay. Free Rad Res 27:533–537. [PubMed: 9518069]

        • Pandey DK, Shekelle R, Selwyn BJ, Tangney C, Stamler J. 1995. Dietary vitamin C and beta-carotene and risk of death in middle-aged men. The Western Electric Study. Am J Epidemiol 142:1269–1278. [PubMed: 7503047]

        • Panush RS, Delafuente JC, Katz P, Johnson J. 1982. Modulation of certain immunologic responses by vitamin C. III. Potentiation of in vitro and in vivo ly phocyte responses. Int J Vitam Nutr Res Suppl 23:35–47. [PubMed: 6288604]

        • Park JB, Levine M. 1996. Purification, cloning and expression of dehydroascorbic acid-reducing activity from human neutrophils: Identification as glutaredoxin. Biochem J 315:931–938. [PMC free article: PMC1217296] [PubMed: 8645179]

        • Parkkinen J, Vaaranen O, Vahtera E. 1996. Plasma ascorbate protects coagulation factors against photooxidation. Thromb Haemost 75:292–297. [PubMed: 8815579]

        • Pelletier O. 1977. Vitamin C and tobacco. Int J Vitam Nutr Res Suppl 16:147–170.

        • Perrig WJ, Perrig P, Stahelin HB. 1997. The relation between antioxidants and memory performance in the old and very old. J Am Geriatr Soc 45:718–724. [PubMed: 9180666]

        • Peters EM, Goetzsche JM, Grobbelaar B, Noakes TD. 1993. Vitamin C suppleme tation reduces the incidence of postrace symptoms of upper-respiratory-tract infection in ultramarathon runners. Am J Clin Nutr 57:170–174. [PubMed: 8185726]

        • Pfeffer F, Valdes-Ramos R, Avila-Rosas H, Meza C, Casanueva E. 1996. Iron, zinc and vitamin C nutritional status is not related to weight gain in pregnant women. Nutr Res 16:555–564.

        • Phull PS, Price AB, White KL, Schorah CJ, Jacyna MR. 1999. Gastroduodenal mucosal vitamin-C levels in Helicobacter pylori infection. Scand J Gastroenterol 34:361–366. [PubMed: 10365895]

        • Pirkle JL, Flegal KM, Bernert JT, Brody DJ, Etzel RA, Maurer KR. 1996. Exposure of the US population to environmental tobacco smoke: The Third National Health and Nutrition Examination Survey, 1988 to 1991. J Am Med Assoc 275:1233–1240. [PubMed: 8601954]

        • Podmore ID, Griffiths HR, Herbert KE, Mistry N, Mistry P, Lunec J. 1998. Vitamin C exhibits pro-oxidant properties. Nature 392:559. [PubMed: 9560150]

        • Pohl H, Reidy JA. 1989. Vitamin C intake influences the bleomycin-induced chr mosome damage assay: Implications for detection of cancer susceptibility and chromosome breakage syndromes. Mutat Res 224:247–252. [PubMed: 2477699]

        • Powers HJ, Loban A, Silvers K, Gibson AT. 1995. Vitamin C at concentrations observed in premature babies inhibits the ferroxidase activity of caeruloplasmin. Free Radic Res 22:57–65. [PubMed: 7889148]

        • Prieme H, Loft S, Nyyssonen K, Salonen JT, Poulsen HE. 1997. No effect of supplementation with vitamin E, ascorbic acid, or coenzyme Q10 on oxidative DNA damage estimated by 8-hydroxy-7,8-dihydro-2'-deoxyguanosine excretion in smokers. Am J Clin Nutr 65:503–507. [PubMed: 9022536]

        • Pryor WA. 1992. Biological effects of cigarette smoke, wood smoke, and the smoke from plastics: The use of electron spin resonance. Free Radic Biol Med 13:659–676. [PubMed: 1334034]

        • Pryor WA. 1997. Cigarette smoke radicals and the role of free radicals in chemical carcinogenicity. Environ Hlth Perspect 105:875–882. [PMC free article: PMC1470037] [PubMed: 9255574]

        • Pryor WA, Prier DG, Church DF. 1983. Electron-spin resonance study of mai stream and sidestream cigarette smoke: Nature of the free radicals in gasphase smoke and in cigarette tar. Environ Hlth Perspect 47:345–355. [PMC free article: PMC1569403] [PubMed: 6297881]

        • Rajalakshmi R, Deodhar AD, Ramarkrishnan CV. 1965. Vitamin C secretion during lactation. Acta Paediatr Scand 54:375–382. [PubMed: 14343448]

        • Rebouche CJ. 1995. Renal handling of carnitine in experimental vitamin C def ciency. Metabolism 44:1639–1643. [PubMed: 8786736]

        • Rees DC, Kelsey H, Richards JDM. 1993. Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency. Br Med J 306:841–842. [PMC free article: PMC1677333] [PubMed: 8490379]

        • Rehman A, Collis CS, Yang M, Kelly M, Diplock AT, Halliwell B, Rice-Evans C. 1998. The effects of iron and vitamin C co-supplementation on oxidative da age to DNA in healthy volunteers. Biochem Biophys Res Commun 246:293–298. [PubMed: 9600109]

        • Reilly M, Delanty N, Lawson JA, Fitzgerald GA. 1996. Modulation of oxidant stress in vivo in chronic cigarette smokers. Circulation 94:19–25. [PubMed: 8964113]

        • Rhead WJ, Schrauzer GN. 1971. Risks of long-term ascorbic acid overdosage. Nutr Rev 29:262–263. [PubMed: 5127162]

        • Rifici VA, Khachadurian AK. 1993. Dietary supplementation with vitamins C and E inhibits in vitro oxidation of lipoproteins. J Am Coll Nutr 12:631–637. [PubMed: 8294717]

        • Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. 1993. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 328:1450–1456. [PubMed: 8479464]

        • Rivers, JM. 1987. Safety of high-level vitamin C ingestion. Ann NY Acad Sci 498:445–454. [PubMed: 3304071]

        • Robertson JM, Donner AP, Trevithick JR. 1989. Vitamin E intake and risk of cataracts in humans. Ann NY Acad Sci 570:372–382. [PubMed: 2629606]

        • Rokitzki L, Hinkel S, Klemp C, Cufi D, Keul J. 1994. Dietary, serum and urine ascorbic acid status in male athletes. Int J Sports Med 15:435–440. [PubMed: 8002125]

        • Rokkas T, Papatheodorou G, Karameris A, Mavrogeorgis A, Kalogeropoulos N, Giannikos N. 1995. Helicobacter pylori infection and gastric juice vitamin C levels. Impact of eradication. Dig Dis Sci 40:615–621. [PubMed: 7895555]

        • Romney SL, Duttagupta C, Basu J, Palan PR, Karp S, Slagle NS, Dwyer A, Wassertheil-Smoller S, Wylie-Rosett J. 1985. Plasma vitamin C and uterine cervical dysplasia. Am J Obstet Gynecol 151:976–980. [PubMed: 3985059]

        • Ronchetti IP, Quaglino D Jr, Bergamini G. 1996. Ascorbic acid and connective tissue. Subcell Biochem 25:249–264. [PubMed: 8821978]

        • Rose RC, Richer SP, Bode AM. 1998. Ocular oxidants and antioxidant protection. Proc Soc Exp Biol Med 217:397–407. [PubMed: 9521086]

        • Rumsey SC, Levine M. 1998. Absorption, transport, and disposition of ascorbic acid in humans. J Nutr Biochem 9:116–130.

        • Russell AL. 1967. Epidemiology of periodontal disease. Int Dent J 17:282–296. [PubMed: 4862723]

        • Sahyoun NR, Jacques PF, Russell RM. 1996. Carotenoids, vitamins C and E, and mortality in an elderly population. Am J Epidemiol 144:501–511. [PubMed: 8781466]

        • Salmenpera L. 1984. Vitamin C nutrition during prolonged lactation: Optimal in infants while marginal in some mothers. Am J Clin Nutr 40:1050–1056. [PubMed: 6496385]

        • Salonen JT, Salonen R, Nyyssonen K, Korpela H. 1992. Iron sufficiency is associated with hypertension and excess risk of myocardial infarction: The Kuopio Ischemic Heart Disease Risk Factor Study (KIHD). Circulation 85:864–876.

        • Samman S, Brown AJ, Beltran C, Singh S. 1997. The effect of ascorbic acid on plasma lipids and oxidisability of LDL in male smokers. Eur J Clin Nutr 51:472–477. [PubMed: 9234031]

        • Sasaki A, Kondo K, Sakamoto Y, Kurata H, Itakura H, Ikeda Y. 1997. Smoking cessation increases the resistance of low-density lipoprotein to oxidation. Atherosclerosis 130:109–111. [PubMed: 9126654]

        • Satarug S, Haswell-Elkins MR, Tsuda M, Mairiang P, Sithithaworn P, Mairiang E, Esumi H, Sukprasert S, Yongvanit P, Elkins DB. 1996. Thiocyanate-independent nitrosation in humans with carcinogenic parasite infection. Carcinogenesis 17:1075–1081. [PubMed: 8640916]

        • Sauberlich HE. 1994. Pharmacology of vitamin C. Annu Rev Nutr 14 371–391. [PubMed: 7946525]

        • Scaccini C, Jialal I. 1994. LDL Modification by activated polymorphonuclear leukocytes: A cellular model of mild oxidative stress. Free Radic Biol Med 16:49–55. [PubMed: 8299996]

        • Schectman G, Byrd JC, Hoffmann R. 1991. Ascorbic acid requirements for smokers: Analysis of a population survey. Am J Clin Nutr 53:1466–1470. [PubMed: 2035475]

        • Schmidt KH, Hagmaier V, Hornig DH, Vuilleumier JP, Rutishauser G. 1981. Urinary oxalate excretion after large intakes of ascorbic acid in man. Am J Clin Nutr 34:305–311. [PubMed: 7211731]

        • Schrauzer GN, Rhead WJ. 1973. Ascorbic acid abuse: Effects on long-term ingestion of excessive amounts on blood levels and urinary excretion. Int J Vitam Nutr Res 43:201–211. [PubMed: 4716569]

        • Schrauzer GN, Ishmael D, Kiefer GW. 1975. Some aspects of current vitamin C usage: Diminished high-altitude resistance following overdosage. Ann NY Acad Sci 258:377–381. [PubMed: 1060408]

        • Schwartz J, Weiss ST. 1994. Relationship between dietary vitamin C intake and pulmonary function in the First National Health and Nutrition Examination Survey (NHANES I). Am J Clin Nutr 59:110–114. [PubMed: 8279390]

        • Schwarz KB, Cox J, Sharma S, Witter F, Clement L, Sehnert SS, Risby TH. 1995. Cigarette smoking is pro-oxidant in pregnant women regardless of antioxidant nutrient intake. J Nutr Environ Med 5:225–234.

        • Sharpe PC, MacAuley D, McCrum EE, Stott G, Evans AE, Mulholland C, Boreham CA, Duly E, Trinick TR. 1994. Ascorbate and exercise in the Northern Ireland population. Int J Vitam Nutr Res 64:277–282. [PubMed: 7883465]

        • Shekelle RB, Lepper M, Liu S, Maliza C, Raynor WJ, Rossof AH. 1981. Dietary vitamin A and risk of cancer in the Western Electric Study. Lancet 2:1185–1190. [PubMed: 6118627]

        • Shilotri PG, Bhat KS. 1977. Effect of mega doses of vitamin C on bactericidal activity of leukocytes. Am J Clin Nutr 30:1077–1081. [PubMed: 327791]

        • Siegel C, Barker B, Kunstadter M. 1982. Conditioned oral scurvy due to megavitamin C withdrawal. J Periodontol 53:453–455. [PubMed: 6956713]

        • Sies H, Stahl W. 1995. Vitamins E and C, beta-carotene, and other carotenoids as antioxidants. Am J Clin Nutr 62:1315S–1321S. [PubMed: 7495226]

        • Simon JA. 1992. Vitamin C and cardiovascular disease: A review. J Am Coll Nutr 11:107–125. [PubMed: 1578086]

        • Simon JA, Hudes ES, Browner WS. 1998. Serum ascorbic acid and cardiovascular disease prevalence in US adults. Epidemiology 9:316–321. [PubMed: 9583425]

        • Singh RB, Ghosh S, Niaz MA, Singh R, Beegum R, Chibo H, Shoumin Z, Postiglione A. 1995. Dietary intake, plasma levels of antioxidant vitamins, and oxidative stress in relation to coronary artery disease in elderly subjects. Am J Cardiol 76:1233–1238. [PubMed: 7503002]

        • Sinha R, Block G, Taylor PR. 1993. Problems with estimating vitamin C intakes. Am J Clin Nutr 57:547–550. [PubMed: 8460610]

        • Skaper SD, Fabris M, Ferrari V, Carbonare MD, Leon A. 1997. Quercetin protects cutaneous tissue-associated cell types including sensory neurons from oxidative stress induced by glutathione depletion: Cooperative effects of ascorbic acid. Free Radic Biol Med 22:669–678. [PubMed: 9013129]

        • Sneed SM, Zane C, Thomas MR. 1981. The effects of ascorbic acid, vitamin B6, vitamin B12, and folic acid supplementation on the breast milk and maternal nutritional status of low socioeconomic lactating women. Am J Clin Nutr 34:1338–1346. [PubMed: 7258124]

        • Solzbach U, Hornig B, Jeserich M, Just H. 1997. Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients. Circulation 96:1513–1519. [PubMed: 9315540]

        • Specker BL, Beck A, Kalkwarf H., Ho M. 1997. Randomized trial of varying mineral intake on total body bone mineral accretion during the first year of life. Pediatrics 99:e12. [PubMed: 9164808]

        • Stein HB, Hasan A, Fox IH. 1976. Ascorbic acid-induced uricosuria. Ann Intern Med 84:385–388. [PubMed: 1259282]

        • Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A. 1998. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation 97:2222–2229. [PubMed: 9631871]

        • Thomas MR, Kawamoto J, Sneed SM, Eakin R. 1979. The effects of vitamin C, vitamin B6, and vitamin B12 supplementation on the breast milk and maternal status of well-nourished women. Am J Clin Nutr 32:1679–1685. [PubMed: 463805]

        • Thomas MR, Sneed SM, Wei C, Nail PA, Wilson M, Sprinkle EE. 1980. The effects of vitamin C, vitamin B6, vitamin B12, folic acid, riboflavin, and thiamin on the breast milk and maternal status of well-nourished women at 6 months postpartum. Am J Clin Nutr 33:2151–2156. [PubMed: 7424809]

        • Timimi FK, Ting HH, Haley EA, Roddy MA, Ganz P, Creager MA. 1998. Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. J Am Coll Cardiol 31:552–557. [PubMed: 9502634]

        • Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. 1996. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 97:22–28. [PMC free article: PMC507058] [PubMed: 8550838]

        • Ting HH, Timimi FK, Haley EA, Roddy MA, Ganz P, Creager MA. 1997. Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia. Circulation 95:2617–2622. [PubMed: 9193429]

        • Tiselius HG, Almgard LE. 1977. The diurnal urinary excretion of oxalate and the effect of pyridoxine and ascorbate on oxalate excretion. Eur Urol 3:41–46. [PubMed: 556987]

        • Tlaskal P, Novakova V. 1990. Vitamins C and E in neonates and their mothers. Cesk Pediatr 45:339–343. [PubMed: 2289252]

        • Tribble DL, Giuliano LJ, Fortmann SP. 1993. Reduced plasma ascorbic acid concentrations in nonsmokers regularly exposed to environmental tobacco smoke. Am J Clin Nutr 58:886–890. [PubMed: 8249873]

        • Tsao CS. 1997. An overview of ascorbic acid chemistry and biochemistry. In: Packer L, editor; , Fuchs J, editor. , eds. Vitamin C in Health and Disease . New York: Marcel Dekker. Pp.25–58.

        • Tsao CS, Leung PY. 1988. Urinary ascorbic acid levels following the withdrawal of large doses of ascorbic acid in guinea pigs. J Nutr 118:895–900. [PubMed: 3392599]

        • Tsao CS, Salimi SL. 1984. Effect of large intake of ascorbic acid on urinary and plasma oxalic acid levels. Int J Vitam Nutr Res 54:245–249. [PubMed: 6500850]

        • Udipi SA, Kirksey A, West K, Giacoia G. 1985. Vitamin B6, vitamin C and folacin levels in milk from mothers of term and preterm infants during the neonatal period. Am J Clin Nutr 42:522–530. [PubMed: 4041128]

        • Urivetzky M, Kessaris D, Smith AD. 1992. Ascorbic acid overdosing: A risk factor for calcium oxalate nephrolithiasis. J Urol 147:1215–1218. [PubMed: 1569652]

        • Valkonen M, Kuusi T. 1998. Passive smoking induces atherogenic changes in low-density lipoprotein. Circulation 97:2012–2016. [PubMed: 9610530]

        • VanderJagt DJ, Garry PJ, Bhagavan HN. 1987. Ascorbic acid intake and plasma levels in healthy elderly people. Am J Clin Nutr 46:290–294. [PubMed: 3618533]

        • Van Eekelen M. 1953. Occurrence of vitamin C in foods. Proc Nutr Soc 12:228–232.

        • Vitale S, West S, Hallfrisch J, Alston C, Wang F, Moorman C, Muller D, Singh V, Taylor HR. 1993. Plasma antioxidants and risk of cortical and nuclear cataract. Epidemiology 4:195–203. [PubMed: 8512984]

        • Vogel RI, Lamster IB, Wechsler SA, Macedo B, Hartley LJ, Macedo JA. 1986. The effects of megadoses of ascorbic acid on PMN chemotaxis and experimental gingivitis. J Periodontol 57:472–479. [PubMed: 3462380]

        • Wandzilak TR, D'Andre SD, Davis PA, Williams HE. 1994. Effect of high dose vitamin C on urinary oxalate levels. J Urol 151:834–837. [PubMed: 8126804]

        • Wang Y, Russo TA, Kwon O, Chanock S, Rumsey SC, Levine M. 1997. Ascorbate recycling in human neutrophils: Induction by bacteria. Proc Natl Acad Sci USA 94:13816–13819. [PMC free article: PMC28390] [PubMed: 9391110]

        • Waring AJ, Drake IM, Schorah CJ, White KL, Lynch DA, Axon AT, Dixon MF. 1996. Ascorbic acid and total vitamin C concentrations in plasma, gastric juice, and gastrointestinal mucosa: Effects of gastritis and oral supplementation. Gut 38:171–176. [PMC free article: PMC1383018] [PubMed: 8801192]

        • Wassertheil-Smoller S, Romney SL, Wylie-Rosett J, Slagle S, Miller G, Lucido D, Duttagupta C, Palan PR. 1981. Dietary vitamin C and uterine cervical dysplasia. Am J Epidemiol 114:714–724. [PubMed: 7304600]

        • Weber C, Wolfgang E, Weber K, Weber PC. 1996. Increased adhesiveness of isolated monocytes to endothelium is prevented by vitamin C intake in smokers. Circulation 93:1488–1492. [PubMed: 8608614]

        • Wen Y, Cooke T Feely, J. 1997. The effect of pharmacological supplementation with vitamin C on low-density lipoprotein oxidation. Br J Clin Pharmacol 44:94–97. [PMC free article: PMC2042803] [PubMed: 9241103]

        • Witt EH, Reznick AZ, Viguie CA, Starke-Reed P, Packer L. 1992. Exercise, oxidative damage and effects of antioxidant manipulation . J Nutr 122:766–773. [PubMed: 1514950]

        • Woolfe SN, Kenney EB, Hume WR, Carranza FA Jr. 1984. Relationship of ascorbic acid levels of blood and gingival tissue with response to periodontal therapy. J Clin Periodontol 11:159–165. [PubMed: 6368610]

        • Yong LC, Brown CC, Schatzkin A, Dresser CM, Slesinski MJ, Cox CS, Taylor PR. 1997. Intake of vitamins E, C, and A and risk of lung cancer. The NHANES I Epidemiologic Followup Study. Am J Epidemiol 146:231–243. [PubMed: 9247007]

        • Young JC, Kenyon EM, Calabrese EJ. 1990. Inhibition of beta-glucuronidase in human urine by ascorbic acid. Hum Exp Toxicol 9:165–170. [PubMed: 2375883]

        • Zatonski W, Przewozniak K, Howe GR, Maisonneuve P, Walker AM, Boyle P. 1991. Nutritional factors and pancreatic cancer: A case-control study from south west Poland. Int J Cancer 48:390–394. [PubMed: 2040534]

        Current Rda For Vitamin C

        Source: https://www.ncbi.nlm.nih.gov/books/NBK225480/

        Share:
        banner