Even higher oral intake does not further raise plasma nor tissue concentrations because absorption efficiency decreases and any excess that is absorbed is excreted in urine.

For research purposes, concentrations can be assessed in leukocytes and tissues, which are normally maintained at an order of magnitude higher than in plasma via an energy-dependent transport system, depleted slower than plasma concentrations during dietary deficiency and restored faster during dietary repletion,[7]: 103–109  but these analysis are difficult to measure, and hence not part of standard diagnostic testing.

[7]: 155–165  In 2006, the European Food Safety Authority (EFSA) also pointed out the disturbances at that dose level, but reached the conclusion that there was not sufficient evidence to set a UL for vitamin C,[23] as did the Japan National Institute of Health and Nutrition in 2010.

Supplemental rations of these highly fortified, blended foods are provided to refugees and displaced persons in camps and to beneficiaries of development feeding programs that are targeted largely toward mothers and children.

Its main loss during processing and storage is from oxidation, which is accelerated by light, oxygen, heat, increased pH, high moisture content (water activity), and the presence of copper or ferrous salts.

Oxidative losses also occur during food processing and preparation, and additional vitamin C may be lost if it dissolves into cooking liquid and is then discarded.

"[39] Ascorbic acid and some of its salts and esters are common additives added to various foods, such as canned fruits, mostly to slow oxidation and enzymatic browning.

[7]: 98–99  In addition, ascorbate also functions as a non-enzymatic reducing agent for mixed-function oxidases in the microsomal drug-metabolizing system that inactivates a wide variety of substrates such as drugs and environmental carcinogens.

[57] Approximately 70%–90% of vitamin C is active-transport absorbed when intakes of 30–180 mg/day from a combination of food sources and moderate-dose dietary supplements such as a multi-vitamin/mineral product are consumed.

[58] In both vitamin C synthesizers (example: rat) and non-synthesizers (example: human) cells maintain ascorbic acid concentrations much higher than the approximately 50 micromoles/liter (μmol/L) found in plasma.

[66] In humans and in animals that cannot synthesize vitamin C, the enzyme l-gulonolactone oxidase (GULO), which catalyzes the last step in the biosynthesis, is highly mutated and non-functional.

The aldehyde group of this compound is reduced to a primary alcohol using the enzyme glucuronate reductase and the cofactor NADPH, yielding l-gulonic acid.

[65] Some mammals have lost the ability to synthesize vitamin C, including simians and tarsiers, which together make up one of two major primate suborders, Haplorhini.

Ascorbic acid is a common enzymatic cofactor in mammals used in the synthesis of collagen, as well as a powerful reducing agent capable of rapidly scavenging a number of reactive oxygen species (ROS).

In fact, anthropoid primates, Cavia porcellus (guinea pigs), teleost fishes, most bats, and some passerine birds have all independently lost the ability to internally synthesize vitamin C in either the kidney or the liver.

[97] Enzyme expression peaks in the morning to supporting biosynthesis for when mid-day sunlight intensity demands high ascorbic acid concentrations.

[6][40][110] Notable human dietary studies of experimentally induced scurvy were conducted on conscientious objectors during World War II in Britain and on Iowa state prisoners in the late 1960s to the 1980s.

[40][7]: 101 People in sepsis may have micronutrient deficiencies, including low levels of vitamin C.[113] An intravenous intake of doses much higher than the RDA, such as 3 g/d or more, appears to be needed to maintain normal plasma concentrations in people with sepsis, as the body's demand for vitamin C may increase significantly due to the heightened inflammatory response and oxidative stress.

[121] The European Food Safety Authority concluded there is a cause and effect relationship between the dietary intake of vitamin C and functioning of a normal immune system in adults and in children under three years of age.

"[125] In an update posted December 2022, the NIH position was unchanged: For people hospitalized with severe COVID-19 there are reports of a significant reduction in the risk of all-cause, in-hospital mortality with the administration of vitamin C relative to no vitamin C. There were no significant differences in ventilation incidence, hospitalization duration or length of intensive care unit stay between the two groups.

A summary of reviews of supplementation in healthy subjects did not report this problem, but left as untested the possibility that individuals with hereditary hemochromatosis might be adversely affected.

[150] "Reports of kidney stone formation associated with excess ascorbic acid intake are limited to individuals with renal disease".

[161] In 1734, the Dutch writer Johann Bachstrom gave the firm opinion, "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens.

[166] Captain James Cook had previously demonstrated the advantages of carrying "Sour krout" on board by taking his crew on a 1772–75 Pacific Ocean voyage without losing any of his men to scurvy.

Later studies on traditional food diets of the Yukon First Nations, Dene, Inuit, and Métis of Northern Canada showed that their daily intake of vitamin C averaged between 52 and 62 mg/day.

[188] Stone introduced Linus Pauling to the theory that humans needed to consume vitamin C in quantities far higher than what was considered a recommended daily intake in order to optimize health.

A few years later he proposed that vitamin C would prevent cardiovascular disease, and that 10 grams/day, initially administered intravenously and thereafter orally, would cure late-stage cancer.

[192] Mega-dosing with ascorbic acid has other champions, among them chemist Irwin Stone[189] and the controversial Matthias Rath and Patrick Holford, who both have been accused of making unsubstantiated treatment claims for treating cancer and HIV infection.

[193][194] The idea that large amounts of intravenous ascorbic acid can be used to treat late-stage cancer or ameliorate the toxicity of chemotherapy is — some forty years after Pauling's seminal paper — still considered unproven and still in need of high quality research.

[195][196][153] There is research investigating whether high dose intravenous vitamin C administration as a co-treatment will suppress cancer stem cells, which are responsible for tumor recurrence, metastasis and chemoresistance.