PLS: Scientific opinion on the tolerable upper intake level for iron

Background to the scientific opinion

• Risk managers need advice on the safety of nutrients to, for example, establish maximum levels that can be allowed in food supplements and in fortified food products. 
• For nutrients, no risk of adverse effects is expected unless a threshold intake is exceeded. The identification of this threshold is used as a basis to establish a tolerable upper intake level (UL).
• Excessive intake of iron, when maintained over prolonged periods of time, can lead to negative health impacts, in particular on the liver. High-dose iron supplements may also cause adverse effects in the gastrointestinal (GI) tract, depending on the form of iron used, the dose, the mode of administration and the predisposition of the individual.
• In 2004, EFSA’s Panel on Nutrition, Novel Foods and Food Allergens (NDA) (the Panel) published a scientific opinion on the UL for iron, but the data then available were insufficient to establish a UL for iron.

What was EFSA asked to do?

• The European Commission requested a review of the Panel's 2004 scientific opinion based on newly available evidence.
• If there were insufficient data to determine a UL for iron, EFSA was asked to advise on the maximum amount that EFSA can confidently conclude poses no risk of adverse effects in the general population, referred to as a ‘safe level of intake’.
• Both ULs and safe levels of intake are meant to protect consumers against potential adverse effects related to excess nutrient intakes. The distinction relates to the different way in which these values are established.
• As opposed to ULs, safe levels of intake are not based on an identified threshold of intake above which the risk of adverse intake starts to increase.
• Intake levels above the safe levels of intake do not necessarily mean that there is a risk of adverse effects.
• These levels cannot be used to characterise the proportion of the population at risk of adverse effects.

How did EFSA carry out this work?

• The University of Copenhagen, in collaboration with the University of Oslo and the Karolinska Institutet, conducted a systematic literature review of human intervention and observational studies for EFSA. Based on this evidence, the Panel assessed the potential negative impact on health related to high iron intake.
• Following the Panel’s Guidance draft on establishing and applying ULs for vitamins and essential minerals from 2002, the Panel addressed the following questions:
  • What is the maximum level of total long-term daily intake of iron (from all sources) that is not expected to pose a risk of negative impact on human health? 
  • What is the daily iron intake from all dietary sources in EU populations? 
  • What is the risk of negative impact on health, related to the iron intake in EU populations, including any uncertainties?
• The evidence was reviewed to assess iron’s:
  • absorption, distribution, metabolism and excretion;
  • biomarkers of intake and status;
  • potential negative impacts on health - liver toxicity, type 2 diabetes, gestational diabetes, adverse GI effects, adverse effects of supplementation in infants and young children and during pregnancy, low zinc absorption, etc.

What were the limitations/uncertainties?

• The data were insufficient to define the safe level of long-term iron consumption, so no UL could be established. This was because liver toxicity information was mainly reported as case reports, describing individual patients.
• It should be noted that observed toxicity in the case reports was solely a result of iron overload from excess iron intake. Thus, liver toxicity was observed even in people without underlying diseases that affect iron absorption and is generally present in patients with liver failure and liver cancer.
• The Panel determined a safe level of intake based on limited data related to the occurrence of black stools. Although black stools are not adverse for health, they do indicate the presence of significant unabsorbed iron in the GI tract and may be a first sign of iron metabolism dysfunction prior to iron overload and toxicity.

What were the outcomes?

• No UL for iron could be established for any age group. Instead, a safe level of total iron intake was set at:
  • 40 mg/day for adults, including pregnant and lactating women;
  • a range of values for minors, from 10 mg/day (children aged 1-3) to 35 mg/day (adolescents aged 15-17); 
  • 5 mg/day for infants aged 4-11 months, covering iron intakes from fortified food and food supplements, but not from infant or follow-on formula. A safe level of supplemental intake was derived for infants due to their particular and distinct iron requirements

What are the key recommendations?

Recommendations for policymakers and risk managers: 

• The safe levels (no UL established) of intake should be used as the intake levels that can be considered ‘safe’ for different age groups.
• The safe levels of intake proposed do not apply to individuals who receive iron under medical supervision as a treatment for iron deficiency anaemia.

Recommendations for the research community: 

• Research the effect of increasing doses of (haem and non-haem) iron on GI tract physiology, pathology and on the microbiome.
• Research the mechanisms of interactions between high intakes of iron and the absorption and metabolism of other minerals, such as copper, zinc, calcium and manganese.
• Identify and characterise physiological limits for iron homeostasis (for example, decreased absorption of iron when iron stores are full) and the level of iron absorption for high iron intakes over a prolonged period of time, using the newest available techniques.
• Continue to collect accurate data on food composition and consumption focusing on fortified foods and food supplements.

Glossary

Biomarker of intake and/or status: a characteristic that is objectively measured and reflects the nutrient intake or the nutrient status of an individual.
Homeostasis: a process by which organisms maintain physiological stability when external conditions change.
 

Disclaimer

• This plain language summary (PLS) is a simplified communication of EFSA’s Scientific opinion on the tolerable upper intake level for iron. The full EFSA opinion can be found here.
• The purpose of the PLS is to enhance transparency and inform interested parties on EFSA’s work on the topic using simplified language to present a summary of the main findings.

Reference

Scientific opinion on the tolerable upper intake level for iron 

DOI: https://doi.org/10.2903/j.efsa.2024.8819