Examining The Potential Risks of Excessive Iron Intake and The Risk of Cancer
Introduction
In 2018, the International Agency for Research on Cancer (IARC) officially classified red meat as Group 2A (probably carcinogenic to humans) and processed red meat as Group 1 (carcinogenic to humans). This classification is based on several factors: first, N-nitroso compounds (NOCs); second, heterocyclic aromatic amines (HAAs); third, polycyclic aromatic hydrocarbons (PAHs); fourth, lipid oxidation products; and fifth, iron intake.
It’s strange, but that’s the paradox: the iron we need can actually backfire, becoming a factor in carcinogenesis. The question is whether it is iron itself or only iron from red meat (heme iron) that is linked to carcinogenesis. Are iron supplements linked to cancer? And what is the limit? The issue is that long-term iron deficiency can lead to anaemia, while excessive daily intake can lead to liver toxicity because the body has difficulty excreting iron, which can accumulate in the liver. Not to mention the potential carcinogenic factors we’ll discuss.
Red Meat and Process Red Meat
In 2018, IARC Monograph Volume 114 officially classified red meat as Group 2A (probably carcinogenic to humans) and processed red meat as Group 1 (carcinogenic to humans). Linked factors include NOCs, HAAs, PAHs, lipid oxidation products and iron intake.
NOCs are major carcinogenic factors formed by the reaction of nitroso compounds with amine or amide compounds. They have been proven to cause cancer in humans because they can damage DNA and induce genetic mutations. HAAs are formed when creatinine reacts with Maillard intermediate compounds at increased temperatures during cooking. In addition to HAAs, PAHs and lipid oxidation products are formed as temperatures rise. Interestingly, iron is one of the carcinogenic factors in processed red meat. But how does iron, an important micronutrient, actually become carcinogenic?
Iron Physiology
Iron is widely utilised by the human body and is therefore classified as a micronutrient. Its most common physiological role is as a component of haemoglobin, which transports oxygen. It also plays crucial roles in DNA synthesis, the electron transport chain, erythropoiesis and hormone synthesis.
Iron Itself as a Carcinogenic Factor
Although many studies have investigated the correlation between iron intake and cancer risk, the research findings are too complex to be summarised in a single answer. Heme iron is often reported to be associated with cancer development. This is because it has a higher bioavailability than non-heme iron. It is protected by a porphyrin ring, which allows it to remain in the intestine where it can catalyse the formation of hydroxyl radicals or nitroso compounds. In contrast, non-heme iron can react with phytic acid, polyphenols and other compounds, which reduces its availability in the intestine.
The role of iron in cancer is viewed from two perspectives: its involvement in the initiation of cancer and its function as a tumour growth factor. One of the most well-known reactions is the Fenton reaction:
Fe²⁺ + H₂O₂ → Fe³⁺ +HO⁻ + HO•
Hydroxyl radicals are closely linked to carcinogenesis due to the damage they cause to cellular components, such as lipids, proteins and DNA. Additionally, iron catalyses the formation of carcinogenic nitroso compounds. These two pathways both have the potential to initiate tumours.
One characteristic of cancer is the rapid division of cells, which requires high levels of DNA synthesis, among other things. In order to produce DNA, cells must first generate deoxyribonucleotides, a process catalysed by the enzyme ribonucleotide reductase (RNR), which converts ribonucleotides into deoxyribonucleotides. Iron acts as a structural and functional component of RNR: without iron, RNR activity decreases, resulting in reduced DNA synthesis. Depletion of iron, caused by reduced dietary intake or the use of iron chelators, inhibits tumour growth.
Now, let's address the main question: What is the actual risk of consuming iron in relation to cancer?
Interestingly, the research produced mixed results. Heme iron, which is iron derived from animal sources, often shows a positive correlation. A meta-analysis by Fonseca-Nunes et al., which combined 59 epidemiological studies published between 1995 and 2012, reported that an increase in heme iron intake of 1 mg/day was associated with an 8% increased risk of colorectal cancer and a 12% increased risk of colon cancer. However, a meta-analysis of nine case-control or cohort studies reported a 17–27% reduction in colorectal cancer risk associated with dietary iron intake (including supplemental iron), but a 23% increased risk associated with dietary heme iron intake. The European Prospective Investigation into Cancer and Nutrition (EPIC) study even showed a 20% reduction in colorectal cancer risk associated with dietary non-heme iron intake, but only among men, suggesting a potential sex-specific relationship between iron intake and cancer risk.
A positive association has been observed between haem iron and various types of cancer, as well as a reduced risk associated with non-haem iron. While the evidence relating to meat intake and cancer risk is consistent, this is not conclusive for iron intake.
Unfortunately, most of these studies have focused only on haem iron, not iron itself. This leaves the question unanswered: what about the intake of iron supplements, such as ferrous sulphate, which often contain large amounts? Since supplement intake does not involve anti-nutrients such as phytic acid and polyphenols, it allows for greater bioavailability in the gut. Does this impact tumour initiation and growth factors?
Haem iron is obtained from animal-based diets, which are closely associated with the content of nitrites or nitrates. Therefore, the correlation between iron itself and cancer remains unclear.
Challenges for Future Research
So far, we have learned a great deal. One thing we now understand is that heme iron is positively correlated with cancer development and that processed red meat is a proven carcinogen. However, dietary intake of heme iron is not the same againts iron intake. There are still many questions we need to explore in order to determine how iron excess relates to the initiation or progression of cancer. Are iron and iron supplements, such as ferrous sulfate, associated with cancer development?
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