Environmental Medicine Update

by Marianne Marchese, ND

The Inflammatory Effects of Carrageenan

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Food Additive

Introduction

Carrageenans are sulfated polysaccharides obtained from red seaweeds (Rhodophyceae). Carrageenan is widely used as a food additive and has been shown to induce inflammatory responses in animal models and human cells. It is used or has been used as a thickener, stabilizer, or emulsifying agent in many foods, including dairy products, processed meats, soymilk, other cow milk alternatives, and infant formula. Carrageenans are also used in various other products, such as cosmetics, toothpaste, room deodorizers, and pharmaceuticals. Current data suggest average consumption of 250 mg/day of carrageenan in the US.¹ Studies show that the inflammatory effects of carrageenans can cause ulcerations, polyps, colitis, and colorectal tumors.² Newer studies outline the mechanism of action of the inflammatory response to CGN. Food-grade carrageenan is generally recognized as safe (GRAS) by the US Food and Drug Administration (FDA).

Carrageenan History and Regulation.

Carrageenan has been used by the food industry in the US since the 1950s. The FDA approved the use of carrageenan as a food additive in 1961; prior to that it was classified as a GRAS substance in foods. As early as the 1970s, safety concerns were raised in regard to carrageenan. Animal studies using hydrolyzed and unhydrolyzed carrageenan showed that both caused alterations in the cecum. Ulcerations were more severe with the degraded form of carrageenan (poligeenan), which is derived by acid hydrolysis.³ Food-grade carrageenan is undegraded.² In light of this study, the FDA reviewed carrageenan safety again in 1972 and found it safe for use in foods except infant formula, wherein it was determined that the risks outweighed the benefits.⁴

During the late 1970s, processed eucheuma seaweed (PES) was introduced for use as carrageenan. Traditionally refined carrageenan is produced by extracting it from the seaweed and filtering the extract to remove cellulose and other substances. The production of PES is different in that the other substances are extracted and the remaining seaweed containing carrageenan and cellulose is processed. In 1990, FDA determined that PES (now called Philippine natural grade [PNG] carrageenan) meets its criteria to be classified as carrageenan in the US. In 1994, there were concerns that PNG could be unsafe as a food additive because it is processed with an illegal pesticide, ethylene oxide.⁵ Treatment by ethylene oxide results in a chemical residue, ethylene chlorohydrin (ECH), in food. The FDA has determined that the levels of ECH residues in carrageen do not represent a safety concern.

In 2001 Dr. Joanne Tobacman, a researcher at the University of Illinois at Chicago College of Medicine, published a safety review of carrageenan in Environmental Heath Perspectives. It was a review of 45 published animal studies and found a link to ulcerations and gastrointestinal inflammation.² This study revealed the contamination of food-grade (undegraded) carrageenan by substantial amounts of degraded carrageenan. The review discussed the possibility of production of degraded carrageenan from undegraded carrageenan under reaction conditions similar to those of normal digestion. The concern has focused on the potential for degraded carrageenan to be formed by acid hydrolysis in the stomach and the possibility that this material could promote cancer of the colon. In 1987, degraded carrageenan was classified by the International Agency for Research on Cancer (IARC) as 2B, a possible human carcinogen, based on animal study data. Native, undegraded carrageenan has been classified by IARC as 3, unclassifiable with respect to carcinogenicity in humans.⁶ To clarify, native, undegraded carrageenan is a mixture of highly sulfated polygalactosides extracted from seaweeds as used in foods. The cancer causing degraded carrageenan is prepared from the extract of Eucheuma spinosum by partial hydrolysis. Again, there is concern that undegraded, native, carrageenan can degrade in the human gut.

In response to Tobacman’s article, the FDA did another review and deemed carrageenan safe. It was also determined to be safe at the 57th meeting of the Joint Food and Agriculture Organization of the United Nations/World Health Organization Expert Committee on Food Additives (JECFA) in Rome in June 2001. No one could agree on an acceptable daily intake for humans. Instead, the FAO/WHO Expert Committee on Food Additives (JECFA) rated the acceptable daily intake (ADI) of carrageenan as “not specified.”⁷ Being convinced of the inflammatory and harmful effects of carrageenan in food, in 2008 Tobacman petitioned the FDA to prohibit the use of carrageenan in food. Her petition cited decades of publicly funded, peer-reviewed studies on carrageenan-induced inflammation in animals and cells. The FDA responded with a letter of denial, without a review.

Inflammatory Effects

Several studies outline the inflammatory effects of carrageenan and various mechanisms of actions in both animal and human cell studies. In a 2013 study, an in vitro model was established to evaluate the inflammatory effects of κ-CGN. A coculture system comprising human intestinal epitheliallike Caco-2 cells and phorbol myristate acetate (PMA)-stimulated THP-1 macrophage cells was used. The results showed that the secretion levels of TNF‑α, IL‑1β, and IL‑6 from the two cell types were increased significantly by carrageenans.⁸ The results also clearly demonstrate that κ-CGN severely damaged the intestinal epithelial Caco-2 cell monolayers in the coculture system.

In 2014, researchers showed that exposure of human colonic epithelial cells in culture and of mouse colonic epithelium in vivo to low concentrations of carrageenan activated the Wnt/β-catenin signaling pathway, leading to increases in nuclear β-catenin, T-cell factor/lymphoid enhancer factor activation, and cyclin D1 expression.⁹ The effects were mediated through carrageenan-induced reactive oxygen species (ROS). Carrageenan exposure and ROS production inhibited thioredoxin reductase activity and increased oxidation of nucleoredoxin. The authors concluded that dietary carrageen could contribute to colon cancer through these mechanisms.⁹

Studies back in 2012 showed the mechanism of the inflammatory effects of dietary carrageenan. In human colonic epithelial cells, carrageenan triggers innate immune pathways of inflammation. The carrageenan-induced inflammatory cascades involve TLR4- and BCL10-dependent activation of NF-κB, leading to increased IL-8 production.¹⁰ It has even been proposed that carrageenan-induced inflammation can cause glucose intolerance, insulin resistance, and impaired insulin. These effects are consistent with the role of TLR4-induced inflammation reported in diabetes and carrageenan stimulation of TLR4-mediated inflammatory cascades.¹⁰

Older studies showed another inflammatory mechanism of carrageenan is through its effects on tumor necrosis factor-alpha (TNF-a). A 2010 study highlighted the effects of carrageenan on TNF-a, demonstrating that exposure to CGN drives TNF-a-stimulated cells toward inflammation rather than toward apoptotic cell death. The authors even suggest that CGN exposure may compromise the effectiveness of anti-TNF-a therapy.¹¹

Safety

So, is carrageenan in food safe? It depends on whom you ask. Most US regulating agencies state that food-grade carrageenan is safe. A two-part review published in Critical Reviews in Toxicology deemed it safe as well.^12,13 Newer studies looking at the mechanism of action of carrageenan clearly show a cellular inflammatory response. Tobacman continues her research and patient case studies demonstrating harmful health effects in the human gut. The Cornucopia Institute is calling for the removal of carrageenan from products and providing consumers with easy-to-use lists of foods with and without carageenan.¹⁴ Recently, WhiteWave Foods has caved in to the pressures of consumer concerns and announced that it will remove carrageenan from its Horizon and Silk products. Stoneyfield Farm and Horizon have already removed the ingredient.

Summary

Carrageenan belongs to a group of polysaccharides extracted from certain species of red seaweeds. It is used primarily as a gelling, thickening, and stabilizing agent. The controversial additive is in numerous foods, including dairy products such as ice cream, milk, cottage cheese, whipped cream, and yogurt, as well as many nondairy and cow’s-milk alternative products. Studies have shown inflammatory effects in animals and humans and links to inflammatory bowel disease. However, the FDA deems carrageenan a safe food additive, as does the US National Organic Standards Board.

Notes

1. Borthakur A et al. Prolongation of carrageenan-induced inflammation in human colonic epithelial cells by activation of an NFκB-BCL10 loop. Biochim Biophys Acta. 2012;1822(8):1300–1307.

2. Tobacman JK. Review of harmful gastrointestinal effects of carrageenan in animal

experiments. Environ Health Perspect 2001;109:983–994.

3. Watt J, Marcus R. Experimental ulcerative disease of the colon in animals. Gut. 1973 Jun;14(6):506–510.

4. Watson DB. Public health and carrageenan regulation. J Appl Phycol. 2007;20(5):55–63.

5. United States General Accounting Office. Food and Drug Administration: Carrageenan Food Additive from the Philippines Conforms to Regulations [online document]. August 2, 1994. http://www.gao.gov/assets/230/220011.pdf. Accessed March 8, 2015.

6. Agents Classified by the IARC Monographs, Volumes 1–112 [online document]. http://monographs.iarc.fr/ENG/Classification/ClassificationsAlphaOrder.pdf. Accessed March 8, 2015.

7. Carthew P. Safety of carrageenan in foods. Environ Health Perspect. 2002 Apr;110(4):A176–A177.

8. Jiang H, Wang F, Chen H, Yan X. K-carrageenan induces the disruption of intestinal epithelial Caco-2 monolayers by promoting the interaction between intestinal epithelial cells and immune cells. Mol Med Rep. 2013:8.6;1635–1642.

9. Bhattacharyya S et al. common food additive carrageenan stimulates wnt/beta-catenin signaling in colonic epithelium by inhibition of nucleoredoxin reduction. Nutr Cancer. 2014;66(1);117–127.

10. Borthakur A et al. Prolongation of carrageenan-induced inflammation in human colonic epithelial cells by activation of an NFκB-BCL10 loop. Biochim Biophys Acta. 2012 Aug;1822(8):1300–1307.

11. Bhattacharyya S, Dudeja PK, Tobacman JK. Tumor necrosis factor α-induced inflammation is increased but apoptosis is inhibited by common food additive carrageenan. J Biol Chem 2010:285;39511–39522.

12. McKim JM. Food additive carrageenan: Part I: A critical review of carrageenan in vitro studies, potential pitfalls, and implications for human health and safety. Crit Rev Toxicol. 2014 Mar;44(3):211–243. doi:10.3109/10408444.2013.861797. Epub 2014 Jan 24.

13. Weiner ML. Food additive carrageenan: Part II: A critical review of carrageenan in vivo safety studies. Crit Rev Toxicol. 2014 Mar;44(3):244–269. doi:10.3109/10408444.2013.861798. Epub 2014 Jan 28.

14. Shopping guide to avoiding foods with carrageenan [Web page]. Cornucopia Institute. http://www.cornucopia.org/shopping-guide-to-avoiding-organic-foods-with-carrageenan.