Food Safety Magazine

GRAS | February/March 2016

Trans Fats: Current Scientific Update

By Michael K. Peterson, M.E.M., DABT, and Kirsten Zu, Ph.D., Sc.D., M.P.H.

Trans Fats: Current Scientific Update

Trans fats have been a source of concern in the public health community for over 30 years. These fats are formed through a manufacturing process that adds hydrogen to vegetable oil in a reaction called hydrogenation. Most of the trans fats in American diets are found in partially hydrogenated oils (PHOs), often used in commercial baked goods because they improve shelf life and reduce costs. Trans fats also naturally occur in the guts of certain ruminants, and small quantities of trans fats can be found in foods made from these animals (e.g., milk and meat products).

Last year, the U.S. Food and Drug Administration (FDA) determined that the use of PHOs is no longer generally recognized as safe (GRAS), announcing this decision on June 16, 2015. Many media outlets reported that FDA “banned” PHOs, but this is incorrect. Rather, the agency has officially removed the GRAS status of PHOs, which means that they are now subject to FDA’s food additive regulations. In addition, FDA has given food manufacturers 3 years to either remove PHOs from their products or submit a Food Additive Petition for the use of PHOs in food. In other words, if companies’ Food Additive Petitions are successful, PHOs could still be used in foods after the 3-year deadline. In August, the Grocery Manufacturers Association (GMA) took this step: It asked FDA to allow low-level uses of PHOs.

However, other news related to PHOs has been released that has added to the discussion of trans fat toxicity. In May 2015, news reports surfaced about class action suits against General Mills and Nestlé. The suits allege that products made by these companies contained trans fats, which caused “…cardiovascular heart disease, diabetes, cancer, Alzheimer’s disease, and accelerates cognitive decline in diabetics.” The lawsuit further alleges that there is no safe level of exposure to trans fats. The judge in the General Mills case recently issued a stay to allow FDA to evaluate the safety of low levels of trans fats.

This article provides an overview of the state of the science on the health effects associated with eating trans fats. It covers the noncardiovascular effects of trans fats briefly, but its main focus is on cardiovascular effects, and in particular whether there is a safe level for consuming this food additive. These questions very likely will be critical to the outcomes of FDA’s evaluation and of the current lawsuits.

Cardiovascular Effects
Consuming high levels of trans fats is known to be associated with an increased risk of cardiovascular disease. However, we have not always understood this risk, because the science on trans fats has evolved throughout the 20th century. During this time, our understanding of the cardiovascular risk associated with consuming trans fats and of the mechanisms behind this risk has changed dramatically. 

Epidemiological Studies
During the first two-thirds of the 20th century, very little human evidence existed to tell us whether trans fatty acids were harmful to cardiovascular health. In the early 1980s, a group of Welsh scientists conducted studies to compare the levels of trans fat content in human body fat between patients dying from heart disease (cases) and others (control subjects) who died of unrelated causes.[1-3] These studies found that the levels of trans fats present in body fat, which were assumed to reflect the PHOs consumed, were higher in cases than in controls. However, a later study that evaluated many more people did not observe increased risks of heart attacks associated with higher levels of trans fats in adipose tissue.[4]

Another line of human evidence came from metabolic studies of cholesterol levels, including low-density lipoprotein-cholesterol (LDL-C, or “bad cholesterol”) and high-density lipoprotein-cholesterol (HDL-C, or “good cholesterol”). Early studies generally found that trans fats did not raise total cholesterol levels as much as saturated fats did.[5] In 1990, Mensink and Katan[6] published a seminal study in the New England Journal of Medicine, in which they compared the effects of three different diets on blood cholesterol levels in a group of healthy volunteers. The three diets were identical in nutrient composition, except that 10 percent of the total daily calories were provided as oleic acid (the most common monounsaturated fat in diet), trans isomers of oleic acid (that is, trans fats) or saturated fats. Replacing the monounsaturated fat with trans fats increased LDL-C levels and decreased HDL-C levels, whereas replacing the monounsaturated fat with saturated fat increased LDL-C by about the same amount and did not change HDL-C. Subsequently, a number of trials confirmed that trans fats increase the ratio of LDL-C to HDL-C more strongly than saturated fats do.[7-14]

Given trans fats’ adverse effects on cholesterol levels and the inherent difficulties of conducting long-term dietary intervention trials, scientists turned to well-conducted observational epidemiology studies to evaluate individual dietary consumption of trans fats and cardiovascular risk directly. In 1993, the Lancet published a study of trans fats and coronary heart disease (CHD) in the Nurses’ Health Study, a prospective cohort study of 121,700 female nurses established in 1976.[15] Women who consumed the most trans fats were 50 percent more likely than those who consumed the least to develop CHD during 8 years of follow-up, taking into account other lifestyle and dietary factors. In updated analyses of the same cohort with longer follow-up periods, the positive association seen between trans fats and CHD risk persisted and was statistically significant.[16,17] These findings have been replicated and confirmed in several prospective cohorts of men[18-20] and also in comprehensive reviews and meta-analyses.[21-23] The meta-analyses also examined trans fats from different sources, and both reported that trans fats from industrial processes, but not those from ruminants, were positively associated with risk of CHD.

Collectively, the metabolic and epidemiology studies provide strong support that consuming high levels of trans fats contributes to increased risks of CHD. It is not clear, however, whether low levels of trans fats in the diet are associated with cardiovascular risk. In the dietary intervention trials, only diets with high trans fat content appeared to affect blood cholesterols negatively. In the epidemiology studies, people who consumed the smallest amounts of trans fats were usually used as the reference group, with which the others were compared, and because trans fats are so common in processed foods, identifying people who consume no trans fats at all is extremely difficult, if not impossible. Also, because people’s diets are highly variable, measurements taken during observational studies were often not very accurate. Such errors are particularly problematic for low exposures, where the dose-response curve may take a linear shape and mask a true threshold effect.[24] A “threshold” refers to a level of exposure below which no response is elicited. Therefore, current human evidence is not sufficient to determine the health effects associated with consuming small amounts of trans fats.

Much of the argument in interpreting epidemiology findings focuses on many researchers’ decision to assume a linear relationship between trans fats and cardiovascular risk and “force” the regression line to fit their data through the origin (or zero). This approach creates an “artificial” data point, but some have argued that it is the only “true” data point available. Intuitively, it makes sense that consuming zero trans fats would entail zero additional risk. However, this logic ignores the possibility that consuming nonzero levels of trans fats could also result in zero risk (i.e., a threshold). By forcing the regression lines through zero, these researchers (and FDA) have ignored that possibility. Although this approach may make sense from a public health perspective (in which the goal is to err on the side of protecting public health), it is not clear that the available data actually support this assumption.

Mechanistic Studies
While human studies have only a limited ability to infer cardiovascular risk from consuming small amounts of trans fats, mechanistic studies provide certain support for a threshold effect.

Trans fats are monounsaturated fatty acids with one trans double bond. Structurally, trans fats have a shape similar to that of saturated fats, while cis-monounsaturated fatty acid molecules bend at the place of the double bond (Figure 1). Therefore, trans fats are expected to behave in the human body in much the same way that saturated fats do.

The human body contains extensive pathways to maintain the balance of lipid metabolism. One key organ, the small intestine, digests, absorbs, assembles and secretes dietary fats, including triglycerides, cholesterol and phospholipids. The liver is the primary organ for fat storage and synthesis. It also maintains the homeostasis of ingested, mobilized and synthesized fats. As Figure 2[25] shows, multiple feedback mechanisms are involved in regulating LDL-C production and metabolism. To cause an effect on LDL-C (or HDL-C), the amount of trans fats would need to be sufficient to disrupt these feedback loops.  

Trans fats induce cardiovascular risk by increasing LDL-C production, decreasing LDL-C clearance or both. Substantial evidence shows that the main steps in these processes are affected by both positive and negative feedback mechanisms.[25,26] That is, the body adapts to increases in LDL-C levels (up to a certain point) without adverse effects. Once those feedback mechanisms are overwhelmed (i.e., the body can no longer adapt), an adverse effect (e.g., an increased risk of cardiovascular disease) is likely.

Regulatory agencies such as FDA often assume that no threshold exists for adverse effects from potentially toxic substances, but evidence suggests that, in reality, the opposite is more often true.[24] Threshold effects in systems with strong feedback mechanisms (such as lipid metabolism and homeostasis) have been demonstrated in a wide variety of scientific experiments, and this concept is basic to the science of toxicology.[27-32]

As already described, the association between consuming large amounts of trans fats and increased cardiovascular risk is well established, but the effect of consuming smaller amounts (< 1% of daily total energy) is less clear. FDA’s recent decision explicitly states, “Therefore, we conclude that the available data show that even at low intake levels (e.g., < 3% energy), there is no identifiable threshold, rather the available data support a conclusion that IP-TFA [inositol phosphate-trans fatty acid] causes a linear increase in blood levels of LDL-C, a validated surrogate biomarker of CHD risk and a linear decrease in blood levels of HDL-C, a major risk biomarker for CHD.” However, the science pointing to a lack of threshold is not as strong as this decision suggests.

Other Health Effects of Trans Fats
In addition to cardiovascular effects, some studies have identified other possible health effects of trans fats, including (as mentioned earlier) diabetes, cancer and Alzheimer’s disease/cognitive decline. Published research to date does not generally support this connection, however, and further study is needed.

For example, in the case of diabetes, several studies have looked at the association between type 2 diabetes and trans fats and reported mixed results. Some reported that consuming large amounts of trans fats increased risk, but others found no association. A recent meta-analysis that compiled the results from these studies concluded that no association exists between trans fat consumption and type 2 diabetes.[23]

The evidence associating trans fats with cognitive decline is also inconsistent. Most recent reviews have found that both positive and negative effects of dietary fats on mental function have been reported, but separating out the effects of different types of fat is difficult.[33,34] In studies that evaluated trans fats specifically, some have found adverse effects, while others did not.

The current case for trans fats causing cancer is weak. A review of the evidence in 2008 found that there were not enough data to distinguish between trans fats and other dietary fats’ potential cancer risks.[35,36]

Not only is the evidence for these other proposed effects inconsistent or weak, but the studies that have found links between trans fats and diabetes, cancer and mental decline also suffer from many of the same problems as the cardiovascular studies—particularly, their ability to determine whether small amounts of trans fats might be associated with these effects.

Summary
Given the legal requirements of the GRAS program, FDA’s decision that PHOs are not GRAS is not surprising. However, given the scientific evidence, it is surprising that FDA and other regulatory agencies have implied that consuming any amount of trans fats is a health risk. Human data on the potential health effects from consuming small amounts of trans fats are scant and do not support the assumption of no threshold. FDA’s approach also hampers the exploration of alternative dose-response functions (e.g., the possibility that a threshold exists). In addition, trans fats’ mode of action and the multiple feedback loops involved in lipoprotein synthesis and metabolism in the body support the idea that a threshold is likely. Given these considerations, it will be interesting to see how FDA responds to GMA’s Food Additive Petition, and that response will quite likely be a significant factor in lawsuits involving food companies that have produced or continue to produce food items containing trans fats or PHOs.  

Michael K. Peterson, M.E.M., DABT, is a senior toxicologist at Gradient with 17 years of experience specializing in human health toxicology and risk assessment and the application of these skills in the area of food safety. His previous experience includes the evaluation of risks from food contaminants and additives, development of chemical toxicity profiles, assessment of the toxicity of novel chemical and commercial products and determining microbial and chemical contamination risks associated with various food safety best practices. While earning a master’s degree in environmental management at Duke University, he researched the oral bioavailability of polycyclic aromatic hydrocarbons from soil.

Kirsten Zu, Ph.D., Sc.D., M.P.H., is a senior epidemiologist at Gradient. Her primary responsibilities include review and evaluation of epidemiology literature for regulatory comments and litigation support and conducting original epidemiological research on environmental factors and health. Dr. Zu obtained her Ph.D. in cancer pathology and prevention at Roswell Park Cancer Institute (Buffalo, NY), where she investigated the cancer chemopreventive characteristics and mechanisms of selenium and vitamin E. Subsequently, she obtained her M.P.H. in quantitative methods and Sc.D. in nutrition and epidemiology at Harvard T.H. Chan School of Public Health.


References
1. Thomas, LH et al. 1981. “Hydrogenated Oils and Fats: The Presence of Chemically-Modified Fatty Acids in Human Adipose Tissue.” Am J Clin Nutr 34(5):877–886.
2. Thomas, LH et al. 1983. “Concentration of 18:1 and 16:1 Transunsaturated Fatty Acids in the Adipose Body Tissue of Decedents Dying of Ischemic Heart Disease Compared with Controls: Analysis by Gas Liquid Chromatography.” J Epidemiol Community Health 37(1):16–21.
3. Thomas, LH et al. 1983. “Concentration of Transunsaturated Fatty Acids in the Adipose Body Tissue of Decedents Dying of Ischemic Heart Disease Compared with Controls.” J Epidemiol Community Health 37(1):22–24.
4. Aro, A et al. 1995. “Adipose Tissue Isomeric Trans Fatty Acids and Risk of Myocardial Infarction in Nine Countries: The EURAMIC Study.” Lancet 345(8945):273–278.
5. Katan, MB et al. 1995. “Trans Fatty Acids and Their Effects on Lipoproteins in Humans.” Annu Rev Nutr 15:473–493.
6. Mensink, RP and MB Katan. 1990. “Effect of Dietary Trans Fatty Acids on High-Density and Low-Density Lipoprotein Cholesterol Levels in Healthy Subjects.” N Engl J Med 323(7):439–445.
7. Zock, PL and MB Katan. 1992. “Hydrogenation Alternatives: Effects of Trans Fatty Acids and Stearic Acid Versus Linoleic Acid on Serum Lipids and Lipoproteins In Humans.” J Lipid Res 33(3):399–410.
8. Nestel, P et al. 1992. “Plasma Lipoprotein Lipid and Lp[a] Changes with Substitution of Elaidic Acid for Oleic Acid in the Diet.” J Lipid Res 33(7):1029–1036.
9. Judd, JT et al. 1994. “Dietary Trans Fatty Acids: Effects on Plasma Lipids and Lipoproteins of Healthy Men and Women.” Am J Clin Nutr 59(4):861–868.
10. Lichtenstein, AH et al. 1993. “Hydrogenation Impairs the Hypolipidemic Effect of Corn Oil in Humans. Hydrogenation, Trans Fatty Acids, and Plasma Lipids.” Arterioscler Thromb 13(2):154–161.     
11. Lichtenstein, AH et al. 1999. “Effects of Different Forms of Dietary Hydrogenated Fats on Serum Lipoprotein Cholesterol Levels.” N Engl J Med 340(25):1933–1940.
12. Aro, A et al. 1997. “Stearic Acid, Trans Fatty Acids, and Dairy Fat: Effects on Serum and Lipoprotein Lipids, Apolipoproteins, Lipoprotein(a), and Lipid Transfer Proteins in Healthy Subjects.” Am J Clin Nutr 65(5):1419–1426.    
13. Sundram, K et al. 1997. “Trans (Elaidic) Fatty Acids Adversely Affect the Lipoprotein Profile Relative to Specific Saturated Fatty Acids in Humans.” J Nutr 127(3):514S–520S.     
14. Baer, DJ et al. 2004. “Dietary Fatty Acids Affect Plasma Markers of Inflammation in Healthy Men Fed Controlled Diets: A Randomized Crossover Study.” Am J Clin Nutr 79(6):969–973.
15. Willett, WC et al. 1993. “Intake of Trans Fatty Acids and Risk of Coronary Heart Disease among Women.” Lancet 341(8845):581–585.
16. Hu, FB et al. 1997. “Dietary Fat Intake and the Risk of Coronary Heart Disease in Women.” N Engl J Med 337(21):1491–1499.
17. Oh, K et al. 2005. “Dietary Fat Intake and Risk of Coronary Heart Disease in Women: 20 Years of Follow-Up of the Nurses’ Health Study.” Am J Epidemiol 161(7):672–679.     
18. Ascherio, A et al. 1996. “Dietary Fat and Risk of Coronary Heart Disease in Men: Cohort Follow Up Study in the United States.” BMJ 313(7049):84–90.
19. Pietinen, P et al. 1997. “Intake of Fatty Acids and Risk of Coronary Heart Disease in a Cohort of Finnish Men. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.” Am J Epidemiol 145(10):876–887.
20. Oomen, CM et al. 2001. “Association between Trans Fatty Acid Intake and 10-Year Risk of Coronary Heart Disease in the Zutphen Elderly Study: A Prospective Population-Based Study.” Lancet 357(9258):746–751.     
21. Mozaffarian, D et al. 2006. “Trans Fatty Acids and Cardiovascular Disease.” N Engl J Med 354(15):1601–1613.
22. Bendsen, NT et al. 2011. “Consumption of Industrial and Ruminant Trans Fatty Acids and Risk of Coronary Heart Disease: A Systematic Review and Meta-Analysis of Cohort Studies.” Eur J Clin Nutr 65(7):773–783.     
23. De Souza, RJ et al. 2015. “Intake of Saturated and Trans Unsaturated Fatty Acids and Risk of All Cause Mortality, Cardiovascular Disease, and Type 2 Diabetes: Systematic Review and Meta-Analysis of Observational Studies.” BMJ 351:h3978.
24. Rhomberg, LR et al. 2011. “Linear Low-Dose Extrapolation for Noncancer Health Effects Is the Exception, Not the Rule.” Crit Rev Toxicol 41:1–19.
25. Haber, LT et al. 2015. “Mode of Action and Meta-Regression Analysis of the Effect of Trans Fatty Acids (TFAs) on LDL-Cholesterol” (presented at the Society of Toxicology 54th Annual Meeting, San Diego, CA, March 22–26).
26. Dourson, ML and LT Haber. 2014. “Mode of Action and Dose-Response Evaluation of the Effect of Partially Hydrogenated Oils on LDL-Cholesterol” [Toxicology Excellence for Risk Assessment (TERA)]. (Presented at the Society of Toxicology FDA Colloquia on Emerging Toxicological Science Challenges in Food and Ingredient Safety: Complexities in Evaluating Human Clinical and Observational Data for Ingredient Safety Assessment: Partially Hydrogenated Oils As a Case Study, College Park, MD, November 7).
27. Calabrese, EJ and LA Baldwin. 2003. “The Hormetic Dose-Response Model Is More Common than the Threshold Model in Toxicology.” Toxicol Sci 71:246–250.     
28. Calabrese, EJ and R Blain. 2005. “The Occurrence of Hormetic Dose Responses in the Toxicological Literature, the Hormesis Database: An Overview.” Toxicol Appl Pharmacol 202(3):289–301.     
29. Cohen, BL. 2002. “Cancer Risk from Low-Level Radiation.” Am J Roentgenol 179(5):1137–1143.     
30. Gallo, MA. 2008. “History and Scope of Toxicology,” in Casarett and Doull’s Toxicology: The Basic Science of Poisons 7th ed., ed. CD Klaassen (New York: McGraw-Hill), 3–10.
31. Rodricks, JV et al. 2007. “Quantitative Extrapolations in Toxicology,” in Principles and Methods of Toxicology, 5th ed., ed. AW Hayes (New York: Informa Healthcare), 453–474.
32. Eaton, DL and DL Gilbert. 2008. “Principles of Toxicology,” in Casarett and Doull’s Toxicology: The Basic Science of Poisons 7th ed., ed. CD Klaassen (New York: McGraw-Hill), 11–43.     
33. Barnard, ND et al. 2014. “Saturated and Trans Fats and Dementia: A Systematic Review.” Neurobiol Aging 35(Suppl. 2):S65–S73.
34. Morris, MC and CC Tangney. 2014. “Dietary Fat Composition and Dementia Risk.” Neurobiol Aging 35(Suppl. 2):S59–S64.     
35. Thompson, AK et al. 2008. “Trans-Fatty Acids and Cancer: The Evidence Reviewed.” Nutr Res Rev 21(2):174–188.
36. Clifton, P. 2010. “Physiological Impact of Saturated and Trans Fat Intake” (presented at ILSI Symposium on Saturated and Trans Fats: Where Do We Stand? June 17).     

Categories: Food Types: Ingredients; Regulatory: FDA, Guidelines

This site uses cookies. By continuing to browse the site you consent to our use of cookies. Learn more. Got it!