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No Longer “GRAS”: The Trans Fatty Acids Debate

      On November 11, 2013, the US Food and Drug Administration (FDA) announced a tentative determination that partially hydrogenated oils (PHOs), which are the dietary sources of industrially produced trans fatty acids (TFA) or trans fat, are no longer categorized as “GRAS”: generally recognized as safe. With that notice, the FDA requested public comments and scientific data, for a period of 60 days, to substantiate or rebut the preliminary ruling. On December 17, 2013, the FDA extended the public comment period for another 60 days, to March 8, 2014. With these notices, the FDA has signaled that it will take an action to address the scientific evidence linking PHOs to an increased risk for cardiovascular disease.
      What the FDA’s action will be and when it will announce that action are unknown. Similarly perplexing is the evidence that is supporting the FDA’s actions, as the body of research suggests an increasingly complex relationship between TFA and human health, with uncomfortable gaps and contradictions in the literature that have become most apparent during the past 10 years.
      In the 1980s, research using vervet monkeys and rabbits was unable to substantiate a link between consumption of TFA and metabolic or mitochondrial functions.
      • Ruttenberg H.
      • Davidson L.M.
      • Little N.A.
      • et al.
      Influence of trans unsaturated fats on experimental atherosclerosis in rabbits.
      • Kritchevsky D.
      • Davidson L.M.
      • Weight M.
      • et al.
      Effect of trans-unsaturated fats on experimental atherosclerosis in vervet monkeys.
      It was not until the recent availability of transgenic animals that an association between TFA and atherosclerosis became apparent. In 2009, with the LDL receptor–deficient mouse, Bassett et al
      • Bassett C.
      • McCullough R.S.
      • Edel A.L.
      • et al.
      Trans-fatty acids in the diet stimulate atherosclerosis.
      demonstrated that a TFA-rich diet contributed to the development of atherosclerotic plaques. In 2010, Bassett et al
      • Bassett C.M.
      • Edel A.L.
      • Patenaude A.F.
      • et al.
      Dietary vaccenic acid has antiatherogenic effects in LDLr-/- mice.
      suggested that there are apparent differences when comparing the impact of industrially produced TFA and ruminant TFA (rTFA), which exist in nature. Each is structurally different and may therefore produce different biological effects. Still using the LDL receptor–deficient mouse, Bassett et al found that, unlike dietary consumption of the industrially produced elaidic acid, the rTFA vaccenic acid protected against plaque formation. In 2005, Mitmesser and Carr
      • Mitmesser S.H.
      • Carr T.P.
      Trans-fatty acids alter the lipid composition and size of apoB-100-containing lipoproteins secreted by HepG2 cells.
      demonstrated that TFA affected the size and composition of apolipoprotein B100–containing lipoproteins. Complicating these findings, however, is that this research and similar studies failed to differentiate between industrial TFA and rTFA. Colandre et al
      • Colandre M.E.
      • Diez R.S.
      • Bernal C.A.
      Metabolic effects of trans fatty acids on an experimental dietary model.
      showed that industrial TFA decreased the HDL:LDL ratio in rats; however, the research of Park and Park,
      • Park S.
      • Park Y.
      Effects of dietary fish oil and trans fat on rat aorta histopathology and cardiovascular risk markers.
      published in 2009, suggests that high TFA intake decreases total plasma cholesterol.
      Despite the attractive notion that “dietary fats contribute to heart disease,”
      • WIllett W.C.
      • Stampfer M.J.
      • Manson J.E.
      • et al.
      Intake of trans fatty acids and risk of coronary heart disease among women.
      • Hu F.B.
      • Stampfer M.J.
      • Manson J.E.
      • et al.
      Dietary fat intake and the risk of coronary heart disease in women.
      the truth within that expansive statement seems to be significantly less unambiguous. For example, it is unclear whether rTFA produce the same deleterious effects that we ascribe to industrial TFA. It is also unclear whether there is a synergistic effect when combining TFA with other dietary components or environmental factors. The contemporary nature of research from the past 10 years, which is guiding regulatory actions all over the world—from Denmark to Nassau County on Long Island, New York—will very likely yield new and perhaps unexpected outcomes in the next 10 years. This conflicting body of research likely contributes to suspicions about the FDA’s motivation for adopting a regulatory approach at this time. For example, the Alliance for Natural Health USA, a political advocacy group, suggests that the FDA is working to protect corporate interests in genetically modified foods, such as a soybean that produces “trans fat free” oil. The advocacy group calls the FDA a “corrupt government agency.”
      Another perplexing component of this discussion is how to deal with rTFA. Gebauer et al
      • Gebauer S.K.
      • Chardigny J.M.
      • Jakobsen M.U.
      • et al.
      Effects of ruminant trans fatty acids on cardiovascular disease and cancer: a comprehensive review of epidemiological, clinical, and mechanistic studies.
      describes rTFA as “naturally occurring fatty acids that are synthesized via bacterial metabolism of unsaturated fatty acids in ruminant animals and found in ruminant-derived food.” Ruminant animals are those with a second stomach, such as cattle and sheep, which generate nutrients from plant-based food by using a cycle called rumination; this cycle consists of fermenting swallowed food in 1 stomach, regurgitating and chewing the fermented material, before swallowing it again. Thus, a proportion of the TFA in the human diet is derived from consuming beef, lamb, and dairy products. Should the FDA take action against dietary TFA, how will they accommodate the consumption of rTFA, or what has been framed by some as “natural trans fat” and which have been suggested as having a protective effect against CVD?
      • Park S.
      • Park Y.
      Effects of dietary fish oil and trans fat on rat aorta histopathology and cardiovascular risk markers.
      • Jakobsen M.U.
      • Overvad K.
      • Dyerberg J.
      • Heitmann B.L.
      Intake of ruminant trans fatty acids and risk of coronary heart disease.
      It is against this backdrop of new and exciting, albeit still controversial, research and regulatory activity that Clinical Therapeutics offers a selection of relevant scholarship. This Trans Fat Special Update consists of 4 articles from scholars with differing backgrounds, who help to frame the issue from different angles. Paul Nestel, MD, professor of medicine, senior faculty, Baker IDI Heart and Diabetes Institute, describes the evidence linking TFA and cardiovascular disease.
      • Nestel P.
      Trans fatty acids: are its cardiovascular risks fully appreciated?.
      Joshua T. Cohen, PhD, deputy director of the Center for the Evaluation of Value and Risk in Health and a research associate professor of medicine at the Institute for Clinical Research and Health Policy Studies at Tufts Medical Center, Boston, measures regulatory action by the FDA from a policy perspective.
      • Cohen J.T.
      FDA’s proposed ban on trans fats—how do the risks and benefits stack up?.
      R. Rammy Assaf, an MD/MPH recent Intern, World Health Organization Health Systems and Services, Geneva, Switzerland, offers context for federal regulatory action by describing the history of TFA regulations by national, state and local governments.
      • Assaf R.R.
      Overview of local, state and national government legislation restricting trans fats.
      Rishi Sood, MPH, health policy analyst, Bureau of Primary Care Access and Planning, New York City Department of Health and Mental Hygiene, rounds out this selection of articles by describing the evaluation outcomes of a voluntary TFA ban in Nassau County from the perspective of compliance rates at food establishments.
      • Sood R.K.
      First time compliance inspections to evaluate an artificial trans fat ban in Nassau County.
      There is purposeful overlap among these articles, in an effort to avoid artificial compartmentalization of this discussion and with the goal of providing readers an opportunity to better understand these authors’ unique perspectives that are derived from their own areas of scholarship, professional and personal experiences, and perspectives.

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