Risk assessment for the amino acids taurine, l-glutamine and l-arginine☆
Introduction
The popularity of amino acids as supplemental ingredients in various dietary supplements and functional foods and beverages has increased tremendously in the past 10 years with their prevalence being highest in sports nutrition and “energy” products (Nutrition Business Journal, 2006). Taurine (Tau)1, l-glutamine (Gln) and l-arginine (Arg) are perhaps the three most widely used and best studied of these supplemental amino acids. However, despite their popularity, these, and indeed all essential and nonessential amino acids, have yet to be subjected to a comprehensive safety review with subsequent establishment of tolerable upper intake levels (ULs), as have most of the essential vitamins and minerals. In this review, we present findings from a series of risk assessments on these three amino acids. Due to a fairly robust human clinical trial dataset and the very large uncertainties associated with quantitative extrapolation from animal data, these risk assessments rely solely on the data from published human clinical trials.
Taurine (2-aminoethanesulfonic acid, Tau) (Fig. 1(a)) is a member of the family of sulfur-containing amino acids that includes methionine, cysteine and homocysteine (Brosnan and Brosnan, 2006). Unlike cysteine and methionine, Tau is not incorporated into proteins, but does play a role in many important physiological functions, including bile acid conjugation, retinal and neurological development, osmoregulation, modulation of cellular calcium levels and immune function (Huxtable, 1992, Huxtable, 1996, Grimble, 2006). One of the most abundant free amino acids in the body, Tau is synthesized endogenously in the liver from cysteine via several enzymatic steps, and therefore is considered nonessential or conditionally essential (Brosnan and Brosnan, 2006, van de Poll et al., 2006). Tau is present in relatively high amounts in the retina and skeletal and cardiac muscle tissue (Timbrell et al., 1995). Good dietary sources include human breast milk and animal proteins, such as meat and fish (Rana and Sanders, 1986).
In recent years, a number of therapeutic benefits have been proposed for Tau supplementation, including treatment for diabetes (Franconi et al., 2006), hypertension (Militante and Lombardini, 2002), heart failure (Sole and Jeejeebhoy, 2000), retinal degeneration (Militante and Lombardini, 2004) and skeletal muscle disorders (Trip et al., 2006). Knowledge of Tau’s role in osmoregulation, modulation of cellular calcium levels and its high concentration in muscle tissue have led to a rapid increase in the prevalence and research of Tau-containing energy and sports beverages (Seidl et al., 2000, Alford et al., 2001, Barthel et al., 2001, Ferreira et al., 2004a, Ferreira et al., 2004b, Ferreira et al., 2006, Runestad, 2005, Bichler et al., 2006), with the category achieving a record $7 billion in sales in 2005 (Nutrition Business Journal, 2006).
Daily Tau consumption from foods alone ranges from approximately 40–400 mg/d (Rana and Sanders, 1986, Laidlaw et al., 1990, Hayes and Trautwein, 1994). Aside from performance enhancement, supplementation is generally not required for most, with the exception being strict vegetarians whose dietary intake may be extremely low (Laidlaw et al., 1988, Laidlaw et al., 1990). Unlike other sulfur-containing amino acids, such as methionine and cysteine, a clear basis for toxicity has not been established for Tau (Baker, 2006, Brosnan and Brosnan, 2006, van de Poll et al., 2006). Thus far, a comprehensive review of the safety of Tau supplementation has yet to be published.
l-Glutamine (2,5-diamino-5-oxo-pentanoic acid, Gln) (Fig. 1(b)), in addition to its role as a substrate for protein synthesis, is the most abundant free amino acid in skeletal muscle tissue and plasma (Tapiero et al., 2002). Gln plays a number of critical physiologic roles, including many aspects of nitrogen metabolism (such as amino transfer, gluconeogenesis, nucleotide synthesis, urea synthesis and neurotransmitter precursor), as an anabolic precursor for muscle growth, in acid–base balance in the kidney and as an important fuel source for the intestine and immune system (Melis et al., 2004). Gln is synthesized endogenously from the amino acid glutamate by glutamine synthase which occurs primarily in skeletal muscle but also in other tissues, including lung, brain, adipose and liver (Stipanuk and Watford, 2006). Although there is no general consensus, some have proposed that Gln is a conditionally essential amino acid, especially in critically ill or trauma patients (Lacey and Wilmore, 1990, Buchman, 2001). Good dietary sources include high quality proteins such as meat, fish, poultry, beans and dairy products (Tapiero et al., 2002). Gln content of protein from food sources is estimated to be approximately 4–5% (Lowe et al., 1990, Kuhn et al., 1996), suggesting that typical daily intake of Gln from food by most adults is approximately 5 g (1.5 g protein/kg body weight in 70 kg adult).
In addition to its usefulness as a tool to offset the catabolic effects of cachexia, trauma or other wasting illnesses, a number of therapeutic and/or performance benefits have been proposed for Gln supplementation. These include ergogenic effects associated with resistance exercise (Antonio and Street, 1999, Kreider, 1999) and abrogation of the exercise-induced depression of the immune system (Rowbottom et al., 1996, Gleeson et al., 2004). These purported benefits of Gln supplementation have led to a rapid increase in the prevalence of Gln-containing dietary supplements on the market. In fact, Gln and other amino acids, such as, Arg and the branched-chains are among the top five most popular sports nutrition supplements (Nutrition Business Journal, 2006) and many are beginning to find their way into more mainstream products (Starling, 2004).
l-Arginine (2-amino-5-guanidino-pentanoic acid, Arg) (Fig. 1(c)) is one of the most important amino acids in the body. Considered by many to be a conditionally essential dietary component, Arg has metabolically essential roles in the formation of a number of important physiologic factors, including nitric oxide (NO, a vasodilator), urea (an excretory product and important component of the urea cycle), creatine (required for storage of high-energy phosphates involved in ATP-dependent processes), all proteins (as a part of the structures), and growth hormone release (Stipanuk and Watford, 2006). Arg is synthesized endogenously through several steps from the amino acids aspartate and citrulline by arginine synthase, primarily in the kidney and liver (Wu et al., 1998). Arg is most prevalent in high quality plant proteins such as soy protein, and daily intake in adults ranges from 3–6 g (Visek, 1986).
In healthy adults with adequate protein intakes, endogenous synthesis is sufficient to meet physiologic needs. Under some catabolic states, such as those resulting from severe burns, HIV/AIDS and cancer cachexia, or during periods of rapid growth, demand may exceed the body’s ability to endogenously synthesize Arg (May et al., 2002, Appleton, 2002, Wilmore, 2004). In such cases, there is evidence that supplemental Arg, provided either orally or parenterally, may help maintain lean body mass, improve wound healing and provide other functional benefits related to its effects on NO production and growth hormone secretion (Lind, 2004, Wilmore, 2004). As a result of this research, several performance-related benefits have been proposed for Arg supplementation. These include ergogenic effects such as enhanced exercise capacity purportedly due to an increase in circulating NO, and increased muscle protein synthesis purportedly due to Arg’s ability to stimulate growth hormone release and protein synthesis (Paddon-Jones et al., 2004). Other proposed uses of Arg include reduction of airway inflammation, improvement of cardiovascular circulation and renal blood flow, and even as a treatment for erectile dysfunction (Appleton, 2002). Supplementation of up to 30 g/d is commonly recommended (Colgan, 1993, Balch et al., 1997).
Although there are some published reports suggesting that supplemental Arg may cause hypotension (Petros et al., 1991), tumor stimulation (Park et al., 1992), acidosis (Barbul, 1986), hyperkalemia (Massara et al., 1981) and cardiac arrest (Gerard and Luisiri, 1997), these were either case reports, uncontrolled studies, studies involving parenteral administration or confirmed overdose. In many cases, these findings are contradicted by a number of other studies, including those reviewed in this analysis.
The safety of Tau, Gln and Arg supplementation has been discussed previously (Garlick, 2001, Garlick, 2004, Wilmore, 2001, Brosnan and Brosnan, 2006, Grimble, 2006, Grimble, 2007). However, while experts have generally acknowledged the absence of adverse effects from supplemental amounts in humans, a UL or its equivalent has yet to be established. This is primarily due to the absence of appropriate data to identify hazards from excessive intakes of common dietary amino acids and consequently no basis for a no observed adverse effect level (NOAEL) or a lowest observed adverse effect level (LOAEL) (Hayashi, 2003), which serve as the basis of a UL or an Acceptable Daily Intake (ADI). The dramatic increase in use of these amino acids in various dietary supplements and functional foods and beverages warrants a comprehensive evaluation of their safety and identification of appropriate maximums through quantitative risk assessment. These values, along with other sources of safety information (such as acute and sub-chronic animal toxicity studies) can serve as an important guideline for dietary supplement manufacturers and regulatory officials to help reduce the potential for overly excessive intakes.
Section snippets
Methods
Most upper safe levels of nutrients and related substances are based on a widely applicable UL risk assessment model used by the US. Food and Nutrition Board (FNB) in its Dietary Reference Intakes (DRI) documents (Institute of Medicine, 1997, Institute of Medicine, 1998a, Institute of Medicine, 1998b, Institute of Medicine, 2000, Institute of Medicine, 2001). The FNB method and reviews are a formalization and extension of the quantitative methods widely used earlier in risk assessment of other
Human studies
There have been more than 30 peer-reviewed, published human clinical trials involving Tau administration. Of these, the 11 most relevant studies regarding safety of oral intake are presented in Table 1. General criteria for study inclusion were mode of administration (oral), study duration (at least 1 week), study design (randomized, placebo-controlled) and study subjects (adults). Uncontrolled studies, those investigating acute effects, bioavailability, parenteral administration,
Human studies
Overall the dataset is robust for human clinical trials involving Gln administration, with hundreds of peer-reviewed studies published to date. Of these, the nine most relevant studies regarding safety of oral intake are presented in Table 2. General criteria for study inclusion were mode of administration (oral), study duration (at least 1 week), study design (randomized, placebo-controlled) and study subjects (healthy adults). Uncontrolled studies, those investigating acute effects,
Human studies
Sample size, dosage and duration, presence of multiple active ingredients and outcome measures varied widely among oral Arg studies. Also, published clinical trials collectively included both healthy subjects and those with a wide variety of diseases or conditions. Overall, there is an absence of any pattern in the adverse effects that are attributable to Arg, and therefore the literature demonstrates a substantial level of safety for supplemental Arg (Table 3).
General criteria for study
Discussion
In many nations, including the US and UK, supplemental amino acids are available for non-prescription sales without any specific limits. Further, the prevalence of many amino acids in various dietary supplements and functional foods and beverages has increased dramatically in recent years. This increase in use and popularity of these ingredients warranted this comprehensive safety review. We found no systematic pattern of adverse effects of any kind at any dose tested, with the exception of
Conflict of interest statement
Both Dr. Shao and Dr. Hathcock are full time employees of the Council for Responsible Nutrition (CRN), a not-for-profit trade association representing and supported by the US dietary supplement industry.
Acknowledgment
We would like to thank Ingrid Lebert for her assistance in acquiring many of the relevant scientific articles for this analysis.
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Funding: No funding was specific to the production of this manuscript. The salaries for authors were provided by the affiliated organization.