Risk assessment for the amino acids taurine, l-glutamine and l-arginine

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Regulatory Toxicology and Pharmacology 50 (2008) 376–399

Risk assessment for the amino acids taurine, L-glutamineand L-arginine q

Andrew Shao *, John N. Hathcock

Council for Responsible Nutrition, 1828 L Street, NW, Suite 900, Washington, DC 20036-5114, USA

Received 13 July 2007Available online 26 January 2008

Abstract

Taurine, glutamine and arginine are examples of amino acids which have become increasingly popular as ingredients in dietarysupplements and functional foods and beverages. Animal and human clinical research suggests that oral supplementation of theseamino acids provides additional health and/or performance benefits beyond those observed from normal intake of dietary protein.The increased consumer awareness and use of these amino acids as ingredients in dietary supplements and functional foods war-rant a comprehensive review of their safety through quantitative risk assessment, and identification of a potential safe upper levelof intake. The absence of a systematic pattern of adverse effects in humans in response to orally administered taurine (Tau),L-glutamine (Gln) and L-arginine (Arg) precluded the selection of a no observed adverse effect level (NOAEL) or lowest observedadverse effect level (LOAEL). Therefore, by definition, the usual approach to risk assessment for identification of a tolerable upperlevel of intake (UL) could not be used. Instead, the newer method described as the Observed Safe Level (OSL) or HighestObserved Intake (HOI) was utilized. The OSL risk assessments indicate that based on the available published human clinical trialdata, the evidence for the absence of adverse effects is strong for Tau at supplemental intakes up to 3 g/d, Gln at intakes up to14 g/d and Arg at intakes up to 20 g/d, and these levels are identified as the respective OSLs for normal healthy adults. Althoughmuch higher levels of each of these amino acids have been tested without adverse effects and may be safe, the data for intakesabove these levels are not sufficient for a confident conclusion of long-term safety, and therefore these values are not selectedas the OSLs.� 2008 Elsevier Inc. All rights reserved.

Keywords: Amino acids; Taurine; L-Glutamine; L-Arginine; Upper level of intake (UL); Observed Safe Level (OSL)

1 Abbreviations used: ADI, Acceptable Daily Intake; CRN, Council forResponsible Nutrition; DRI, Dietary Reference Intakes; SCF, European

1. Introduction

The popularity of amino acids as supplemental ingredi-ents in various dietary supplements and functional foodsand beverages has increased tremendously in the past 10years with their prevalence being highest in sports nutritionand ‘‘energy” products (Nutrition Business Journal, 2006).

0273-2300/$ - see front matter � 2008 Elsevier Inc. All rights reserved.

doi:10.1016/j.yrtph.2008.01.004

q Funding: No funding was specific to the production of this manuscript.The salaries for authors were provided by the affiliated organization.

* Corresponding author. Fax: +1 202 204 7980.E-mail address: [email protected] (A. Shao).

Taurine (Tau)1, L-glutamine (Gln) and L-arginine (Arg) areperhaps the three most widely used and best studied of

Commission Scientific Committee on Food; FAO/WHO, Food andAgriculture Organization/World Health Organization; HOI, HighestObserved Intake; IOM, Institute of Medicine; LOAEL, Lowest observedadverse effect level; Arg, L-arginine; Gln, L-glutamine; OSL, Observed SafeLevel; NOAEL, No observed adverse effect level; Tau, Taurine; UL,tolerable upper intake level; UF, uncertainty factor; EVM, UnitedKingdom Expert Group on Vitamins and Minerals; ULS, Upper levelfor supplements; FNB, US Food and Nutrition Board.

mailto:[email protected]

A. Shao, J.N. Hathcock / Regulatory Toxicology and Pharmacology 50 (2008) 376–399 377

these supplemental amino acids. However, despite theirpopularity, these, and indeed all essential and nonessentialamino acids, have yet to be subjected to a comprehensivesafety review with subsequent establishment of tolerableupper intake levels (ULs), as have most of the essentialvitamins and minerals. In this review, we present findingsfrom a series of risk assessments on these three aminoacids. Due to a fairly robust human clinical trial datasetand the very large uncertainties associated with quantita-tive extrapolation from animal data, these risk assessmentsrely solely on the data from published human clinical trials.

1.1. Taurine

Taurine (2-aminoethanesulfonic acid, Tau) (Fig. 1(a)) isa member of the family of sulfur-containing amino acidsthat includes methionine, cysteine and homocysteine (Bros-nan and Brosnan, 2006). Unlike cysteine and methionine,Tau is not incorporated into proteins, but does play a rolein many important physiological functions, including bileacid conjugation, retinal and neurological development,osmoregulation, modulation of cellular calcium levels andimmune function (Huxtable, 1992, 1996; Grimble, 2006).One of the most abundant free amino acids in the body,Tau is synthesized endogenously in the liver from cysteinevia several enzymatic steps, and therefore is considerednonessential or conditionally essential (Brosnan and Bros-nan, 2006; van de Poll et al., 2006). Tau is present in rela-tively high amounts in the retina and skeletal and cardiacmuscle tissue (Timbrell et al., 1995). Good dietary sourcesinclude human breast milk and animal proteins, such asmeat and fish (Rana and Sanders, 1986).

In recent years, a number of therapeutic benefits havebeen proposed for Tau supplementation, including treat-ment for diabetes (Franconi et al., 2006), hypertension(Militante and Lombardini, 2002), heart failure (Sole andJeejeebhoy, 2000), retinal degeneration (Militante andLombardini, 2004) and skeletal muscle disorders (Tripet al., 2006). Knowledge of Tau’s role in osmoregulation,modulation of cellular calcium levels and its high concen-tration in muscle tissue have led to a rapid increase in theprevalence and research of Tau-containing energy andsports beverages (Seidl et al., 2000; Alford et al., 2001; Bar-thel et al., 2001; Ferreira et al., 2004a,b, 2006; Runestad,

Fig. 1. Chemical structure of supplemental amino acids. (a) Taurine, (b)L-glutamine, (c) L-arginine.

2005; Bichler et al., 2006), with the category achieving arecord $7 billion in sales in 2005 (Nutrition Business Jour-nal, 2006).

Daily Tau consumption from foods alone ranges fromapproximately 40–400 mg/d (Rana and Sanders, 1986;Laidlaw et al., 1990; Hayes and Trautwein, 1994). Asidefrom performance enhancement, supplementation is gener-ally not required for most, with the exception being strictvegetarians whose dietary intake may be extremely low(Laidlaw et al., 1988, 1990). Unlike other sulfur-containingamino acids, such as methionine and cysteine, a clear basisfor toxicity has not been established for Tau (Baker, 2006;Brosnan and Brosnan, 2006; van de Poll et al., 2006). Thusfar, a comprehensive review of the safety of Tau supple-mentation has yet to be published.

1.2. L-Glutamine

L-Glutamine (2,5-diamino-5-oxo-pentanoic acid, Gln)(Fig. 1(b)), in addition to its role as a substrate for proteinsynthesis, is the most abundant free amino acid in skeletalmuscle tissue and plasma (Tapiero et al., 2002). Gln plays anumber of critical physiologic roles, including manyaspects of nitrogen metabolism (such as amino transfer,gluconeogenesis, nucleotide synthesis, urea synthesis andneurotransmitter precursor), as an anabolic precursor formuscle growth, in acid–base balance in the kidney and asan important fuel source for the intestine and immune sys-tem (Melis et al., 2004). Gln is synthesized endogenouslyfrom the amino acid glutamate by glutamine synthasewhich occurs primarily in skeletal muscle but also in othertissues, including lung, brain, adipose and liver (Stipanukand Watford, 2006). Although there is no general consen-sus, some have proposed that Gln is a conditionally essen-tial amino acid, especially in critically ill or trauma patients(Lacey and Wilmore, 1990; Buchman, 2001). Good dietarysources 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 tobe approximately 4–5% (Lowe et al., 1990; Kuhn et al.,1996), suggesting that typical daily intake of Gln from foodby most adults is approximately 5 g (1.5 g protein/kg bodyweight in 70 kg adult).

In addition to its usefulness as a tool to offset the cata-bolic effects of cachexia, trauma or other wasting illnesses,a number of therapeutic and/or performance benefits havebeen proposed for Gln supplementation. These includeergogenic effects associated with resistance exercise (Anto-nio and Street, 1999; Kreider, 1999) and abrogation of theexercise-induced depression of the immune system (Row-bottom et al., 1996; Gleeson et al., 2004). These purportedbenefits of Gln supplementation have led to a rapidincrease in the prevalence of Gln-containing dietary supple-ments on the market. In fact, Gln and other amino acids,such as, Arg and the branched-chains are among the topfive most popular sports nutrition supplements (Nutrition

378 A. Shao, J.N. Hathcock / Regulatory Toxicology and Pharmacology 50 (2008) 376–399

Business Journal, 2006) and many are beginning to findtheir way into more mainstream products (Starling, 2004).

1.3. L-Arginine

L-Arginine (2-amino-5-guanidino-pentanoic acid, Arg)(Fig. 1(c)) is one of the most important amino acids inthe body. Considered by many to be a conditionally essen-tial dietary component, Arg has metabolically essentialroles in the formation of a number of important physio-logic factors, including nitric oxide (NO, a vasodilator),urea (an excretory product and important component ofthe 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 hor-mone release (Stipanuk and Watford, 2006). Arg is synthe-sized endogenously through several steps from the aminoacids aspartate and citrulline by arginine synthase, primar-ily in the kidney and liver (Wu et al., 1998). Arg is mostprevalent 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, endog-enous synthesis is sufficient to meet physiologic needs.Under some catabolic states, such as those resulting fromsevere burns, HIV/AIDS and cancer cachexia, or duringperiods of rapid growth, demand may exceed the body’sability to endogenously synthesize Arg (May et al., 2002;Appleton, 2002; Wilmore, 2004). In such cases, there is evi-dence that supplemental Arg, provided either orally or par-enterally, may help maintain lean body mass, improvewound healing and provide other functional benefitsrelated to its effects on NO production and growth hor-mone secretion (Lind, 2004; Wilmore, 2004). As a resultof this research, several performance-related benefits havebeen proposed for Arg supplementation. These includeergogenic effects such as enhanced exercise capacity pur-portedly due to an increase in circulating NO, andincreased muscle protein synthesis purportedly due toArg’s ability to stimulate growth hormone release and pro-tein synthesis (Paddon-Jones et al., 2004). Other proposeduses of Arg include reduction of airway inflammation,improvement of cardiovascular circulation and renal bloodflow, and even as a treatment for erectile dysfunction(Appleton, 2002). Supplementation of up to 30 g/d is com-monly recommended (Colgan, 1993; Balch et al., 1997).

Although there are some published reports suggestingthat supplemental Arg may cause hypotension (Petroset al., 1991), tumor stimulation (Park et al., 1992), acidosis(Barbul, 1986), hyperkalemia (Massara et al., 1981) andcardiac arrest (Gerard and Luisiri, 1997), these were eithercase reports, uncontrolled studies, studies involving paren-teral administration or confirmed overdose. In many cases,these findings are contradicted by a number of other stud-ies, including those reviewed in this analysis.

The safety of Tau, Gln and Arg supplementation hasbeen discussed previously (Garlick, 2001, 2004; Wilmore,2001; Brosnan and Brosnan, 2006; Grimble, 2006, 2007).

However, while experts have generally acknowledged theabsence of adverse effects from supplemental amounts inhumans, a UL or its equivalent has yet to be established.This is primarily due to the absence of appropriate datato identify hazards from excessive intakes of common die-tary amino acids and consequently no basis for a noobserved adverse effect level (NOAEL) or a lowestobserved adverse effect level (LOAEL) (Hayashi, 2003),which serve as the basis of a UL or an Acceptable DailyIntake (ADI). The dramatic increase in use of these aminoacids in various dietary supplements and functional foodsand beverages warrants a comprehensive evaluation oftheir safety and identification of appropriate maximumsthrough quantitative risk assessment. These values, alongwith other sources of safety information (such as acuteand sub-chronic animal toxicity studies) can serve as animportant guideline for dietary supplement manufacturersand regulatory officials to help reduce the potential foroverly excessive intakes.

2. Methods

Most upper safe levels of nutrients and related substances are based ona widely applicable UL risk assessment model used by the US. Food andNutrition Board (FNB) in its Dietary Reference Intakes (DRI) documents(Institute of Medicine, 1997, 1998a,b, 2000, 2001). The FNB method andreviews are a formalization and extension of the quantitative methodswidely used earlier in risk assessment of other substances, and by the foodand dietary supplement industries. Because of the systematic, comprehen-sive and authoritative character of the FNB UL risk assessment methodfor nutrients, this approach has gathered widespread support and adop-tion by others such as the European Commission Scientific Committeeon Food (SCF) (European Commission, 2001), the United KingdomExpert Group on Vitamins and Minerals (EVM) (Food StandardsAgency, 2003) and more recently by the Food and Agriculture Organiza-tion/World Health Organization (FAO/WHO, 2006) with some slightmodifications. All these reports reflect the concepts and procedures estab-lished much earlier for the risk assessment of non-carcinogenic chemicals,which include identification of a NOAEL or LOAEL and adjustment forthe degree of uncertainty associated with the dataset (National ResearchCouncil, 1983). All nutrient risk assessments are intended to apply to nor-mal, healthy adults, unless otherwise specified.

The safety evaluation method applied to orally administered Tau, Glnand Arg is from the Council for Responsible Nutrition’s (CRN) Vitamin

and Mineral Safety, 2nd edition (Hathcock, 2004), which contains thebasic features of the FNB method and also the Observed Safe Level(OSL) modification that was adopted in 2006 under the name HighestObserved Intake (HOI) in the FAO/WHO report (FAO/WHO, 2006).

Overall, this risk analysis was based on relevant human clinical trialsidentified in the Medline database (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) and was conducted using the following basic steps:

1. Derive a UL if the data are appropriate:a. Search for data that identify a hazard (adverse effect) related to

excessive intakeb. Assess the dose–response relationship for the identified hazard and

identify a NOAEL or LOAELc. Consider uncertainty and assign an uncertainty factor (UF)d. Calculate the UL as UL = NOAEL � UF.

2. If no data establish an adverse or critical effect (adverse effect thatoccurs at the lowest intake level) in humans, the above procedure can-not be used. In these circumstances, identify the highest intake levelwith sufficient evidence of safety as a value named the OSL by CRNand the HOI by FAO/WHO (Fig. 2).

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi

Fig. 2. Observed Safe Level (OSL). The classic UL approach involves identification of a hazard or critical effect and, selection of a no observed adverseeffect level (NOAEL), upon which the UL is based. By definition, the absence of toxicity precludes selection of a NOAEL and in turn, a UF. In such casesthe new approach referred to as the Observed Safe Level (OSL) or Highest Observed Intake (HOI) is applied and is defined as the highest level of a nutrientstudied with convincing evidence of safety for which no toxicity can be identified at any level.

Select clinical trials for size/duration

Arrange in decreasing


We applied the first procedure separately to the Tau, Gln and Arghuman clinical trial data and found no basis for neither a NOAEL norLOAEL for any of the three amino acids, and thus could not derive aUL. Consequently, to each dataset we applied the OSL procedure, definedas the highest level of a nutrient studied with convincing evidence of safetyfor these nutrients for which no toxicity can be identified at any level. Theresults are described in the sections below.

order of intake

Evaluate each level for uncertainty

Select highest intake with little uncertainty

High-confidence NOAEL

NOAEL with UF of 1.0

= UL

Fig. 3. Approach to uncertainty. The classic UL approach is to identifythe highest possible dose with no adverse effects, i.e. the NOAEL, thendivide by an uncertainty factor (UF) to obtain the UL. The new approachused with the OSL method instead arranges the clinical trials in order ofdecreasing intake, identifying all possible NOAEL values. The highestintake level with the lowest uncertainty is chosen that does not requirefurther correction, i.e. UF = 1.0.

2.1. Uncertainty evaluation

The traditional UL method utilized by the FNB and others involvesselection of the highest possible NOAEL value from the available dataand application of a UF to correct for uncertainty related to the extrapo-lation of the data to the general population (Institute of Medicine, 1998a).This process itself carries much uncertainty, as there are no well estab-lished and widely accepted quantitative methods or approaches for theselection of specific UF values. In this series of risk assessments, uncer-tainty was addressed in a different manner (Fig. 3). All relevant clinicaltrial data were analyzed in decreasing order of intake. Possible NOAELvalues were identified, and the strength of the data evaluated. Those pos-sible values with substantial uncertainty were rejected and a NOAELselected that provides high enough confidence to justify a UF of unity(1.0). This does not imply no uncertainty whatsoever; it implies that thelevel of uncertainty is small enough that it is judged not to require quan-


titative adjustment in identification of a level deemed safe. For example,the IOM has applied UF of 1.0 to fluoride and manganese datasets (Insti-tute of Medicine, 1997, 2001).

This approach to uncertainty has been the basis of many other recentlypublished risk assessments on both essential and nonessential nutrients(Hathcock, 2004; Hathcock and Shao, 2006a,b, 2007; Shao and Hathcock,2006a,b; Hathcock et al., 2007).

No efforts were made in any of the clinical trials to limit or quantifydietary amino acids or identify dietary protein levels, and therefore theassumption is that the subjects consumed normal dietary levels of eachsubstance. Thus, the OSL value identified from the trials does not requirecorrection for dietary intakes or endogenous synthesis and can be identi-fied as a safe upper level for supplements (ULS).

3. Scientific evidence related to safety—Taurine

3.1. Human studies

There have been more than 30 peer-reviewed, pub-lished human clinical trials involving Tau administration.Of these, the 11 most relevant studies regarding safety oforal intake are presented in Table 1. General criteria forstudy inclusion were mode of administration (oral), studyduration (at least 1 week), study design (randomized,placebo-controlled) and study subjects (adults). Uncon-trolled studies, those investigating acute effects, bioavail-ability, parenteral administration, pharmacokinetics orpost-prandial responses from single bolus doses wereexcluded from this analysis and used solely as supportiveinformation. Only a few of the studies undertaken toassess the beneficial effects of Tau have monitored anypossible adverse side effects and then primarily throughself-reporting. There are no published human studies thathave focused specifically on the safety aspects of Tausupplementation.

Sample size, dosage and duration, presence of multipleactive ingredients and outcome measures varied consider-ably between studies. Also, the clinical trials involvedboth healthy subjects and those with a range of diseasesor conditions. Overall, the literature demonstrates a sub-stantial level of safety for supplemental Tau. The highestoral Tau dosage utilized in a published human clinicaltrial was up to 10 g/d for 6 months (Durelli et al.,1983). The longest duration trial was 12 months at adose range of 500–1500 mg/d in teenage cystic fibrosispatients (Colombo et al., 1996). Tau levels in the bodyappear to be regulated in part by the kidney (Rozenand Scriver, 1982; Chesney et al., 1985). Therefore,excess dietary Tau is excreted in the urine, whichincreases in response to increased dietary intake (Hayes,1985; Sturman, 1988). Where measured in the collectionof reviewed studies, both serum and urinary Tau levelsincreased with supplementation, but relative effects variedwidely. With the exception of minor gastrointestinal dis-turbances reported in one study (Jeejeebhoy et al., 2002),no adverse effects were reported in any of the reviewedstudies. As noted, these trials were designed primarilyto test the beneficial effects of Tau supplementation,tended to focus on short-term use and did not specifi-

cally test the effects of exposures lasting greater than12 months. Adverse effects noted in uncontrolled trialsinclude temporary itching in psoriasis patients (Kendler,1989) and hypothermia in patients with adrenal insuffi-ciency (Shin and Linkswiler, 1974). Neither of theseadverse effects was observed in any of the controlledstudies reviewed.

Tau consumption from foods by US adults is estimatedat up to 400 mg/d (Rana and Sanders, 1986; Laidlaw et al.,1990; Hayes and Trautwein, 1994), suggesting that thedoses used in the reviewed trials (up to 20-fold higher thanwhat is typically consumed in the diet) are adequate toassess safety of supplementation. The absence of any con-sistent pattern of adverse effects related to oral Tau admin-istration in any of the published human trials providessupport for a substantial level of confidence in the safetyof this aminoacid.

3.2. Human NOAEL

None of the human clinical trials reviewed found a sig-nificant adverse effect related to Tau administration. There-fore, by definition, there is no basis for identifying aNOAEL or LOAEL. In the absence of either of thesetwo values a UL usually is not set (Institute of Medicine,1998a).

3.3. Human OSL

Published relevant human clinical trials involved oralTau doses ranging from 500 mg/d to 10 g/d (Table 1) (Azu-ma et al., 1983, 1985; Durelli et al., 1983; Fujita et al., 1987;Colombo et al., 1996; Mizushima et al., 1996; Jeejeebhoyet al., 2002; Sirdah et al., 2002; Chauncey et al., 2003;Brons et al., 2004; Zhang et al., 2004a,b; Spohr et al.,2005). All studies reviewed were double-blind, randomizedcontrolled trials involving both healthy adults and thosewith a range of disease and conditions. Where measured,clinically relevant safety outcome assessments are noted,along with adverse effects, if any, described in the studypublication.

A series of clinical trials involving infants or children,acute (less than 1 week) administration, parenteral admin-istration, non-randomized, uncontrolled or open-label hasalso been published (Van Gelder et al., 1975; Azumaet al., 1982, 1992; Jarvenpaa et al., 1983; Rassin et al.,1983; Watkins et al., 1983; Cooke et al., 1984; Darlinget al., 1985; Belli et al., 1987; Galeano et al., 1987; Thomp-son et al., 1987; Thompson and Tomas, 1987; Colomboet al., 1988; Michalk et al., 1988; Harding et al., 1989;Tyson et al., 1989; Ishizaka et al., 1990; Rassin et al.,1990; Smith et al., 1991; Wang and Liaw, 1991; Wasserhesset al., 1993; Gray et al., 1994; Merli et al., 1994; Paauw andDavis, 1994; Yamashiro et al., 1994; Franconi et al., 1995;Obinata et al., 1996; Raiha et al., 1996; Kreider et al., 1998;Seidl et al., 2000; Alford et al., 2001; Barthel et al., 2001;Rudolph et al., 2002; Ferreira et al., 2004a, 2006, Spencer

Table 1Published safety observations* for human taurine (Tau) supplementation

Study Studypopulation

Dosage and study design Duration(days)

Key observations OSL Considerations

Durelli et al.(1983)

18 myotonicdystrophypatients

100–150 mg/kg bw Tau/d(equivalent to 7–10 g/d inan adult); randomized,controlled, crossover

6 months(180 d)

Approximate doubling of serum Taulevels; increased urinary Tau observed;no other outcome measures related tosafety reported

Up to 10 g, relatively long duration,but diseased nature of population,relatively small sample size, lack ofclinically relevant safety outcomemeasures argue against use of thisstudy for identification of an OSL

Azuma et al.(1985)

14congestiveheart failurepatients

6 g Tau/d; randomized,controlled, crossover

4 weeks(28 d)

No adverse effects observed; no changein heart rate or blood pressure

6 g, but diseased nature of population,small sample size and short durationargue against use of this study foridentification of an OSL

Azuma et al.(1983)


6 g Tau/d; randomized,controlled, crossover

4 weeks(28 d)

No adverse effects reported, but nospecific safety parameters wereassessed

6 g, but diseased nature of population,short duration and lack of safetyassessment argue against use of thisstudy for identification of an OSL

Fujita et al.(1987)

31borderlinehypertensiveadults;normaladults

6 g Tau/d; randomized,controlled

7 d Significant decrease in blood pressureand serum catecholamines (borderlinehypertensives); no change in normalcontrols; no adverse effects reported;no other safety parameters assessed

6 g, but diseased nature of population,small sample size and short durationargue against use of this study foridentification of an OSL

Mizushimaet al.(1996)

11 healthyadult males

6 g Tau/d in presence ofhigh fat (40% kcal), highcholesterol (1000 mg/d)diet; randomized,controlled

3 weeks(21 d)

Significant increase in VLDL andtriglycerides; significant decrease inurinary norepinephrine; no change inblood pressure; no adverse effectsobserved

6 g in healthy men, but small samplesize, and short duration argue againstthe use of this study for identificationof an OSL

Jeejeebhoyet al.(2002)


3 g Tau/d (plus coenzymeQ10, carnitine, creatine)randomized, controlled

Up to45 d

Significant increase in myocardial Taulevels; no effect on blood biochemistry;4 patients complained of GIdisturbances

3 g, but diseased nature of population,small sample size, short duration andpresence of multiple ingredients argueagainst use of this study foridentification of an OSL

Chaunceyet al.(2003)

22 type IIdiabetespatients


4 months(120 d)

Significant 33% increase in serum Tau;no effect on HBA1C or fasting glucose;no other relevant safety parametersassessed

3 g, but diseased nature of population,small sample size, and modest durationargue against use of this study foridentification of an OSL

Zhang et al.(2004a)

13 healthyadults


12 d Significant 8-fold increase in urinaryTau; no other safety parametersassessed

3 g, healthy adults but small samplesize, short duration and lack ofrelevant safety measurements argueagainst the use of this study foridentification of an OSL

Zhang et al.(2004b)

15 healthyoverweightadults


7 weeks(49 d)

Significant decrease in serumtriglycerides; no change in HDL-C orfasting glucose; no adverse effectsreported; no other relevant safetyparameters assessed

3 g, small sample size, but modestduration; given the lack of adverseeffects in studies using doses above andbelow this amount, this study is chosenas the basis for the OSL forsupplemental Tau

Colomboet al.(1996)

12 teenagecysticfibrosispatients w/liver disease

500–1500 mg Tau/d;randomized, controlled

1 yr(365 d)

No clinically relevant changes inbiochemical measurements, includingliver enzymes, bilirubin, albumin, urea,etc . . .No adverse effects observed

Up to 1.5 g/d, small sample size butlong duration; supports the OSLselected above

Brons et al.(2004) andSpohret al.(2005)

18 healthymen

1.5 g Tau/d; randomized,controlled

8 weeks(56 d)

No clinically relevant changes inbiochemical measurements; no adverseeffects observed

1.5 g, small sample, modest duration;supports the OSL selected above

Sirdah et al.(2002)

26 anemicwomen

1.0 g Tau/d (+325 mg/dferrous sulfate);randomized, controlled

20 weeks(140 d)

No adverse effects observed; no otherrelevant safety parameters assessed

1 g, small sample size but reasonableduration; supports the OSL selectedabove

*No adverse effects reported = safety or adverse effects not addressed in study publication.No adverse effects observed = investigators report observing no adverse effects and/or study subjects reported no adverse effects.


et al., 2005; Cangemi, 2007). The doses involved in thesestudies range from 5 mg/kg/d up to 7 g/d, the results of

which are consistent with respect to safety, showing noobserved or reported adverse effects.


3.4. 610 g/d

The highest oral Tau dose tested in a randomized, con-trolled trial was 10 g/d by Durelli et al. (1983). In this studymyotonic dystrophy patients were treated in a cross-overmanner with 100–150 mg/kg/d (equivalent to 7–10 g/d ina 70 kg adult) acutely via parenteral administration fol-lowed by oral administration for 6 months. Approximatedoubling of serum Tau levels was achieved following theoral phase and an increase in urinary Tau was observedin some patients. No other adverse effects were reported.Although this study had a relatively long duration, the rel-atively small sample size (n = 18) and lack of clinically rel-evant safety outcome measures argue against its use foridentification of an OSL.

3.5. 6 g/d

In a series of two studies by Azuma et al. 14 (Azumaet al., 1985) and 58 patients (Azuma et al., 1983), respec-tively, with congestive heart failure were administered 6 gTau/d for 4 weeks in a cross-over manner. No adverseeffects were observed in either study. Among clinically rel-evant safety measurements, there was no change in eitherheart rate or blood pressure (Azuma et al., 1985). Inanother study, borderline hypertensive adults (n = 31) wereadministered 6 g/d for 7 days (Fujita et al., 1987). Noadverse effects were reported, but researchers did note asignificant decrease in blood pressure and serum catechol-amines. In a study involving healthy adult males (n = 11)who were administered 6 g Tau/d for 3 weeks, investigatorsobserved a slight but significant increase in VLDL and tri-glycerides and a significant decrease in urinary norepineph-rine, but no change in blood pressure (Mizushima et al.,1996). No adverse effects were reported. Although noadverse effects were observed or reported in the reviewedstudies using 6 g/d, the relatively small sample sizes andshort duration of these studies argue against their use foridentification of an OSL.

3.6. 3 g/d

A total of four randomized, controlled trials havebeen conducted using 3 g Tau/d with supplementationperiods ranging from 12 days up to 4 months. Jeejeebhoyet al. (2002) administered 3 g/d (formulation alsoincluded coenzyme Q10, carnitine and creatine amongother ingredients) to congestive heart failure patients(n = 18) for up to 45 days. There was a significantincrease in myocardial Tau levels and no effect on anyblood biochemistry measurements (with the exceptionof an elevated creatinine level, presumably due to thepresence of creatine in the formula). Four patients com-plained of GI disturbances. The small sample size, shortduration and potential confounding due to the presenceof multiple ingredients argue against use of this studyfor identification of an OSL.

Chauncey et al. (2003) administered 3 g/d to type II dia-betic patients (n = 22) for 4 months. There was a significant33% increase in serum Tau, no effect on glycosylated hemo-globin (HBA1C) or fasting glucose levels, and no adverseeffects were reported. The small sample size and modestduration argue against the use of this study for identifica-tion of an OSL. Zhang et al. conducted two studies inwhich healthy adults were administered 3 g Tau/d for 12days (Zhang et al., 2004a) and 7 weeks (Zhang et al.,2004b), respectively. In the shorter of the two trials(n = 13) there was a significant 8-fold increase in urinaryTau and no adverse effects were reported. In the longerof the two (n = 15), there was a significant decrease inserum triglycerides and no change in HDL cholesterol orfasting glucose. No adverse effects were reported. Despitethe small sample size and modest duration, the lack ofsignificant adverse effects observed in this trial involvinghealthy adults and in other trials using doses equal to, aboveand below 3 g/d, justifies this study as the basis of an OSL.

Several other trials have been conducted at doses rang-ing from 0.4 to 1.5 g/d for up to 1 year. These were rela-tively small studies in which there were no changes inbiochemical measurements and/or no adverse effectsobserved (Colombo et al., 1996; Sirdah et al., 2002; Bronset al., 2004; Spohr et al., 2005; Cangemi, 2007). Collectivelythese studies support the selected OSL of 3 g/d.

The OSL was identified from data on subjects consum-ing a variety of diets and having endogenous synthesis ofTau. These additional sources of Tau are already consid-ered and do not need to be subtracted from the OSL toidentify a ULS. Thus, a ULS based on the toxicologicalevidence in human clinical trials is 3 g Tau/d.

3.7. Animal data

There are a number of animal studies that have exam-ined the effect of Tau supplementation on models of vari-ous diseases and conditions. Many of these have beenconducted in cats, in which, unlike humans, Tau is anessential nutrient required in the diet (Hayes and Trautw-ein, 1989). There are no published animal studies examin-ing the safety and toxicological aspects of acute, sub-chronic or chronic oral Tau administration. Given theavailability of a reasonably reliable dataset of publishedhuman clinical trials, combined with the uncertainty asso-ciated with extrapolating results from animal studies tohumans, we have chosen to rely solely on the human datafor this risk assessment.


For Tau, the highest daily dose used in a randomized,controlled trial is up to 10 g (Durelli et al., 1983) and thisvalue could be considered as the OSL. However, the studyhas several limitations, including small sample size and lackof clinically relevant safety outcome measures. Use of thisstudy to serve as the basis of the OSL would require some


level of correction for uncertainty (i.e. UF > 1.0). Exactlywhat UF value should be assigned is unclear. Therefore,the approach of evaluating the clinical trials in order ofdecreasing daily doses and the selection of a study usinga much lower dose of 3 g/d (Zhang et al., 2004b), whilemore conservative, also inspire a higher level of confidenceand less uncertainty (i.e. UF = 1.0).

Thus:NOAEL and LOAEL >10 g/d TaurineOSL 3 g/dULS 3 g/d

4. Scientific evidence related to safety—L-glutamine

4.1. Human studies

Overall the dataset is robust for human clinical trialsinvolving Gln administration, with hundreds of peer-reviewed studies published to date. Of these, the nine mostrelevant studies regarding safety of oral intake are pre-sented in Table 2. General criteria for study inclusion weremode of administration (oral), study duration (at least 1week), study design (randomized, placebo-controlled) andstudy subjects (healthy adults). Uncontrolled studies, thoseinvestigating acute effects, addressing only bioavailability,using parenteral administration, focused on pharmacoki-netics or post-prandial responses from single bolus doseswere excluded from the overall analysis and are used solelyas supportive information. Also excluded from the analysiswere studies using patients under hypercatabolic states (i.e.cancer, HIV/AIDS, trauma, post-surgical, burn victims,etc . . .) whose amino acid metabolism is drastically alteredand studies using patients with compromised gastrointesti-nal function (i.e. short bowel syndrome, Crohn’s disease,etc . . .) whose ability to digest, absorb and assimilate maybe significantly compromised. Although the vast majorityof clinical studies on Gln have been conducted in thesepatient populations, the uncertainty associated withextrapolation of data from such studies to the general pop-ulation precludes their use in this analysis. Only a few ofthe studies undertaken to assess the beneficial effects ofGln have monitored any possible adverse side effects andthen primarily through self-reporting. There are no pub-lished human studies that have focused solely on the safetyof oral Gln supplementation.

Sample size, dosage and duration, presence of multipleactive ingredients and outcome measures varied consider-ably between studies. All clinical trials reviewed involvedonly healthy adult subjects. Overall, the literature demon-strates a substantial level of safety with supplemental Gln.The highest oral Gln dose utilized in a published humanclinical trial was up to 45 g/d for 6 weeks in healthyadults (Candow et al., 2001). The longest duration trialwas 10 weeks at a dose of 5 g/d in healthy adult males(Kerksick et al., 2006). A number of factors have beennoted that are important to address vis-a-vis the investiga-

tion of potential Gln toxicity. These include direct effectson serum levels, metabolic end products (such as ammo-nia), competition/antagonism of other amino acids, andeffects on liver and kidney function (Garlick, 2001,2006). Where measured in the collection of reviewed stud-ies, the effect on serum Gln levels varied, although noeffects were observed on serum levels of ammonia, creat-inine, albumin, glucose, lipids, liver enzymes or hemato-logical variables.

Overall, no adverse effects were observed or reported inany of the reviewed studies. For this reason, studies usingdosing regimens that involved multiple active ingredientsin addition to Gln were included in this analysis. Typically,the presence of multiple actives would be presumed to con-found the outcome. However, in the case of Gln, no pat-tern of adverse effects was observed, irrespective of thedosing regimen (i.e. Gln alone or in combination with otheractives vs. placebo), and thus confounding effects withrespect to safety seem unlikely. As noted, these trials weredesigned primarily to test the beneficial effects of Gln sup-plementation, tended to focus on short-term use and didnot specifically test the effects of exposures lasting greaterthan 10 weeks.

Glutamine consumption from foods is estimated atapproximately 5 g/d, an amount that tends to be equal toor up to 9-fold less than the doses used in the reviewed tri-als. The absence of any consistent pattern of adverse effectsrelated to oral Gln administration in any of the publishedhuman trials at any dose level provides support for a sub-stantial level of confidence in the safety of this amino acid.

4.2. Human NOAEL

None of the human clinical trials reviewed found a sig-nificant hazard or adverse effect related to Gln administra-tion. Therefore, by definition, there is no basis foridentifying a NOAEL or LOAEL. In the absence of eitherof these two values a UL usually is not set (Institute ofMedicine, 1998a).

4.3. Human OSL

Published relevant human clinical trials involved oralGln doses ranging from 3 to 45 g/d (Table 2) (Candowet al., 2001; Williams et al., 2002; Falk et al., 2003;Lehmkuhl et al., 2003; Krieger et al., 2004; Rathmacheret al., 2004; Thistlethwaite et al., 2005; Kerksick et al.,2006). All studies reviewed were double-blind, random-ized controlled trials using healthy adults. One studyinvolving parenteral Gln administration in healthyadults (Lowe et al., 1990) was reviewed due to itsemphasis on the safety of Gln (see Table 2), but isnot included in the risk assessment, although the resultsare supportive of the conclusions reached on the basisof the oral studies. Another study was presented as anabstract at a scientific meeting (Thistlethwaite et al.,2005) and publication of the full study is currently in

Table 2Published safety observations* for human L-glutamine (Gln) supplementation

Study Studypopulation

Dosage and study design Duration(days)

Key observations OSL considerations

Candow et al.(2001)

17 healthyadults

0.9 g Gln/kg lean body mass/d(equivalent to 45 g/d) withsupervised resistance training;randomized, controlled

6 weeks(42 d)

No clinical outcome measuresrelated to safety reported; noadverse effects observed

45 g, modest duration in healthyadults, but small sample size, andlack of clinically relevant safetyoutcome measures argue againstuse of this study for identificationof an OSL

Krieger et al.(2004)

6 healthyadults

0.4 g Gln/kg body weight/d(equivalent to 28 g/d) with highintensity running training (‘‘over-training”); randomized, controlled

14 d No effect on serum Gln or salivaryIgA concentrations; significantincrease in nasal IgA; no otherclinical outcome measures relatedto safety reported; no adverseeffects reported

28 g, but short duration, smallsample size and lack of clinicallyrelevant outcome measures relatedto safety argue against the use ofthis study for identification of anOSL

Thistlethwaiteet al. (2005)

6 healthyadults

20 g Gln/d with supervisedresistance training; randomized,controlled

7 weeks(49 d)

No clinical outcome measuresrelated to safety reported; noadverse effects reported

20 g, modest duration, but smallsample size and lack of clinicallyrelevant outcome measures relatedto safety argue against the use ofthis study for identification of anOSL (abstract)

Williams et al.(2002)

18 healthyelderly

14 g Gln (combined informulation with 14 g Arg, 3 ghydroxymethylbutyrate)/d;randomized, controlled

14 d No clinical outcome measuresrelated to safety reported; noadverse effects observed

14 g, but short duration, smallsample size and lack of clinicallyrelevant outcome measures relatedto safety argue against the use ofthis study for identification of anOSL

Rathmacheret al. (2004)

19 healthyadultmales

14 g Gln (combined informulation with 14 g arginine,3 g hydroxymethylbutyrate)/d;randomized, controlled

4 weeks(28 d)

Significant increase in blood urea,no change in blood creatinine, noeffect on liver enzymes; no adverseeffects observed

14 g, relatively short duration andsmall sample size, but a broadspectrum of relevant safetyoutcome measures were assessed;this study is chosen as the basis foran OSL

Kerksick et al.(2006)

15 healthyadultmales

5 g Gln (combined in formulationwith 40 g whey protein, 3 g branchchain amino acids)/d withsupervised resistance training;randomized, controlled

10 weeks(70 d)

No significant effect on serumalbumin, glucose, liver enzymes,lipid profile, creatinine,hematological variables, ureanitrogen, uric acid; no adverseeffects observed

5 g, modest duration and smallsample size, but included clinicallyrelevant outcome measures relatedto safety; given the lack of adverseeffects observed or reported in thestudies above, this study is chosenas the basis for the OSL forsupplemental Gln

Lehmkuhl et al.(2003)

10 healthyadults

4 g Gln/d with supervised strengthand conditioning; randomized,controlled

8 weeks(56 d)


Supports the OSL selected above

Falk et al. (2003) 15 healthyadults

3 g Gln (combined in formulationwith 5 g creatine, 2 g ribose, 1 gphosphorous)/d with supervisedresistance training; randomized,controlled

8 weeks(56 d)


Supports the OSL selected

Lowe et al.(1990)

7 healthyadults

20, 40, 57 g Gln/d by intravenousadministration; controlled

5 d Significant increase in serum Gln;no significant effect on liverenzymes, blood urea nitrogen,ammonia or creatinine; no adverseeffects observed at any dose

Supports the OSL selected

*No adverse effects observed = investigators report observing no adverse effects and/or study subjects reported no adverse effects.No adverse effects reported = safety or adverse effects not addressed in study publication.


process. A third study which met all the aforementionedcriteria was excluded due to the lack of quantitativeinformation on the dose of Gln used (Arwert et al.,2003). Where measured, clinically relevant safety out-come assessments are noted, along with adverse effects,if any, described in the study publication.

A vast number of clinical trials involving infants or chil-dren, trauma, HIV/AIDS, cancer, burn, surgical patientsand patients with gastrointestinal diseases or conditions,acute (less than 1 week) administration, parenteral admin-istration, non-randomized, uncontrolled, or open-labelstudies have also been published. These have been recently


reviewed elsewhere (De-Souza and Greene, 2005; Tubmanet al., 2005; Alpers, 2006; Avenell, 2006; Noble and Ave-nell, 2006). The doses involved in these studies range fromseveral mg/kg/d up to 60 g/d, the results of which are con-sistent with respect to safety, showing no observed orreported adverse effects.

4.4. 45 g/d

The highest oral Gln dose tested in non-cachectic sub-jects in a randomized, controlled trial was 45 g/d by Can-dow et al. (2001). In this study, healthy adults wereadministered 0.9 g Gln/kg lean body mass/d (equivalentto 45 g/d) for 6 weeks in combination with a resistancetraining program. There were no adverse effects observedin the group, but there were no other clinical outcome mea-sures related to safety reported. The relatively small samplesize (n = 17) and lack of clinically relevant safety outcomemeasures argue against the use of this study for identifica-tion of an OSL.

4.5. 28 g/d

In a study by Krieger et al. (2004) healthy adults wereadministered 0.4 g Gln/kg body weight/d (equivalent to28 g/d) in combination with high intensity running training(‘‘over-training”) for 14 days. The study reported no effecton serum Gln or salivary IgA concentrations, althoughthere was a significant increase in nasal IgA. No other clin-ical outcome measures related to safety were reported andthe study did not address reporting of adverse effects. Theshort duration, small sample size (n = 6) and lack of clini-cally relevant outcome measures related to safety argueagainst the use of this study for identification of an OSL.

4.6. 20 g/d

Thistlethwaite et al. (2005) examined the effect of 20 gGln/d combined with supervised resistance training inhealthy adults for 7 weeks. There were no clinical outcomemeasures related to safety reported and the study did notaddress the reporting of adverse effects. Although of mod-est duration, the small sample size (n = 6), lack of clinicallyrelevant outcome measures related to safety and the factthat this abstract has yet to be published in a peer-reviewedjournal all argue against the use of this study for identifica-tion of an OSL.

4.7. 14 g/d

Two studies administered 14 g Gln/d for 14 days (bothin combination with L-arginine and hydroxymethylbuty-rate). Williams et al. (2002) treated healthy elderly, whileRathmacher et al. (2004) treated healthy adult males. Inthe former study, investigators observed no adverse effectsin the subjects, but no clinical outcome measures relatedto safety were reported. In the latter study, investigators

also observed no adverse effects and assessed several clin-ically relevant safety outcome measures. There was a sig-nificant increase in blood urea which remained in thenormal range, no change in blood creatinine, no adverseeffects on a number of other blood chemistry values andno effect on liver enzymes. Although of relatively shortduration and small sample size (n = 19), the Rathmacheret al. (2004) study included a broad spectrum of relevantsafety outcome measures. Given that intakes well abovethe levels used in this study have not resulted in anyadverse effects, the data from this study are chosen toserve as the basis of the OSL.

The remainder of the reviewed clinical trials adminis-tered 5, 4 and 3 g Gln/d, respectively, in healthy adults.Kerksick et al. (2006) administered 5 g/d (in a formula-tion also containing whey protein and branched-chainamino acids) in healthy adult males (n = 15) in combina-tion with supervised resistance training for 10 weeks.Investigators assessed a number of clinically relevantsafety outcome measures including serum albumin, glu-cose, liver enzymes, lipid profile, creatinine, hematologi-cal variables, urea nitrogen and uric acid. Nosignificant changes were observed in any of these vari-ables and no adverse effects were observed in the studysubjects. Lehmkuhl et al. (2003) administered 4 g/d tohealthy adults (n = 10) in combination with supervisedstrength and conditioning training for 8 weeks. No clin-ical outcome measures related to safety were reported,and investigators observed no adverse effects. Falket al. (2003) treated healthy adults (n = 15) with 3 g/d(in a formulation also containing creatine, ribose andphosphorous) in combination with supervised resistancetraining for 8 weeks. No clinical outcome measuresrelated to safety were reported, and investigatorsobserved no adverse effects. Collectively, these three stud-ies support the OSL selected above.

The OSL was identified from data on subjects consum-ing a variety of diets and having presumably normalendogenous synthesis of Gln. These additional sources ofGln are already considered and do not need to be sub-tracted from the OSL to identify a ULS. Thus, a ULSbased on the toxicological evidence in human clinical trialsis 14 g Gln/d.

4.8. Animal data

There are a number of published animal studies thathave examined the effect of Gln supplementation on mod-els of various diseases and conditions. The acute toxicity(LD50) value in rats after oral administration of Gln wasreported to be P16 g/kg body weight (L-Glutamine,2005). Sprague–Dawley rats fed diets of 1.25%, 2.5% and5% Gln, respectively, over a 13-week period did not expe-rience any serious adverse effects (Tsubuku et al.,2004a,b). While there were some minor increases in certainhematological and urinary parameters in the 2.5% and 5%groups, all changes were within the physiologic range. The


study authors concluded a rat NOAEL of 1.25% orapproximately 0.9 g/kg body weight/d. These data helpto provide confidence in the safety of oral Gln, but, inour opinion are not adequate to serve as the basis for aUL or OSL for humans because of the great uncertaintyin the extrapolation between species. Given the availabilityof a reasonably reliable dataset of published human clinicaltrials, combined with the uncertainty associated withextrapolating results from animal studies to humans, wehave chosen to rely solely on the human data for this riskassessment.


For Gln, the highest daily oral dose used in a random-ized, controlled trial in healthy adults is up to 45 g (Can-dow et al., 2001) and this value could be considered asthe OSL. However, the study has several limitations,including small sample size (n = 17) and lack of clinicallyrelevant safety outcome measures. Use of this study toserve as the basis of the OSL would require significant cor-rection for uncertainty (i.e. UF > 1.0). Exactly what UFvalue should be assigned is unclear. Therefore, theapproach of evaluating the clinical trials in order ofdecreasing daily doses and the selection of a study usinga much lower dose of 14 g/d (Rathmacher et al., 2004),while more conservative, also inspire a higher level of con-fidence and less uncertainty (i.e. UF = 1.0).

Thus:NOAEL and LOAEL >45 g/d L-glutamineOSL 14 g/dULS 14 g/d

5. Scientific evidence related to safety—L-arginine

5.1. Human studies

Sample size, dosage and duration, presence of multipleactive ingredients and outcome measures varied widelyamong oral Arg studies. Also, published clinical trials col-lectively included both healthy subjects and those with awide variety of diseases or conditions. Overall, there isan absence of any pattern in the adverse effects that areattributable to Arg, and therefore the literature demon-strates a substantial level of safety for supplemental Arg(Table 3).

General criteria for study inclusion were mode ofadministration (oral), study duration (at least 1 week),study design (randomized, placebo-controlled) and studysubjects (adults). Uncontrolled studies (Barbul et al.,1981; Evans et al., 2004), those involving children (Ben-nett-Richards et al., 2002), and those investigating acuteeffects, bioavailability, parenteral administration, phar-macokinetics or post-prandial responses from singlebolus doses were excluded from the overall analysis. Alsoexcluded from the analysis were studies using patients

under hypercatabolic states (i.e. cancer, HIV/AIDS,trauma, post-surgical, burn victims, etc . . .) (Daly et al.,1988; Park et al., 1992; Pichard et al., 1998; Clarket al., 2000; Swanson et al., 2002; May et al., 2002;Braga et al., 2002; Marcora et al., 2005) whose aminoacid metabolism is drastically altered and those usingpatients with compromised gastrointestinal function (i.e.short bowel syndrome, Crohn’s disease, etc . . .) whoseability to digest, absorb and assimilate may be signifi-cantly compromised. Only a few of the studies under-taken to assess the beneficial effects of Arg havemonitored any possible adverse side effects and then pri-marily through self-reporting. There are no publishedhuman studies that have focused solely on the safety oforal Arg supplementation.

The highest oral Arg dosage utilized in a publishedhuman clinical trial was up to 42 g/d for 6 weeks (42 d)in cystic fibrosis patients (Grasemann et al., 2005). The lon-gest duration trial was 3 years at 9 g Arg/d in renal trans-plant patients (Alexander et al., 2005), followed by severaltrials of 6 months in duration at various doses (Lermanet al., 1998; De Nicola et al., 1999; Schulman et al.,2006). Due to the absence of a significant pattern ofadverse effects, studies using dosing regimens that involvedmultiple active ingredients in addition to Arg were includedin this analysis.

A number of factors have been noted that are importantto address vis-a-vis the investigation of potential Arg toxic-ity. These include direct effects on serum levels, metabolicend products (such as ammonia), competition/antagonismof other amino acids and effects on liver and kidney func-tion (Garlick, 2001, 2006). Where measured in the collec-tion of reviewed studies, the effect on serum Arg levelsvaried, although no effects were observed on serum levelsof ammonia, creatinine, albumin, glucose, lipids, liverenzymes or hematological values.

There have been occasional reports of gastrointestinalupset associated with Arg supplementation. These werehighlighted in a recent review on Arg and other aminoacids (Grimble, 2007). However, the studies cited in thereview were either uncontrolled (Barbul et al., 1981; Evanset al., 2004), involved cancer patients undergoing surgery(Daly et al., 1988; Park et al., 1992) or had equal incidenceof reports between the Arg and control groups (Adamset al., 1995; Yin et al., 2005). None of the randomized, con-trolled trials evaluated in this risk assessment (i.e. thoseinvolving adult, non-cachectic subjects) reported any gas-trointestinal adverse effects, or any other adverse effectsin response to oral Arg supplementation. The absence ofadverse gastrointestinal effects in well-controlled studiesusing oral Arg doses above, equal to and below those usedin these few studies argues against the presence of a dose-responsive hazard. Furthermore, it is questionable whethermild or transient gastrointestinal upset is truly a ‘‘hazard”per se, or merely a nuisance.

Arg consumption from foods is estimated at approxi-mately 3–6 g/d (Visek, 1986), amounts that are up to

Table 3Published safety observations * for human L-arginine (Arg) supplementation

Study Study population Dosage and studydesign

Duration(days)


Grasemannet al. (2005)

10 cystic fibrosispatients

Arg 200 mg/kg = 14 g/70 kg, 3xd = 42 g/d;randomized,crossover

6 weeks (42 d) Increased nitric oxide production;no adverse effects reported

42 g, relatively short duration andsmall sample size argue against theuse of this study for identificationof an OSL

Buchman et al.(1999)

23 marathon runners 30 g Arg/d (dividedinto 3 doses) priorto marathon;randomized,controlled

14 d Slightly decreased performance;no adverse effects on metabolicand muscle breakdown indicators;no adverse effects reported

30 g, small sample size and shortduration argue against the use ofthis study for identification of anOSL

Barbul et al.(1990)

36 healthy adults 24.8 g Arg/d as ArgHCl, or 17 g Arg/das Arg-aspartate;randomized,controlled

2 weeks (14 d) Increased collagen synthesis incatheters experimentally insertedinto deltoid region; no adverseeffects on indices of wound healingand immune response and noadverse effects reported

24.8 g, short duration arguesagainst the use of this study foridentification of an OSL

Clarkson et al.(1996)

27 young adults withhypercholesterolemia

21 g Arg/d; prior tomarathon;randomized,controlled

4 weeks (28 d) Improved endothelial dilation; noadverse effects observed in clinicalchemistries

21 g, but relatively small samplesize and short duration argueagainst the use of this study foridentification of an OSL

Chin-Dustinget al.(1996b)

20 heart failurepatients

20 g Arg/d;randomized,controlled

28 d Increased urea and aspartatetransaminase levels;gastrointestinal upset reported byboth Arg and placebo groups; noother adverse effects observed

20 g, but relatively small samplesize and short duration argueagainst the use of this study foridentification of an OSL

Chin-Dustinget al.(1996a)

16 healthy males 20 g Arg/d;randomized,controlled

28 d Some physiological effects onarteries, but of uncertain benefit;no adverse effects on clinicalchemistries and no other adverseeffects observed

20 g, relatively short duration andsmall sample size, but presence ofrelevant safety outcome measuresand absence of adverse effects; thisstudy is chosen as the basis for theOSL for supplemental Arg

Kelly et al.(2001)

26 control, kidneytransplant, anddialysis patients

18 g or 9 g Arg/d;randomized,crossover

Up to 60 d No changes in renal function; nochanges in clinical indices and noadverse effects observed

18 g, supports the OSL selectedabove

Langkamp-Henkenet al. (2000)

32 elderly withpressure ulcers

17 or 8.5 g Arg/d;randomized,controlled

4 weeks (28 d) No improvement in lymphocyteproliferation; no adverse effectsobserved


Kirk et al.(1993)

30 healthy elderly 17 g Arg/d as Arg-aspartate;randomized,controlled

14 d Improved indices of woundhealing (mitogenic and allogenicresponses); no adverse effectsreported


Hurson et al.(1995)

45 healthy elderly 17 g Arg/d as Arg-aspartate;randomized,controlled

14 d Decreased serum cholesterol; noadverse effects observed


Bode-Bogeret al. (2003)

12 healthy elderly(>70y)

16 g Arg/d;randomized,crossover

14 d Improved flow-mediated dilation;no adverse effects reported


Moriguti et al.(2005)

29 older adults 15 g Arg/d;randomized,controlled

4 weeks (28 d) Improved immune functions; noadverse effects on any immuneindex; no other adverse effectsreported


Walker et al.(2001)

40 men with stableangina


2 weeks (14 d) No benefits for endothelium-dependent vasodilation, oxidativestress or exercise performance; noadverse effects observed


De Nicolaet al. (1999)

24 chronic renalfailure patients

14 g Arg/d (per70 kg);randomized,controlled

6 months(182 d)

No beneficial effects on kidneyfunction; no adverse effects onrenal function indices; no otheradverse effects reported


(continued on next page)


Table 3 (continued)


Duration(days)


Williams et al.(2002)

18 healthy elderly(P70y)

14 g Arg/d,combined withglutamine andHMB; randomized,controlled

14 d Enhanced collagen synthesis bytreatments; no adverse effectsreported


Doutreleauet al. (2006)

10 patients withstable angina andchronic heart failure


6 weeks (42 d) Increased exercise tolerance,decreased lactate accumulation,decreased heart rate; no adverseeffects were observed on exercise,metabolic or hemodynamicparameters; no other adverseeffects reported


Nagaya et al.(2001)

19 precapillarypulmonaryhypertension patients

10.5 g Arg/d;randomized,controlled

1 week (7 d) Improved hemodynamics andexercise capacity; no adverseeffects on cardiopulmonarycapacity indices; no other adverseeffects reported

10.5 g, supports OSL selectedabove

Siani et al.(2000)

6 healthy adults 10 g Arg/dsupplement to dietlow Arg diet (3.5–4.0 g); randomized,crossover

1 week (7 d) Lowered blood pressure; higherrenal clearance of creatinine; noadverse effects on renal function.No other adverse effects reported


Yin et al.(2005)

31 coronary arterydisease patients

10 g Arg/d orvitamin C;randomized,crossover

4 weeks (28 d) Improved endothelial function,reduction of LDL oxidation; GIdisturbance reported for bothinterventions; no other adverseeffects observed


Lerman et al.(1998)

26 coronary arterydisease


6 months(182 d)

Improved endothelial functionand patient symptom scores; noadverse effects on cardiac functionindices; no other adverse effectsreported


Oka et al.(2005)

80 adults withperipheral arterialdisease


12 weeks(84 d)

Some improvement in walkingdistance tests; no adverse effectsobserved


Alexanderet al. (2005)

76 adult renaltransplant patients

9 g Arg/d + canolaoil as source ofomega-3;randomized,controlled

3 yr (1092 d) Reduced transplant rejection andinfections; no adverse effectsreported


Bednarz et al.(2004)

21 congestive heartfailure patients


7 d Prolonged exercise capability; noadverse effects reported


Schulmanet al. (2006)

153 patients withacute ST-segmentelevation MI

9 g Arg/d as ArgHCl; randomized,controlled

6 months(182 d)

Significant increase in death withArg (8.6% vs. none, in 6 months;p = 0.01), authors assume to becaused by Arg

9 g, study is inconsistent withbody of literature and appears tobe an anomaly (Abumrad andBarbul, 2006)

Bednarz et al.(2005)

792 patients withacute ST-segmentelevation MI


30 d No adverse effects observed 9 g, supports the OSL selectedabove

Colombaniet al. (1999)

Marathon runners, 8.55 g Arg/d asArg-aspartate priorto marathon run;randomized,crossover

2 weeks (14 d) Some metabolites increased, somedecreased some unaffected,possibly affecting marathonperformance; no other adverseeffects observed

8.55 g, supports the OSL selectedabove

Stechmilleret al. (2005)

26 elderly (P65 y)with pressure ulcers


4 weeks (28 d) No increase in NO; no adverseeffects reported


Theilmeieret al. (1997)

Hypercholesterolemicadults


2 weeks (14 d) Decreased (normalized)mononuclear cell adhesiveness; noadverse effects reported



Table 3


Duration(days)


Lucotti et al.(2006)

33 type 2 diabeticpatients

8.3 g Arg/d withsupervised exerciseprogram;randomized,controlled

21 d Improved in No adverse effects onindices of diabetes; no adverseeffects reported


Battaglia et al.(2002)

32 infertile women inin vitro fertilizationprogram


Approximately10 d

Lower number of mature follicleswith Arg. Uncertain aboutwhether this is adverse, changedtiming only, or unique to infertilewomen; no other adverse effectsreported


Hambrechtet al. (2000)

40 adults with severechronic heart failure

8 g Arg/d withsupervise exerciseprogram;randomized,controlled

4 weeks (28 d) Improved endothelia-dependentvascular dilation; no adverseeffects on heart function andphysical performance indices; noother adverse effects reported


Khan et al.(1997)

Adults with systemicsclerosis


28 d No effect on symptoms; noadverse effects reported


Khan andBelch (1999)

15 adults withsystemic sclerosis and13 healthy controls


28 d No effects on vascular responses;no adverse effects reported


Abdelhamedet al. (2003)

47 adults withhypercholesterolemia


14 d No benefits on heart function; noadverse effects reported


Maxwell et al.(2002)

36 adults with stableangina


2 weeks (14 d) Improved flow-mediated dilation,longer exercise capacity and betterquality of life scores; no adverseeffects on clinical chemistry andhematological indices; equal toplacebo in reports of minoradverse events


Maxwell et al.(2000a,b)

43 adults withhypercholesterolemia


7 d Improved flow-mediated dilation;no adverse effects observed


Rytlewskiet al. (2006)

83 preeclampticpregnant women


Variousdurations upto severalweeks

Promising outcomes on neonateshealth; no adverse effects reported


Dudek et al.(2004)

60 diabetic men 6 g Arg/d oral after14 g (per 70 kg)i.v.; randomized,controlled

14 d oral No effects; no adverse effectsreported


*No adverse effects observed = investigators report observing no adverse effects and/or study subjects reported no adverse effects.No adverse effects reported = safety or adverse effects not addressed in study publication.


many-fold less than the doses used in the reviewed trials.The absence of any consistent pattern of adverse effectsrelated to oral Arg administration in any of the publishedhuman trials provides support for a substantial level ofconfidence in the safety of this amino acid.

5.2. Human NOAEL

None of the human clinical trials reviewed found anysystematic and credible hazard or adverse effect related toArg administration. Therefore, by definition, there is nobasis for identifying a NOAEL or LOAEL. In the absenceof either of these two values a UL usually is not set (Insti-tute of Medicine, 1998a).

5.3. Human OSL

5.4. 42 g/d (per 70 kg)

In a double-blind, placebo-controlled cross-over trialinvolving cystic fibrosis patients (n = 10), 200 mg/kg Argor placebo was administered for 6 weeks before the cross-over for the same duration (Grasemann et al., 2005). TheArg treatment resulted in increased NO production. Noadverse effects were reported, but the absence of datadirectly relevant to safety and discussion of potential safetyissues limits the utility of this research in a risk assessment.Although no adverse effects were reported, the evidence isnot adequate to identify a high-confidence OSL.


5.5. 30 g/d

Twenty-three marathon runners were given 30 g Arg/dfor 2 weeks prior to a marathon (Buchman et al., 1999).Arg administration resulted in a slight but significantdecrease in performance (i.e. longer than ‘‘expected” runtimes). There were no adverse impacts of Arg on the sev-eral metabolic and muscle breakdown indicators. Thechanges observed were expected with the increased meta-bolic load, but were not adverse. No adverse effects of anytype were observed. The relatively short duration, smallsize (n = 23) and/or atypical character of this cohort,and absence of standard clinical and hematological mea-sures limit the usefulness of these data in a risk assess-ment. The uncertainty surrounding this study renders itinsufficient to serve as the basis for a high-confidenceOSL.

5.6. 24.8 g Arg/d, as 30 g Arg-aspartate

Healthy adults (n = 36) were given 24.8 g or 17 g Arg/dfor 4 weeks as Arg-aspartate to determine the effects onwound healing (Barbul et al., 1990). The treatmentsincreased collagen synthesis in small catheters experimen-tally inserted subcutaneously in the deltoid region, indicat-ing an improved rate of healing. There were no adverseeffects on indices of wound healing and immune function.No adverse effects were reported. The use of an alternateform of Arg diminishes the confidence in these data foruse in a risk assessment for Arg. Thus, these data arejudged not to support an OSL.

5.7. 21 g/d

Treatment of young hypercholesterolemic adults(n = 27) with 21 g/d Arg for 4 weeks improved endothelialdilation (Clarkson et al., 1996). No adverse effects wereobserved in the standard clinical chemistry indices. Noadverse effects were reported. The absence of adverseeffects in the clinical chemistries would be consistent withselection of this level of Arg as the OSL, but the modestduration, together with the absence of strong studies athigher intake, detracts from confidence in the data neededto for a high-confidence OSL.

Treatment of hypercholesterolemic adults (n = 10)with up to 21 g/d Arg for up to 12 weeks resulted inno adverse effects on functional indices (Tangphaoet al., 1999). Five of the subjects also received 30 gArg intravenously on four occasions. No adverse effectswere reported. The consistency between these data andthose of Clarkson et al. (1996) increases the confidencein the results, but the lack of a control group and thesmall number of subjects at the highest dosage limit con-fidence in the data. Overall, these data for 21 g/d Argsupplementation would require application of an uncer-tainty factor greater than unity to calculate a high-confi-dence OSL.

5.8. 20 g/d

Heart failure patients (n = 20) were administered 20 g/dArg for 4 weeks (Chin-Dusting et al., 1996b). Plasma Argwas not measured but there was a significant increase inplasma urea levels. Plasma liver enzyme levels of aspartatetransaminase also increased slightly (from 26 to 32 Units/L) but remained well within the normal range (17–59 Units/L). There was no difference in adverse effects observedbetween active and placebo groups. The authors concludedthat oral administration with Arg was ineffective in influenc-ing endothelial function in these heart failure patients.

Healthy adult males (n = 16) were administered 20 g/dArg for 4 weeks in a double-blind, placebo-controlled clin-ical trial (Chin-Dusting et al., 1996a). No adverse effectswere reported by the subjects, and there were no adverseimpacts on standard clinical chemistry indices. The absenceof any adverse effects at this level of supplementation inhealthy men, together with the absence of reported adverseeffects in six clinical trials involving Arg doses ranging from21 to 42 g/d, gives high confidence in the safety of the 20 g/d level of supplemental Arg for healthy adults. Thus, 20 g/dis selected as the OSL for supplemental Arg.

5.9. 18 g/d

A group of kidney transplant and dialysis patients alongwith control subjects (total n = 26) were treated with 18 gArg/d for 60 days in a cross-over design (Kelly et al.,2001). An extensive array of renal function tests wasapplied and no adverse effects of any type were reported.Although the duration of each treatment was only 20 days,the absence of adverse effects on indices of renal function inpatients with compromised function suggests that adverseeffects of this or a similar level of Arg on kidney healthare not likely. Nothing in this clinical trial contradicts the20 g/d OSL identified above.

5.10. 17 g/d as 30 g Arg-aspartate

Healthy elderly subjects (n = 30) were given 30 g/d Argaspartate, equivalent to 17 g/d Arg for 14 days (Kirket al., 1993). Indices of wound healing (mitogenic and allo-genic responses) improved with the supplement. There wereno adverse effects on these indices, and no reported adverseeffects.

Another group of healthy elderly adults (n = 45) weregiven 30 g Arg-aspartate/d, equivalent to 17 g Arg for 14days (Hurson et al., 1995). The treatment decreased serumtotal cholesterol. There were no adverse effects on serumlipid profiles and no adverse effects were reported. Theauthors concluded that oral Arg is safe to use.

5.11. 16 g/d

Healthy elderly adults (n = 12) were given 16 g Arg/dfor 14 days (Bode-Boger et al., 2003). Arterial flow medi-


ated dilation improved with Arg supplementation. Noadverse effects were reported.

5.12. 15 g/d

A group of older adults (n = 29) were given 15 g Arg/dfor 4 weeks (Moriguti et al., 2005). The treatment resultedin some improved immune function indices, and no adverseeffects were reported. Men with stable angina (n = 40) weretreated with 15 g Arg/d for 14 days (Walker et al., 2001).No benefits or harm to endothelium dependent vasodila-tion, oxidative stress indicators or exercise performancewere observed. No adverse effects were reported.

5.13. 14 g/d

Chronic renal failure patients (n = 24) were given200 mg/kg (14 g/70 kg) Arg/d for 6 months (De Nicolaet al., 1999). The treatment did not improve any renal func-tion indices. No adverse effects on renal function indiceswere observed, and no adverse effects were reported.

Healthy elderly (P70 yr) (n = 25) were given 14 g/d Argin combination with 14 g glutamine and 3 g HMB for 14 d(Williams et al., 2002). Collagen synthesis was increased bythe treatment. No adverse effects were observed on indica-tors of wound healing and no adverse effects were reported.

5.14. 12 g/d

Patients with stable angina (n = 10) were given 12 g/dArg for 6 weeks (Doutreleau et al., 2006). Some benefitson exercise capacity and related parameters occurred withArg treatment. No adverse effects were observed on hemo-dynamic, exercise or metabolic indices, and no otheradverse effects were reported.

5.15. 10.0 and 10.5 g/d

Patients with recapillary pulmonary hypertension(n = 19) were given 10.5 g Arg/d for 1 week (Nagayaet al., 2001). The treatment improved hemodynamics andexercise capacity. No adverse effects on cardiopulmonarycapacity indices were observed and no adverse effects werereported.

Healthy adults (n = 6) were given 10 g Arg/d while con-suming a series of three low-sodium diets (Siani et al.,2000). Each diet was administered for 7 days in a cross-over design. Arg administration lowered blood pressureand increased renal creatinine clearance. No adverse effectson renal function indicators were observed and no otheradverse effects were reported.

5.16. 9 g/d

Adults with coronary artery disease (n = 26) were given9 g Arg/d for 6 months (Lerman et al., 1998). The treat-ment improved endothelial function and patient symptom

scores. No adverse effects on cardiac function indices wereobserved, and no adverse effects were reported by thesubjects.

Adults with peripheral aerial disease (n = 80) weregiven 9 g Arg/d for 12 weeks (Oka et al., 2005). Thetreatment resulted in a moderate improvement in walkingdistance. A slightly decreased hematocrit was not consid-ered to be adverse. No other adverse effects wereobserved.

A large group of patients with acute ST-segment myo-cardial infarct (n = 792) were given 9 g Arg/d for 30 days(Bednarz et al., 2005). Adverse gastrointestinal effectswere reported less frequently by the Arg group thanthe placebo group. No adverse effects were observed.The authors concluded that the treatment was ‘‘welltolerated.”

Renal transplant patients (n = 76) were given 9 g Arg/d,and canola oil as a source of omega-3 fatty acids (Alexan-der et al., 2005) for 3 years. The treatments reduced infec-tions and rejection of transplants.

Congestive heart failure patients (n = 21) were given 9 gArg/d for 7 days (Bednarz et al., 2004). The treatmentresulted in prolonged exercise capability. No adverse effectswere reported.

Patients with acute ST-segment elevation myocardialinfarcts (n = 153) were given 9 g Arg/d for 6 months(Schulman et al., 2006). This trial was stopped earlybecause of a significant increase in the death rate (8.6%with Arg vs. zero with the placebo group; P = 0.01). Theauthors assumed that the treatment caused the deaths, eventhough the trial was not powered for mortality. A letter tothe editor (Abumrad and Barbul, 2006) noted that theresults are not supported by other data; that there was pooradherence to the treatment, which raises questions of reli-ability; and that some of the specific causes of mortalitywere in conflict with known effects of Arg. Taken at facevalue, these data would lead to the assignment of aLOAEL status to this intake value (9 g). However, this isnot justified for the reasons discussed by Abrumrad andBarbul and the design power being too low to test for mor-tality differences, as acknowledged by Schulman et al.(2006). The rationale is discussed in greater detail in Sec-tion 6.

5.17. 6–9 g/d

These trials involved athletes trained for long-distancerunning (Colombani et al., 1999), elderly persons with pres-sure ulcers (Langkamp-Henken et al., 2000; Stechmilleret al., 2005) and patients with a variety of health impair-ments or chronic diseases (Khan et al., 1997; Theilmeieret al., 1997; Pichard et al., 1998; Hambrecht et al., 2000;Maxwell et al., 2000a,b; Battaglia et al., 2002; Abdelhamedet al., 2003; Dudek et al., 2004; Palloshi et al., 2004; Lucottiet al., 2006; Rytlewski et al., 2006). None of these trialsgave any evidence of adverse effects caused by Arg admin-istration. In one trial or another, biochemical and clinical

392 A. Shao, J.N. Hathcock / Regulatory Toxicolo

indices that might have shown adverse effects by Argincluded measurements of physical performance and aminoacid metabolism, immunological function, cardiac functionand related physical performance, and type II diabetesindices.

5.18. Animal data

There are a number of published animal studies thathave examined the effect of Arg supplementation onmodels of various diseases and conditions, with only afew that examined aspects of safety. A recently pub-lished review by Wu et al. concluded that chronic Argdoses up to 2 g/kg body weight/d were well toleratedby rats and pigs, with no observed side effects (Wuet al., 2007). The acute toxicity (LD50) value in ratsafter oral administration of Arg was reported to be16 g/kg body weight (L-Arginine, 2005). Tsubuku et al.(2004a,b) conducted a 13-week study in Sprague–Dawleyrats with diets consisting of 1.25%, 2.5% and 5% Arg,respectively. No adverse effects were observed for anyof the parameters assessed. Slight elevations in somehematological measures were found in the rats on the5% diet, but these remained within the normal range.The study authors concluded a rat NOAEL of approx-imately 3.6 g/kg body weight/d. These data help to pro-vide confidence in the safety of oral Arg, but on theirown are not sufficient to support selection of an OSLvalue in humans because of the uncertainty in extrapo-lation between species. Given the availability of a rea-sonably reliable dataset of published human clinicaltrials, combined with the uncertainty associated withextrapolating results from animal studies to humans,we have chosen to rely solely on the human data forthis risk assessment.


For Arg, the highest daily oral dose used in a random-ized, controlled trial in healthy adults without adverseeffects is 42 g (Grasemann et al., 2005), and this value couldbe considered as the OSL. However, the study has severallimitations, including the absence of clinically relevant datarelated to safety and discussion of potential safety issues,and it is the only study using this dose. Use of this studyto serve as the basis of the OSL would require some levelof correction for uncertainty (i.e. UF > 1.0). Exactly whatUF value should be assigned is unclear. Therefore, theapproach of evaluating the clinical trials in order ofdecreasing daily doses and the selection of a study usinga much lower dose (20 g/d (Chin-Dusting et al., 1996a)),while more conservative, also inspire a higher level of con-fidence and less uncertainty (i.e. UF = 1.0).

Thus:NOAEL and LOAEL >42 g/d L-arginineOSL 20 g/dULS 20 g/d

6. Discussion

In many nations, including the US and UK, supplemen-tal amino acids are available for non-prescription saleswithout any specific limits. Further, the prevalence of manyamino acids in various dietary supplements and functionalfoods and beverages has increased dramatically in recentyears. This increase in use and popularity of these ingredi-ents warranted this comprehensive safety review. We foundno systematic pattern of adverse effects of any kind at anydose tested, with the exception of gastrointestinal upset,nearly all of which were observed in uncontrolled studies.

In the absence of toxicity a NOAEL or LOAEL cannotbe established (Institute of Medicine, 1998a). In particular,for the common dietary amino acids, unique toxicologicalhazards have not been identified and thus the UL methodhas not been applied (Hayashi, 2003). Consequently, analternate approach to risk assessment is needed for aminoacids. We chose to use the OSL (or HOI) approach andidentify the highest oral intake level for Tau, Gln andArg tested in a randomized, controlled trial within whichwe had sufficient confidence of safety [Tau = 3 g/d (Zhanget al., 2004b); Gln = 14 g/d (Rathmacher et al., 2004);Arg = 20 g/d (Chin-Dusting et al., 1996a)] (summarizedin Table 4).

For Tau, there were several studies involving doses sev-eral-fold higher than the chosen OSL, including one studyusing up to 10 g/d (Azuma et al., 1983; Durelli et al., 1983;Azuma et al., 1985; Fujita et al., 1987; Mizushima et al.,1996). However, these studies had several important limita-tions, including small sample size, short duration and lackof relevant safety outcome measures. Therefore, while 10 gcould be ostensibly considered a NOAEL, the limitationsassociated with the trial, combined with the absence ofother studies conducted using a Tau dose at or above10 g, would require a UF of some magnitude to be applied.Determining that value carries a fair amount of uncertaintyitself. Our approach is to examine the data in order ofdecreasing dose and rather than choosing the highest dosewith no reported adverse effects and assigning a judgmentalbut arbitrary UF, we chose a lower dose in which we havesufficient confidence to justify a UF of 1.0 (Fig. 3). Thereare at least eight other clinical trials involving Tau dosesat or above the chosen OSL of 3 g/d. Thus, the confidencethat justifies application of a UF of 1.0 to the chosen valuestems not only from the modest strengths of that studyitself, but also from the existence of trials at higher dosesthat also produced no adverse effects. For Tau, we choseto include studies involving diseased patients due to theabsence of any pattern of adverse effects regardless of thepopulation studied. There were studies involving patientswith neuromuscular disease, heart failure, hypertension,cystic fibrosis, diabetes and anemia, along with healthyadults (Durelli et al., 1983; Azuma et al., 1985, 1983; Fujitaet al., 1987; Mizushima et al., 1996; Jeejeebhoy et al., 2002;Chauncey et al., 2003; Zhang et al., 2004a,b; Colomboet al., 1996; Brons et al., 2004; Spohr et al., 2005; Sirdah

gy and Pharmacology 50 (2008) 376–399

Table 4Summary of Risk Assessment Findings

Amino Acid Human NOAEL or LOAEL (g/day) Animal NOAEL OSL (g/day) Estimated intake from dietary sources ULS (g/day)

Taurine >10 N/A 3 40–400 mg/day 3L-Glutamine >45 0.9 g/kg (63 g) 14 5 g/day 14L-Arginine >42 3.6 g/kg (252 g) 20 3–6 g/day 20

NOAEL – No observed adverse effect level.LOAEL – Lowest observed adverse effect level.OSL – Observed safe level.ULS – Upper level for supplements.


et al., 2002). It is unlikely that the data are all confoundedin the same manner by a variety of unrelated diseases so asto provide the same outcome—no adverse effects. Further-more, there was no metabolic basis to exclude those studiesinvolving diseased patients, i.e. no evidence suggesting Tauis metabolized any differently in the presence of any ofthese diseases. There was one study that reported gastroin-testinal upset in several subjects consuming the 3 g/d dose(Jeejeebhoy et al., 2002). However, confounding due tothe presence of multiple active ingredients in addition toTau present in the tested formula, combined with theabsence of any adverse effects in any of the other Tau trialsreviewed, suggests this was likely an anomaly in this spe-cific study. Therefore we have a high level of confidencein the 3 g/d OSL selected for Tau.

For Gln, we chose to exclude studies involving patientscoping with any kind of cachectic state. These include stud-ies using cancer patients on chemotherapy, HIV/AIDSpatients, burn victims, surgery or trauma victims, andother critically ill patients whose metabolism of Gln (andother amino acids) is severely compromised. We alsoexcluded studies involving parenteral administration onthe grounds that the UL and OSL are intended for orallyingested substances and that many such studies are con-ducted in hypercatabolic patients. Certainly, use of paren-teral data would require separate consideration of thedose–response relationship and uncertainty. While thesestudies collectively represent the majority of clinical trialsconducted on Gln (more than six hundred), the resultsfrom these studies cannot be confidently extrapolated tothe general population without some kind of correctionfor uncertainty, the value of which is itself uncertain. Theone exception is the study by Lowe et al. (1990), in whichhealthy adults were parenterally administered various Glndoses for 5 days. Although not formally included in the riskassessment, the use of healthy adults contributes to theconfidence in Gln safety. Investigators examined the effectof 20, 40 and 57 g Gln/d on a variety of safety outcomes.Aside from an increase in serum Gln, no effect wasobserved on liver enzymes, blood urea nitrogen, ammoniaor creatinine, and no adverse effects were observed in thestudy subjects at any dose. While these data, along withthe LD50 (16 g/kg) and NOAEL (0.9 g/kg) identified inrats, cannot be confidently extrapolated to identify anOSL for oral intake in humans, they do help support thechosen value of 14 g/d.

A number of well-designed human trials have been con-ducted using doses well above the chosen OSL for Arg withno adverse effects (Barbul et al., 1990; Clarkson et al., 1996;Buchman et al., 1999; Tangphao et al., 1999; Bennett-Rich-ards et al., 2002; Grasemann et al., 2005). As with Tau, ourrisk assessment of Arg included studies involving patientscoping with a variety of diseases; and with respect to safety,no pattern of adverse effects was observed. It is extremelyunlikely that this outcome is confounded in a similar wayby the variety of unrelated diseases, so we felt it appropri-ate to extrapolate these data to select an OSL. However, aswith Gln, we excluded Arg studies involving cachecticpatients due to the vast differences in amino acid metabo-lism. Technically, the highest oral Arg dose used in a clin-ical trial, 42 g/d by Grasemann et al. (2005), could beconsidered the OSL. However, due to the absence of othertrials using this or higher doses with no adverse effects,there is not sufficient confidence in the safety of this dose,requiring a UF of some value greater than 1.0 to beassigned. As described above our approach was to proceeddown in dose until we identified a study in which there wasconfidence to assign the OSL with a UF of 1.0. That study,combined with the other studies using doses at and wellabove the OSL, helps to provide a high level of confidencein the OSL of 20 g/d. The LD50 (16 g/kg) and NOAEL(3.6 g/kg) identified in rats help to provide confidence inthe selection of this OSL.

In the study by Schulman et al. patients with acute ST-segment elevation myocardial infarcts were given 9 g Arg/dor placebo for 6 months (Schulman et al., 2006). This trialwas stopped early because of a significant increase in thedeath rate (8.6% with Arg vs. zero with the placebo group;P = 0.01). This outcome appears to be a random anomalyand consequently this supplement level (9 g/d) is not iden-tified as a LOAEL. While this study received considerablemedia attention, and prompted regulatory officials in Can-ada to issue an abrupt warning for Arg-containing prod-ucts (Health Canada, 2006), there are several apparentlimitations that render its conclusions unreliable. Althoughthey acknowledged that the study was not powered todetect mortality differences, the authors assumed that theArg treatment was the likely cause of the deaths. Further,the results are not supported by other data; there seemsto have been poor adherence to the treatment, which raisesquestions of reliability; the lack of detail provided in theSchulman study regarding the patient deaths precludes


any conclusions about the possible mode of action of Arg(Abumrad and Barbul, 2006). Finally, some of the specificcauses of mortality in the Arg group are in conflict withknown effects of Arg, and the one death that occurred sub-sequent to termination of Arg supplementation suggests acausal relationship is unlikely. Overall, this report is notsupported by any other evidence of increased mortalityand seems to reflect an anomalous result rather than a reli-able or expected outcome. Consequently, this result is notselected as the basis of a LOAEL. These data are at besta questionable basis for a LOAEL in myocardial infarctpatients, and have no identifiable meaning for healthyadults. Certainly, anyone with a history of myocardialinfarction should be under the care of a physician and fol-low that medical advice. Even if future data should confirmthe Schulman et al. findings for myocardial infarct patients,there is no evidence that the results should impact thechoice of the OSL for normal, healthy adults.

The choice to completely rely on the human studiesinvolving oral administration is not because we view datafrom animal, parenteral or intravenous studies as invalid.Instead, our concern is that the apparent absence of toxic-ity of these amino acids in the range of dosages for whichthere are data in humans could be misinterpreted by poli-cymakers. We are aware that the dataset on the impactof human exposure to high intakes of amino acids is lim-ited. This risk assessment would be more secure if the avail-able data were much more extensive. The limitations in thehuman data set are accounted for by applying the conser-vative OSL ‘‘top–down” approach (Fig. 3).

However, the absence of evidence of toxicity even in theface of extensive data has led to the decision by the FNBnot to establish ULs for several nutrients, including thia-min, riboflavin, biotin and vitamin B12 (Institute of Med-icine, 1998b). Often, this is the easiest action to take, butit fails to meet the obligations of researchers and policy-makers to take the best actions possible to protect thepublic. The absence of a UL has been erroneously misinter-preted to indicate that there is insufficient evidence for thesafety of these substances. Vitamin B12 is perhaps the bestexample of this misinterpretation. Despite a large body ofdata indicating safety at doses as high as several mg/d(Hathcock, 2004), the absence of a UL from the FNBhas been cited by some international policy makers in anattempt to justify an arbitarily low UL [9 lg/d proposedin Germany (Domke et al., 2006) and 3 lg/d in France(Le ministre de l’economie, 2006)]. To reduce this type ofmisinterpretation of the absence of a UL, the OSL wasdeveloped and its use is advocated (Fig. 2). In early 2006,the FAO/WHO issued a report adopting the same conceptunder the name Highest Observed Intake (HOI) (FAO/WHO2006), although the report did not include examplesof the application of the method.

When properly done, long-term animal studies can con-tribute greatly to establishing confidence regarding safetyin humans. The animal studies cited in this review areexemplary of that. However, animal data, no matter how

extensive and robust, will always carry major uncertaintiesto the extrapolation of a quantitative dosage limit forhumans and risk assessment outcomes, and these uncer-tainties are likely to be larger than those related to even avery modest human dataset. This is the central basis forour exclusive reliance on the human datasets in our riskassessments. In fact, with some authoritative risk assess-ments based on animal data, the composite uncertainty fac-tors are selected in a manner that seems intended to bringthe outcome in line with the evidence from a scientificallylimited human clinical trial dataset, e.g. the FNB riskassessment of vitamin E (Institute of Medicine, 2000),which applied a composite UF of 36. Finally, in the caseof Tau, Gln, Arg and many other amino acids, extensiveand robust datasets from both humans and animals aresimply not available for direct comparison and determina-tion of the relative uncertainties.

While studies involving intravenous or parenteraladministration of amino acids may provide some furtherinsight into the pharmacokinetics of the compound(s) ofinterest (and in the case of all three amino acids, the factthat no toxicity was observed at very high doses providesome further confidence of safety) these studies cannot beconfidently extrapolated to a quantitative risk assessmentfor an orally administered substance. Rather, such studieshelp to provide further confidence in the already chosenOSL values.

We recognize the conservative nature of our exclusivereliance on human data and a method that identifies thehighest intake with sufficient human data to confidentlyassert a high likelihood of the absence of toxicity. Oneadvantage of this approach is that the level identified assafe warrants an extremely high level of confidence. Asecond advantage is that the uncertainties in selectingthe quantitative factors for extrapolation from animaldata to humans are avoided. We acknowledge the manylimitations in the human dataset for all three aminoacids (i.e. uncertainty). However, the absence of anycritical effect for any of these three amino acids in allthe clinical trials does provide a high level of confidencein their safe use. Future research should focus on thepotential risks or hazards in subpopulations, such aschildren, pregnant women and other sensitive groups.But the absence of such studies should not precludethe selection of an upper limit for generally healthyadults. The identified OSLs for these amino acids areby no means static values and will likely evolve withcontinued research. The literature should be continu-ously monitored to identify studies that may warrantmodification of the chosen values.

Conflict of interest statement

Both Dr. Shao and Dr. Hathcock are full time employ-ees of the Council for Responsible Nutrition (CRN), a not-for-profit trade association representing and supported bythe US dietary supplement industry.


Acknowledgment

We would like to thank Ingrid Lebert for her assistancein acquiring many of the relevant scientific articles for thisanalysis.

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Risk assessment for the amino acids taurine, l-glutamine and l-arginine

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