Highest Observed Intake: Definition, regulatory uses and provisional values

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<ul><li><p>la</p><p>thon</p><p>RegulationsVitaminsBioactives</p><p>ubsnt mL htheigheto s</p><p>adverse effects. The need for the HOI concept and value is illustrated by the unjustied policy and regu-</p><p>have tcts anr othehistoryisk assefor wh</p><p>and selection of an Uncertainty Factor (UF), and calculation of theUL (Institute of Medicine, 1998a). That is, UL = NOAEL</p><p>has been identied and no UL can be established, to identify a riskassessment value that is nowofcially termed theHighest ObservedIntake (HOI) (FAO/WHO, 2006), although the concept has also beencalled the Observed Safe Level (OSL) (Hathcock and Shao, 2008).Simply, in the absence of a UL, the HOI is the highest intake withadequate data to show, with acceptable condence, of the absenceof adverse effects up to that intake, i.e., safety up to that level ofintake. The HOI is not literally the highest observed intake, but isthe highest with adequate data to support safety.</p><p>In the HOI procedure, the available data are screened to identifyanyobservable hazard, that is, a possible critical effect. If one is found,</p><p>Abbreviations: UL, Tolerable Upper Intake Level; UF, Uncertainty Factor; FAO,Food and Agriculture Organization; WHO, World Health Organization; WTO, WorldTrade Organization; SPS, Sanitary and Phytosanitary Standards; IOM, Institute ofMedicine; EFSA, European Food Safety Authority; SCF, Scientic Committee onFood; HOI, Highest Observed Intake; NOAEL, No Observed Adverse Intake Level;LOAEL, Lowest Observed Intake Level; EVM, Expert Group on Vitamins andMinerals. Corresponding author. Fax: +1 202 204 7001.</p><p>Regulatory Toxicology and Pharmacology 61 (2011) 115118</p><p>Contents lists availab</p><p>Regulatory Toxicology</p><p>journal homepage: www.eE-mail address: jhathcock@crnusa.org (J. Hathcock).Adverse Effect Level (LOAEL) or a No Observed Adverse Effect Level(NOAEL) can be identied, quantitative risk assessment commonlyinvolves application of an uncertainty factor to the LOAEL or NOAELto calculate an Acceptable Daily Intake (ADI) (National ResearchCouncil, 1983). For nutrients with known adverse effects, the Toler-able Upper Intake Level (UL) method has become internationallyaccepted. Application of the ULmethod involves a few simple steps:identication of the critical effect (the hazard occurring at the low-est intake), doseresponse assessment, evaluation of uncertainty</p><p>sence of a UL or comparable risk assessment value has been usedto argue for establishing maximums based on the RecommendedDietary Allowances (Domke et al., 2006) rather than safety as eval-uated by risk assessment.</p><p>2. Highest Observed Intake (HOI)</p><p>In contrast to the limitations inherent in the UL method, anexpanded alternative approach is, for nutrients for which no hazard1. Introduction</p><p>Policy and regulatory authoritiesdetermining the safety of food produassessment based on toxicological o(b) evaluation of whether there is a ulatory policies specically require rof ingredients. With food substances0273-2300/$ - see front matter 2011 Elsevier Inc. Adoi:10.1016/j.yrtph.2011.07.001latory actions taken in relation to vitamin B12. Regulatory utility is explained and tentative HOI valuesare identied for several vitamins and non-essential nutrients. Endorsement of the concept and develop-ment of HOI values by authoritative bodies is likely to be required for broad acceptance and use.</p><p> 2011 Elsevier Inc. All rights reserved.</p><p>wo basic approaches tod components (a) riskr appropriate data, andof safe use. Some reg-ssment for many typesich a Lowest Observed</p><p>(or LOAEL) UF. A common further step, often termed risk charac-terization, is to compare the UL with the actual observed range ofintakes to determine whether some fraction of the population islikely be at risk of adverse effects. The major limitation of the ULmethod as applied by authoritative groups thus far is that no ULhas been set for nutrients without established adverse effects. Theabsence of an established critical effect has been interpreted as pre-cluding the derivation of a risk assessment value. Further, the ab-Acceptable Daily Intake (ADI)Risk assessmentToxicity</p><p>intake. With this concept dened and accepted in a report by the authoritative international organiza-tions FAO and WHO, a complete risk assessment for the nutrients and related substances would haveto identify UL values for those with known adverse effects and HOI values for those without knownHighest Observed Intake: Denition, regu</p><p>John Hathcock a,, Wantanee Kriengsinyos baCouncil for Responsible Nutrition, 1828 L St., NW, Suite 510, WA 20036, USAb Institute of Nutrition, Mahidol University, Phutthamonthon 4 Rd., Salaya, Phutthamon</p><p>a r t i c l e i n f o</p><p>Article history:Received 4 April 2011Available online 23 July 2011</p><p>Keywords:Highest Observed IntakeTolerable Upper Intake Level (UL)</p><p>a b s t r a c t</p><p>For nutrients and related sally accepted risk assessmegroups thus far is that no Uthe limitations inherent inment value termed the Hintake with adequate datall rights reserved.tory uses and provisional values</p><p>, Nakhon Pathom 73170, Thailand</p><p>tances, the Tolerable Upper Intake Level (UL) has become the internation-ethod. The major limitation of the UL method as applied by authoritative</p><p>as been set for nutrients without established adverse effects. In contrast toUL method, an alternative approach is available; it identies a risk assess-st Observed Intake (HOI). In the absence of a UL, the HOI is the highesthow, with acceptable condence, the absence of adverse effects up to that</p><p>le at ScienceDirect</p><p>and Pharmacology</p><p>l sevier .com/locate /yr tph</p></li><li><p>of an adverse effect is adequately excluded by the available data.Thedata evaluationproceduresare exactly analogous to those in risk</p><p>longer-term studies are almost always planned to detect possiblelong-term benets.</p><p>xicolassessment for established hazards. With this concept dened andaccepted in a report by the authoritative international organizationsFAO and WHO, a complete risk assessment for the nutrients andrelated substances would identify UL values for those with knownadverse effects and HOI values for those without known adverseeffects. The demands for data should be similar for establishing ULandHOI values. If thedatawith toxicological utility are not sufcientto identify aUL or anHOI value, themore general evidence related touse should be evaluated to determine whether the history of usedemonstrates safety. Althoughmultiple papers have been publishedon history of safe use (Sybesma et al., 2006; Constable et al., 2007;Health Canada, http://www.hc-sc.gc.ca/fn-an/consult/_novel_-foods/consultation_guidelines-directives09-eng.php), there is notyet any general agreement on the details of the method and typesof evidence that should be required.</p><p>The HOI has been dened by FAO/WHO (2006):</p><p>Highest Observed Intake the highest level of intake observedor administered as reported within a stud(ies) of acceptablequality. It is derived only when no adverse health effects havebeen identied.</p><p>The HOI has been accepted by the Codex Alimentarius in itsNutritional Risk Analysis Principles and Guidelines for applicationto the Work of the Committee on Nutrition and Foods for SpecialDietary Uses (Codex Alimentarius Commission, Procedural Manual,19th Edition, 2010):</p><p>With this sanction, the HOI concept acquires global policy andregulatory importance because Codex is recognized as the preem-inent international authority on food safety by the World TradeOrganization in its Sanitary and Phytosanitary (SPS) Agreement(World Trade Organization, 2011).</p><p>To support developing international standards and regulations,the HOI concept and its acceptance by the Codex Alimentarius needsto be recognized, and generally accepted values should be devel-oped. In the reviews by the Institute of Medicine and the EuropeanCommission Scientic Committee on Food (now superseded by theEuropean Food Safety Authority, EFSA) no data were found to iden-tify any hazard related to high intakes of thiamin, riboavin, vita-min B-12, biotin, and pantothenic acid (IOM, 1998b; SCF, 2000,b,2001a,b, 2002). By standard practice by the IOM and SCF/EFSA, aUL cannot be set if a NOAEL or LOAEL was not identied due tothe absence of established adverse effect or hazard. The UnitedKingdoms Expert Group on Vitamins and Minerals did not denethe HOI or any similar concept, but identied an Advisory Levelon a similar basis for a few nutrients, including vitamin B12 (EVM,2003). They did not dene or describe the procedure, but it seemsquite similar to the HOI denition.</p><p>Use of the HOI approach based exclusively on human data hasthe obvious limitation of the quantity and quality of those datasets.The choices are to use the usually more robust animal data andencounter the larger uncertainty of cross-species extrapolation,or to use the much less robust human data and avoid the uncer-tainty of this extrapolation. The net uncertainty could be reducedby combining the two approaches.</p><p>3. Application of the HOIthe UL procedure is used. If none is found, the available evidence isevaluated to determine the highest intake for which the possibility</p><p>116 J. Hathcock, W. Kriengsinyos / Regulatory ToThe need for the HOI concept and its value are illustrated by theillogical policy and regulatory actions taken in relation to vitaminB12. Apparently, the absence of a UL led to the misinterpretationWhen risk assessments based on animal data were available,such as for lutein and lycopene, the HOI values were comparedwith the animal data ADI values (Shao and Hathcock, 2006). Inthese cases, any policy or regulatory decision based on the HOI val-ues would be more conservative.</p><p>The HOI approach has also been applied in risk assessments oftaurine, L-glutamine, and L-arginine, amino acids without knownspecic toxic effects. The HOI risk assessment method indicatesthe evidence for the absence of adverse effects is strong for taurineat supplemental intakes up to 3 g/d, L-glutamine at intakes up to14 g/d, and L-arginine at intakes up to 20 g/d (Hathcock and Shao,2008).</p><p>Although the United Kingdom Expert Group on Vitamins andMinerals (EVM) did not name the procedure, it applied the termGuidance Level in 2 ways: (1) in a manner analogous to the HOIdenition, e.g. their 2000 lg guidance level for vitamin B12 (EVM,2003), and also (2) as a cautious term where they judged the datato be weak.</p><p>In the published risk assessments of lutein and lycopene (Shaothat there is insufcient data to evaluate the safety of this vitamin.This interpretation occurred despite the accumulation of largeamounts of human clinical data demonstrating a lack of adverse ef-fects of oral vitamin B12 at doses hundreds or thousands of timeshigher than the nutritional requirement or recommended intakes(USDA, 2007). Nonetheless, the absence of a UL for this vitaminhas led to the proposal or implementation of scientically unjusti-ed and unnecessarily restrictive policies for maximum amountsthat may be incorporated into products. For example, Germanyproposed and later withdrew a regulatory limit of 9 mg for vitaminB12 (Domke et al., 2006) and France (le Ministre, 2006) imple-mented a limit of 3 lg in supplement products even though theamounts in unfortied conventional foods can range upward of100 lg per serving of some foods, e.g., beef liver (USDA, 2007).There is no public health purpose of such restrictions and the reg-ulatory actions taken by France and considered by Germany seemdisproportionate to the (lack of) hazard, and thus violate the Euro-pean Commissions guidelines for proportionality in its documenton the precautionary principle (European Commission, 2000).</p><p>4. Provisional HOI values</p><p>The quantitative values identied in this section are offered on aprovisional basis to illustrate the methodology; we recognize thatfor wider acceptance and use, HOI values would need to be estab-lished by an authoritative scientic group such as the US IOM orthe EFSA.</p><p>The HOI risk assessment method (called the Observed Safe Levelby the authors) has been used in a series of published risk assess-ments for several non-essential nutrients, i.e. bioactive food com-ponents, including carnitine, chondroitin sulfate, coenzyme Q10,glucosamine, lutein, and lycopene (Hathcock and Shao, 2006a,b,2007; Shao and Hathcock, 2006). None of these substances hasany established causally related adverse effects, although most ofthem have been tested at a range of intakes in human clinical trialsand some have extensive supporting animal data. Some of thesedatasets are quite small and also vary in quality from one to an-other of these substances. Most of the studies are relatively shortterm, and condence would be enhanced with longer term data.Acquisition of such data is difcult for multiple reasons humanstudies seldom have safety measures as primary endpoints, and</p><p>ogy and Pharmacology 61 (2011) 115118and Hathcock, 2006), the outcomes of the HOI method applied tohuman data were compared with standard risk assessments basedon animal data. With no known adverse effects (other than</p></li><li><p>F)</p><p>Lycopene 75 mg (human data); 270 mg(animal data)</p><p>1 human data; 1000animal data</p><p>xicolcarotenodermia), the lutein and lycopene HOI were restricted so-lely by the dosages used in good quality clinical trials. The riskassessments based on animal data employed 1000-X uncertaintyfactors, and conversion to a standard human body weight of60 kg. The human data HOI for lutein indicated a value of 20 mg/d, but the animal data risk assessment suggested that 38 mgshould be safe for human adults. Similarly, the human data HOIfor lycopene led to identication of a 75 mg/d HOI, but the animaldata risk assessment indicated that 270 mg/d should be safe forhuman adults.</p><p>In the denition and policy context described, authoritativegovernment groups need to review the nutrients to identify HOIas well as UL values. Since no authoritative group has yet published</p><p>Chondroitin 1200 mg 1</p><p>Glucosamine 2000 mg 1</p><p>Coenzyme Q10 1200 mg 1</p><p>Carnitine 2000 mg 1Table 1Tentative Highest Observed Intake (HOI) values.</p><p>Nutrient Tentative HOI Uncertainty Factor (Uapplied</p><p>Thiamin(hydrochloride)</p><p>100 mg (described as guidancelevel)</p><p>1</p><p>Riboavin 40 mg (described as guidancelevel)</p><p>10</p><p>Vitamin B12(cyanocobalamin)</p><p>2000 mcg (described asguidance level)</p><p>1</p><p>Biotin 900 mcg (described as guidancelevel)</p><p>10</p><p>Pantothenic acid 200 mg (described as guidancelevel)</p><p>10</p><p>Lutein 20 mg (human data); 38 mg(animal data)</p><p>1 human data; 1000animal data</p><p>J. Hathcock, W. Kriengsinyos / Regulatory Tosuch work, we provide the provisional HOI values from previouspublications. See Table 1 for several guidance levels identied bythe EVM, and OSL (equivalent to HOI) values from the peer-re-viewed literature. We emphasize that these HOI values are the re-sult of risk assessment; the data were assessed for evidence ofadverse effects and none was found, but standard doseresponseevaluation indicated that the data should be judged reliable onlyup to the levels suggested as HOI values.</p><p>5. Regulatory uses of the HOI</p><p>In development of regulatory values, it may be argued that nomaximums should be set...</p></li></ul>

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