What is a food and what is a medicinal product in the European Union? Use of the benchmark dose (BMD) methodology to define a threshold for " pharmacological action"

Regulatory Toxicology and Pharmacology

Volumn 64, Issue 2, 2012, Pages 286-295

  Lachenmeier, Dirk W ^a   Steffen, Christian ^b   El Atma, Oliver ^a   Maixner, Sibylle ^a   Löbell Behrends, Sigrid ^a   Kohl Himmelseher, Matthias ^a  

^a Chemisches und Veterinaruntersuchungsamt CVUA Karlsruhe   (Germany)

^b NONE   (Germany)

Author keywords

Benchmark dose; Borderline product; Caffeine; Demarcation; Food; Food supplements; Ginkgo biloba; Glucosamine; Lovastatin; Medicinal product; Melatonin; Pharmacological action; Red yeast rice

Indexed keywords

EID: 84866517419     PISSN: 02732300     EISSN: 10960295     Source Type: Journal    
DOI: 10.1016/j.yrtph.2012.08.017     Document Type: Article

References (67)

1. Aghazadeh-Habashi A., Jamali F. The glucosamine controversy; a pharmacokinetic issue. J. Pharm. Pharm. Sci. 2011, 14:264-273.
2. Alberts A.W., Chen J., Kuron G., Hunt V., Huff J., Hoffman C., Rothrock J., Lopez M., Joshua H., Harris E., Patchett A., Monaghan R., Currie S., Stapley E., Albers-Schonberg G., Hensens O., Hirshfield J., Hoogsteen K., Liesch J., Springer J. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc. Natl. Acad. Sci. USA 1980, 77:3957-3961.
3. Anderson J.W., Nicolosi R.J., Borzelleca J.F. Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy. Food Chem. Toxicol. 2005, 43:187-201.
4. Astrup A., Toubro S., Cannon S., Hein P., Breum L., Madsen J. Caffeine: a double-blind, placebo-controlled study of its thermogenic, metabolic, and cardiovascular effects in healthy volunteers. Am. J. Clin. Nutr. 1990, 51:759-767.
5. Attenburrow M.E., Cowen P.J., Sharpley A.L. Low dose melatonin improves sleep in healthy middle-aged subjects (Berl.). Psychopharmacology 1996, 126:179-181.
6. BfR Verwendung von Glucosamin und dessen Verbindungen in Nahrungsergänzungsmitteln. Stellungnahme Nr. 032/2007 des BfR vom 15. Juni 2007 2007, Bundesinstitut für Risikobewertung, Berlin, Germany.
7. Bi J. Using the Benchmark Dose (BMD) methodology to determine an appropriate reduction of certain ingredients in food products. J. Food Sci. 2010, 75:R9-R16.
8. Buscemi N., Vandermeer B., Hooton N., Pandya R., Tjosvold L., Hartling L., Vohra S., Klassen T.P., Baker G. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 2006, 332:385-393.
9. Clegg D.O., Reda D.J., Harris C.L., Klein M.A., O'Dell J.R., Hooper M.M., Bradley J.D., Bingham C.O., Weisman M.H., Jackson C.G., Lane N.E., Cush J.J., Moreland L.W., Schumacher H.R., Oddis C.V., Wolfe F., Molitor J.A., Yocum D.E., Schnitzer T.J., Furst D.E., Sawitzke A.D., Shi H., Brandt K.D., Moskowitz R.W., Williams H.J. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N. Engl. J. Med. 2006, 354:795-808.
10. Committee for Medicinal Products for Human Use Opinion following an article 29(4)1 referral for Glucomed and associated names. EMEA/405628/2006 2006, European Medicines Agency, London, UK.
11. Council of Europe Homeostasis, a model to distinguish between foods (including food supplements) and medicinal products. Partial agreement in the Social and Public Health field 2008, Council of Europe, Strasbourg, France.
12. Council of the European Economic Community Council Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by Law, Regulation or Administrative Action relating to proprietary medicinal products. Off. J. 1965, 022:369-373.
13. Crump K.S. A new method for determining allowable daily intakes. Fundam. Appl. Toxicol. 1984, 4:854-871.
14. Crump K.S. Calculation of benchmark doses from continuous data. Risk Anal. 1995, 15:79-89.
15. Davidson M.H., Palmisano J., Wilson H., Liss C., Dicklin M.R. A multicenter, randomized, double-blind clinical trial comparing the low-density lipoprotein cholesterol-lowering ability of lovastatin 10, 20, and 40mg/d with fluvastatin 20 and 40mg/d. Clin. Ther. 2003, 25:2738-2753.
16. EFSA Opinion of the Scientific Committee on a request from EFSA related to a harmonised approach for risk assessment of substances which are both genotoxic and carcinogenic. EFSA J. 2005, 282:1-31.
17. EFSA Use of the benchmark dose approach in risk asssessment. Guidance of the scientific committee. EFSA J. 2009, 1150:1-72.
18. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) Scientific opinion on the substantiation of health claims related to glucosamine alone or in combination with chondroitin sulphate and maintenance of joints (ID 1561, 1562, 1563, 1564, 1565) and reduction of inflammation (ID 1869) pursuant to Article 13(1) of Regulation (EC) No. 1924/2006. EFSA J. 2009, 7:1264.
19. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) Scientific opinion on the substantiation of health claims related to melatonin and alleviation of subjective feelings of jet lag (ID 1953), and reduction of sleep onset latency, and improvement of sleep quality (ID 1953) pursuant to Article 13(1) of Regulation (EC) No. 1924/2006. EFSA J. 2010, 8:1467.
20. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) Scientific opinion on the substantiation of a health claim related to melatonin and reduction of sleep onset latency (ID 1698, 1780, 4080) pursuant to Article 13(1) of Regulation (EC) No. 1924/2006. EFSA J. 2011, 9:2241.
21. Endo A., Monacolin K. A new hypocholesterolemic agent produced by a Monascus species. J. Antibiot. (Tokyo) 1979, 32:852-854.
22. European Commission Medical Devices: Guidance Document 2001, European Commission, Brussels, Belgium.
23. European Parliament and European Council Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Off. J. Europ. Comm. 2001, L311:67-128.
24. European Parliament and European Council Directive 2002/46/EC of the European Parliament and of the Council of 10 June 2002 on the approximation of the laws of the member states relating to food supplements. Off. J. Europ. Union 2002, L183:51-57.
25. European Parliament and European Council Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use. Off. J. Europ. Union 2004, L136:34-57.
26. European Parliament and European Council Regulation (EC) No. 110/2008 of the European Parliament and of the Council of 15 January 2008 on the definition, description, presentation, labelling and the protection of geographical indications of spirit drinks and repealing Council Regulation (EEC) No. 1576/89. Off. J. Europ. Union 2008, L39:16-54.
27. European Parliament and European Council Regulation (EU) No. 1169/2011 of the European Parliament and of the Council of 25 October 2011 on the provision of food information to consumers, amending Regulations (EC) No. 1924/2006 and (EC) No. 1925/2006 of the European Parliament and of the Council, and repealing Commission Directive 87/250/EEC, Council Directive 90/496/EEC, Commission Directive 1999/10/EC, Directive 2000/13/EC of the European Parliament and of the Council, Commission Directives 2002/67/EC and 2008/5/EC and Commission Regulation (EC) No. 608/2004. Off. J. Europ. Union 2011, L304:18-63.
28. Filipsson A.F., Sand S., Nilsson J., Victorin K. The benchmark dose method - review of available models, and recommendations for application in health risk assessment. Crit. Rev. Toxicol. 2003, 33:505-542.
29. Hahn A. Gesundheitsprodukte: Wo hört das Lebensmittel auf, wo fängt das Arzneimittel an?. Pharm. Unserer Zeit 2011, 40:306-315.
30. Hamajima N., Hirose K., Tajima K., Rohan T., Calle E.E., Heath C.W., Coates R.J., Liff J.M., Talamini R., Chantarakul N., Koetsawang S., Rachawat D., Morabia A., Schuman L., Stewart W., Szklo M., Bain C., Schofield F., Siskind V., Band P., Coldman A.J., Gallagher R.P., Hislop T.G., Yang P., Kolonel L.M., Nomura A.M., Hu J., Johnson K.C., Mao Y., De S.S., Lee N., Marchbanks P., Ory H.W., Peterson H.B., Wilson H.G., Wingo P.A., Ebeling K., Kunde D., Nishan P., Hopper J.L., Colditz G., Gajalanski V., Martin N., Pardthaisong T., Silpisornkosol S., Theetranont C., Boosiri B., Chutivongse S., Jimakorn P., Virutamasen P., Wongsrichanalai C., Ewertz M., Adami H.O., Bergkvist L., Magnusson C., Persson I., Chang-Claude J., Paul C., Skegg D.C., Spears G.F., Boyle P., Evstifeeva T., Daling J.R., Hutchinson W.B., Malone K., Noonan E.A., Stanford J.L., Thomas D.B., Weiss N.S., White E., Andrieu N., Bremond A., Clavel F., Gairard B., Lansac J., Piana L., Renaud R., Izquierdo A., Viladiu P., Cuevas H.R., Ontiveros P., Palet A., Salazar S.B., Aristizabel N., Cuadros A., Tryggvadottir L., Tulinius H., Bachelot A., Le M.G., Peto J., Franceschi S., Lubin F., Modan B., Ron E., Wax Y., Friedman G.D., Hiatt R.A., Levi F., Bishop T., Kosmelj K., Primic-Zakelj M., Ravnihar B., Stare J., Beeson W.L., Fraser G., Bullbrook R.D., Cuzick J., Duffy S.W., Fentiman I.S., Hayward J.L., Wang D.Y., McMichael A.J., McPherson K., Hanson R.L., Leske M.C., Mahoney M.C., Nasca P.C., Varma A.O., Weinstein A.L., Moller T.R., Olsson H., Ranstam J., Goldbohm R.A., van den Brandt P.A., Apelo R.A., Baens J., De L.C., Javier B., Lacaya L.B., Ngelangel C.A., La V.C., Negri E., Marubini E., Ferraroni M., Gerber M., Richardson S., Segala C., Gatei D., Kenya P., Kungu A., Mati J.G., Brinton L.A., Hoover R., Schairer C., Spirtas R., Lee H.P., Rookus M.A., van Leeuwen F.E., Schoenberg J.A., McCredie M., Gammon M.D., Clarke E.A., Jones L., Neil A., Vessey M., Yeates D., Appleby P., Banks E., Beral V., Bull D., Crossley B., Goodill A., Green J., Hermon C., Key T., Langston N., Lewis C., Reeves G., Collins R., Doll R., Peto R., Mabuchi K., Preston D., Hannaford P., Kay C., Rosero-Bixby L., Gao Y.T., Jin F., Yuan J.M., Wei H.Y., Yun T., Zhiheng C., Berry G., Cooper B.J., Jelihovsky T., MacLennan R., Shearman R., Wang Q.S., Baines C.J., Miller A.B., Wall C., Lund E., Stalsberg H., Shu X.O., Zheng W., Katsouyanni K., Trichopoulou A., Trichopoulos D., Dabancens A., Martinez L., Molina R., Salas O., Alexander F.E., Anderson K., Folsom A.R., Hulka B.S., Bernstein L., Enger S., Haile R.W., Paganini-Hill A., Pike M.C., Ross R.K., Ursin G., Yu M.C., Longnecker M.P., Newcomb P., Bergkvist L., Kalache A., Farley T.M., Holck S., Meirik O. Alcohol, tobacco and breast cancer - collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br. J. Cancer 2002, 87:1234-1245.
31. Herxheimer, A., Petrie, K.J., 2002. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst. RevCD001520.
32. Houpt J.B., McMillan R., Wein C., Paget-Dellio S.D. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J. Rheumatol. 1999, 26:2423-2430.
33. IPCS Environmental Health Criteria 70: Principles for the Safety Assessment of Food Additives and Contaminants in Food 1987, World Health Organization, International Programme on Chemical Safety, Geneva.
34. IPCS Environmental Health Criteria 240: Principles and Methods for the Risk Assessment of Chemicals in Food 2009, World Health Organization, International Programme on Chemical Safety, Geneva.
35. Kennedy D.O., Scholey A.B., Wesnes K.A. The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers. Psychopharmacology (Berl.) 2000, 151:416-423.
36. Lachenmeier D.W., Kanteres F., Rehm J. Epidemiology-based risk assessment using the benchmark dose/margin of exposure approach: the example of ethanol and liver cirrhosis. Int. J. Epidemiol. 2011, 40:210-218.
37. Lachenmeier D.W., Monakhova Y.B., Kuballa T., Löbell-Behrends S., Maixner S., Kohl-Himmelseher M., Waldner A., Steffen C. NMR evaluation of total statin content and HMG-CoA reductase inhibition in red yeast rice (Monascus spp.) food supplements. Chin. Med. 2012, 7:8.
38. Lachenmeier D.W., Uebelacker M. Risk assessment of thujone in foods and medicines containing sage and wormwood - evidence for a need of regulatory changes?. Regul. Toxicol. Pharmacol. 2010, 58:437-443.
39. Läkemedelsverket Medical Products Agency Public Assessment Report. Scientific Discussion Glucomed Glucosamine hydrochloride 2006, http://www.lakemedelsverket.se/SPC_PIL/Pdf/par/Glucomed%20625%20mg%20tablet.pdf, accessed on [March 16, 2012], Läkemedelsverket Medical Products Agency, Uppsala, Sweden.
40. Lamson M., Phillips G., Shen J., Lukacsko P., Friedhoff L., Niecestro R.M. Pharmacokinetics of lovastatin extended-release dosage form (Lovastatin XL) in healthy volunteers. Biopharm. Drug Dispos. 2002, 23:143-149.
41. Lieberman H.R., Wurtman R.J., Emde G.G., Roberts C., Coviella I.L. The effects of low doses of caffeine on human performance and mood. Psychopharmacology (Berl.) 1987, 92:308-312.
42. Löbell-Behrends S., Böse W., Maixner S., Kratz E., Kohl-Himmelseher M., Marx G., Lachenmeier D.W. Surveillance of internet marketing of food products - categorization of borderline products and concepts for effective control strategies. J. Verbr. Lebensm. 2011, 6:385-393.
43. Löbell-Behrends S., Maixner S., Kratz E., Kohl-Himmelseher M., Bauer-Aymanns H., Marx G., Lachenmeier D.W. Surveillance of internet marketing of borderline products (anti-aging and weight-loss supplements): a pilot study. Deut. Lebensm. Rundsch. 2008, 104:265-270.
44. Meisterernst A., Schneider S. The pharmacological effect: an inappropriate characteristic for the demarcation of food and drugs?. Deut. Lebensm. Rundsch. 2004, 100:302-315.
45. Muri S.D., Schlatter J.R., Brüschweiler B.J. The benchmark dose approach in food risk assessment: is it applicable and worthwhile?. Food Chem. Toxicol. 2009, 47:2906-2925.
46. Nawrot P., Jordan S., Eastwood J., Rotstein J., Hugenholtz A., Feeley M. Effects of caffeine on human health. Food Addit. Contam. 2003, 20:1-30.
47. Passmore A.P., Kondowe G.B., Johnston G.D. Renal and cardiovascular effects of caffeine: a dose-response study. Clin. Sci. (Lond.) 1987, 72:749-756.
48. Persiani S., Roda E., Rovati L.C., Locatelli M., Giacovelli G., Roda A. Glucosamine oral bioavailability and plasma pharmacokinetics after increasing doses of crystalline glucosamine sulfate in man. Osteoarthritis. Cartilage. 2005, 13:1041-1049.
49. Rehm J. The risks associated with alcohol use and alcoholism. Alcohol Res. Health 2011, 34:135-143.
50. Rehm J., Baliunas D., Borges G.L., Graham K., Irving H., Kehoe T., Parry C.D., Patra J., Popova S., Poznyak V., Roerecke M., Room R., Samokhvalov A.V., Taylor B. The relation between different dimensions of alcohol consumption and burden of disease: an overview. Addiction 2010, 105:817-843.
51. Reppert S.M., Godson C., Mahle C.D., Weaver D.R., Slaugenhaupt S.A., Gusella J.F. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc. Natl. Acad. Sci. USA 1995, 92:8734-8738.
52. Roerecke M., Rehm J. The cardioprotective association of average alcohol consumption and ischaemic heart disease: a systematic review and meta-analysis. Addiction 2012, 107:1246-1260.
53. Sand S., Victorin K., Filipsson A.F. The current state of knowledge on the use of the benchmark dose concept in risk assessment. J. Appl. Toxicol. 2008, 28:405-421.
54. Schrenk D. Lebensmittel-Nahrungsergänzungsmittel-Arzneimittel. Toxikologische Bewertung und Abgrenzung. Pharm. Unserer Zeit 2011, 40:316-324.
55. Shear C.L., Franklin F.A., Stinnett S., Hurley D.P., Bradford R.H., Chremos A.N., Nash D.T., Langendorfer A. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. Effect of patient characteristics on lovastatin-induced changes in plasma concentrations of lipids and lipoproteins. Circulation 1992, 85:1293-1303.
56. Steffen C. Abgrenzungsproblematik. Klinische Studien mit Nahrungsergänzungsmitteln. Pharm. Unserer Zeit 2011, 40:332-337.
57. Strauss W.E., Lapsley D., Gaziano J.M. Comparative efficacy and tolerability of low-dose pravastatin versus lovastatin in patients with hypercholesterolemia. Am. Heart J. 1999, 137:458-462.
58. Streit H. Abgrenzung Lebensmittel - Arzneimittel. Handbuch für Lebensmittelchemiker 2010, 909-933. Springer, Berlin, Heidelberg, Germany. W. Frede (Ed.).
59. Streso, K., 2005. Demarcation of medicinal products and food in the European Union - focus: food supplements. Master thesis. University of Bonn, Bonn, Germany.
60. Suhner A., Schlagenhauf P., Johnson R., Tschopp A., Steffen R. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiol. Int. 1998, 15:655-666.
61. USEPA The Use of the Benchmark Dose Approach in Health Risk Assessment. EPA/630/R-94/007 1995, Office of Research and Development, US Environmental Protection Agency, Washington, DC.
62. USEPA Benchmark Dose Technical Guidance Document EPA/630/R-00/001 2000, Office of Research and Development, US Environmental Protection Agency, Washington, DC.
63. USEPA Benchmark Dose Software (BMDS) Tutorial 2008, Office of Research and Development, US Environmental Protection Agency, Washington, DC.
64. Walker J.F., Tobert J.A. The clinical efficacy and safety of lovastatin and MK-733 - an overview. Eur. Heart J. 1987, 8(Suppl. E):93-96.
65. Weinmann S., Roll S., Schwarzbach C., Vauth C., Willich S.N. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr. 2010, 10:14.
66. Winters J. Rechtliche Abgrenzung von Lebensmitteln und Arzneimitteln unter besonderer Berücksichtigung naturwissenschaftlicher Aspekte. Dissertation 2011, Shaker Verlag, Aachen, Germany.
67. Winters J., Hahn A. Die " pharmakologische Wirkung" als Kriterium bei der Abgrenzung Arzneimittel/Lebensmittel - eine Betrachtung aus der Praxisperspektive. Lebensm. Recht 2009, 13:173-181.