Letters to the Editor 698 References McTavish SF, Cowen PJ, Sharp T (1999). Effect of a tyrosine-free amino acid mixture on regional brain catecholamine synthesis Battaglia FC, Regnault TRH (2001). Placental transport and metabo- and release. Psychopharmacology (Berl) 141, 182–188. lism of amino acids. Placenta 22, 145–161. Mead MN (2006). Sour finding on popular sweetener. Environ Health Christian B, McConnaughey K, Bethea E, Brantley S, Coffey A, Perspect 114, A176. Hammond L et al. (2004). Chronic aspartame affects T-mase Mead MN (2007). Aspartame cancer risks revisited: prenatal exposure performance, brain cholinergic receptors and Na þ ,Kþ -ATPase in may be greatest concern. Environ Health Perspect 115, A460. rats. Pharmacol Biochem Behav 78, 121–127. Olney JW, Ho OL (1970). Brain damage in infant mice following oral Coulombe Jr RA, Sharma RP (1986). Neurobiochemical alterations intake of glutamate, aspartate or cysteine. Nature 227, 609–611. induced by the artificial sweetener aspartame (NutraSweet). Toxicol Olney JW, Sharpe LG, Feigin RD (1972). Glutamate-induced brain Appl Pharmacol 83, 79–85. damage in infant primates. J Neuropathol Exp Neurol 31, 464–488. Dow-Edwards DL, Scribani LA, Riley EP (1989). Impaired perfor- Olney JW (1969a). Brain lesions, obesity, and other disturbances in mance on odor-aversion testing following prenatal aspartame mice treated with monosodium glutamate. Science 164, 719–721. exposure in the guinea pig. Neurotoxicol Teratol 11, 413–416. Olney JW (1988). Excitotoxic food additives:Functional teratological Fountain SB, Hennes SK, Teyler TJ (1988). Aspartame exposure and in aspects. Prog Brain Res 73, 283–294. vitro hippocampal slice excitability and plasticity. Fundam Appl Palmour RM, Ervin FR, Baker GB, Young SN (1998). An amino acid Toxicol 11, 221–228. mixture deficient in phenylalanine and tyrosine reduces cerebro- Gibson CJ, Wurtman RJ (1977). Physiological control of brain spinal fluid catecholamine metabolites and alcohol consumption catechol synthesis by brain tyrosine concentrations. Biochem in vervet monkeys. Psychopharmacology (Berl) 136, 1–7. Pharmacol 26, 1137–1142. Pan-Hou H, Suda Y, Ohe Y, Sumi M, Yoshioka M (1990). Effect of 3 Hayasaka Y, Hayasaka S, Nagaki Y (2001). Ocular changes after aspartame on N-methyl-D-aspartate-sensitive L-[ H]glutamate intavitreal injection of methanol, formaldehyde, or formate in binding sites in rat brain synaptic membranes. Brain Res 520, rabbits. Pharmacol Toxicol 89, 74–78. 351–353. Jozwik M, Teng C, Timmerman M, Chung M, Meschia G, Battaglia FC Paolini CL, Marconi AM, Ronzoni S, Di Noio M, Fennessey PV, Pardi (1998). Uptake and transport by the ovine placenta of neutral G et al. (2001a). Placental transport of leucine, phenylalanine, nonmetabolizable amino acids with different transport system glycine, and proline in intrauterine growth-restricted pregnancies. affinities. Placenta 19, 531–538. J Clin Endrocrinol Metab 86, 5427–5432. Lau K, McLean WG, Williams DP, Howard CV (2006). Synergistic Paolini CL, Meschia G, Fennessey PV, Pike AW, Teng C, Battaglia FC interactions between commonly used food additives in a develop- et al. (2001b). An in vivo study of ovine placental transport of mental neurotoxicity test. Toxicol Sci 90, 178–187. essential amino acids. Am J Physiol 280, E31–E39. Leyton M, Dagher A, Boileau I, Casey K, Baker GB, Diksic M et al. Prodolliet J, Bruelhart M (1993). Determination of aspartame and its (2004). Decreasing amphetamine-induced dopamine release by major decomposition products in foods. J AOAC Int 76, 275–282. acute phenylalanine/tyrosine depletion: A PET/[11C]raclopride Rothman SM, Olney JW (1995). Excitotoxicity and the NMDA study in healthy men. Neuropsychopharmacology 29, 427–432. receptor—still lethal after eight years. Trends Neurosci 18, 57–58. Leyton M, Kwai Pun V, Benkelfat C, Young SN (2003). A new method Rouse B, Matalon R, Koch R, Azen C, Levy H, Hanley W et al. (2000). for rapidly and simultaneously decreasing serotonin and catecho- Maternal phenylketonuria syndrome: congenital heart defects, lamine synthesis in humans. Rev Psychiatr Neurosci 28, 464–467. micocephaly, and developmental outcomes. J Pediatr 136, 57–61. Lim S (2007). Metabolic acidosis. Acta Med Indones 39, 145–150. Soffritti E, Belpoggi F, Espasti DD, Lambertini L, Tibaldi E, Rigano A Lin SY, Cheng YD (2000). Simultaneous formation and detection of (2006). First experimental demonstration of the multipotential the reaction product of solid-state aspartame sweetener by FT-IR/ carcinogenic effects of aspartame administered in the feed to DSC microscopic system. Food Addit Contam 17, 821–827. Sprague-Dawley rats. Environ Health Perspect 114, 379–385. Maher TJ, Wurtman RJ (1987). Possible neurologic effects of aspartame, Sturtevant FM (1985). Use of aspartame in pregnancy. Int J Fertil 30, awidelyusedfoodadditive.Environ Health Perspect 75,53–57. 85–87. Matalon KM, Acosta PB, Azen C (2003). Role of nutrition in Ward KW, Pollack GM (1996b). Use of intrauterine microdialysis to pregnancy with phenylketonuria and birth defects. Pediatrics 112 investigate methanol induced alterations in uteroplacental blood (6 Part 2), 1534–1536. flow. Toxicol Appl Pharmacol 140, 203–210. McKean CM (1972). The effects of high phenylalanine concentra- Yokogoshi H, Wurtman RJ (1986). Acute effects of oral or parenteral tions on serotonin and catecholamine metabolism in the human aspartame on catecholamine metabolism in various regions of rat brain. Brain Res 47, 469–476. brain. J Nutr 116, 356–364.

Aspartame effects on the brain

European Journal of Clinical Nutrition (2009) 63, 698–699; The key point about aspartame is that very little is doi:10.1038/ejcn.2008.5; published online 30 January 2008 consumed. Because it is 180 times sweeter than sugar, relatively little shows up in products. For example, a 355 ml can of diet soda contains 180 mg of aspartame, which The following comments relate to the review by Humphries for a 70 kg human is a 2.5 mg kgÀ1 dose (1.25 mg kgÀ1 et al. (2008). The premise of the review, that the high- phenylalanine). After its introduction, its use was monitored intensity sweetener aspartame is neurotoxic, ignores a very for years, revealing that average daily dosing is barely large scientific literature to the contrary, recently compre- 5mgkgÀ1 dayÀ1 (2.5 mg kgÀ1 dayÀ1 phenylalanine), not hensively summarized (Butchko et al., 2002; Magnuson et al., much. As a comparison, the amount of phenylalanine in a 2007). quarter-pound hamburger is about 1000 mg, or 14 mg kgÀ1

European Journal of Clinical Nutrition Letters to the Editor 699 phenylalanine (70 kg individual), or much more. It is saturated placental blood flow’ caused by maternal aspar- important to keep this fact in mind when considering the tame consumption. (i) Finally, many erroneous statements authors’ arguments, which relate to studies in animals have been obtained from two websites, one cited as Mehl- involving extremely high aspartame doses (for example, up Madrona and the other as Bowen and Evangelista. These to 2000 mg kgÀ1 in rats, a huge dose). Such studies have no seem to me to be inappropriate references, as their contents relevance to human use. And, for aspartame to have effects have not been subjected to peer review, and contain in animals, blood levels of aspartame constituents (aspartate, unsupported speculation. phenylalanine, methanol) must increase to very high values. While I recognize the need for a continuing dialog on any At the levels ingested by humans, such increases in blood do issue relevant to human nutrition and health, here in not occur, even at high levels of intake (Butchko et al., 2002; relation to aspartame, in my view, the article by Humphries Magnuson et al., 2007). does not make an informed contribution. The errors in this article are too numerous to enumerate in a letter of limited length. I note those most obvious to me. JD Fernstrom (a) Formate is not converted to diketopiperazine (abstract). Department of Psychiatry and Pharmacology, University of (b) The authors are incorrect in stating that tyrosine cannot Pittsburgh School of Medicine, Pittsburgh, PA, USA be synthesized in brain from phenylalanine. (c) Despite the E-mail: [email protected] authors’ statement, even very large increases in phenylala- nine levels produced by aspartame administration to rats do not suppress catecholamine synthesis rate (Fernstrom et al., 1991). (d) Contrary to the authors’ statement, my 1983 Life References Sciences paper did not find changes in regional brain catecholamine concentrations following aspartame dosing Butchko HH, Stargel WW, Comer CP, Mayhew DA, Benninger C, Blackburn GL et al. (2002). Aspartame: review of safety. Regul of rats. (e) Maher and Wurtman gave rats aspartame up to Toxicol Pharmacol 35, S1–S93. 2000 mg kgÀ1, a huge dose. And their results could not be Fernstrom JD, Fernstrom MH, Massoudi MS (1991). In vivo tyrosine confirmed (see Butchko et al., 2002; Magnuson et al., 2007). hydroxylation in rat retina: effect of aspartame ingestion in p Am J Clin Nutr (f) Aspartame does not enter the blood from the gut, and rats pretreated with -chlorophenylalanine. 53, 923–929. thus does not get into brain. Hence, brain glutamate Humphries P, Pretorius E, Naude H (2008). Direct and indirect receptors cannot be engaged directly by aspartame, despite cellular effects of aspartame on the brain. Eur J Clin Nutr 62, the authors’ assertions. (g) Despite the authors’ statement, 451–462. Magnuson BA, Burdock GA, Doull J, Kroes RM, Marsh GM, Pariza my 1994 Journal of the American Dietetic Association article MW et al. (2007). Aspartame: a safety evaluation based on current does not state that aspartame increases brain levels of acidic use levels, regulations, and toxicological and epidemiological amino acids. (h) There is no such thing as ‘excitotoxic- studies. Crit Rev Toxicol 37, 629–727.

Is the zinc intake of young people in the UK adequate?

European Journal of Clinical Nutrition (2009) 63, 699–700; (a) Although the problem of underreporting was previously doi:10.1038/ejcn.2008.23; published online 5 March 2008 reported in this survey, the impact of the error was not considered to be high enough to alter the major findings of the survey. Dietary zinc intake in the investigation of ‘zinc and vitamin (b) The feasibility study of this National Diet and Nutrition A intake and status in a national sample of British young Survey, including estimates of energy expenditure using people aged 4–18 years’ (Thane et al., 2004) was reported to the ‘doubly labelled water’ technique, indicated that be ‘adequate’ for most of the population. This conclusion there was sufficient validity for adopting the methodo- was based on: logy for the main stage survey (Gregory et al., 2000).  A consideration of the likely error of underreporting in (c) Plasma zinc is generally considered to be a poor measure participants of marginal zinc deficiency, as the level of zinc in plasma  And the fact that ‘low’ plasma zinc concentration was is homeostatically controlled and, in marginal zinc only detected in a very small minority of participants deficiency, may remain within the normal range. (d) Several confounding factors can affect plasma zinc We would like to offer a different interpretation of these levels. For instance, plasma zinc concentration may vary results for the reasons set out below: according to time of the day, proximity of meals,

European Journal of Clinical Nutrition