March 22, 2011

Attn: Carolyn Jeletic

FDA, Center for Food Safety and Applied Nutrition (HFS 024), 5100 Paint Branch Pkwy, College Park, MD 20740

RE: Link Between Consumption of Synthetic Color Additives in Food and Adverse Effects on Behavior

                                                                                                                         
FD &C Yellow 6 and FD & C Yellow 5 have both been linked to hyperactivity in children by McCann et al who published the results of his study in the Lancet in 2007 (1). As a result of McCann's findings the United Kingdom has asked manufacturers to voluntarily ban the use of these food colors in food products (2).  These and other food colors may be produced with mercury cell hydrogen chloride and are allowed to contain up to 1 ppm mercury (3, 4).  Because mercury inhibits cysteine ligands in the metal clearing metallothionein (MT) proteins that normally bind with metal ions such as copper and zinc (5), consumption of mercury containing substances over time by sensitive individuals may induce MT malfunction (6).  Such a malfunction may lead to severe zinc deficiency creating conditions of oxidative stress in the brain that impair learning (6, 7).   Many children with ADHD are zinc deficient (8, 9).  Ward et al found that consumption of FD &C 6 and FD &C 5 food color additives led to a significant reduction in blood and urine zinc levels in hyperactive children (10, 11).   The mercury content in these food colors may be responsible for the observed deficiency in zinc that can occur over time in hyperactive children who consume these food color additives (6).  As mercury displaces zinc in the MT molecule, copper may reach toxic levels compromising MT functioning in autistic children (6).  Three peer reviewed papers published in 2009 report findings that support the link between low-dose mercury exposure and MT dysfunction and an association with Autism Spectrum Disorders (12, 13, 14). MT is an important protein in the immune system and required to clear metals from the body (7, 15, 16). The consumption of food colors that contain inorganic mercury and lead to zinc loss can upset MT functioning (6). Autistic children are often found to be zinc deficient and exhibit MT dysfunction (12, 13, 14, 17).  Zinc deficiency along with oxidative stress predisposes the brain by disruption of the blood-brain barrier in rats and when they consume zinc depleting food chemicals there is a reduction in neuronal plasticity and learning (18).  Furthermore, pre-natal zinc deficiency has pronounced effects on postnatal MT metabolism in rats which can persist into adulthood (19).  Consumption of any food ingredient containing mercury or leading to zinc loss is detrimental to neurodevelopment in children (6).

We urge FDA to follow the United Kingdom's lead and provide consumers with the information they need to make informed choices about the consumption of food colors and their effect on child behavior and brain function.  We also recommend the FDA remove mercury cell chlor-alkali products from the GRAS food additive list.  If you have any questions, please feel free to contact any one of us. 

                                                                                                                                                                                                                               
Respectfully Submitted,

                                                                                                                                                                                                                             
Steven G. Gilbert, PhD, Institute of Neurotoxicology and Neurological Disorders, sgilbert@innd.org

Renee Dufault, MAT, Food Ingredient and Health Resesarch Institute, rdufault@phaccountability.org

Amanda Hitt, MPH, MD, Government Accountability Project, Food Integrity Campaign, amandah@whistleblower.org

David Wallinga, MD, Institute for Agriculture and Trade Policy, dwallinga@iatp.org

Martha Herbert, MD, Director, TRANSCEND Research/Neuroscience, transcend@partners.org

Joyce Martin, JD, American Association of Intellectual and Developmental Disabilities, joyce@aaidd.org

REFERENCES 

1. McCann D, Barrett A, Cooper A, Crumpler D, Dalen L, Grimshaw K, Kitchin E, Lok K, Porteus L, Prince E, Sonuga-Barke E, Warner JO, Stevenson J: Food additives and hyperactive behavior in 3-year-old and 8/9-year-old children in the community: a randomized, double-blinded placebo-controlled trial. Lancet 2007, 370(9598):1560-1567.

2. United Kingdom Food Standards Agency http://www.food.gov.uk/safereating/chemsafe/additivesbranch/colours/colourfree/

3. World Health Organization Joint Expert Committee on Food Additives http://whqlibdoc.who.int/trs/WHO_TRS_928.pdf webcite

4. United States Code of Federal Regulations http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr&sid=1070b19eb50e562daa872cfa1755aa09&rgn=div5&view=text&node=21:1.0.1.1.27&idno=21#21:1.0.1.1.27.1.31.9

5. Ladner L, Lindstrom L: Copper in society and the environment. 2nd revised edition. Environmental Research Group (MFG); 1999.

6. Dufault R, Schnoll R, Lukiw WJ, LeBlanc B, Cornett C, Patrick L, Wallinga D, Gilbert SG, Crider R:  Mercury exposure, nutritional deficiencies and metabolic disruptions may affect learning in children. Behavioral and Brain Functions 2009, 5:44 http://www.behavioralandbrainfunctions.com/content/5/1/44

7. Olanow CW, Arendash GW: Metals and free radicals in neurodegeneration. Curr Opin Neurol 1994, 7(6):548-558.

8. Konofal E, Lecendreux M, Arnulf I, Mouren MC: Iron deficiency in children with attention-deficity/hyperactivity disorder. Arch Pediatr Adolesc Med 2004, 158(12):1113-1115.

9. Starobrat-Hermelin B: The effect of deficiency of selected bioelements on hyperactivity in children with certain specified mental disorders. Ann Acad Med Stetin 1998,44:297-314.

10. Ward NI, Soulsbury K, Zettel VH, Colquhoun ID, Bunday S, Barnes B: The influence of the chemical additive tartrazine on the zinc status of hyperactive children-a double-blind placebo-controlled study. J Nutr Med 1990,1:51-57.

11. Ward NI: Assessment of chemical factors in relation to child hyperactivity. J Nutr Environ Med 1997, 7:333-342.

12. Faber S, Zinn GM, Kern JC, Kingston HM: The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders. Biomarkers 2009, 14(3):171-180.

13. Blaylock RL: A possible central mechanism in autism spectrum disorders, part 2:immunoexcitotoxicity. Altern Ther Health Med 2009, 15(1):60-67.

14. Minami T, Miyata E, Sakamoto Y, Yamazaki H, Ichida S: Induction of metallothionein in mouse cerebellum and cerebrum with low-dose thiomerosal injection. Cell Biol Toxicol 2009, in press.

15. Park JD, Liu Y, Klaassen CD: Protective effect of metallothionein against the toxicity of cadmium and other metals. Toxicology 2001, 163(2-3):93-100.

16. Shimada A, Nagayama Y, Morita T, Yoshida M, Suzuki JS, Satoh M, Tohyama C: Localization and role of metallothioneins in the olfactory pathway after exposure to mercury vapor. Exp Toxicol Pathol 2005, 57(2):117-125.

17. Jory J, McGinnis WR. Red-cell trace minerals in children with autism. American Journal of Biochemistry and Biotechnology 2008, 4(2):101-104.

18. Noseworthy MD, Bray TM: Zinc deficiency exacerbates loss in blood-brain barrier integrity induced by hyperoxia measured by dynamic MRI. Proc Soc Exp Biol Med 2000, 223:175-182.

19. Vruwink KG, Hurley LS, Gershwin ME, Keen CL: Gestational zinc deficiency amplifies the regulation of metallothionein induction in adult mice. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine 1988, 188(1):30-34.