1. Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus of Psychiatry Ohio State University

2. Disclaimers Have not done original research on behavioral effect of food dyes – Just an Educated Consumer But much research on ADHD Tx Selected by FDA to represent CHADD – Awkward position – Consulted with CHADD, but not common detailed position No financial interest either direction

3. Implementation of In Dubitas, Libertas Charge is to present ADHD 101 complementing Andrea Chronis-Toscanos presentation First present CHADD position, then speak for self Clarify relevant features of ADHD as diagnosis and general-population symptoms Show relevance to dyes Finally interim conclusions awaiting further research

4. CHADD Statement 1.There does not appear to be compelling scientific evidence that food dyes cause ADHD. 2.There may be a small subset of children with a hypersensitivity to certain foods or food additives, that result in an increase in activity level and/or inattention. 3.These children may benefit from an elimination of these foods or food additives from their diets 4.CHADD has no stand on the inclusion of food dyes in food consumed by the general population. We do not support or oppose the use of food dyes. 5.CHADD looks to the FDA to protect the health and well being of all our children, including those with ADHD. 6.And in doing so, we encourage the FDA to make decisions that are well grounded in the available scientific evidence.

5. Some Clarifications ADHD is phenomenological, not causal Dx Many causes common phenotype However, the phenotype itself is pleomorphic: – Predominantly inattentive type – Predominantly hyperactive-impulsive – Combined type – Not otherwise specified

6. Diagnostic Procedure Diagnosis requires 5 criteria: 1.Symptom count and severity 2.Impairment 3.Pervasive across settings 4.Chronicity 5.Not better explained by other mental disorder Because of first criterion, ADHD is dimensional diagnosis, like hypertension

7. Analogy to Hypertension Everyone has some blood pressure (BP) Too much is problem How to set the threshold for problematic BP? Wherever it is set, some people on the cusp Stress, excess salt, obesity can nudge some over the BP threshold Dont need diagnosable hypertension to be harmed by stress, excess salt, obesity.

8. Chronicity & Pervasiveness Criteria Affect measurement Consistent pattern of Behavior over time In more than one setting. Therefore cannot be measured or appreciated in short time fragments in artificial setting Must depend on caregiver ratings: P & T – Or at least caregiver informants Subjective, but most valid FDA indications for ADHD drugs on basis of caregiver info.

9. Causes of ADHD Are Multifactorial Genetics and Epigenetics – Up to 80% heritable (at least 50%) – Does not mean its only 20% environmental Genes expressed only by interaction with environment (including diet) PKU example: 100% heritable, 100% environmental/dietary Heritability could partly be genes for vulnerability to specific environmental factors

10. Multifactorial Hydraulic parfait for ADHD

11. First Suspected Causes: MBD Reproductive casualty – Increased fetal salvage – More hypoxia, trauma, bleeds; Kernicterus? Infections, parasites – Von Economos encephalitis – Intrauterine rubella – Measles, Streptococcal infection, etc. – New pathogens Head trauma, child abuse interaction

12. Increased Prevalence & Putative Causes ADHD 3-5% in 1970, as late as 1994 DSM; now estimated up to 10-12% Increased recognition, more liberal Dx Multiple environmental changes in past century – Educational setting and demands – Parents working outside home – Social breakdown – Color TV? --lack of cerebellar exercise? – New chemicals in environment

13. Environmental Contaminants & ADHD Sx Lead, other heavy metals – 1970s correlations, Pb in gasoline removed – Subclinical levels correlated same as dyes in Southhampton results. ---Needleman Insecticides associated with ADHD Sx severity – Organophosphate insecticide residues & metabolites in childrens urine, 2X the risk -- Bouchard et al, Pediatrics, 2009, June 2010, 125(6). – Maternal gestational serum insecticide delayed effect on child age 5 -- National Institute of Environmental Health Sciences, 2009

14. Environmental Contaminants --2 Industrial, construction, & consumer product chemicals – Cord blood PCB: top 25% 1.76X risk of ADHD Sx as bottom 25% --- Sagiv SK, et al. American Journal of Epidemiology, January 27, 2010, Online Early. – Polyfluoralkyl levels age 12-15 associated with ADHD -- Hoffman K,. Environmental Health Perspectives, June 15, 2010, Online Early. National Institute of Environmental Health Sciences Artificial food dyes – Evidence already presented

15. Consumption of Dye over Time

16. Nutritional Issues over Time Foods fewer minerals from 1930s to now – Intensive farming fertilizes only with big 3 Deficiencies of Fe, Zn, Mg reported in ADHD cf. to controls Non-anemic Fe deficiency can result from high carb diet (fries, chips, sugar, pastry) Fe is cofactor for synthesizing DA and NE, implicated in ADHD Some may be genetically more vulnerable

17. Nutritional Issues over Time Change of PUFA ratio from 5:1 to 50:1 omega3 : omega6 with intensively grain-fed meat animals and vegetable oils – Compete for desaturase enzymes – Omega3 deficiency impaired visual attn – Differences in PUFA profiles reported in ADHD – Omega 3 supplementation medium effect

18. Nutritional Issues over Time Interaction with intra-uterine stress: nicotine exposure from gestational smoking – Association of maternal smoking prenatally and postnatally with ADHD in child. Possible genetic link Thrifty phenotype (epigenetic) On average, kids with ADHD taller and heavier, with higher BMI (if not treated with a stimulant) ---MTA data

19. Food Dye Interaction with Nutrient 10 HA vs. 10 controls: lower serum, urine, nail Zn Tartrazine challenge: serum & saliva Zn down, urine Zn significantly up in HA, not controls Behavior deterioration correlated with Zn change Replicated in 23 HA parent-reported to react to food dye, compared to age/sex-matched controls 50 mg dye challenge: – Again serum Zn down, urine Zn up compared to controls Zn changes from dye challenge were associated with behavioral deterioration in both studies Ward NI et al (1990), J. Nutr. Med. 1(1):51-58. Ward NI (1997), J. Nutritional & Environmental Medicine 7(4): 333-342

20. Prevalent Flaws in Published Research on Dietary Sensitivities (Not Every Study) Diagnosis often not following DSM – Often just rating scale or clinical impression Blinding partial – Better blinding for food dyes Various mixes of dyes – Cant tell how much each contributes to effect Sometimes also preservatives – Not same class – Different economic, PH implications

21. Mixing Study of Dyes with Other Dietary Components Often start with oligoantigenic few foods diet and openly add back components to find offenders Then double-blind challenge with offenders that can be blinded Dyes one of the easier things to blind – Tasteless, camouflaged by dark food or drink – Preservatives also easy to blind – Therefore better studied than other components, but should not be considered the whole problem

22. Elimination Diets: Dyes Prominent But Not Solely Responsible 76 selected HA children 62 improved on open oligoantigenic diet – also headaches, bellyaches, fits improved 28 into DB, placebo crossover Sx returned more often with suspected food 48 foods incriminated – colors and preservatives most often, not alone » Egger J. et al, Lancet Mar.9, 1985, pp.540-545

23. Elimination Diets: Food Coloring 55 selected from 220 hyperactive children 40 improved on Feingold diet (no dyes) 26 remained improved after liberalization Parents of 14 claimed specific HA behavior 8 had DB Xover with 50 mg tartrazine or camoisine 2 reactors: irritabilility, restless, insomnia » Rowe KS Australian Ped. J. 24(2):143-147, 1988

24. Elimination Diets: Denominator Problem & Controls Reaction 200 selected from 800 hyperactive 150 improved openly to elimination of dye, with deterioration on open addition of dye 34 of these and 20 controls in Db challenge with 6 doses tartrazine and placebo. 19/23 suspected reactors, 3/11 uncertain reactors, and 2/20 controls clearly reacted Irritable, restless, sleep disturbance » Rowe & Rowe, J. Ped. 125(:691-698, 1994

25. Southhampton Studies Puzzling results by age: interaction with A & B Preschool reacted to Mix A same as in first study --constitutes replication Mix B substituted quinoline yellow and allura AC for tartrazine and ponceau 4R Could tartrazine and/or ponceau 4R be necessary for preschool reaction? Older children reacted to Mix B, not A on ITT: – More sensitive to quinoline yellow and/or allura AC --or higher dose?

26. Biological Basis of Dye Sensitivity Gene polymorphisms moderated effect of dye mixes on global hyperactivity score Significant Histamine genes: HNMT Thr105Ile both ages (Southhampton) HNMT T939C for 8-9 year olds Significant Dopamine gene: DAT1 in 8-9 year-olds Not significant: COMT val108met, ADRA C1291G, DRD4 rs740373

27. Interaction of Dye Effect with Histamine Genotype (8-9-yr-olds) --2 Stevenson et al, AJP, 2010

28. Physiological Evidence: Brain Topographical Mapping BEAM with and without provoking food (preceding weeks and same day) Crossover with blind interpretation of EEG With provoking food, increase in frontotemporal Beta-1 band activity and behavioral symptoms Actual challenge not blinded – Parents could have influenced childs EEG Uhlig T et al, Eur. J. Pediatr. 1997, 156(7):557-561

29. Other Evidence Biological Effect Erythrosine-induced inhibition of serotonergic activity in rats Dalal &Poddar, Pharmacology, Biochemistry, & Behavior, 2009, 92:574-582 Corticosterone effects of erythrosine in rats Dalal &Poddar, Toxicology Mechanisms & Methods, 2010, 20:287-297 Changes in liver function tests from mixtures in rats Aboel-Zahab et al, Boll.chim.Farmaceutico, 1997, 136:615-627 Human mast cell degranulation w. tartrazine, histamine release Schaubschlager, 1987; Murdock, 1987

30. Conclusions Need more research: Sample selection/characterization – Specialty clinics vs. general, normal controls – Address the denominator problem Careful diagnosis by DSM Unbundling: – Specific dyes as well as mixes – Dyes separate from preservatives Age effects: adolescents, adults?

31. Conclusions: Need more research (contd): Dose effects: how much is too much? How much by the highest ingesting children? Careful blinding – Double-blinding to prevent telegraphing Standard scales & observations Examine interaction with nutrients Examine interaction with medications Examine effects on whole classroom as well as individual children

32. Interim Working Conclusions (LEA) Food dyes not the main cause of ADHD But may contribute significantly to some cases – May additively push over the diagnostic threshold Several threads of biological mechanism Probably not an Immune-mediated reaction Deleterious effect not confined to ADHD (general effect replicated) Probably more a general public health problem than an ADHD problem

33. Working Conclusions – PH Issue (LEA) Small deleterious effect regardless of Dx was replicated and possible mechanism identified Magnitude of reported effect reminiscent of subclinical lead poisoning (<10 mcg/dL): d=0.17 after correction for social factors --Needelman Per capita consumption quadrupled last 50 yr. – The dose alone makes the poison --Paracelsus Possible effect on classroom climate from most children deteriorating slightly