Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for

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-Toscano’s 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 • There does not appear to be compelling scientific evidence that food dyes cause ADHD. • 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. • These children may benefit from an elimination of these foods or food additives from their diets • 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.  • CHADD looks to the FDA to protect the health and well being of all our children, including those with ADHD. • 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: • Symptom count and severity • Impairment • Pervasive across settings • Chronicity • 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 • Don’t need diagnosable hypertension to be harmed by stress, excess salt, obesity.

8. Chronicity & Pervasiveness CriteriaAffect 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 it’s 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 Economo’s 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 children’s 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 • Can’t 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 child’s 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 (cont’d): • 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