1. The Cincinnati Lead Studies: A 36 Year Perspective Ohio Healthy Homes Network Spring Forum Thursday, June 9, 2016 Kim N. Dietrich, Ph.D., M.A. Professor of Epidemiology The University of Cincinnati College of Medicine

2. Lead (Pb) and Health: The Flint, Michigan ‘Crisis’ (2014-2015)

3. The Cincinnati Lead Study (1979 – 2016)

4. The Cincinnati Lead Study (1979-2016)

5. Prospective, longitudinal study examined the early and late effects of childhood lead exposure on growth and development with a particular emphasis on central nervous system outcomes. Longest, continuously active prospective study of lead exposure and child health and development in the world. Data collected on exposure (blood lead concentrations), neurobehavior, child health, nutrition, environmental nurture, and sociodemographic variables on a quarterly to yearly basis since its inception.

6. The human brain has a protracted period of development and potential vulnerability to environmental toxicants such as lead. The human cerebral cortex eventually consists of 30 billion neurons, interconnected by 64,000 miles of axons and dendrites and more than a trillion supportive neuroglia. Lead is known to interfere with this developmental process In the womb and over at least the first five years of life. Pyramidal Cells Why Lead and the Developing Brain?

7. Cincinnati Lead Study: Blood Lead Assessment

8. Blood Lead Concentrations in the Cincinnati Lead Study Dietrich, et al., Pediatrics, 1993 Dietrich, et al. Pediatrics, 1993. CDC “Action Level” 1991 CDC “Action Level” 1985 CDC “Reference Level” 2012 CDC “Action Level” 1979

9. Cincinnati Lead Study Findings (1979-2016)

10. Early Exposure to Lead and Child IQ Low-Level Environmental Lead Exposure and Children’s Intellectual Function: An International Pooled Analysis Bruce P. LanphearBruce P. Lanphear, 1,2 Richard Hornung, 1,2,3 Jane Khoury, 1,2 Kimberly Yolton, 1 Peter Baghurst, 4 David C. Bellinger, 5 Richard L. Canfield, 6 Kim N. Dietrich, 1,2 Robert Bornschein, 2 Tom Greene, 7 Stephen J. Rothenberg, 8,9 Herbert L. Needleman, 10 Lourdes Schnaas, 11 Gail Wasserman, 12 Joseph Graziano, 13 and Russell Roberts 14Richard HornungJane KhouryKimberly Yolton Peter BaghurstDavid C. BellingerRichard L. CanfieldKim N. Dietrich Robert BornscheinTom GreeneStephen J. RothenbergHerbert L. NeedlemanLourdes SchnaasGail WassermanJoseph Graziano Russell Roberts N = 1,333

11. Beyond IQ

12. Adolescent and Adult Anti-Social Behavior as an Outcome of Childhood Lead Poisoning

13. Association of Blood Lead Levels and Self-Reported Delinquency in 16 Year-Old Adolescents in the Cincinnati Lead Study Dietrich, et al. Neurotoxicol Teratol. 2001

14. Questions from a Lead Study Cohort Why can’t I hold onto a job? Why can’t I get along with my girl friend/wife? Why am I angry all of the time? Why can’t I concentrate? Why can’t my son/daughter stay out of trouble?

15. Blood Lead Concentration Profile of a 26 Year-Old CLS Male Subject with a History of Domestic Violence and Delinquent/Criminal Behavior Age in Months Blood Lead Concentration (ug/dL)

16. Blood Lead Concentration Profile of a 26 Year-Old CLS Male Subject with a History of Adult Criminal Behavior and Repeated Incarcerations Age in Months Blood Lead Concentration (ug/dL)

17. Lead’s Effects across the Lifespan

18. Does Early Exposure to Pb Leave a Long- Term Signature in the Brains and Behaviors of Adults? The Cincinnati Lead Study (1979-2016) Neuroimaging studies Criminality studies

19. Environmental Factors in Criminal Disposition Parental dysfunction Community violence Poverty Media Lead Nutrition Alcohol Illicit Drugs Cincinnati, 1956

20. Covariates in Analyses of Adult Criminality Data Home Environment (HOME score) Birth Weight Gender Age Maternal Smoking During Pregnancy Maternal Drug/ETOH Use During Pregnancy Maternal Education Maternal IQ Total Prior Maternal Arrests Socioeconomic Status Household Size Public Assistance

21. Average Number of Criminal Arrests in the Cincinnati Lead Study Cohort (M Age = 22 years) by Average Blood Lead Concentration and Gender (Unadjusted) Average Number of Arrests Blood Lead Level ug/dL N = 250 Wright, Dietrich, Ris et al. 2008

22. Blood Lead Concentrations to Six Years and Arrest Rate Ratio for Violent Offenses* *Any 5 ug/dL elevation in blood lead increased the rate of arrests for violent offenses by 48 percent. Wright, Dietrich, Ris et al. 2008

23. Early Exposure to Lead and Career Criminality

24. Imaging Studies of the Cincinnati Lead Study Cohort: Volumetric and Functional MRI, MRS, and Diffusion Tensor Imaging

25. Covariates in Analyses of CLS Adult MRI Data Home Environment (HOME score) Birth Weight Gender Maternal Smoking During Pregnancy Maternal Drug/ETOH Use During Pregnancy Maternal Education Maternal IQ Socioeconomic Status Household Size Public Assistance Age at time of imaging Positive drug screen

26. Cincinnati Neuroradiological Studies of Childhood Lead Exposure and Adult Brain Outcomes fMRI – dose-dependent reductions in brain activation in the traditional language areas (Yuan et al. 2006). HR Anatomical MRI – dose-dependent reductions in cortical gray matter in the frontal lobe (Cecil et al. 2008). DT MRI – dose dependent injury to both myelin and axonal structures (Brubaker et al. 2008). Proton MRS – dose-dependent reduction in gray matter NAA along with white matter choline declines (Cecil et al. 2011).

27. Adult Cortical Gray Matter Loss in Cincinnati Lead Study Subjects in Relationship to Postnatal Lead Exposure to Six Years less significant more significant Single voxel significance Composite rendering Cecil K.M., Brubaker C.J., Adler C.M., Dietrich K.N., et al. (2008). Decreased brain volume in adults with childhood lead exposure. PLoS Medicine, 5m 741-750.

28. The Cincinnati Lead Study (1979-2016) New Investigations into the 21 st Century ‘Early Exposure to Lead and Bone Health in African-American Women’

29. Bone Health in African-American Women Exposed to Lead as Children (Bhattacharya, Dietrich, Chettle, & Kalkwarf) K-Shell XRF

30. Treatment of Lead-Exposed Children (TLC) Clinical Trial (First and Only Controlled Clinical Trial of a Drug to Reduce Lead Body Burden and Neurodevelopmental Impact in Children)

31. CDC Policy at TLC Start Blood lead level ( µg/dL) Actions Time frame for beginning intervention 10-14Provide caregiver lead education. Provide follow-up testing. Refer the child for social services if necessary. Within 30 days 15-19Above actions, plus: If BLLs persist (i.e., 2 venous BLLs in this range at least 3 months apart) or increase, proceed according to actions for BLLs 20-44. Within 2 weeks 20-44Above actions, plus: Provide coordination of care (case management). Provide clinical evaluation and care. Provide environmental investigation and control current lead hazards. Within 1 week 45-70Above actions and chelation therapy.Within 48 hours 70 or higherAbove actions, plus hospitalize child for chelation therapy immediately. Within 24 hours

32. Succimer COOH H - C - SH COOH

33. TLC Goal TLC was designed to test the hypothesis that children with moderate blood lead levels who were given succimer would have better scores than children given placebo on measures of central nervous system function.

34. At referral –12-33 months old at randomization –referral blood lead 20- 44 ug/dL –no disqualifying medical condition TLC Eligibility

36. Succimer and Placebo 26-day course of therapy to provide 1050 mg/m 2 of body surface area per day for the first seven days, 700 mg/m 2 day thereafter. Up to three courses of treatment to achieve PbB < 15 ug/dL. Placebo subjects were assigned retreatment to match the frequency of retreatment in the Succimer group.

37. TLC Mean Blood Lead Concentrations Over Time at Baseline & By Weeks After Treatment By Treatment Group 1994-1997

38. TLC Neuropsychological Domains Cognition, Learning, Memory, and Attention Academic Achievement Behavioral Conduct Neuromotor Performance

39. Unadjusted Effects of Treatment at Age 7 Years Succimer Placebo (323) (319) Variable Mean SD Mean SD p-value Full-Scale IQ 86.9 13.2 86.6 13.5 0.77 Reading 94.8 18.4 93.8 18.4 0.47 Externalizing 58.9 16.5 57.3 14.2 0.18 Problems Executive 86.6 16.5 88.5 17.7 0.20 Functions Dietrich, Ware, Salganik, et al., Pediatrics, 2004

40. Normalized Effect of Succimer at 7 Years Dietrich, Ware, Salganik, et al., Pediatrics, 2004

41. TLC Summary Chelation therapy is ineffective in reversing or minimizing adverse neurobehavioral consequences of childhood lead exposure in the range of 20-44 ug/dL. The only way to avoid lead-associated neurodevelopmental morbidity is to prevent exposure in the first place.

42. Funding for This Research

43. Recent Collaborators Kim M. Cecil (CCHMC) M. Douglas Ris (formerly CCHMC) Richard Hornung (CCHMC, UC DEH) Bruce P. Lanphear (CCHMC, UC DEH) John P. Wright (UC Criminal Justice) Sandra Roda (UC DEH) Mona Ho (CCHMC) Stephanie Wessel (UC DEH) Lisa Tully (CCHMC) Caleb Adler (UC Psychiatry) Kelly Jarvis (UC Psychiatry) Mekibib Altaye (CCHMC) John C. Egelhoff (UC Radiology) Ilayaraja Elangovan (UC Radiology) Christopher Brubaker (UCCM MD/PhD Program) Mary N. Rae (UC DEH) Aimin Chen (UC DEH) Amit Bhattacharya (UC DEH) Cyndy Cox (UC DEH) Lorenna Altman (UC DEH) Subjects and Families of the Cincinnati Lead Studies

44. Copies of Research Reports (kim.dietrich@uc.edu) All of the studies reviewed today on the fetus, infant and child exposed to lead in Cincinnati and elsewhere have been published in major peer-reviewed medical journals. I would be happy to provide copies of these upon request.

45. Questions and Discussion