1. of Massachusetts Department ENVIRONMENTAL PROTECTION NE-SRA June 19, 2007 Why are Kids Different? Underlying Biological and Physiological Characteristics MassDEP Office of Research and Standards Sandy, Ph.D. Sandy Baird, Ph.D.

2. of Massachusetts Department ENVIRONMENTAL PROTECTION Topics to Cover Susceptibility Lifestage approach Ontogeny of organ systems Physiology underlying increased susceptibility –Exposure –Effects

3. of Massachusetts Department ENVIRONMENTAL PROTECTION Evolution of Kids Risk – A Quick Review 1993 Pesticides in the Diets of Infants and Children (NAS) 1996 Food Quality Protection Act (FQPA) 1997 Executive Order 13045 1997 Office of Children’s Health established 2005 Supplemental Guidance for Early-life Exposures to Carcinogens 2005 Guidance on Selecting Age Groups for Monitoring and Assessing Childhood Exposures to Environmental Contaminants 2006 Framework for Assessing Health Risks of Environmental Exposures to Children

4. of Massachusetts Department ENVIRONMENTAL PROTECTION Why the interest in kids risk? Evidence of increased susceptibility Exposure/Dose –Physiology –Behavior –Location Health Effects –Incidence –Severity –Reversibility –Type –Latency

5. of Massachusetts Department ENVIRONMENTAL PROTECTION Susceptibility Increased likelihood of an adverse effect or exposure, often discussed in terms of relationship to a factor, that can be used to describe a human subpopulation, e.g., lifestage, demographic feature, or genetic characteristic (USEPA 2006) USEPA 2006 A Framework for Assessing Health Risks of Environmental Exposures to Children

6. of Massachusetts Department ENVIRONMENTAL PROTECTION Vulnerability Physical, chemical, biological and cultural factors affecting communities and subpopulations Recovery Exposure Susceptibility Preparedness

7. of Massachusetts Department ENVIRONMENTAL PROTECTION Adapted from USEPA 1994, USEPA 2002 Susceptibility Exposure Assessment Dose-Response Exposure Absorption Distribution Metabolism Excretion Tissue Dose Toxophore Tissue Interaction Altered Structure/ Function Observable Response -Cellular -Tissue -Organ -Whole organism ToxicokineticsToxicodynamics Exposure Assessment Exposure Characteristics Dose-Response Elements of a Chemical Exposure-Dose-Response Pathway

8. of Massachusetts Department ENVIRONMENTAL PROTECTION Lifestage Approach 2006 Children’s Framework Temporal Stages of Life have distinct characteristics –Anatomical –Physiological –Behavioral –Functional USEPA 2006 A Framework for Assessing Health Risks of Environmental Exposures to Children

9. of Massachusetts Department ENVIRONMENTAL PROTECTION Lifestage Approach Considers Mode of Action of Substance Critical Windows of Sensitivity Immediate and Later-life Effects USEPA 2006 A Framework for Assessing Health Risks of Environmental Exposures to Children

10. of Massachusetts Department ENVIRONMENTAL PROTECTION Lifestage Dose-Response Exposure Absorption Distribution Metabolism Excretion Tissue Dose Toxophore Tissue Interaction Altered Structure/ Function Observable Response Conceptus Exposure Absorption Distribution Metabolism Excretion Tissue Dose Toxophore Tissue Interaction Altered Structure/ Function Observable Response Birth to <3 months Exposure Absorption Distribution Metabolism Excretion Tissue Dose Toxophore Tissue Interaction Altered Structure/ Function Observable Response Postmenopausal women ToxicokineticsToxicodynamics Exposure Assessment Exposure Characteristics Dose-Response

11. of Massachusetts Department ENVIRONMENTAL PROTECTION Definition of a Child 2006 Children’s Framework USEPA 2006 A Framework for Assessing Health Risks of Environmental Exposures to Children ConceptionBirth Day 0 Sexually Mature Adult 16-21 yo Puberty 10-15 yo PreconceptionFetusNeonateInfantPreschoolChild Adolescent 11-<16 Adult 16-<21 1 month1 year6 years Child Developmental Exposure Period

12. of Massachusetts Department ENVIRONMENTAL PROTECTION Recommended Age Groups Based on behavioral and physiological exposure characteristics Birth < 1 month 1 to <3 months 3 to < 6 months 6 to < 12 months 12 to < 24 months 2 to < 6 years 6 to < 11 years 11 to < 16 years 16 to < 21 years USEPA 2005 Guidance on Selecting Age Groups for Monitoring and Assessing Childhood Exposure to Environmental Contaminants < 1 year> 1 year

13. of Massachusetts Department ENVIRONMENTAL PROTECTION Increased Exposure Rate Physiology –Inhalation – Ventilation Rate, alveolar surface area, lung architecture –Ingestion – water consumption, breast milk –Dermal - surface area –Body water content Behavior –Crawling, eating limited food items, activities Location –Floors, schools, playgrounds

14. of Massachusetts Department ENVIRONMENTAL PROTECTION 20 m 3 /day m 3 /day 0 -<2 yo>2 to <6 yo>6 - <21 yo Male Age-Specific Ventilation Rates m 3 /kg-day Child Default =10 m 3 /day/20kg =0.5 m 3 /kg-day Age (years) Draft Child EFH, Lordo et al 2006 Ratio of child- specific and adult default ventilation rates 4.4-5.2x 3.0-3.9x 1-2x Adult Default =20 m 3 /70 kg =0.28 m 3 /kg-day

15. of Massachusetts Department ENVIRONMENTAL PROTECTION Layton (1993) and Lordo et al. (2006) Ventilation Rate (m 3 /day) by Age in Males Age (years) Ventilation Rate (m 3 /day) Table 7-17 – Draft Child Specific Exposure Factors Handbook Data: Lordo et al. 2006 20 m 3 /day Layton 1993 15 9.3 7.3

16. of Massachusetts Department ENVIRONMENTAL PROTECTION Layton (1993) and Lordo et al. (2006) Ventilation Rate Adjusted for BW (m 3 /kg- day) by Age in Males Age (years) Ventilation Rate (m 3 /kg-day) Table 7-17 – Draft Child Specific Exposure Factors Handbook Data: Lordo et al. 2006 Adult Default =20 m 3 /70 kg =0.286 m 3 /kg-day 0.521 0.283 0.404 Layton 1993

17. of Massachusetts Department ENVIRONMENTAL PROTECTION Layton vs. Lordo Ventilation Rates Ratio male child by age to default adult (m 3 /kg-day) Age Groups (2005)Layton (1993) Lordo et al. (2006) 95th% Years RatioYearsRatio 0 - <10.5- <31.80 - <14.5 1 - <2 5.2 2 - <33.9 2 - <63 - <101.43 - <63.2 6 - <1110 - <1816 - <112 11 - <16 1.3 16 - <21 1

18. of Massachusetts Department ENVIRONMENTAL PROTECTION Increased Adverse Effects Effects that occur result from the interaction of the agent with the specific processes that are occurring in a tissue or organ system during the time of exposure. Effects may be observable immediately or may not be evident until later, after additional development or exposures occur.

19. of Massachusetts Department ENVIRONMENTAL PROTECTION Timelines for Development Age (years)

20. of Massachusetts Department ENVIRONMENTAL PROTECTION Synaptogenesis Migration Proliferation Cell Death Transmitters and receptors Trimming of connections Developing Brain as a Target of Toxicity Rodier EHP, 1995 Very complex system Dozens of different types of neurons Specific functions Specific timing Pre- and Postnatal development No blood-brain barrier in utero and in early-life

21. of Massachusetts Department ENVIRONMENTAL PROTECTION Development of the Respiratory System Trachea Alveoli Primary Bronchi Extrathoracic Region: Nose, nasal passages, larynx, pharynx, mouth Tracheobronchiole Region: Trachea, bronchi, bronchioles, terminal bronchioles (<25,000) Alveolar-Interstitial Region: Respiratory bronchioles, alveolar ducts, sacs with alveoli (<300 million), interstitial connective tissue 40 different cell types More than 80% of the alveoli in the adult arise postnatally. Dietert et al. EHP 2000

22. of Massachusetts Department ENVIRONMENTAL PROTECTION Lung Development Timeline Dietert et al. 2000 Humans

23. of Massachusetts Department ENVIRONMENTAL PROTECTION Immune Development Timeline Dietert et al. 2000 Humans

24. of Massachusetts Department ENVIRONMENTAL PROTECTION Increased Adverse Effects Incidence – vinyl chloride Irreversible – ozone, neurotoxicants Type – lead, mercury, DES Latency – DES, vinyl chloride Severity – lead, mercury

25. of Massachusetts Department ENVIRONMENTAL PROTECTION Thank You!