Elaine M. Faustman, PhD, DABT Professor and Director

Institute for Risk Analysis and

Risk Communication

Department of Environmental and Occupational Health

Sciences

Children Matter: Using a Lifecourse Approach to Understanding Safety Assessment Needs for Children

Conflict of Interest

Dr. Faustman has no conflicts of interest

Faustman, 2016

Children Are Not Just Tiny Adults

Introducing Concepts of Life Course Analysis A. Use of Risk Assessment Frameworks Across Life Stage B. Building upon Social Ecological Models of Development ‒ How do we organize our data across lifestage? ‒ How do we analyze our data across lifestage? ‒ Example from out EPA-NIEHS funded Children’s Health Centers

Importance of Community Based Participatory Research (CBPR) Need for Temporal Assessment and Evaluation to identify exposures and

response and identifying effectiveness of interventions.

Next steps for Life Course Models

Outline

Faustman, 2016

Overall Framework for Assessing the Effects of a Toxicant on Development

Child Specific Behaviors Can Result in Child Specific Exposures

WHO (2006) Principles for Evaluating Health Risks in Children Associated with Exposure to Chemicals, Environmental Health Criteria, 237

Children’s Activities That Impact Exposures As a Function of Developmental Age (from USEPA, 2003b)

Food

Con

sum

ptio

n by

Infa

nts

(gra

ms/

kg b

ody

wei

ght/d

ay)

120

100

80

60

40

20

0

6-9m

9-12

m

11/2

-21/

2yr

2 1/2

-31/

2yr

3 1/2

-41/

2yr

16-6

4yr

Age

Infant products

Breast milk

Infant formulaCows milk

Family foods

Family beverages

Alcoholic drinks

Lawrie 1998

Age Related Consumption of Foods and Beverages As a Ratio of Intake to Body Weight

0.5 5.0 50.0

5060

7080

9010

0

Adult NHANES 2001-2002Child 12-19 NHANES 2001-2002Child 6-11 NHANES 2001-2002

Cum

ulat

ive

Prob

abili

ty

DMTP Concentration in Urine (ug/L)

DMTP in Urine: National Survey Children Higher Than Adults

Faustman, 2016

Questionnaire/ Diary/

Observation

Biological Measurements

“True” Exposure

(or Dose)

Community

Household

Individual

Scale Life Stage

Environmental Measurements

NCS, 2010

Combined Approaches for NCS Exposure Assessment

Need to Consider Both Exposure and Toxicological Differences across Life Stage

Faustman, 2016

Overall Framework for Assessing the Effects of a Toxicant on Development

Initial Appearance of Organs during Gestation in Humans Can Define Windows of Sensitivity

Differentiation

Proliferation

Migration time

Ventricular zone

Intermediate Zone

Cortical Plate

time

Radial glial cell

Ventricular zone

Cortical Plate

time

Radial glial cell

Dying cell

Glial proliferation

Key Processes of Neurodevelopment

Faustman, 2016

Faustman et al 2006

MIDBRAINproliferationmigrationapoptosis

CEREBRAL CORTEXproliferationmigrationapoptosis

CEREBELLUMproliferationmigrationapoptosis

HIPPOCAMPUS (FIELDS CA1–3)proliferationmigrationapoptosis

GLIAL PROLIFERATION9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2 3 4 5 6 7 8 9 10 11 12

Rat embryonic days (E9 – E22) Rat postnatal days (P1 – P12)

Sensitive Life-Stage and Region Specific Neurodevelopmental Processes

Each set of hashed bars represents the time of origin for each structure of the nervous system. Solid bars represent time to structural development for each nervous system structure (Rice and Barone 2000; Rodier 1977). Faustman et al 2003, Daston et al (2004) A

Framework for Assessing Risks to Children from Exposure to Environmental Agents. EHP 112:238-256

Nervous System Development in Humans and Rodents

Cresteil 1998

Metabolic Scheme for CP

Faustman et al. (2006)

PON1 levels plateau at 6 to more than 24 months of age May not reach adult levels until 5-7 yr

(Karen Huen, Nina Holland—UC Berkeley)

Developmental onset of PON1 activity in individual children

0

20

40

60

80

100

120

140

0 5 10 15 20 25

105 QQ 102 QQ

108 QQ 109 QQ

113 QQ

0

20

40

60

80

100

120

140

0 5 10 15 20 25

106 RR 107 RR

110 RR 100 QR

HUMANS: 192 Q/Q HUMANS: 192 R/R and 192 Q/R

Age (months) Age (months)

Ary

lest

eras

e(U

/mL)

0

20

40

60

80

100

120

140

0 5 10 15 20 25

105 QQ 102 QQ

108 QQ 109 QQ

113 QQ

0

20

40

60

80

100

120

140

0 5 10 15 20 25

106 RR 107 RR

110 RR 100 QR

HUMANS: 192 Q/Q HUMANS: 192 R/R and 192 Q/R

Age (months) Age (months)

Ary

lest

eras

e(U

/mL)

Cole et al. 2003. Pharmacogenetics 13:357–364

PON1 Levels Are Low in Children

Inhalation Oral Dermal

Exposure Absorption Distribution Metabolism Elimination

Toxicokinetics

Adolescent Child Newborn Conceptus Organ, Tissues Cellular Organelle Molecular

Cel

l Sig

nalin

g

Toxicodynamics

Normal Parameters Developmental Disorder • Lethality • Growth Retardation • Malformation • Altered Function

Outcome Incorporating Population Level Sustainability Factors, Polymorphism and Variability Data

00

.10

.20

.30

.40

.50

.6

0 1 2 3 4 5 6 7 8 9 10

00

.10

.20

.30

.40

.50

.6

0 1 2 3 4 5 6 7 8 9 10

Population

Pre-natal

Post-natal Infant Adolescent LIFESTAGE

RISK ASSESSMENT

Faustman, 2016

Risk Assessment Framework Across Life Stage

Life Stages Preconception Emb /Fetal

NB/Pre- weaning Juvenile Adulthood Old Age

Study Designs: Prenatal Developmental Toxicity Study

Reproduction and Fertility Study

Litter size, sex ratio, fetal survival, weight, gross structure

Developmental Neurotoxicity Study

F1 sexual maturatio

n

F1 estrous cycles, sperm measures, fertility,

pregnancy maintenance, parturition, organ weight, gross structure, histology

Adolescence

P

F1

Litter size, sex ratio, F1 & F2 survival, weight, gross structure, brain, spleen,

thymus weights

Subchronic/chronic

Embryonic death

Dominant Lethal

Clinical observations, viability, body weight,

food & water consumption

Neurotoxicity evaluations

Litter size, sex ratio, survival, weight, gross structure,

developmental landmarks including sexual maturation

Functional observations, motor activity, auditory startle

Clinical pathology (every 6 mos), ophthalmological exam, gross &

microscopic pathology

Motor activity, auditory startle, learning &

memory, neuropathology

Pestrous cycles, sperm measures, fertility, pregnancy

maintenance, parturition, organ weight, gross structure,

histology

Spectrum of Reproductive Toxicity Evaluations

Adapted from Kimmel et al, 2000

• Signaling pathways • Cell cycle kinetics • Viability including

mechanism of cell death

• Differentiation • Neuronal

phenotype

• Signaling pathways • Cell cycle kinetics • Viability including

mechanism of cell death

• Differentiation • Neuronal

phenotype • Migration • Brain structure and

morphology • Function • Behavior

• Signaling pathways • Cell cycle kinetics • Viability including

mechanism of cell death

• Signaling pathways • Cell cycle kinetics • Viability including

mechanism of cell death

• Differentiation • Neuronal phenotype • Migration • Brain structure and

morphology • Function • Behavior

MEFs Human Mouse NPCs

Faustman, 2016

Ability of Experimental Systems to Assess and Predict Neurodevelopmental Toxicity across Multiple Levels of Biological COMPLEXITY

Inhalation Oral Dermal

Exposure Absorption Distribution Metabolism Elimination

Toxicokinetics

Adolescent Child Newborn Conceptus Organ, Tissues Cellular Organelle Molecular

Cel

l Sig

nalin

g

Toxicodynamics

Normal Parameters Developmental Disorder • Lethality • Growth Retardation • Malformation • Altered Function

Outcome Incorporating Population Level Sustainability Factors, Polymorphism and Variability Data

00

.10

.20

.30

.40

.50

.6

0 1 2 3 4 5 6 7 8 9 10

00

.10

.20

.30

.40

.50

.6

0 1 2 3 4 5 6 7 8 9 10

Population

Pre-natal

Post-natal Infant Adolescent

LIFESTAGE

RISK ASSESSMENT

Aging

Faustman, 2016

Extending our Life Stage Framework

Multiple Sources: K. Sabon et al, 2014; D. Foley et al, 2009

Life Course Considerations for Epigenetics

IPCS, May 2007

Principles for Evaluating Health Risks in Children Associated with Exposure to Chemicals

NOAEL Uncertainty

Factors =

“Safe Dose” (RFD)

NOAEL Approach

Benchmark Dose Approach BMDx

Uncertainty Factors

= “Safe Dose” RFD

X = Response Level

Risk Assessment Approaches

NOAEL-No Observed Adverse Effect Level Exposure level at which there are no statistically or

biologically significant increases in observed adverse effects between exposed population and control population.

BMD-Benchmark Dose Modeling of the dose response for adverse

endpoints and identification of effect levels. For example identification of the dose that results in a 10% change and the 95% confidence limit on that dose

Two Approaches Frequently Used for Identifying Critical Effects

Guideline Factors

Average Sensitive human 10x

Animal Human 10x

LOAEL NOAEL 10x

Data base inadequacies 10x

Guidelines for Uncertainty (Safety) Factors

Food Quality Protection Act (FQPA) Child Specific Uncertainty Factor Age Adjustment Factors

Additional Factors to Consider

Framework to Describe Assessment of the Effects of a Toxicant on Development

Faustman, 2016

Age

Span

Neu

rolo

gica

lRe

prod

uctiv

eRe

nal

Endo

crin

e

Adverse Effects of Developmental Stage-Specific Exposures on Various Organ Systems

Preconception Preimplantation Embryonic Age Fetus Neonate Infant Child AdolescentCa

rdia

cIm

mun

eRe

spira

tory

Canc

er

Agent: Folic AcidOutcome: rate of NTDs

Agent: Retinoic acid,valproic acid, arsenicOutcome: NTDs

Agent: LeadOutcome: Intelligence, behavioral problemsAgent: MethylmercuryOutcome: cerebral palsy,mental retardation

Agent: Dioxin (TCDD)Outcome: Fertility infemale rats

Agent: Folic AcidOutcome: rate of NTDs

Agent: PhthalatesOutcome: AGD,malformationsAgent: PBB, Outcome:Pubertal development delayAgent: DES, Outcome: Vaginaladenocarcinoma in youngwomen

Agent: EthanolOutcome: Delayed pubertyAgent: AtrazineOutcome: Delayed pubertyin rats

Agent: DioxinOutcome: Hydronephrosis

Agent: Maternal exposure toangiotensin inhibitorsOutcome: ACE fetopathy andrenal failure

Agent: DioxinOutcome: Hydronephrosisin rats

Agent: DioxinOutcome: Hydronephrosisin rats

Agent: PesticidesOutcome: Parkinson-likedeclines in dopaminergicneurons in adulthood

Agent: High-dose ionizingradiationOutcome: Brain tumors andmeningiomas

Agent: Maternal smokingOutcome: Birth weight, Diabetes, osteoporosisAgent: PCBsOutcome: T3/T4 levels ininfant and juvenile rats

Agent: LeadOutcome: Abnormal bonestructure, poor growth

Action: Maternal groomingOutcome: Adult ability torespond to stress in rats

Agent: X-rays, urethanOutcome: Cancer inoffspring of male mice

Agent: MethylmercuryOutcome: Heart ratevariability in childrenAgent: IUGROutcome: risk ofcoronary heart disease

Agent: Atomic bombradiationOutcome: Leukaemia

Agent: Ionizing radiationOutcome: LeukaemiaAgent: Radioisotopes ofiodine from ChernobylOutcome: Thyroidcarcinoma

Agent: High-dose ionizingradiationOutcome: Breast cancer

Agent: Air particulatesOutcome: Exacerbation ofpre-existing asthmaAgent: Chronic ozoneexposureOutcome: Lung function

Agent: Air particulatesOutcome: Respiratorymortality

Agent: Air particulatesOutcome: Respiratorymortality

Agent: Methoxyclor,heptachlorOutcome: Cell-mediatedimmunity in male ratsAgent: Lead, Outcome:Th1 immune capability,Th2 response in ratsAgent: Maternal smokingOutcome: Collagendeposition in airway walls,

Postnatal hypoxicresponse

Agent: Inorganic arsenicOutcome: Adrenal tumorsin male offspring, ovarianand lung tumors in femaleoffspring

IUGR - Interuterine growth retardation, NTD - Neural Tube Defect Adapted from WHO/IPCS 2006 EHC 237

33

Hirschfeld NCS, 2010

IOM, 2004

Multiple, Interacting Influences Affect Children’s Health including Chemical and Non-Chemical Stressors

Source: Children’s Health, Nation’s Health, IOM report, 2004

A New Life Course Based Model of Children’s Health and Its Influences

• Importance of early exposures • Complexity of factors affecting development • Complexity of Environmental Exposures • Need to consider these across multiple stages of

development and at difference levels of assessment • Need for framework for evaluating risks • Need for Life Course Frameworks for incorporating

both chemical and non-chemical stressors

Observations

Acknowledgements • The NIEHS, EPA funded Center for Children’s Environmental

Health Risks Research (RD-83170901, 5P01ES-09601) • National Institute of Child Health and Human Development,

National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN267200700023C

• US Environmental Protection Agency Biomarkers grant (RD-83273301) and contract (2W-2296-NATA)

• EPA funded Predictive Toxicology Center (USEPA STAR grant RD-83573801)

Acknowledgements

Moore JA, Daston GP, Faustman EM, Golub MS, Hart WL, Hughes C, Kimmel CA, Lamb JC, Schwetz BA and Scialli AR An Evaluative Process for Assessing Human Reproductive and Developmental Toxicity of Agents. Reproductive Toxicology. 1995: 9(1): 61-95.

Faustman EM, Silbernagel S, Fenske R, Burbacher T and Ponce R. Mechanisms underlying children's susceptibility to environmental toxicants. Environ Health Perspect. 2000; 108 Suppl 1: 13-21.

Daston G, Faustman EM, Ginsberg G, Fenner-Crisp P, Olin S, Sonawane B, Bruckner J, Breslin W and McLaughlin TJ. A framework for assessing risks to children from exposure to environmental agents. Environmental Health Perspectives. 2004; 112(2): 238-56.

Eskenazi B, Gladstone EA, Berkowitz G, Drew CH, Faustman EM, Holland NT, Lanphear B, Meisel SJ, Perera FP, Rauh VA, Sweeney A, Whyatt RM and Yolton K. Methodologic and logistic issues in conducting longitudinal birth cohort studies: Lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research. Environmental Health Perspectives. 2005; 113(10): 1419-1429.

Faustman EM, Omenn GS. Risk assessment. In: Casarett and Doull's Toxicology: The Basic Science of Poisons, 8th Edition, C. Klaassen (ed.), New York: McGraw-Hill, Inc., 2013.

Faustman EM (Contributing author). Principles for Evaluating Health Risks in Children Associated with Exposure to Chemicals. Environmental Health Criteria Series, United Nations Environment Programme, International Labour Organization, and World Health Organization. 237. 2007

References