5. childrens health
TRANSCRIPT
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Effects on Children: Beyond Asthma
NESCAUM Health Effects Workshop
Joann Held
July 29, 2008
with thanks to: Gary Ginsberg, Ph.D.
Connecticut De t Public Health
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Child-Adult Differences Exposure Rates
Damage to Developing Organs
Immature Defense Mechanisms
Sensitive Life Stages In utero
Post-natal
Puberty Carcinogens in Early Life
Implications for Risk Assessment
and Standard-Setting
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Childrens Predictable Exposures
More food, more water / body weight
Inhale more air per body weight and per
lung surface area
Toxicokinetic factors
Less Predictable Exposures
Soil ingestion rate
Swimming/bathtub water ingestion rate
Unusual behaviors
Pica, glue sniffing, accidental
poisoning
Child-Adult Differences
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What is Toxicokinetics?
Toxicokinetics is essentially the study of"how a substance gets into the bodyand what happens to it in the body".
Four processes are involved intoxicokinetics.
Absorption
DistributionBiotransformationExcretion
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High Energy DemandGrowth Play Activities
High Caloric Needs
Faster Metabolism
High Ventilation Rate
Child-Adult Differences
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Child-Adult Differences: Ventilation
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Child - Adult Differences:
Ventilation Rate per Lung Surface Area
Lung Region 3 Month Old Adult Child/Adult
Ratio
Extra-thoracic 0.32 0.125 2.56
Tracheobron-
chial (Upper)
0.22 0.07 3.1
Tracheobron-
chial(Lower)
0.0084 0.0096 0.88
Pulmonary 0.00034 0.000026 13.1
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More Child-Adult Differences
There are many physiological differencesbetween children and adults
Important immaturities in clearance pathways infirst year of life
Liver metabolism
Renal clearance
Internal dose of parent chemical often higher invery young children but metabolite may belower
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Why Should We Be Concerned About
Greater Exposure Rate in Early Life?
Acute effects that are not a chronic concern: Irritation, anemia, internal organ damage, neurological
impacts
Chronic effects from long or short-term exposure: do we need to worry about brief exposures that are high?
Chronic toxicity (non-cancer) 30 to 70 yrsMinimal chronic period of 7 yrs
Cancer relevant exposure period --70 yrs
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Windows of Vulnerability: In Utero
Organ system development Critical windows of even a few days
Thalidomide limb malformation
Fetal Alcohol Syndrome (FAS)
Brain development irreversible neurotoxicity
Pesticides affect nerve impulse transmission Mercury attacks neurons; dont organize properly
Lead prenatal period is the most sensitive
PCBs, perchlorate, PBDEs affect thyroid function
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Windows of Vulnerability: In Utero
In utero Development
Hormone/endocrine imprinting in early life
DES(diethylstilbestro): female reproductive tractabnormalities and cancer can result from in utero
exposure
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In Utero Vulnerability: Air
Pollutants Los Angeles Studies
Higher CO and PM: 10-25% more pre-term
births 2500 births; Ritz, et al., 2007
Higher CO and ozone: 2-3xheart defects
Effect most in 2nd
month of pregnancy 9000 babies; Ritz, et al., 2003
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Post-Natal Vulnerability
Modified organ function, maybe modified structure
Lung growth in surface area and branching during first 8-12 yrs
Critical brain development Lead example, impaired learning, reduced IQ
Immune system development
Critical recognition of self vs non-self Endocrine systems - disruption of hormone levels early
puberty?
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Post-natal Effects of Ozone on
Respiratory Tract Monkey model Plopper, et al. 2007
Newborn monkey model for asthma
Combined exposure to HDMA and ozone
Intermittent ozone exposure: 0.5 ppm, 8 hr/day
5 days on, 9 days off for first 6 months of life
6 months to evaluate recoveryStructure and function of the airways damaged
HDMA = House Dust Mite Allergen
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Difference in size of a bronchial of an
infant monkey after various exposures
FA= Filtered Air
HDMA=House Dust
Mite Allergen
O3=Ozone
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Carcinogen Susceptibility
Good mechanistic grounds for heightened neonatalsensitivity to mutagens
Cell division rates
Longer time for tumor to be expressed
Figure 1.B
Change in Liver Weight (g) with Age
(Derived from equations in Haddad, et al., 1999)
0
10
20
30
40
50
60
70
80
90
0 - 0.5
yrs
0.5 - 1
yr
1-2 yrs 2-4 yrs4-6 yrs 6-8 yrs 8-10
yrs
10-15
yrs
15-20
yrs
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Cancer Vulnerability in Early
Life Cancer bioassays begin at 6 weeks of age
Miss juvenile and in utero periods
Isolated studies in 1960s thru 1990s injuvenile animalsSurprisingly high potency per exposure period
Haber Law not true
(Dose x Time = constant toxicity)Cannot pro-rate exposure over lifetime
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Chemicals Which Show Early
Life Cancer Vulnerability Mutagens
Nitrosoamines
BaP
Benzidine
Vinyl chlordie
Non-mutagensDDT, dieldrin, tamoxifen
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Hattis, et al., EHP 113: 509-516, 2005
MLEs of Cancer by sex and age compared to
adult rates at similar dosage
MLE= MaximumLikelihood Estimate
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Implications for Risk Assessment& Standard Setting
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from USEPA, Supplemental
Guidance for Childrens Cancer
Risk Assessment (2005)
Framework for Early Life Cancer
Risk Assessment
2 Yr 15 Yr 70 Yr
10x 3x 1xBirth
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I l t ti O ti 2
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Implementation Option 2:
Additive
1x Potency * Early Life (0-2) Dose
+
1x Potency * Adult Dose
Total Lifetime Cancer Risk
====================================
Each window of vulnerability receives adult slope factor without pro-rating;for example: Vinyl Chloride in Drinking Water
Risk for continuous lifetime exposure in adulthood is 2.1E-05/ug/L
Risk for continuous lifetime exposure from birth is 4.2E-05/ug/L
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Outstanding Issues with Cancer
Vulnerability Mutagens vs non-mutagens
Only address mutagens quantitatively? Non-mutagens on a case-by-case basis
Apply default to non-mutagen potency based uponlimited data currently available?
Treat mutagens and non-mutagens alike?
Any carcinogen with low dose linear potency basis
assume mutagen-like vulnerability in early life? Need to apply exposure and kinetics factors for
vulnerability windows to the risk estimate
I h l ti Ri k E ti
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Inhalation Risk Equation
Adjustments for Early Life:
Dose Approach Modifying adult risk equation for Mutagenic Toxic
Air Contaminant (TAC)
0-2 year old critical period
Inhalation rate/Body wt = 1.25 m3/kg/day
Adult Exposure for 30 years Inhalation rate/Body wt = 0.286 m3/kg/d
Pro-rate for 30/70 yrs = 0.123
Child/Adult Dose Adjustment Factor 1.25/0.123 = 10.2
Lifetime cancer risk = (10.2*CSF)+(1*CSF) = 11.2*CSF
CSF = Cancer Slope Factor
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Risk Equation Adjustments
(cont.) Non-mutagens: Adjustment factor = 2.3
(CSF* 10.2/8) + (CSF*1)
Non-Carcinogens: Minimum chronic period= 7 yrs
Inhalation rate for 0-7 = 1.1 m3
/kg/dAdult = 0.286 (not prorated)
Adjustment Factor = 1.1/0.286 = 3.8
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Summary
Children represent critical stages ofchemical vulnerability due to:
Greater dose rateToxicokinetics
Vulnerability for some endpoints
Initial steps now possible for incorporatingchildrens exposures and vulnerabilities intoRisk Assessment