Toxicology data on susceptible populations and its implications for risk assessment Lauren Zeise Office of Environmental Health Hazard Assessment California Environmental Protection Agency Presentation to The Food Advisory Committee US Food and Drug Administration Center for Food Safety and Applied Nutrition December 16, 2014 Silver Springs, Maryland The views in this presentation are those of the author and do not necessarily reflect those of the California Environmental Protection Agency or the its Office of Environmental Health Hazard Assessment
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Toxicology data on susceptible populations and its implications for risk assessment Lauren Zeise Office of Environmental Health Hazard Assessment California.
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Toxicology data on susceptible populations and its implications for risk assessment
Lauren ZeiseOffice of Environmental Health Hazard Assessment California Environmental Protection Agency
Presentation to The Food Advisory CommitteeUS Food and Drug AdministrationCenter for Food Safety and Applied NutritionDecember 16, 2014 Silver Springs, Maryland
The views in this presentation are those of the author and do not necessarily reflect those of the California Environmental Protection Agency or the its Office of Environmental Health Hazard Assessment
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Outline
• Human variability, susceptibility and population risk
• Toxicology data-based approaches to address susceptibility generically
• Case examples of approach to susceptible populations in regulatory advice
• Emerging data stream example
Human variability and individual and population risk
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Sources of differences in response among people
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Food/nutrition
Psycho-social
stressors
Coexposu
re
Existing Health
Conditions
Heredity
Gender, Lifestage
Source-to-outcome continuum and variability
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Source-to-Outcome Continuum
Source/media concentrations
Internal concentrations
Biological response measurements
Physiological/health status
External doses
Exposure
Toxicokinetics
Toxicodynamics
Systems dynamics
Types of Biological Variability
Co-exposures
Food/Nutrition
Gender, Lifestage
Heredity (genetic & epigenetic)
Existing health
conditions
Psychosocial stressors
Modifying source-to-outcome parameters
Modifying baseline conditions.
Outcome latency, likelihood, and
severity
Baseline biomarker values
Background and co-exposure doses
Endogenous concentrations
Exposure parameters
Pharmacokinetic parameters
Pharmacodynamicparameters
Systemsparameters
Susceptibility Indicators
Zeise et al. 2014
Context dependent, low dose effects
6Kim Boekelheide slide, NRC Emerging Sciences Workshop, June 2012
Decreased AR activity at target tissue
Interference with androgen mediated development
Reproductive tract malformationsAGD
Nipple Retention
Hypospadias
Sperm quality
Leydig cell tumors Cryptorchism Other reproductive
tract malformations
Other Decreased Decreased Blockade of Androgen Mutated Stressors Testosterone Dihydrotestosterone Receptor (AR) Receptor
Varied related outcomes – upstream endpoint
“Phthalate Syndrome”
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Variability: Implications for Risk
• Population
• Subpopulations
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Distinct Susceptible Groups
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Assay limitations to addressvariabilty and susceptibility
Data, models, theories, concepts
Source-to-Outcome Continuum
Source/media concentrations
Internal concentrations
Biological response measurements
Physiological/health status
External doses
Exposure
Toxicokinetics
Toxicodynamics
Systems dynamics
Epidemiology
Animalbioassays
PBPKmodels
In vitroassays,Toxicitypathways
AdverseOutcome Networks
In vitro systems are typically genetically homogeneous.
Traditional epidemiology:• Limited power to examine
susceptibility factors.• Generalizing from
occupational cohorts to the overall population.
Use genetically homogeneous experimental animals in uniform environments.
Few examples and data to support population PBPK
modeling
Currently do not focus on variability and susceptibility
Addressing susceptibility generically
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Examples of data and analyses
Early-life susceptibility to carcinogens
• Human examples• Diethylstilbestrol (DES)
in utero • Radioactive iodine early
childhood• Immunosuppressive
agents during childhood• X-irradiation during
adolescence
• Animals• Many examples • Systematic study of
literature (e.g., EPA,
Age windows evaluated
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Prenatal
Postnatal
Adult
Juvenile
conception birth day 22 day 49//
23 Chemicals to Evaluate Cancer Age-Susceptibility • Benzidine
- Pharmacokinetics 10, if no model and no specific data
- Pharmacodynamics 3, if no additional child susceptibility 10, otherwise: (e.g., asthma exacerbation or neurotoxicity)
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Respiratory Tract Tissue
Gas Exchange
Respiratory Tract Lumen (Inhalation)
Respiratory Tract Lumen (Exhalation)
Venous Blood
Rapidly Perfused
Slowly Perfused
Fat
Gut
Liver
Kidney
Oxidation & Conjugation
Oxidation
(Dead space)
Stomach
Duodenum
Oral
IV
IA
PV
Inhaled air Exhaled air
Addressing Specific Susceptible Populations
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Case examples
Case examples for populations with identified susceptibility to toxicant
• Age• Perchlorate interference of I- uptake in bottle fed infants (CalEPA
OEHHA)• Cadmium and renal toxicity in older adults (CalEPA OEHHA 2006)• Developmental and reproductive toxicity – many examples
• Health status• Effects of ozone on asthma sufferers (EPA 2006)• Effects of copper on Wilson’s disease heterozygotes (NRC 2006)
• Co-exposure and health status• Cancer risks to smokers for radon (EPA 2006) and arsenic (CA
2009)
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Genetic susceptibility example: Wilson’s heterozygotes and copper toxicity
• Wilson’s disease• Autosomal recessive disorder• Defective biliary excretion of copper• Copper ccumulation in brain and liver leads to chronic
cirrhosis and neuropsychiatric disorder• Frequency: at least 1 in 40,000 births
• Wilson’s heterozygotes• Abnormal biliary excretion observed in 50% of
heterozygotes• Cases of liver toxicity also observed• Frequency: at least 1% of general population
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Urinary copper in 206 Wilson’s disease siblings
24-Hour Urine Copper (μg/day)
No.
of S
ubje
cts
Distribution in normal adults
Wils
on’s
Dis
ease
Adapted from NRC (2000)
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NAS Committee on Copper in Drinking Water
Concern for infants with altered copper metabolism• High drinking water consumption compared to adults
Bottle fed infant with several fold higher consumption• Factor of 3 higher levels of liver copper compared to
adults• Liver toxicity from in Wilson’s heterozygotes and others
genetic polymorphisms that affect copper elimination• Concern supported by experimental animal strains
sensitive to copper due to genetic alterations Models provide insights on effects and mechanisms
Perchlorate Mode of Action
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Pituitary
THYROIDGLAND
T4 and T3
TSHPerchlorate
Iodide
Perchlorate
Considerations
• Thyroid hormone-dependent brain and neurodevelopment (Haddow et al., 1999; Klein et al., 2001; Kooistra et al., 2006; Pop et al., 2003; Pop et al., 1999; Vermiglio et al., 2004)
• Low stores of thyroid hormone (van den Hove, 1999)
• Low iodine intakes (Pearce et al., 2007: 47% women with breast milk iodine levels below Institute of Medicine recommendations for infant intake)
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Maternal influences on infant susceptibility
• About 2.5% of pregnant women in U.S. suffering from subclinical hypothyroidism
• About 15% women had low iodide excretion in NHANES III
• Mother is infant’s major source of iodine if she is breast-feeding
• Perchlorate excreted in milk if mother is consuming it in food and water
• If mother is a smoker, she delivers less iodine in milk
California Advisory Level for Perchlorate
• Upstream adverse event• Interference of I- uptake
• Identifiable subgroup at risk• Infants • Pregnant women and fetus via mom’s exposure
• Exposure estimate to ensure adequate margin of safety
• 95th %tile water intake : body weight ratio Addresses bottle fed infant
• Other exposures to perchlorate• Food• Infant formula
Emerging data stream example
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Experimental in vivo data: genetically diverse animal models
• Large panel of new inbred mouse strains
• Combines genomes of 8 genetically diverse founder strains
• Population structure randomizes existing genetic variation
• Captures ≈ 90% known variation in lab mice
Example: Collaborative Cross
Image by D. Threadgill
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Proof of concept studies: Genetically diverse “Mouse model of human population” • Acetaminophen liver
injury (Harrill 2009)o panel of 36 inbred mouse
strainso whole-genome
association analysis o polymorphisms in Ly86,
Cd44, Cd59a, and Capn8 correlated strongly with liver injury
o orthologous human gene, CD44, associated with susceptibility in two independent cohorts.