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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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Presentation on theme: "Toxicology data on susceptible populations and its implications for risk assessment Lauren Zeise Office of Environmental Health Hazard Assessment California."— Presentation transcript:

1 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

2 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 2

3 Human variability and individual and population risk 3

4 Sources of differences in response among people 4 Food/nutriti on Psycho- social stressors Coexposur e Existing Health Conditions Heredity Gender, Lifestage

5 Source-to-outcome continuum and variability 5 Susceptibility Indicators Zeise et al. 2014

6 Context dependent, low dose effects 6 Kim Boekelheide slide, NRC Emerging Sciences Workshop, June 2012

7 Decreased AR activity at target tissue Interference with androgen mediated development Reproductive tract malformations  AGD 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”

8 Variability: Implications for Risk 8 Population Subpopulations

9 Distinct Susceptible Groups 9

10 Assay limitations to address variabilty and susceptibility 10 Data, models, theories, concepts Epidemiology Animal bioassays PBPK models In vitro assays, Toxicity pathways Adverse Outcome 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

11 Addressing susceptibility generically 11 Examples of data and analyses

12 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,

13 Age windows evaluated 13 Prenatal Postnatal Adult Juvenile conception birth day 22  day 49 //

14 23 Chemicals to Evaluate Cancer Age- Susceptibility Benzidine Benzo[a]pyrene Butylnitrosourea DDT Dibutylnitrosamine Diethylnitrosamine Diethylstilbesterol (DES) 7,12-Dimethylbenz[a]anthracene (DMBA) 1,2-Dimethylhydrazine Dimethylnitrosamine Di-n-propylnitrosamine 1-Ethylnitrosobiuret Ethylnitrosourea 2-Hydroxypropylnitrosamine 3-Hydroxyxanthine 3-Methylcholanthrene 4-(Methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK) Methylnitrosourea  -Propiolactone Safrole Tetrachlorodibenzodioxin (TCDD) Urethane Vinyl chloride

15 Carcinogenic activity ratio – Early Postnatal : Adult Early Postnatal

16 16 Early-life increased sensitivity to cancer Lifestage Fold Increase more than adult Mean Percentile 50 th 70 th 95 th Prenatal21310115 Postnatal791328350 Juvenile75720 Source: OEHHA, 2009

17 Variable physiology and pharmacokinetics Data sources Phase I and II metabolism and renal excretion with age (Dorne 2010; Ginsberg et al. 2002, 2004; Hattis et al. 2003) Bodymass, surface area, BMI, health status in older adults (Thompson et al. 2009) Metabolic enzyme polymorphisms (Ginsberg et al. 2009a,b; Bois et al. 1995, 1996; Walker et al. 2009; Neafsey et al. 2009a,b) 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 17

18 In vitro: Exploring genetic variability in human cell lines Originally studied to: Quantify variability in drug response Drug class signatures of cytotoxicity Prioritize drugs for investigation Utility in toxicology: Obtain measures of genetically derived variability Explore mode of action hypotheses Identify determinants of genetic susceptibility 18

19 Variable activation in 240 lymphoblastoid cell lines O’Shea et al. (2011), Toxicol Sci 119:398-407 19 Individuals 6 2 4 Activity

20 Example: Toxicodynamic variability estimated using population of human cells (Abdo et al. 2014) Distribution of inter- individual TD variability after correction for technical variability Repeat with 179 compounds Cytotoxicity across 1086 human cell lines 20 Slide source: Weihsueh Chiu

21 Differential Susceptibility with Hazard Trait Genotoxicity Traits named in NRC 2014, p. 35 Oncogenesis Cardiovascular Developmental Neurologic and sensory Hepatic Renal Gastrointestinal Endocrine Metabolic Disease Respiratory Reproductive Hematopoietic Immunologic Musculoskeletal Dermal Other

22 California’s consideration of sensitivity Evidence based adoption of defaults Infant and child specific exposure intakes - food, water, breast feeding, home grown food consumption, … Revised default intraspecies adjustment, absent data: - Pharmacokinetics 10, if no model and no specific data - Pharmacodynamics 3, if no additional child susceptibility 10, otherwise: (e.g., asthma exacerbation or neurotoxicity) 22 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

23 Addressing Specific Susceptible Populations 23 Case examples

24 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) 24

25 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 25

26 Urinary copper in 206 Wilson’s disease siblings 26 24-Hour Urine Copper (μg/day) No. of Subjects Distribution in normal adults Wilson’s Disease Adapted from NRC (2000)

27 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 27

28 Perchlorate Mode of Action 28 Pituitary THYROID GLAND T4 and T3 TSH Perchlorate Iodide Perchlorate

29 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)

30 30 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

31 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 95 th %tile water intake : body weight ratio  Addresses bottle fed infant Other exposures to perchlorate Food Infant formula

32 Emerging data stream example 32

33 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 33

34 Proof of concept studies: Genetically diverse “Mouse model of human population” Acetaminophen liver injury (Harrill 2009) o panel of 36 inbred mouse strains o 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. Trichloroethylene liver toxicity (Bradford 2011) o interindividual differences in 14 inbred stains - TCE metabolism and molecular signaling in the liver. 34


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