Overview of US EPA Assessment Activities for Perfluorooctanoic Acid (PFOA) and Perfluorooctane Sulfonate (PFOS)

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1 Overview of US EPA Assessment Activities for Perfluorooctanoic Acid (PFOA) and Perfluorooctane Sulfonate (PFOS) Jennifer Seed, PhD Risk Assessment Division Office of Pollution Prevention and Toxics US EPA 1

2 Background Interest in perfluorinated compounds began in the late 1990 s Unique chemical properties which make them commercially valuable However, some members of the class: Persistent in the environment Persistent in many biological organisms Toxic to many biological organisms Present in blood of the general US population 2

3 PFOA Activities September 2002, Director of OPPT announced priority review process for PFOA November, 2002 Released draft hazard assessment of PFOA April, 2003 Released preliminary risk assessment of developmental toxicity January, 2005 Released draft risk assessment February, 2005: Reviewed by EPA s Science Advisory Board Final report is not yet available 3

4 Scope of the Draft Risk Assessment Focus on potential for human health effects in the general US population Considers information available as of June, 2004 Considers all potential human health effects Draft assessment is NOT intended to provide final risk estimates Seeking advice from SAB on significant scientific issues New information continues to be generated Assessment will need to be revised as appropriate 4

5 Current Database on PFOA Epidemiology studies in workers Data in rodents and monkeys Pharmacokinetics in rats and monkeys Carcinogenicity in rats Systemic toxicity in rats and monkeys Developmental and reproductive toxicity in rabbits and rats Immunotoxicity in mice Human biomonitoring data 5

6 Pharmacokinetics and Distribution Well absorbed Distributed mainly in serum and liver Not metabolized Enterohepatic circulation Half-life: Female rats estimates range from hours Male rats estimates range from days Elimination in young male and female rats is developmentally regulated Female monkey 20.9 days Male monkey 32.6 days Human 4.4 years 6

7 Epidemiology Studies Two mortality studies, a morbidity study, and studies examining effects on the liver, pancreas, endocrine system, and lipid metabolism, have been conducted to date. Studies have not shown any effects directly associated with PFOA exposure. 7

8 Animal Carcinogenicity Data Two 2-year bioassays in Sprague-Dawley rats show that PFOA exposure results in liver adenomas, Leydig cell adenomas, and pancreatic acinar cell tumors Disagreement as to whether there is an increase in mammary fibroadenomas 8

9 Key Events in the Mode of Action for PPARα- Agonist Induced Rodent Liver Tumors PPARα Agonist Causative Events Activation of PPAR α Cell Proliferation Decreased Apoptosis Associative Events* Expression of Peroxisomal Genes Increase in Peroxisomes (number & size) Preneoplastic Foci Clonal Expansion Liver Tumors *Although there are other biological events (e.g., Kupffer cell mediated events, inhibition of gap junctions), the measurements of peroxisome proliferation and peroxisomal enzyme activity (in particular acyl-coa) are widely used as reliable markers of PPARα activation. 9

10 Human Relevance of Rodent Liver Tumors Induced by the PPARα-agonist MOA The overall weight of evidence suggests that the rodent MOA for liver tumors is unlikely to occur in humans, taking kinetics and dynamic factors into account. Species differences in peroxisome proliferation and liver effects in response to PPARα-agonists. Humans are much less responsive or refractory to PPARα-agonists than rodents Human livers have about 10-fold less PPARα compared with the rat and mouse Evidence that there are species differences in PPARα - mediated gene regulation (e.g., different gene promoters, different receptor activities) No evidence of increased cell proliferation in hepatocytes of humans or non-human primates exposed to PPARα agonists 10

11 Evidence that PFOA-induced Rat Liver Tumors is via PPARα-agonist MOA PFOA has been shown to: activate PPARα COS1 cells transfected with a luciferase reporter gene induce peroxisome proliferation in the liver of rats and mice cause hepatomegaly (an early biomarker of peroxisome proliferator hepatocarcinogenesis) in rats and mice induce oxidative DNA damage in liver of rats Dose-response and temporal associations of the key events for the PPARα-agonist mode of action with the liver tumors have been characterized 11

12 Cancer Descriptor Rat liver tumors Data are sufficient to establish PPARα-agonist MOA for PFOA In general, PPARα-agonist MOA unlikely to occur in humans Rat Leydig cell tumors Assume relevant for humans Rat pancreatic acinar cell tumors Assume relevant for humans Based on the weight of the evidence of the epidemiology and animal data, PFOA best described as: Suggestive evidence of carcinogenicity No quantitative risk assessment 12

13 Endpoints Used in Risk Assessment for Adult Toxicity Cynomolgus monkey liver weight and possible mortality in 6-month study LOAEL = 3 mg/kg-day; no NOAEL Male rat F1 body weight from 2-generation reproductive toxicity study LOAEL = 1 mg/kg-day; no NOAEL Female rat body weight from 2-year study NOAEL = 10 mg/kg-day 13

14 Developmental Endpoints Used in Risk Assessment All endpoints are from a rat 2-generation reproductive toxicity study Decreased preweaning litter body weight in F1 pups NOAEL = 10 mg/kg-day Decreased postweaning body weight in F1 males NOAEL = 3 mg/kg-day Decreased postweaning body weight in F1 females NOAEL = 10 mg/kg-day Increased postweaning mortality and delayed sexual maturation in F1 males and females NOAEL = 10 mg/kg-day Unknown whether prenatal, lactational and/or postweaning exposures are critical. Therefore, important to assess risks for each of these periods. 14

15 Risk Assessment Approach Margin of Exposure (MOE) compares animal NOAEL/LOAEL with human exposure to evaluate potential for adverse outcomes. Exposure Dose NOAEL Rat (mg/kg/day) Exposure Dose Human (mg/kg/day) Internal Dose NOAEL Rat (AUC) Internal Dose Human (AUC) 15

16 Risk Assessment Approach Human blood concentrations have been measured. Apply directly or assume steady state. Animal blood concentrations in toxicity studies or in pharmacokinetic studies permit prediction of NOAEL/LOAEL blood concentrations. 16

17 PK Model Options PBPK Model Potentially gives comprehensive description of determinants of kinetics, Very limited data available in humans and even for rodents appears to require a research effort Noncompartmental analysis Used in several reports of rat PK Compartmental analysis Human blood concentrations interpretable as approximating steady state levels given estimates of long half life Extensive rat PK studies permit estimation of parameters in compartmental models (4 rats/dose/sex, 0.1, 1, 5, 25 mg/kg oral, 1 mg/kg intravenous) 17

18 Compartmental Modeling 1 compartment model Generally fitted data well, though there were indications of poorer fitting at late times at higher doses for females and some doses for males Values for volume of distribution, absorption rate, and elimination rate used to predict dose metrics for adults 2 compartment model Improved fit at late times, but not overall 18

19 Predicting Chronic Steady State Diet* (ppm) Dose Rate (mg/kg/day) Predicted C ss (µg/ml)** Measured* Avg 5, 8, 14 wks (µg/ml) *Palazzolo 1993 **1 Compartment Model 19

20 Predicting Rat Dose Metrics Have adequate data and satisfactory model (1 compartment) to predict Cmax and AUC for adult male & female rats at NOAEL/LOAEL in toxicity studies to evaluate MOE Limited predictions made for weanling pups, but not lactational period, for MOE evaluation 20

21 Predicting Human Dose Metrics Measured PFOA blood concentrations in two population studies. No information in risk assessment on sources or pathways of exposure, but blood levels are indicative of cumulative exposure Use directly for MOE comparison based upon Cmax. Assume steady state to calculate AUC for MOE 21

22 Biomonitoring Data U.S. General Population US Adults males, 313 females age yrs 6 ARC blood banks in various geographic locations (LA to Boston) Samples collected in 2000 ~10 samples/10-yr age interval/ sex US Children males, 298 females age 2-12 yrs Study of group A streptococcal infections Samples collected in from 23 states and DC 22

23 Human Biomonitoring Data Arithmetic 90th Geometric Population Mean Percentile Range Mean Adults (20-69 years, American Red Cross blood banks, 2000, n=645) Children (2-12 years, 1995, n=598)

24 MOE Adult Toxicity Monkey Data Steady-state for liver and mortality (LOAEL) Steady-state for adult humans Male Rat Data AUC for body weight (LOAEL 2-gen) AUC for adult humans Female Rat Data AUC for body weight (NOAEL 2-year) AUC for adult humans 24

25 MOEs for Developmental Toxicity Prenatal Rat Data Cmax or AUC pregnant rat (NOAEL) AUC for adult human females Postweaning Rat Data AUC for 4-week weanlings pup mortality (NOAEL) AUC for humans age 2-12 yrs - AUC for 4-5 week female delay/body weight (NOAEL) AUC for humans age 2-12 yrs AUC for 4-8 week male delay/body weight (NOAEL) AUC for humans age 2-12 yrs 25

26 Charge to EPA s SAB Seeking advice from SAB on: Conclusions on carcinogenicity Appropriateness of endpoint selection Pharmacokinetic modeling Use of internal dose metrics for the margin-of-exposure like approach Cross species extrapolation Robustness of human biomonitoring data 26

27 Ongoing Activities for PFOA Working with industry to gather information on pathways of human exposure CDC is including PFOA (and other perfluorinated compounds) in NHANES NTP conducting class study of perfluorinated compounds EPA participating in OECD hazard assessment April, 2006 EPA in process of IRIS assessment - RfD 27

28 PFOS Activities No risk assessment OECD hazard assessment completed in 2002 EPA IRIS assessment in progress -RfD 28

29 Acknowledgments Kathy Anitole Angela Auletta Hugh Barton Colette Hodes David Lai Chris Lau Elizabeth Margosches David Monroe Andrea Pfahles-Hutchens 29