Health-Based Maximum Contaminant Level Support Document ...
HEALTH-BASED MAXIMUM CONTAMINANT LEVEL SUPPORT DOCUMENT: PERFLUOROOCTANE SULFONATE (PFOS) New Jersey Drinking Water Quality Institute Health Effects Subcommittee Subcommittee Members: Jessie A. Gleason, M.S.P.H., Chair Keith R. Cooper, Ph.D. Judith B. Klotz, M.S., Dr. P.H. Gloria B. Post, Ph.D., DABT George Van Orden, Ph.D. November 28, 2017 Acknowledgements This document is based on the Health Effects Subcommittees review of an earlier draft document by Brian Pachkowski, Ph.D. and Alan Stern, Dr.P.H., DABT, with contributions from Lori Lester, Ph.D., of the NJDEP Division of Science, Research and Environmental Health. 2 Background
Drinking Water Quality Institute (DWQI) Established by NJ SDWA (1984) Charged with recommending Maximum Contaminant Levels (MCLs) Health Effects Subcommittee of DWQI is responsible for developing Health-based MCLs Carcinogens: One in one million risk level from lifetime exposure (10-6) Non-carcinogens: Not expected to result in any adverse physiological effects from ingestion for a lifetime March 2014: NJDEP Commissioner requested DWQI recommend an MCL for perfluorooctane sulfonate (PFOS) 3 Perfluorinated Chemicals (PFCs) Perfluorinated chemicals (PFCs) are a class of human made chemicals Part of larger group of highly fluorinated compounds: per- and polyfluoroalkyl substances (PFAS) Totally fluorinated carbon chains with charged functional group
PFOS is the eight-carbon sulfonate Extremely stable and resistant to chemical reactions Persists indefinitely in the environment Water-soluble 4 Occurrence in NJ Public Water Systems UCMR3 Detections (All large [>10,000 users] and a few smaller PWS; finished water; Reporting Limit= 40 ng/L): New Jersey PWS - 3.4% United States PWS -1.9% NJDEP Database Lower Reporting Limits, generally <5 ng/L 76 PWS; raw or finished water, or individual wells or intakes; NJDEP studies & other NJDEP data - excludes UCMR3 Detected - 42% of PWS >10 ng/L - 23% of PWS Some PWS with detections have taken action (stopping use of contaminated wells, blending, or installing treatment) 5
Sources of Human Exposure Food and possibly house dust from non-specific sources such as consumer product use and breakdown Drinking water and house dust (in some cases) from point source emissions Sources include industrial discharge; release of aqueous fire fighting foam in firefighting and training Recreationally caught fish may be an important source of PFOS exposure 6 Human Biomonitoring PFOS is found in serum of 99% of the U.S. general population (NHANES) Most recent (2013-14) data: Median: 5.2 ng/ml 95th percentile: 18.5 ng/ml
Levels decreasing over time (1999=30.4 ng/ml) Primarily from non-drinking water sources including diet and consumer products Found in human cord blood serum, breast milk and seminal fluid 7 Toxicokinetics Non-reactive and not metabolized Primarily distributed to liver > blood serum > kidney > lung > brain; does not accumulate in fat PFOS half-life estimates: about 5 years Remains in body for many years after exposure ends Large variation in half-life among species Higher serum level from same dose in humans v. animals. Interspecies comparisons made on basis of internal dose Urine is major route of elimination; other routes: bile; menstruation and breastfeeding in women Accumulates in the body over time; reaches steady state after prolonged exposure Clearance factor: 8.1 x 10-5 L/kg/day relates external exposure to serum level.
8 Increases in Serum PFOS Concentrations Predicted from Ongoing Exposure to PFOS in Drinking Water 9 Developmental Exposure Serum levels in infants At birth, similar to maternal serum levels Increases during first few months of life Exposures in infants higher than in older individuals From breastmilk or formula prepared with contaminated water Consume more fluid per body weight Of concern because developmental effects and other effects from short term exposures are sensitive toxicological endpoints Mogensen et al. 2015
10 Health Effects Subcommittee Document Development Process Comprehensive literature search Approximately 2900 citations; 700 identified as potentially useful for assessment of health effects Detailed review: Animal toxicology 76 studies Human epidemiology 121 studies Individual and/or Summary tables for epidemiology and toxicology studies 9 Epidemiology - Study Populations Study
populations include the U.S., Canada, and several European and Asian countries. General population (low-level exposures) Occupationally exposed workers No studies of communities with PFOS drinking water exposures 10 Associations with Health Effects Health effects investigated include: Body weight, thyroid function, metabolic function, sex hormones, hepatic, immune, neurologic, and renal effects, serum lipids, non-lipid blood chemistry, and reproductive/developmental effects Strongest evidence Decrease antibody response following vaccination Increased serum uric acid/hyperuricemia Increased total cholesterol 13 Epidemiology Conclusions Associations
of PFOS with health endpoints Such human data are not available for many other drinking water contaminants evaluated by DWQI Epidemiology findings are notable: Consistency among results in different populations Concordance with effects from animal toxicology studies, specifically for decreased immune response Use of serum concentrations as measure of internal exposure Associations within exposure range of the general population Potential clinical importance Limitations preclude use of human data as quantitative basis for Health-based MCL: But provides support for public health protective approach based on animal toxicology data
14 Toxicological Studies Numerous toxicological endpoints evaluated in rodents and nonhuman primates (monkeys) Notable toxicological effects include: Hepatic: liver weight and histopathological changes Immune: immune response (i.e. plaque forming cell response), relative weight and cellularity of spleen and thymus, levels of immunoglobulins and cytokines, changes in immune cell populations Serum lipids: cholesterol, HDL, LDL, triglycerides Thyroid: Changes in thyroid hormone levels Neurobehavioral: Changes in performance on behavioral tests Reproductive/Developmental: neonatal mortality; body weight at birth and beyond; Hepatic, thyroid, metabolic, and immune effects from gestational exposure Carcinogenicity: increased hepatic and thyroid tumors 15 Mode of Action Hepatic effects
Sometimes assumed to occur through peroxisome proliferator- activated receptor-alpha (PPAR)) Lower levels and/or intrinsic activity of hepatic PPAR-) in humans than in rodents Relevance for human health risk assessment is subject to debate However several lines of evidence suggest minor role, if any, for PPAR) in hepatic effects of PFOS PFOS is much less potent than known PPAR) activators for in vitro binding to PPAR) PFOS caused liver weight increase and liver pathology in PPAR)-null mice In chronic two-year rat study, PFOS caused hepatocellular hypertrophy, necrosis, and liver tumors without evidence of peroxisome proliferation 16
Mode of Action Immune effects Possible role for PPAR) In contrast to hepatic effects, no data suggesting lack of relevance to humans Other potential modes of action Developmental/fetal effects Observed effects do not necessarily share same MOA Developmental effects, including neonatal mortality, following gestational PFOS exposure are PPAR)-independent Possibly, PFOS interference with lung surfactant and other proposed MOAs 17 Mode of Action - Carcinogenicity Hepatocellular tumors
PFOS does not appear to be genotoxic or mutagenic Evidence indicates minor role, if any, for PPAR) dependent MOA No evidence to suggest lack of human relevance Thyroid follicular cell tumors No evidence to inform possible MOA Considered relevant to humans in risk assessment 18 Health-based MCL Derivation 19 Identification of Most Sensitive Noncancer Endpoints Dose-response analysis focused on health endpoints from subset of animal studies: Exposure durations greater than 30 days Shorter-term reproductive and developmental studies involving exposure during gestation and/or the immediate
post-natal period Reporting of serum PFOS concentrations at relevant timepoints Considered endpoints with LOAELs in the lower end of the range of serum PFOS concentrations (lowest quartile) 20 Identification of Most Sensitive Noncancer Endpoints - continued In the lowest quartile, the maximum LOAEL serum PFOS was 24,000 ng/ml Clustering of animal endpoints with LOAEL serum PFOS 10,000 ng/ ml Endpoints at or below this concentration were considered most sensitive animal endpoints (n=21) Further exclusions were made for study-specific concerns and/or lack of biological significance Four endpoints were carried forward for non-cancer dose-response analysis: Increased relative liver weight, adult mice (Dong et al., 2009) Increased relative liver weight, adult mice (Dong et al., 2012a) Increased hepatocellular hypertrophy, adult rats (Butenhoff et al., 2012) Decreased plaque forming cell response, adult mice (Dong et al., 2009) 21
Dose Response Analysis Non-cancer endpoints Based on serum PFOS concentrations (internal dose) rather than administered dose Dose-response investigated using USEPA benchmark dose modeling (BMD) software (ver. 22.214.171.124) Fitting and assessing benchmark dose model fit follows USEPA guidance If data did not support BMDL development, NOAEL or LOAEL used as point of departure (POD) 22 Points of Departure Two of four non-cancer endpoints provided acceptable fits and BMDL derived. Other two endpoints based on NOAEL Reference Endpoint
Basis of POD POD (ng/ml) Dong et al., 2009* Increased relative liver weight BMDL 5,585 Butenhoff et al., 2012 Increased hepatocellular hypertrophy BMDL 4,560
Dong et al., 2012a Increased relative liver weight NOAEL 4,350 Dong et al., 2009 Decreased plaque forming response NOAEL 674 Two studies of same endpoint: Dong et al., 2012a is more sensitive than Dong et al., 2009 (dropped from further consideration) 23 Target Human Serum Levels Analogous to Reference Dose (RfD) but in terms of internal dose rather
than administered dose. POD(PFOS serum) / Uncertainty Factors = Target Human Serum Level Endpoint and Reference Uncertainty Factors (UF) UF Total POD (ng/ ml) Target Human Serum Level (ng/ml) Heptacellular hypertrophy, 2 years (Butenhoff et al., 2012) 3 interspecies toxicodynamics
10 sensitive subpopulations 30 4,560 152 Liver weight, 60 days (Dong et al., 2012a) 3 interspecies toxicodynamics 10 sensitive subpopulations 3 subchronic duration 100 4,350 43.5 Plaque forming response, 60 days (Dong et al., 2009)
3 interspecies toxicodynamics 10 sensitive subpopulations 30 674 22.5 24 Development of RfDs from Target Human Serum Levels Clearance factor is a constant which relates human serum levels to administered doses such as RfDs Used to develop RfDs from Target Human Serum Levels USEPA derived clearance factor for PFOS of 8.1 x 10 -5 L/kg 152 RfD (ng/kg/day) 12.3
RfD (mg/kg/day) 1.23 x 10-5 Liver weight (Dong et al., 2012a) 43.5 3.5 3.5 x 10-6 Plaque forming response (Dong et al., 2009) 22.5 1.8 1.8 x 10-6 Endpoint and Reference
Target Human Serum (ng/ml) Heptacellular hypertrophy (Butenhoff et al., 2012) 25 Relative Source Contribution Factor (RSC) Accounts for non-drinking water sources including food, soil, air, water, and consumer products Default value for RSC is 20% 20% of total exposure is assumed to come from drinking water And 80% from non-drinking water sources If supported by available data, a higher chemical-specific value (up to 80%) can be used Insufficient data to develop chemical-specific RSC for PFOS No New Jersey specific biomonitoring data (U.S. - NHANES) PFOS occurs in public water more frequently in NJ than in US overall Communities with contaminated drinking water may also have more exposure from
non-drinking water sources such as dust, contaminated soil, or other environmental media Recreationally caught fish from contaminated waters may be important exposure source Default of 20% also implicitly accounts for higher exposures in infants than older individuals 26 Potential Health-based MCL Calculation Default exposure assumptions: 2 L/day drinking water consumption, 70 kg adult body weight, and 20% RSC Health-based MCL (ng/L) = RfD (ng/kg/day) Body weight (kg) Calculation: RSC Daily drinking water intake (L/day) Endpoint and Reference Target
Human Serum Level (ng/ml) RfD (ng/kg/day) Health-based MCL (ng/L = ppt) Heptacellular hypertrophy (Butenhoff et al., 2012) 152 12.0 84 Liver weight (Dong et al., 2012a) 43.5
3.5 25 Plaque forming response (Dong et al., 2009) 22.5 1.8 13 27 x Health-based MCL Recommendation Based on decreased plaque forming cell response in mice (Dong et al., 2009) Well established toxicological effect of PFOS four positive studies and
only one negative study. Identified as sensitive and relevant endpoint in several other scientific evaluations of PFOS Appropriate basis for risk assessment Indicator of decreased immune function and potential disease risk Used as basis for EPA IRIS risk assessments of other chemicals Supported by epidemiological evidence for analogous effect in humans - decreased vaccine response Lowest of the potential Health-based MCLs for non-cancer effects Recommended Health-based MCL is 13 ng/L 28 Weight of Evidence for Carcinogenicity Weight of Evidence Descriptor: Suggestive Evidence Of Carcinogenic Potential Only one study assessed carcinogenic potential: Chronic (2 year) rat study (Butenhoff et al., 2012) Increased incidence of:
Hepatocellular tumors in males (high dose only) and females Thyroid tumors in male recovery group only (exposed to high dose for 1st year, not exposed for 2nd year) 29 Estimation of Cancer Risk Concluded that cancer risk estimates are too uncertain for use as basis of Health-based MCL Thyroid tumor data not appropriate for dose-response modeling Hepatocellular tumor data from females support cancer slope factor development Slope factor from males highly uncertain - tumors only at high dose Slope factor based on female data is 9.0 x 10-6 (ng/kg/day)-1 Uncertainties include inclusion of recovery group data and dose metric based on area under the curve (AUC) serum levels At the recommended Health-based MCL of 13 ng/L, lifetime cancer risk was estimated as 3 in one million Close to cancer risk goal for New Jersey MCLs of one in one million 30
Uncertainties Health effects are associated with general population-level exposures to PFOS, indicating a need for caution about additional exposure from drinking water. Importantly, continued human exposure to even relatively low concentrations of PFOS in drinking water results in elevated serum PFOS concentrations. These elevations are greater in infants, a sensitive subpopulation for PFOSs effects Associations of PFOS with health effects in communities with contaminated drinking water have not been studied Potential additive toxicity of PFOS and other PFCs that may co-occur in NJ drinking water was not considered. Recommended Health-based MCL is 13 ng/L (0.013 g/L). 31
Comparison to USEPA Health Advisory Parameter Drinking Water Concentration Reference Dose (RfD) USEPA Office of Water (OW) Lifetime Health Advisory DWQI Draft Health-based MCL Recommendation 70 ng/L (applies to total of PFOS & PFOA) 13 ng/L 20 ng/kg/day (2 x 10-5 mg/kg/day) 1.8 ng/kg/day (1.8 x 10-6 mg/kg/day) Based on decreased body weight in
neonatal rats (F2 generation) Interspecies conversion Estimated lifetime cancer risk at Health Advisory /Healthbased MCL Based on decreased plaque forming cell response in adult male mice Based on pharmacokinetic modeling used Based on measured serum PFOS to predict average serum PFOS concentrations at end of dosing period. concentrations. Not assessed by EPA. Estimated as 2 x 10-5 based on DWQI cancer slope factor Estimated as 3 x 10-6 based on DWQI cancer slope factor suggestive evidence of carcinogenic potential Relative Source Contribution Factor Assumed Drinking
Water Consumption 20%. To account for non-drinking water exposures. . 0.054 L/kg/day; 90th percentile for lactating woman 32 0.029 L/kg/day; Based on NJDEP default upper percentile adult assumptions: 2 L/day, 70 kg Comparison to USEPA Health Advisory Endpoint Selection Endpoint (study) Administered dose at LOAEL (mg/kg/day) Serum PFOS concentration at LOAEL (ng/ml)
USEPA - neonatal body weight (Luebker et al. 2005) 0.4 25,000 Predicted average over exposure duration DWQI - plaque forming cell response (Dong et al., 2009) 0.083 7,132 Measured at terminal sacrifice Lower LOAEL for plaque forming cell response than neonatal body weight, based on both administered dose and internal dose USEPA acknowledges that plaque forming cell response is consistently found
in animals, and that concerns for adverse immune system effects are supported by human data Rationale for USEPA precluding plaque forming cell response for use in risk assessment is unclear to Health Effects Subcommittee 33 Increase in Serum PFOS Predicted from USEPA Health Advisory (70 ng/L) Average Water Ingestion Upper Percentile Water Ingestion Predicted increases of ~4-fold with average ingestion; ~6-fold with upper percentile (2 L/day) Greater increases in infants, a sensitive subpopulation for PFOS effects Increases in serum levels not considered by USEPA.
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