Health Effects of GenX: What do we know and what do we need to know to protect public health?

Transcription

1 Health Effects of GenX: What do we know and what do we need to know to protect public health? Jamie DeWitt, PhD, DABT Department of Pharmacology & Toxicology Brody School of Medicine East Carolina University Greenville, NC Presented for: 45 th Annual Meeting of the Cape Fear River Assembly May 23, 2018

2 PFASs are diverse synthetic compounds used mostly as surfactants or raw materials for surfactants and surface protection products for many industrial and consumer products important in our everyday lives. Image source: 2

3 However, due to their use, PFASs have become environmental contaminants, not only in the U.S., but across the world. Areas highlighted in blue indicate zip codes where PFASs were detected in one or more water samples from that were at or above minimum reporting levels required by the EPA s third unregulated contaminant monitoring rule. Image source: Hu et al Environmental Science & Technology Letters. 3

4 Part of the problem is that we re still trying to trace how humans get exposed and what PFASs do to us once they get in our bodies. Source of emission Atmosphere Terrestrial ecosystems Aquatic ecosystems (lakes, rivers, streams, estuaries, oceans, groundwater) Sediments 4

5 GenX is only one among thousands of compounds that we classify as perand polyfluoroalkyl substances (PFASs). > 10,000 may exist in the environment as a result of breakdown and/or transformation Figure from: Wang et al Environmental Science & Technology. 51:

6 In the Cape Fear River, at least 11 other PFESA and PFECA compounds that are not GenX have been identified. All of unknown toxicology. All making it to drinking water plants and into people. Can we protect ourselves in the absence of robust toxicological data? Are protections necessary? Figure from: Sun et al Environmental Science & Technology Letters. 6

7 What we KNOW about health effects of GenX in humans: What can we surmise from studies of perfluorooctanoic acid (PFOA) and from experimental animal studies of GenX?

8 Determined probable links associated with PFOA exposure in this mid-ohio valley community.

9 Probable links for the C8 Science Panel study: given the available evidence, it is more likely than not that among the class members [those in the Class Action Settlement] a connection exists between PFOA exposure and a particular human disease. Probable links for PFOA in this community included: Cancer - kidney and testicular Diagnosed elevated cholesterol Pregnancy-induced hypertension and preeclampsia Thyroid Disease Ulcerative colitis

10 Other studies of exposed humans have reported positive associations between PFOA (or in some cases, perfluorooctane sulfonate; PFOS or both PFOA and PFOS) and additional adverse health effects, notably: Developmental toxicity, including dyslipidemia, immunotoxicity, renal function, and age at menarche (as reviewed by Rappazzo et al., 2017) as well changes to fertility and birth weight. Immunotoxicity, including decreased responses to vaccines and increased risk of asthma (as reviewed by Rooney et al, 2016). Liver damage indicated by changes to liver enzymes (various). Studies of experimental animal models (i.e., laboratory rats and mice) support many of these epidemiological findings.

11 Studies in experimental animal models are necessary to help us to understand how individual PFASs are associated with specific adverse health effects. Such studies have demonstrated that PFOA is capable of consistently inducing the following adverse health effects in experimental animal models (mostly rats and mice): Liver toxicity Developmental and reproductive toxicity Immunotoxicity Cancer (liver, testicular, and pancreatic)

12 PFOA has been associated with adverse health effects in exposed human populations and studies in experimental animal models support that many of these adverse health effects are induced by exposure to PFOA alone. Are these data sufficient to protect human health? What other information do we need to understand effects of PFOA (and other emerging contaminants) on human health?

13 True, in part, because dose is not the only part of the equation. Dose = how much PFOA does it take to produce adverse health outcomes in humans? Experimental animal models? But, we also have to consider other factors, such as: How long is exposure (duration)? What is developmental stage/age at exposure? By what route are people getting exposed? Other?

14 What has the U.S. EPA done to evaluate health risks from PFOA in drinking water? 1. Under the guidelines of the Safe Drinking Water Act, U.S. EPA conducted an analysis of available data (400+ publications!) to a) Describe the toxicological properties of PFOA and b) Determine the risk PFOA poses to humans exposed to it in their drinking water. 2. The results of the analysis were published in 2016 as the Health Effects Support Document for Perfluorooctanoic Acid (PFOA). 14

15 Reference dose = mg/kg/day derived from a study by Lau et al. (2006) demonstrating developmental toxicity in an experimental animal model. 15

16 Reference dose (RfD) an estimate of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Often derived from studies in experimental animal models. Is designed to assess risks from non-cancer effects. Based on NOAEL or LOAEL for critical effect from a single study, but that is supported by weight of evidence, and an adjustment for uncertainty factors that reflect variability and uncertainty. RfD = NOAEL (or LOAEL)/uncertainty factors Generally in mg/kg/day 16

17 17

18 Critical point The RfD was based on the human equivalent dose rather than dose administered to experimental animal models. For example: Lau et al. (2006) reported a LOAEL of 1.0 mg/kg/day with an average serum concentration of 38 mg/l, which corresponds to a human equivalent dose of mg/kg/day. Why is this important for PFOA and other PFASs? This value represents the translation of experimental animal data to the human situation and for PFOA was based largely on differences in half-life or elimination of PFOA from serum. It takes much longer for PFOA to leave humans compared to mice. 18

19 U.S. EPA health advisory level for PFOA (and PFOS) in drinking water Health advisory levels are based on the RfD for PFOA (and for PFOS) derived in the health effects document. 19

20 Great! But what does all of this stuff about PFOA mean for 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate or GenX??? 20

21 Publicly available peer-reviewed publications on GenX toxicity: Gannon et al ADME properties and half-life determination. Half-lives: 5 hours rat, 20 hours mice. Gomis et al Toxic potency of long-chain PFAS alternatives. Evaluated potential of various PFASs to enlarge liver based on liver and serum concentrations; indicated that GenX is more potent than PFOA. Hoke et al Aquatic toxicity and bioaccumulation. Predicted no effect concentration = mg/l. Rae et al Chronic toxicity and carcinogenicity in Sprague-Dawley rats. Author identified NOAELs based on non-neoplastic liver and kidney lesions = 0.1 mg/kg (males) and 1 mg/kg (females). Rushing et al Immunomodulation. NOAEL based on immune suppression in female mice = 10 mg/kg. Sheng et al Cytotoxicity. Could not determine cytotoxicity of GenX due to low boiling point and high volatility. Seems to have similar binding as PFOA to some proteins. Wang et al Mechanisms of hepatotoxicity in mice. RNA-sequencing analysis indicated changes to genes associated with lipid metabolism. These references may be viewed at: 21

22 Rae et al. (2015) demonstrated that chronic exposure to GenX: Induces liver toxicity Induces liver, testicular, and pancreatic tumors Wang et al. (2016) demonstrated that sub-chronic exposure to GenX: Induces liver toxicity (increased liver weight to a greater degree than similar doses of PFOA for the same duration) Alters genes associated with fat metabolism in liver, similar to PFOA Rushing et al. (2017) demonstrated that sub-chronic exposure to GenX: Suppresses the ability of the immune system to generate antigenspecific antibodies Take home: Based on this small number of studies, GenX appears to produce a suite of toxicological effects similar to PFOA. But what about the dose question? 22

23 The question of dose or relative potency of GenX to PFOA. Figure from: Gomis et al Environment International. 23

24 The question of dose or relative potency of GenX to PFOA. Major conclusions of Gomis et al. (2018): Alternatives, such as GenX, appear less toxic than the legacy compounds because they are eliminated more rapidly and have lower distribution to the liver. However, the concentration of alternatives at the target site (i.e., liver), which we can calculate from the internal dose, is what really determines the toxicity. Therefore, GenX is more potent than PFOA at inducing increases in liver weight, on an internal dose basis. What this means for other adverse health outcomes is unknown. Figure from: Gomis et al Environment International. 24

25 NC DHHS GenX DWEL DNEL (i.e., RfD) = mg/kg/day DWEL = 140 ng/l DWEL for GenX based on: Liver toxicity from a 28-day study in mice (sub-chronic); NOAEL supported by a 90-day study in rats, a 90-day study in mice, and a onegeneration study in mice). Protection of bottle-fed infants; used body weight and water intake for bottle-fed infants. Relative source contribution of 20% to account for exposure to GenX from air, soil, dust, food, and other non-water routes. 25

26 Take home for health effects of GenX: GenX appears to produce a suite of toxicological effects similar to PFOA, including liver toxicity, immunotoxicity, and cancer. For some health effects (i.e., liver toxicity), it may be more toxicologically potent than PFOA. Although we have no experimental data on developmental toxicity, developing organisms represent sensitive subgroups. The next big question: How will the other PFAS compounds found in the Cape Fear River be managed? Figure from: Wang et al Environmental Science & Technology. 26

27 Thank you to my colleagues and thank you for listening! Where it all started, at the U.S. EPA in the Luebke Lab Dr. Chris Higgins a the CO School of Mines Dr. Mark Strynar at the U.S. EPA (one of the hardest working chemists in the world!) Amazing students and technical staff at ECU, even those who leave! Qing, Chastity (summer student), Sam (gone to MS), more summer students, Jason (postdoc at EPA), Anna (postdoc at UC-Davis), Blake (summer student). 27