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Reproductive Toxicology Division
Reproductive Toxicology Division
Perfluoroalkyl Acids Team (PFAA)
Overview
Perfluoroalkyl acids (PFAAs) and their derivatives are organic fluoro-chemicals possessing unique surfactant properties and having wide industrial and household applications. The most prominent representatives of those chemicals are perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) which are very stable in the environment. Mammalian studies with PFOS and PFOA have suggested that hepatotoxicity, carcinogenicity, immunotoxicity, and developmental toxicity may be associated with chemical exposure. EPA is interested in assessing the health risks of PFAAs because of (1) their persistence and wide distribution in the environment; (2) their presence and accumulation in humans and wildlife; and (3) related toxicological findings with laboratory animal models. Only sparse information is available concerning modes of action (MOA) for PFOS and PFOA in relation to their toxicity. Work on these chemicals is necessary to support risk assessment. Research projects are described within 3 categories: (1) hazard characterization of PFAAs; (2) mechanistic investigations; and (3) novel discovery for risk assessments
The team's research is focused on these the following Long-Term Goals (LTG) in EPA's Multi-Year Plans (MYP):
- MYP: Safe Pesticides/Safe Products
- LTG 1: Understand the impacts of novel and newly discovered hazards MYP: Human Health
- LTG 3: Characterize and provide adequate protection for susceptible subpopulations (susceptibility)
- Team Leader
- Christopher Lau, Lead Research Biologist Biosketch
- Principal Investigators
- Research Support
- David Kuhn, Scientist (SEEP) *
- Dan Zehr, Technician (SEEP) *
- Post-Doctoral Trainee
- Erin Hines, EPA Post-Doc Biosketch
- Pre-Doctoral Trainees
- Sally White (UNC Graduate Student)
*Senior Environmental Employment Proram
PFAA Team Projects
Developmental Toxicology of Perfluoroalkyl Acids
Contact: John Rogers
Public concerns about the environmental risks of perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and other perfluoroalkyl acids (PFAA) are based on five factors: (1) environmental persistence of these chemicals; (2) their ubiquitous distribution, even to remote regions of the world; (3) the detection of PFOS, PFOA and other PFAAs in humans; (4) the presence of these compounds in a variety of wildlife populations; and (5) toxicity findings of PFOS and PFOA from laboratory animal models, including developmental toxicity of PFOS and PFOA in rodents. Research objectives of this project are to (1) conduct hazard assessment and dose response studies on the toxicity of prenatal exposures to PFOS, PFOA and other PFAAs that are relevant to human health risk assessment; (2) conduct critical period studies to identify those periods in development that are most sensitive to exposure to PFOS, PFOA, or other PFAAs found to be developmentally toxic; and (3) carry out studies to understand the mode of action for developmental toxicity of these compounds, especially neonatal mortality in rodents. The PFAAs are of great concern to the EPA, other regulatory bodies, and the general public. The developmental toxicities of PFOS and PFOA are of primary concern as they are among the lowest dose effects of these chemicals described to date.
Developmental Toxicology of Perfluoroalkyl Acids
Contact: Sue Fenton
The research objectives of this project are to (1) evaluate the early dose-related effects of perfluorooctanoic acid (PFOA) in the appropriate animal model; (2) evaluate timing of exposure and body burden as it relates to effects on mammary development and differentiation, and (3) identify sensitive health endpoints and their potential endocrine-related mechanisms of action following developmental exposure that can be used for risk assessment. A series of studies was designed to evaluate the dose-response relationships of health effects following developmental exposure to PFOA in the mouse. The mammary gland is sensitive to this compound, needing only a few days of exposure to result in persistent developmental abnormalities in female offspring. The effects on mammary tissue can be seen following in utero or lactational exposure, with the most severe effects from both exposures. Studies have also included a mouse developmental exposure paradigm to determine (1) the effects on lactogenesis in the dam and (2) the impact of lactogenic effects on postnatal pup weight gain. Further work will focus on modes or mechanisms of action for these early life events. These data will provide valuable endpoints for human health risk assessment of PFOA.
Mode of Action for Perfluorooctanoic Acid (PFOA) Induced Developmental Toxicity: Evaluating the Role of PPAR-alpha
Contact: Barbara Abbott
This work addresses the potential health risks of perfluoroalkyl acids (PFAAs) through research specifically addressing the significance of peroxisome proliferator-activated receptor (PPAR) transcriptional signaling in developmental responses to PFAAs. PPAR-alpha, PPAR-beta/delta, and PPAR-gamma exhibit specific patterns of expression in the embryo, extra-embryonic membranes, uterus and placenta, and have roles in implantation and development of the embryo, maintenance of pregnancy, and initiation of labor at term. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are known to exhibit developmental toxicity. Questions addressed by this research team are: (1) is the PPAR-alpha pathway involved in the mode of action for PFOA-induced developmental toxicity? and (2) do PFAA compounds activate PPAR-alpha, PPAR-beta/delta and/or PPAR gamma? PPAR- alpha knockout mice and transiently transfected cell lines are used to address these questions. This project supports the Office of Prevention, Pesticides, and Toxic Substances in their risk assessment for PFOA by elucidating the mode of action of its toxicity.
Gene Profiling in the PFOA Treated Adult and Fetal Mouse: A Mechanistic Approach
Contact: Mitchell Rosen
Perfluorooctanoic acid (PFOA) is a developmental toxicant in mice and a peroxisome proliferator-activated receptor (PPAR) -alpha agonist in both rodents and humans. Questions that arise include: (1) is the fetal response to PFOA robust? (2) is the fetal liver the principal target of PFOA or, based on findings in the PFOS treated rat, is the fetal lung also involved? and (3) can gene profiling help identify modes of action, including non-PPAR-alpha related effects? Research objectives addressed in this project are to (1) conduct gene profiling studies in PFOA-exposed mouse fetuses using a range of doses and evaluate compound-related effects in the fetal liver and lung; and (2) conduct gene profiling studies to directly address the role of PPAR-alpha signaling in the PFOA-exposed wild-type and PPAR-alpha knock-out adult mice. Mechanistic data for PFOA and other PFAAs are vitally important, and these data will be used by EPA's Office of Prevention, Pesticides, and Toxic Substances.
A Compendium of Pharmacokinetic and Toxicity Studies of Perfluoroalkyl Acids
Contact: Chris Lau
The perfluoroalkyl acids (PFAAs) detected in the environment include compounds with a range of chemical structures and include perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorobutanoic acid (PFBA), perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS) and perfluorononanoic acid (PFNA). For human health risk assessment, it is prudent to take the entire class into consideration. Searches for common toxicological features for the PFAA chemicals will provide insight toward understanding the modes of action for this class of compound and bolster the confidence of data extrapolation from animal models to humans. Questions addressed by this project include the following: (1) since PFOS alters thyroid hormone levels, does this effect extend to other PFAAs and what are the mechanisms of this effect? (2) the peroxisome proliferator-activated receptor (PPAR) -alpha signaling pathway has been implicated for PFOA-induced hepatotoxicity, so do other PFAAs produce liver toxicity and are these effects mediated by the same PPAR-alpha-dependent and independent pathways? and (3) what are the pharmacokinetic characteristics of PFAAs in animal models and would PBPK models provide insights to the persistence of these chemicals in humans? The comparative findings among different PFAAs can be used for risk evaluation of the entire class of chemicals. This research is instrumental to EPA's Program Offices in the risk assessment of PFAAs, PFOA and PFOS data will be incorporated in the Integrated Risk Information System (IRIS) database and the Office of Economic Cooperation and Development (OECD) risk assessment.
Recent Publications
Publications are listed in reverse chronological order. The names of current RTD investigators are in bold.
Chang SC, Thibodeaux JR, Eastvold ML, Ehresman DJ, Bjork JA, Froehlich JW, Lau C, Singh RJ, Wallace KB, Butenhoff JL. 2008. Thyroid hormone status and pituitary function in adult rats given oral doses of perfluorooctanesulfonate (PFOS). Toxicology 243(3):330-339. Abstract
Lau C, Anitole K, Hodes C, Lai D, Pfahles-Hutchens A, Seed J. 2007. Perfluoroalkyl acids: A review of monitoring and toxicological findings. Toxicol Sci. 99:366-394. Abstract
Martin MT, Brennan RJ, Hu W, Ayanoglu E, Lau C, Ren H, Wood CR, Corton JC, Kavlock RJ, Dix DJ. 2007. Toxicogenomic study of triazole fungicides and perfluoroalkyl acids in rat livers predicts toxicity and categorizes chemicals based on mechanisms of toxicity. Toxicol Sci. 97:595-613. Abstract
Abbott BD, Wolf CJ, Schmid JE, Das K, Zehr R, Helfant L, Nakayama S, Lindstrom AB, Strynar MJ, Lau C. 2007. Perfluorooctanoic acid (PFOA)-induced developmental toxicity in the mouse is dependent on expression of peroxisome proliferator activated receptor-alpha (PPAR-a). Toxicol Sci. 98:541-581. Abstract
Rosen MB, Thibodeaux JR, Wood CR, Zehr RD, Schmid JE, Lau C. 2007. Gene expression profiling in the lung and liver of PFOA-exposed mouse fetuses. Toxicology. 239:15-33. Abstract
Chang S, Thibodeaux JR, Eastvold ML, Ehresman DJ, Bjork J, Froehlich JW, Lau C, Singh RJ, Wallace KB, Butenhoff JL. 2007. Negative bias from analog methods used in the analysis of free thyroid hormones in rat serum containing perfluorooctanesulfonate (PFOS). Toxicology. 234:21-33. Abstract
Takacs ML, Abbott BD. 2007. Activation of mouse and human peroxisome proliferator-activated receptors (PPAR-a a, ß/d, ?) by perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Toxicol Sci. 95:108-117. Abstract
White SS, Calafat AM, Kuklenyik Z, Thibodeaux JR, Wood CR, Fenton SE. 2007. Gestational PFOA exposure of mice is associated with altered mammary gland development in dams and female offspring. Toxicol Sci. 96:133-144. Abstract
Wolf CJ, Fenton SE, Schmid JE, Calafat AM, Kuklenyik Z, Thibodeaux JR, Das K, White SS, Lau C, Abbott BD. 2007. Developmental toxicity of perfluorooctanoic acid (PFOA) after cross foster and restricted gestational exposures. Toxicol Sci. 95:462-473. Abstract
Lau C, Thibodeaux JR, Hanson R, Narotsky MG, Rogers JM, Lindstrom AB, Strynar MJ. 2006. Effects of perfluorooctanoic acid exposure during pregnancy in the mouse. Toxicol Sci. 90:510-519. Abstract
Grasty R, Bjork JA, Wallace KB, Wolf DC, Lau C, Rogers JM. 2005. Effects of prenatal perfluorooctane sulfonate (PFOS) exposure on lung maturation in the perinatal rat. Birth Defects Res B Dev Reprod Toxicol. 74:405-416. Abstract
Lau C, Butenhoff JL, Rogers JM. 2004. The developmental toxicity of perfluoroalkyl acids and their derivatives. Toxicol Appl Pharmacol. 198:231-41. Abstract
Grasty RC, Wolf DC, Grey BE, Lau C, Rogers JM. 2003. Prenatal window of susceptibility to perfluorooctane sulfonate-induced neonatal mortality in the Sprague-Dawley rat. Birth Defects Res B Dev Reprod Toxicol. 68:465-71. Abstract
Lau C, Thibodeaux JR, Hanson RG, Rogers JM, Grey BE, Stanton ME, Butenhoff JL, Stevenson LA. 2003. Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. II: Postnatal evaluation. Toxicol Sci. 74:382-92. Abstract
Thibodeaux JR, Hanson RG, Rogers JM, Grey BE, Barbee BD, Richards JH, Butenhoff JL, Stevenson LA, Lau C. 2003. Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. I: Maternal and prenatal evaluations. Toxicol Sci. 74:369-81. Abstract
Hu W, Jones PD, Upham BL, Trosko JE, Lau C, Giesy JP. 2002. Inhibition of gap junctional intercellular communication by perfluorinated compounds in rat liver and dolphin kidney epithelial cell lines in vitro and Sprague-Dawley rats in vivo. Toxicol Sci. 68:429-36. Abstract