Association Between Serum Perfluorooctanoic Acid (PFOA) and Thyroid Disease
Association Between Serum Perfluorooctanoic Acid (PFOA) and Thyroid Disease
Background: Perfluorooctanoic acid (PFOA, also known as C8) and perfluorooctane sulfonate (PFOS) are stable compounds with many industrial and consumer uses. Their persistence in the environment plus toxicity in animal models has raised concern over low-level chronic exposure effects on human health.
Objectives: We estimated associations between serum PFOA and PFOS concentrations and thyroid disease prevalence in representative samples of the U.S. general population.
Methods: Analyses of PFOA/PFOS versus disease status in the National Health and Nutrition Examination Survey (NHANES) for 1999–2000, 2003–2004, and 2005–2006 included 3,974 adults with measured concentrations for perfluorinated chemicals. Regression models were adjusted for age, sex, race/ethnicity, education, smoking status, body mass index, and alcohol intake.
Results: The NHANES-weighted prevalence of reporting any thyroid disease was 16.18% (n = 292) in women and 3.06% (n = 69) in men; prevalence of current thyroid disease with related medication was 9.89% (n = 163) in women and 1.88% (n = 46) in men. In fully adjusted logistic models, women with PFOA ≥ 5.7 ng/mL [fourth (highest) population quartile] were more likely to report current treated thyroid disease [odds ratio (OR) = 2.24; 95% confidence interval (CI), 1.38–3.65; p = 0.002] compared with PFOA ≤ 4.0 ng/mL (quartiles 1 and 2); we found a near significant similar trend in men (OR = 2.12; 95% CI, 0.93–4.82; p = 0.073). For PFOS, in men we found a similar association for those with PFOS ≥ 36.8 ng/mL (quartile 4) versus ≤ 25.5 ng/mL (quartiles 1 and 2: OR for treated disease = 2.68; 95% CI, 1.03–6.98; p = 0.043); in women this association was not significant.
Conclusions: Higher concentrations of serum PFOA and PFOS are associated with current thyroid disease in the U.S. general adult population. More work is needed to establish the mechanisms involved and to exclude confounding and pharmacokinetic explanations.
The perfluoroalkyl acids (PFAAs) are a family of synthetic, highly stable perfluorinated compounds with a wide range of uses in industrial and consumer products, from stain- and water-resistant coatings for carpets and fabrics to fast-food contact materials, fire-resistant foams, paints, and hydraulic fluids (Organisation for Economic Co-operation and Development 2005). The carbon–fluoride bonds that characterize PFAAs and make them useful as surfactants are highly stable, and recent reports indicate the widespread persistence of certain PFAAs in the environment and in wildlife and human populations globally (Fromme et al. 2009; Giesy and Kannan 2001; Lau et al. 2007; Saito et al. 2004). Two of the PFAAs of most concern are the eight-carbon–chain perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA, also known as C8).
Most persistent organic pollutants are lipophilic and accumulate in fatty tissues, but PFOS and PFOA are both lipo- and hydrophobic, and after absorption will bind to proteins in serum rather than accumulating in lipids (Hundley et al. 2006; Jones et al. 2003). The renal clearance of PFOA and PFOS is negligible in humans, leading to reported half-lives in blood serum of 3.8 and 5.4 years for PFOA and PFOS, respectively (Olsen et al. 2007). Human biomonitoring of the general population in various countries has shown that, in addition to the near ubiquitous presence of PFOS and PFOA in blood, these may also be present in breast milk, liver, seminal fluid, and umbilical cord blood (Lau et al. 2007).
Extensive laboratory studies of the toxicology of PFOA and PFOS have reported enlargement of the liver, modulation of sex hormone homeostasis, developmental and immune system toxicity, hypolipidemia, and reduced body weight in rodent and nonhuman primate models [reviewed by Lau et al. (2004, 2007)]. Research interest has focused on the ability of these compounds to bind to nuclear receptors, including the peroxisome proliferator–-activating receptor (PPARα), and to disrupt serum protein ligand binding (Luebker et al. 2002), highlighting PFOA and PFOS as potential endocrine disruptors (Jensen and Leffers 2008).
Endocrine systems that may be targets of endocrine-disrupting chemicals include the hypothalamus–pituitary–thyroid (HPT) axis (Boas et al. 2006). Thyroid hormone is essential for the normal physiologic function of nearly all mammalian tissues. Thyroid hormone status is controlled by a well-established feedback mechanism, in which thyroid-stimulating hormone (TSH) stimulates the thyroid to synthesize thyroxine (T4), which is then converted to the biologically active triiodothyronine (T3). The rate of release of TSH is regulated by the hypothalamus as well as by the circulating levels of T3 and T4. Therefore, multiple physiologic steps, including hormone biosynthesis, transport, metabolism, and action on target cells, are required for thyroid hormone homeostasis.
Numerous studies have now shown PFAAs to impair thyroid hormone homeostasis in animal studies. Depression of serum T4 and T3 in PFOS-exposed rats has been reported by several authors (Lau et al. 2003; Luebker et al. 2005; Seacat et al. 2003), without the concomitant increase in TSH that would be expected through feedback stimulation. Earlier mechanistic studies of structurally related perfluorodecanoic acid showed that it could reduce serum thyroid hormone levels apparently by reducing the responsiveness of the HPT axis and by displacing circulating thyroid hormones from their plasma protein-binding sites (Gutshall et al. 1989). Although circulating hormone levels were depressed, the activities of thyroid hormone–sensitive liver enzymes were elevated, suggesting that functional hypothyroidism was not occurring. A similar mechanism for PFOS has been hypothesized (Chang et al. 2007). A recent study of the mechanisms involved in PFOS-induced hypothyroxinemia in rats has indicated that increased conjugation of T4 in the liver, catalyzed by the hepatic enzyme uridine diphosphoglucuronosyl transferase (UGT1A1), and increased thyroidal conversion of T4 to T3 by type 1 deiodinase may be partly responsible for the effects (Yu et al. 2009). Taken together, these findings suggest that the effects of PFAAs on thyroid hormone physiology are multiple and complex.
Extrapolations from animal laboratory studies such as these to an estimation of the risks posed by PFOA and PFOS to thyroid function in humans are complicated by the extreme variations reported in their toxico-kinetic profile between species (Johnson et al. 1979; Olsen et al. 2007). The extremely long half-lives of PFOA and PFOS in humans contrast with the relatively rapid elimination seen in animal models (e.g., serum half-life of PFOS in rats is around 100 days) (Hundley et al. 2006), drawing attention to the potential risks to human health. Disruption to thyroid hormone balance was not found in previous studies of community exposure to PFOA (Emmett et al. 2006; Olsen et al. 2003b) or PFOS (Inoue 2004). Modest associations between PFOA and thyroid hormones (negative for free T4 and positive for T3) were reported in 506 PFOA production workers across three production facilities (Olsen and Zobel 2007); there were no associations between TSH or T4 and PFOA, and the free hormone levels were within the normal reference range.
Given the evidence from animal studies of thyroid hormone imbalance and the varied epidemiologic results from community and occupational exposures, we aimed to explore the hypothesis that higher serum PFOA and PFOS concentrations would be associated with thyroid disease in the general adult population. The environmental chemical biomonitoring program of the U.S. Centers for Disease Control and Prevention, using samples from the U.S. National Health and Nutrition Examination Survey (NHANES), provides large-scale data on serum PFAA concentrations in population-representative samples. In this study we used these data to estimate associations between PFOA/PFOS concentrations and thyroid disease in representative samples of the U.S. general population.
Abstract and Introduction
Abstract
Background: Perfluorooctanoic acid (PFOA, also known as C8) and perfluorooctane sulfonate (PFOS) are stable compounds with many industrial and consumer uses. Their persistence in the environment plus toxicity in animal models has raised concern over low-level chronic exposure effects on human health.
Objectives: We estimated associations between serum PFOA and PFOS concentrations and thyroid disease prevalence in representative samples of the U.S. general population.
Methods: Analyses of PFOA/PFOS versus disease status in the National Health and Nutrition Examination Survey (NHANES) for 1999–2000, 2003–2004, and 2005–2006 included 3,974 adults with measured concentrations for perfluorinated chemicals. Regression models were adjusted for age, sex, race/ethnicity, education, smoking status, body mass index, and alcohol intake.
Results: The NHANES-weighted prevalence of reporting any thyroid disease was 16.18% (n = 292) in women and 3.06% (n = 69) in men; prevalence of current thyroid disease with related medication was 9.89% (n = 163) in women and 1.88% (n = 46) in men. In fully adjusted logistic models, women with PFOA ≥ 5.7 ng/mL [fourth (highest) population quartile] were more likely to report current treated thyroid disease [odds ratio (OR) = 2.24; 95% confidence interval (CI), 1.38–3.65; p = 0.002] compared with PFOA ≤ 4.0 ng/mL (quartiles 1 and 2); we found a near significant similar trend in men (OR = 2.12; 95% CI, 0.93–4.82; p = 0.073). For PFOS, in men we found a similar association for those with PFOS ≥ 36.8 ng/mL (quartile 4) versus ≤ 25.5 ng/mL (quartiles 1 and 2: OR for treated disease = 2.68; 95% CI, 1.03–6.98; p = 0.043); in women this association was not significant.
Conclusions: Higher concentrations of serum PFOA and PFOS are associated with current thyroid disease in the U.S. general adult population. More work is needed to establish the mechanisms involved and to exclude confounding and pharmacokinetic explanations.
Introduction
The perfluoroalkyl acids (PFAAs) are a family of synthetic, highly stable perfluorinated compounds with a wide range of uses in industrial and consumer products, from stain- and water-resistant coatings for carpets and fabrics to fast-food contact materials, fire-resistant foams, paints, and hydraulic fluids (Organisation for Economic Co-operation and Development 2005). The carbon–fluoride bonds that characterize PFAAs and make them useful as surfactants are highly stable, and recent reports indicate the widespread persistence of certain PFAAs in the environment and in wildlife and human populations globally (Fromme et al. 2009; Giesy and Kannan 2001; Lau et al. 2007; Saito et al. 2004). Two of the PFAAs of most concern are the eight-carbon–chain perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA, also known as C8).
Most persistent organic pollutants are lipophilic and accumulate in fatty tissues, but PFOS and PFOA are both lipo- and hydrophobic, and after absorption will bind to proteins in serum rather than accumulating in lipids (Hundley et al. 2006; Jones et al. 2003). The renal clearance of PFOA and PFOS is negligible in humans, leading to reported half-lives in blood serum of 3.8 and 5.4 years for PFOA and PFOS, respectively (Olsen et al. 2007). Human biomonitoring of the general population in various countries has shown that, in addition to the near ubiquitous presence of PFOS and PFOA in blood, these may also be present in breast milk, liver, seminal fluid, and umbilical cord blood (Lau et al. 2007).
Extensive laboratory studies of the toxicology of PFOA and PFOS have reported enlargement of the liver, modulation of sex hormone homeostasis, developmental and immune system toxicity, hypolipidemia, and reduced body weight in rodent and nonhuman primate models [reviewed by Lau et al. (2004, 2007)]. Research interest has focused on the ability of these compounds to bind to nuclear receptors, including the peroxisome proliferator–-activating receptor (PPARα), and to disrupt serum protein ligand binding (Luebker et al. 2002), highlighting PFOA and PFOS as potential endocrine disruptors (Jensen and Leffers 2008).
Endocrine systems that may be targets of endocrine-disrupting chemicals include the hypothalamus–pituitary–thyroid (HPT) axis (Boas et al. 2006). Thyroid hormone is essential for the normal physiologic function of nearly all mammalian tissues. Thyroid hormone status is controlled by a well-established feedback mechanism, in which thyroid-stimulating hormone (TSH) stimulates the thyroid to synthesize thyroxine (T4), which is then converted to the biologically active triiodothyronine (T3). The rate of release of TSH is regulated by the hypothalamus as well as by the circulating levels of T3 and T4. Therefore, multiple physiologic steps, including hormone biosynthesis, transport, metabolism, and action on target cells, are required for thyroid hormone homeostasis.
Numerous studies have now shown PFAAs to impair thyroid hormone homeostasis in animal studies. Depression of serum T4 and T3 in PFOS-exposed rats has been reported by several authors (Lau et al. 2003; Luebker et al. 2005; Seacat et al. 2003), without the concomitant increase in TSH that would be expected through feedback stimulation. Earlier mechanistic studies of structurally related perfluorodecanoic acid showed that it could reduce serum thyroid hormone levels apparently by reducing the responsiveness of the HPT axis and by displacing circulating thyroid hormones from their plasma protein-binding sites (Gutshall et al. 1989). Although circulating hormone levels were depressed, the activities of thyroid hormone–sensitive liver enzymes were elevated, suggesting that functional hypothyroidism was not occurring. A similar mechanism for PFOS has been hypothesized (Chang et al. 2007). A recent study of the mechanisms involved in PFOS-induced hypothyroxinemia in rats has indicated that increased conjugation of T4 in the liver, catalyzed by the hepatic enzyme uridine diphosphoglucuronosyl transferase (UGT1A1), and increased thyroidal conversion of T4 to T3 by type 1 deiodinase may be partly responsible for the effects (Yu et al. 2009). Taken together, these findings suggest that the effects of PFAAs on thyroid hormone physiology are multiple and complex.
Extrapolations from animal laboratory studies such as these to an estimation of the risks posed by PFOA and PFOS to thyroid function in humans are complicated by the extreme variations reported in their toxico-kinetic profile between species (Johnson et al. 1979; Olsen et al. 2007). The extremely long half-lives of PFOA and PFOS in humans contrast with the relatively rapid elimination seen in animal models (e.g., serum half-life of PFOS in rats is around 100 days) (Hundley et al. 2006), drawing attention to the potential risks to human health. Disruption to thyroid hormone balance was not found in previous studies of community exposure to PFOA (Emmett et al. 2006; Olsen et al. 2003b) or PFOS (Inoue 2004). Modest associations between PFOA and thyroid hormones (negative for free T4 and positive for T3) were reported in 506 PFOA production workers across three production facilities (Olsen and Zobel 2007); there were no associations between TSH or T4 and PFOA, and the free hormone levels were within the normal reference range.
Given the evidence from animal studies of thyroid hormone imbalance and the varied epidemiologic results from community and occupational exposures, we aimed to explore the hypothesis that higher serum PFOA and PFOS concentrations would be associated with thyroid disease in the general adult population. The environmental chemical biomonitoring program of the U.S. Centers for Disease Control and Prevention, using samples from the U.S. National Health and Nutrition Examination Survey (NHANES), provides large-scale data on serum PFAA concentrations in population-representative samples. In this study we used these data to estimate associations between PFOA/PFOS concentrations and thyroid disease in representative samples of the U.S. general population.
