Thyroid function and perfluoroalkyl acids in children living near a chemical plant

University at Albany, State University of New York

Thyroid Function and Perfluoroalkyl Acids in Children Living Near a Chemical PlantMaria-Jose Lopez-Espinosa Debapriya MondalUniversity of Salford, [email protected] Ben ArmstrongLondon School of Hygiene & Tropical Science, [email protected] Michael S. BloomUniversity at Albany, State University of New York, [email protected] Tony FletcherLondon School of Hygiene & Tropical Medicine, [email protected] Follow this and additional works at: Recommended CitationLopez-Espinosa M-J, Mondal D, Armstrong B, Bloom MS, Fletcher T. Thyroid Function and Perfluoroalkyl Acids in Children LivingNear a Chemical Plant. Environmental Health Perspectives. 2012;120(7):1036-1041. doi:10.1289/ehp.1104370.
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Research Children's Health
Thyroid Function and Perfluoroalkyl Acids in Children Living Near
a Chemical Plant
Maria-Jose Lopez-Espinosa,1 Debapriya Mondal,1 Ben Armstrong,1 Michael S. Bloom,2,3 and Tony Fletcher1
1Department of Social and Environmental Health Research, London School of Hygiene & Tropical Medicine, London,
United Kingdom; 2Department of Environmental Health Sciences, and 3Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, State University of New York, Rensselaer, New York, USA Health and Nutrition Examination Survey Background: Animal studies suggest that some perfluoroalkyl acids (PFAAs), including
(NHANES) population (Melzer et al. 2010).
perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA)
PFOA has been used in the manufac­ may impair thyroid function. Epidemiological findings, mostly related to adults, are inconsistent.
ture of fluoropolymers at a chemical plant oBjectives: We investigated whether concentrations of PFAAs were associated with thyroid func-
in Parkersburg, West Virginia, since 1951. tion among 10,725 children (1–17 years of age) living near a Teflon manufacturing facility in the
In 2001, a group of residents from the Ohio Mid-Ohio Valley (USA).
and West Virginia communities in the vicin­ Methods: Serum levels of thyroid-stimulating hormone (TSH), total thyroxine (TT4), and PFAAs
ity of the Washington Works plant filed a were measured during 2005–2006, and information on diagnosed thyroid disease was collected by
class­action lawsuit, alleging health damage questionnaire. Modeled in utero PFOA concentrations were based on historical information on
due to contamination of human drinking­ PFOA releases, environmental distribution, pharmacokinetic modeling, and residential histories.
water supplies with PFOA. The settlement We performed multivariate regression analyses.
of this lawsuit led to a baseline survey, called results: Median concentrations of modeled in utero PFOA and measured serum PFOA, PFOS,
the C8 Health Project, conducted during and PFNA were 12, 29, 20, and 1.5 ng/mL, respectively. The odds ratio for hypothyroidism
2005 and 2006 on residents who lived in six (n = 39) was 1.54 [95% confidence interval (CI): 1.00, 2.37] for an interquartile range (IQR) con-
contaminated water districts surrounding the trast of 13 to 68 ng/mL in serum PFOA measured in 2005–2006. However, an IQR shift in serum
chemical plant, as described by Frisbee et al. PFOA was not associated with TSH or TT4 levels in all children combined. IQR shifts in serum
PFOS (15 to 28 ng/mL) and serum PFNA (1.2 to 2.0 ng/mL) were both associated with a 1.1%
(2009). In the Mid­Ohio Valley child popu­ increase in TT4 in children 1–17 years old (95% CIs: 0.6, 1.5 and 0.7, 1.5 respectively).
lation 8–18 years of age, PFOA concentra­ tions were markedly higher (Lopez­Espinosa conclusions: This is the first large-scale report in children suggesting associations of serum PFOS
and PFNA with thyroid hormone levels and of serum PFOA and hypothyroidism.
et al. 2011b) than in 2005–2006 NHANES children 12–19 years of age (median = 23 vs. key words: children, PFAA, PFNA, PFOA, PFOS, T4, thyroid disease, thyroid hormones, TSH.
3.8 ng/mL, respectively) (Kato et al. 2011).
Environ Health Perspect 120:1036–1041 (2012). [Online
27 March 2012]
Assessment of possible PFAA effects on thyroid hormone function in children is of special interest for the reasons outlined above. Thyroid hormones play important roles in with thyroid status (Lau et al. 2007; Liu et al. regulating metabolism, growth, and develop­ 2011). There had been some concern that Address correspondence to M­J. Lopez­Espinosa. ment, especially in normal brain maturation these apparent associations may derive from Department of Social and Environmental Health and development (Porterfield and Hendrich the analysis of analog free thyroxine (FT Research, London School of Hygiene & Tropical Medicine, 15–17 Tavistock Place, London WC1H 1993). They regulate the processes of neuro­ being affected by the presence of PFOS, as 9SH, UK. Telephone: 44 20 7927 2066. Fax: 44 20 genesis, denditric and axonal growth, synap­ observed in rats highly exposed to PFOS 7580 4524. E­mail: maria­[email protected] togenesis, and myelination (Bernal 2007). It is (Chang et al. 2007). However, such bias has We thank the participants for their contributions now recognized that even slight differences in not been observed in a human population to this study. We are grateful for the information on the concentration of thyroid hormones dur­ with typical U.S. serum PFOS concentrations maternal and neonatal variables from C. Stein and ing pregnancy or after delivery may be associ­ but higher PFOA concentrations (Lopez­ manuscript editing from A. Beierholm.
Funding for this work, the "C8 Science Panel ated with neurological impairment (Freire Espinosa et al. 2011a).
Community Study at LSHTM [London School of et al. 2010; Pop et al. 1999). Thyroid hor­ Published epidemiological findings are Hygiene & Tropical Medicine]," comes from the C8 mones are also essential for children because not consistent (Steenland et al. 2010), have Class Action Settlement Agreement (Circuit Court some neurodevelopmental processes, such as generally focused on adults, and have been of Wood County, WV, USA) between DuPont and myelination, are not completed until adoles­ cross­sectional in nature—leaving a gap in plaintiffs, which resulted from releases of perfluoro­ cence (Rice and Barone 2000), and they are our understanding of possible PFAA effects in octanoate (PFOA, or C8) into drinking water. It is one of the C8 Science Panel Studies undertaken by also important for the behavior and cognitive children. Whereas associations were reported the Court­approved C8 Science Panel established function of the young and adolescent brain for some PFAAs and thyroid hormones in under the same Settlement Agreement. The task of (Anderson 2001). In addition, thyroid hor­ some studies of nonoccupational exposure the C8 Science Panel, of which T.F. is a member, mone deficiency causes growth delay, preco­ (Dallaire et al. 2009; Kim et al. 2011; Knox is to undertake research in the Mid­Ohio Valley, cious puberty in both sexes, and hirsutism in et al. 2011), others found little or no evidence and subsequently evaluate the results along with females (Papi et al. 2007).
of associations (Bloom et al. 2010; Chan other available information to determine if there are any probable links between PFOA and disease. There is a growing concern that environ­ et al. 2011; Emmett et al. 2006). Studies in Funds were administered by the Garden City Group mental toxicants may be related to thyroid occupational settings also reported some sta­ (Melville, NY) that reports to the Court. impairment (Boas et al. 2009). Animal stud­ tistically significant associations with thyroid The authors of this manuscript declare that their ies have suggested that exposure to some hormones, although at high PFAA concen­ ability to design, conduct, interpret, or publish perfluoroalkyl acids (PFAAs), including trations (Olsen and Zobel 2007; Olsen et al. research was unimpeded by and fully independent of perfluorooctanoate (PFOA, also called C8), 2003). A higher odds ratio (OR) of reported the court and/or settling parties. The authors declare they have no actual or potential perfluorooctane sulfonate (PFOS), and per­ thyroid disease was recently associated with competing financial interests.
fluorononanoic acid (PFNA), may interfere PFOA or PFOS exposure in the National Received 19 August 2011; accepted 27 March 2012.
volume 120 number 7 July 2012 • Environmental Health Perspectives PFAAs and thyroid function Accordingly, we designed the present study to (n = 0, n = 16, and n = 107 in the case of of subclinical hypothyroidism if the TSH estimate associations of thyroid function with PFOA, PFOS, and PFNA, respectively, for value was above the upper bound of the a) modeled in utero PFOA concentrations and this study population).
normal reference range given for the labora­ b) measured serum PFOA, PFOS, and PFNA Historical PFOA exposures for all par­ tory (which varies according to age groups, concentrations col ected during 2005–2006 ticipants in the C8 Health Project were esti­ i.e., TSH > 5.97, > 4.84, > 4.5 μIU/mL in in children 1–17 years of age from these Ohio mated through environmental, exposure, and children < 6, 6–10, > 10 years of age, respec­ and West Virginia communities.
pharmaco kinetic modeling in conjunction with tively), whereas TT4 was within its reference self­reported residential histories. Information range (4.5–12 μg/dL). The number of children on plant operations and chemical releases was with high TSH (> 10 μIU/mL) and low TT4 Study population. The C8 Health Project combined with environmental characteristics (< 4.5 μg/dL) was too small (n = 8) for sepa­
enrolled participants between August 2005 of the region through a series of linked models rate analyses, and these children were included and July 2006. All participants gave written to estimate air and water concentrations of in the category of subclinical hypo thyroidism. informed consent before inclusion: Parents PFOA from 1951 to 2008 (Shin et al. 2011a). We classified children in the subclinical hyper­ or guardians provided consent on behalf of Based on estimates of individual air and water thyroidism category if the TSH value was children. The London School of Hygiene intake rates and linkage of residential geocodes below the lower bound of the normal refer­ & Tropical Medicine Ethics Committee for participant address histories to public water ence range given by the laboratory (which var­ approved this study. The purpose of the Project distribution systems and private wells, yearly ies according to age groups, i.e., TSH < 0.7, was to collect health data from members of PFOA serum concentrations were estimated < 0.6, < 0.45 μIU/mL in children < 6, 6–10, the class action lawsuit through questionnaires for each participant in the C8 Health Project > 10 years of age, respectively) and TT4 within and blood tests, including measurements of (Shin et al. 2011b). Historical individual mod­ the normal reference range (4.5–12 μg/dL). PFAAs. Individuals were eligible to partici­ eled serum PFOA was calibrated by factors Children with low TSH (< 0.1 μIU/mL) and pate in the C8 Health Project if they had con­ derived from comparisons of observed with high TT4 (> 12 μg/dL) (n = 4) were included sumed water for at least 1 year between 1950 predicted serum concentrations in 2005–2006. in the subclinical hyperthyroidism category.
and 2004 from six contaminated water dis­ The ratio of observed to predicted (before cali­ Self-reported thyroid disease and medica-
tricts or private wells in proximity to a Teflon bration) estimates for these mothers showed a tion. Parents or legal guardians completed a
manufacturing facility. The C8 Health Project geometric mean (GM) of 1.36, and the inter­ questionnaire, including information on diag­ collected data on 69,030 people, of whom quartile range (IQR) of these ratios was 0.7 to noses for thyroid disease. Respondents were 12,476 were 1–17 years of age at enroll­ 2.2. In utero, modeled exposures for each child asked whether they had ever been told by a ment. Participation rates for age groups 5–10, were estimated as the modeled serum concen­ health­care provider that the child had thyroid 11–14, and 15–19 years, and residing in the trations in the mother who had been success­ disease. If the answer was yes, they were asked area at the time of the survey, were 77%, 87%, fully matched to the child, at the time of the to select between one of these types of thy­ and 95%, respectively (Frisbee et al. 2009). first trimester of pregnancy (n = 4,713); these roid diseases: goiter, Hashimoto's thyroiditis, Of the 12,476 children, 10,725 (86%) had pregnancies occurred from 1987 to 2005.
Graves disease, or others. In the last category, serum PFAA and thyroid hormone measure­ Thyroid hormone determination and they were asked to provide the type of thyroid
ments or information on reported thyroid dis­ subclinical hypo- and hyperthyroidism. We disease (most of whom noted hypothyroid­
eases (from questionnaire responses), and were assessed thyroid function by measuring thyroid­ ism). We considered three classifications of included in the present analyses. Within this stimulating hormone (TSH) and total T4 (TT4), thyroid diseases: a) reported diagnosis with population, 4,713 children were successfully in serum samples (LabCorp, Inc., Burlington, any thyroid disease; b) reported Hashimoto's matched to their mothers (also participating in NC, USA). TSH was measured using an electro­ thyroiditis or hypothyroidism; and c) a nar­ the C8 Health Project) (Mondal et al. 2012); chemiluminescence immunoassay (ECLIA; rower self­reported thyroid disease definition effects on child thyroid function in relation Roche Diagnostics, Indianapolis, IN, USA) with formed by combining report of any type of to modeled in utero PFOA exposure was also an LOD of 0.005 μIU/mL. TT4 was meas ured thyroid disease diagnosis with reported current estimated for this subsample.
using a cloned enzyme donor immunoassay use of one of the following medications com­ PFAA determinations. Laboratory analy­
(CEDIA; Roche Diagnostics) with an LOD monly used to treat thyroid disease: Armour ses of PFAA were conducted by a commer­ of 0.5 μg/dL. Normal ranges for TSH accord­ thyroid, Levothroid, Levothyroxine, Levoxil, cial laboratory (Exygen, State College, PA, ing to the laboratory were 0.7–5.97, 0.6–4.84, Methimazole, or Synthroid.
USA). Samples collected at survey were and 0.45–4.5 μIU/mL for children 1–5, 6–10, Covariates. Covariates available for anal­
analyzed for 10 PFAAs including PFOA, > 10 years of age, respectively. Normal range for ysis included age (years), sex, race/ethnicity PFOS, and PFNA. The laboratory analyti­ TT4 was 4.5–12 μg/dL for all ages. The repro­ (non­Hispanic white vs. others), body mass cal methods and quality control procedures ducibility for the analytical methods of TSH index (BMI) expressed as kilograms per meter have been described elsewhere (Frisbee et al. (n = 60) and TT4 (n = 21) was 7.2% and 9.2%, squared and transformed to a z­score based on 2009). Briefly, serum concentrations of PFAA for the lowest concentrations (0.035 μIU/mL the 2000 U.S. Centers for Disease Control and were determined using liquid chromatog­ and 3.7 μg/dL, respectively).
Prevention (CDC) growth charts of BMI­for­ raphy separation with detection by tandem We generated categories of subclinical age (CDC EpiInfo 2010), month of sampling, mass spectrometry. Estimates of precision hypothyroidism and hyperthyroidism based average household family income (≤ $10,000, for PFOA were within ± 10% for multiple on the measured thyroid hormone levels, after $10,001–20,000, $20,001–30,000, $30,001– replicates over the range of 0.5–40 ng/mL, excluding participants who reported any thy­ 40,000, $40,001–50,000, $50,001–60,000, with a more precise relative precision meas­ roid disease and/or medication. Subclinical $60,001–70,000, > $70,000, or not known), ure of approximately 1% for highly fortified hypo/hyperthyroidism cutoffs are preferably ever smoking (yes or no), and ever alcohol (10,000 ng/mL) samples. Relative precision based on normal laboratory reference ranges intake (yes or no).
estimates for PFOS and PFNA were similar to of TSH and FT4, but in the absence of FT4 In models of in utero exposure, for a sub­ those for PFOA. The detection limit (LOD) we used TSH and TT4, as reported previ­ sample, we also had information on newborn's was 0.5 ng/mL, and observations below the ously (Wu et al. 2006). Based on hormone birth weight (grams) and gestational age LOD were assigned a value of 0.25 ng/mL levels, we classified children in the category (weeks) and maternal weight gain (pounds), Environmental Health Perspectives • volume 120 number 7 July 2012 Lopez-Espinosa et al.
smoking habit (yes or no), and alcohol con­ associated with the IQR—the 75th compared variables considered met our operational defi­ sumption (yes or no) during pregnancy.
with the 25th percentile for each PFAA expo­ nition of confounder because there was < 10% Statistical analyses. We conducted a sure estimate. IQRs were calculated for each change in the PFAA coefficients when includ­
regression analysis among participants 1–17 sex/age group. For TSH, this is the exponen­ ing or excluding them from the final regression years of age at survey to assess the relation­ tiated value of the product of the coefficient models. These included maternal (age, weight ship between thyroid function and modeled for the interquartile difference in ln(PFAA). gain, smoking habit, and alcohol consumption in utero PFOA concentrations or measured For non­log­transformed TT4, we estimated during pregnancy) and child (birth weight, serum PFOA/PFOS/PFNA concentrations in the absolute change in TT4 associated with gestational age, BMI, average household family samples col ected during 2005–2006. Levels one IQR of ln(PFAA) as the coefficient times income, race/ethnicity, and smoking habit and of TSH and PFAAs showed a non­normal the IQR and expressed this as a percent of alcohol intake) variables. For variables with distribution and were natural log–transformed the mean TT4. We also fit linear regression missing values (Table 1), the above criterion before inclusion in the models. We used sim­ models including other PFAAs. In addition, was applied for the subsample of participants ple Pearson correlations to describe pairwise we performed a sensitivity analysis including without missing values. We used the statisti­ relationships between thyroid hormones and children with untreated thyroid diseases (i.e., cal software package STATA for all statistical also between PFAAs.
without reported thyroid medication use), analyses (STATA Statistical Software, release We ran linear regression analyses after but because no major differences were found, 12; StataCorp, College Station, TX, USA). exclusion of individuals with reported thyroid we did not present these results.
Where associations are referred to as statistically disease and/or thyroid medication, to calcu­ We ran logistic regression models to cal­ significant, this implies a p­value of < 0.05.
late the regression coefficient (beta) and 95% culate ORs and 95% CIs for three categories confidence intervals (CIs) for thyroid hor­ of reported disease (any thyroid disease, hypo­ Results
mone levels and PFAA quartiles or ln(PFAA) thyroidism, and thyroid disease plus medica­ Table 1 shows the characteristics of the study concentrations (the later stratified by sex and tion) and for subclinical hypothyroidism or population. A slight majority of participants age groups). Adjusted differences in thyroid hyperthyroidism (based on measured thyroid were boys (52%), and the mean age in the hormone levels between quartile groups of hormone levels) in association with IQR shifts population was 11.4 years. Most of the popu­ PFAA exposure were expressed as percentages in PFAA concentrations. Finally, we assessed lation (97.4%) was white, whereas other relative to the lowest exposure quartile, calcu­ modeled in utero and measured serum PFOA reported race/ethnicity groups were black lated as the complement of the exponentiated in the same models.
(1.2%), Hispanic (0.2%), Asian (0.1%), regression coefficient {100 × [exp(beta)–1]} We adjusted final models by child age American Indian (0.2%), and other (0.9%). for TSH and the ratio of beta to the mean and sex (when not stratified by this variable) Of the 10,725 children 1–17 years of age in [(beta/mean) × 100], for TT4. After fitting and month of sampling [because there was a this study, 61 individuals (0.6%) reported models of ln(PFAA) on ln(TSH) or TT4, trend in measured PFAA during the collection a diagnosis of thyroid disease and 39 of the regression coefficients were transformed to year as well as seasonal variations in thyroid 61 reported a diagnosis of hypothyroidism represent percent change in TSH or TT4 hormone levels (Maes et al. 1997)]. No other (including Hashimoto's thyroiditis). A total Table 1. Study population (n =10,725), Mid-Ohio
Table 2. TSH, TT4, and PFAA concentrations in children 1–17 years of age, Mid-Ohio Val ey, 2005–2006
[median (IQR)].
Measured serum TSH levels (µIU/mL) 1.93 (1.43, 2.62) 2.02 (1.49, 2.72) 1.83 (1.38, 2.54) 2.08 (1.52, 2.79) 2.08 (1.54, 2.77) 2.07 (1.50, 2.81) 1.71 (1.22, 2.38) 1.78 (1.28, 2.47) 1.62 (1.15, 2.31) 1.83 (1.31, 2.55) 1.89 (1.36, 2.59) 1.76 (1.26, 2.50) Gestational age (weeks) Measured serum TT4 levels (µg/dL) 7.80 (7.00, 8.70) 7.70 (6.80, 8.60) 8.00 (7.10, 8.80) Race/ethnicity (white) 7.70 (6.80, 8.60) 7.50 (6.70, 8.40) 7.80 (7.00, 8.70) 7.20 (6.30, 8.20) 7.00 (6.10, 7.90) 7.50 (6.60, 8.50) Alcohol consumption 7.40 (6.50, 8.40) 7.20 (6.30, 8.10) 7.70 (6.80, 8.60) Modeled in utero PFOA concentrations (ng/mL) 23.8 (10.1, 57.2) 25.4 (11.0, 63.2) 20.2 (9.35, 53.7) 14.5 (6.39, 44.9) 15.0 (6.67, 47.4) 14.4 (6.21, 41.0) 9.32 (4.61, 27.7) 8.98 (4.63, 25.6) 9.63 (4.61, 26.6) 11.5 (5.36, 37.2) 11.5 (5.46, 38.7) 11.5 (5.27, 35.4) Measured serum PFOA concentrations (ng/mL) 33.8 (16.1, 83.3) 36.4 (17.9, 87.8) 32.0 (13.7, 78.3) 32.2 (14.3, 77.7) 34.6 (15.1, 78.2) 30.1 (13.7, 73.4) Weight gain (lbs) 26.9 (12.2, 62.7) 30.5 (13.6, 72.1) 23.6 (11.1, 52.3) Alcohol consumption 29.3 (13.1, 67.7) 32.2 (14.2, 74.8) 26.3 (12.1, 60.5) Measured serum PFOS concentrations (ng/mL) 16.3 (11.3, 24.2) 16.7 (11.4, 24.4) 16.0 (11.2, 23.9) Values are n (%) or mean ± SD. Missing values were 21.8 (16.0, 30.9) 22.9 (16.8, 32.1) 20.7 (15.2, 29.3) not considered for percentage calculation. The per- cent of missing values in children's variables was for 19.6 (14.4, 27.0) 20.6 (15.4, 28.3) 18.5 (13.4, 25.3) birth weight: 51%, gestational age: 58%, BMI: 8.2%, ever 20.0 (14.5, 27.8) 20.8 (15.3, 29.0) 18.9 (13.7, 26.3) alcohol consumption: 21%, and ever smoking: 0.1%, Measured serum PFNA concentrations (ng/mL) household family income at survey: 21%. The percent of 1.40 (1.10, 1.90) 1.50 (1.10, 1.90) 1.40 (1.10, 1.90) missing values in maternal variables during pregnancy 1.80 (1.30, 2.30) 1.70 (1.40, 2.30) 1.70 (1.30, 2.40) was for weight gain: 60%, alcohol consumption: 68%, 1.40 (1.10, 1.90) 1.50 (1.20, 1.90) 1.40 (1.10, 1.70) smoking habit: 53%. 1.50 (1.20, 2.00) 1.50 (1.20, 2.00) 1.50 (1.10, 1.90) During pregnancy.
volume 120 number 7 July 2012 • Environmental Health Perspectives PFAAs and thyroid function of 53 children who reported thyroid disease Modeled in utero PFOA concentration had a Associations between quartiles of PFAAs were > 10 years old, and 46 out of 61 were median of 12 (IQR = 5.4, 37) ng/mL. At the and ln(TSH) and TT4 are shown in Table 3, girls. Using the stricter definition of reported time of the survey, median measured serum where the lowest quartile is the reference thyroid disease diagnosis plus use of thyroid PFOA, PFOS, and PFNA concentrations exposure category. Associations between IQR medication, 0.4% of children (n = 40) were were 29 (IQR = 13, 68), 20 (IQR = 15, 28), contrasts in ln(PFAAs) are shown in Table 4. counted as cases.
and 1.5 (IQR = 1.2, 2.0) ng/mL, respectively. There was little evidence for an association Table 2 shows the levels of thyroid hor­ There was a positive correlation between con­ of PFOA with either ln(TSH) or TT4 in mones and PFAAs in children. The distribu­ centrations of the PFAAs at the time of the children 1–17 years of age (Tables 3 and 4). tion of TT4 levels was close to normality with survey (PFOA vs. PFOS: r = 0.24; PFOA vs. However, an IQR contrast of 10 to 57 ng/mL mean and median values of 7.5 and 7.4 μg/dL, PFNA: r = 0.09; PFOS vs. PFNA: r = 0.41; for modeled in utero PFOA was associated respectively. TSH mean and median values p < 0.001 in all cases), and between modeled with a 2% increase in TT4 in children up to were 2.1 and 1.8 μIU/mL. TSH was negatively in utero and at survey PFOA concentrations 5 years of age (95% CI: 0.1, 3.9), with similar correlated with TT4 (r = –0.07, p < 0.001). (r = 0.42, p < 0.001).
but less precise estimates for boys and girls separately in this age group. A change in mea­ Table 3. Change in thyroid hormone levels by PFAA quartiles in children 1–17 years of age, Mid-Ohio
sured serum PFOA from 16 to 83 ng/mL was associated with a 4% drop in TSH in all chil­ Children [percent change (95%CI)] dren ≤ 5 years, but the association appeared to be limited to girls (Table 4). In children ≤ 5 years, associations between measured Modeled in utero PFOA concentrations serum PFOA and TSH remained significant 0.9 (–3.3, 5.3) 0.1 (–1.4, 1.6) after adjusting for PFOS (–5.7% change; 95% –0.2 (–4.5, 4.2) –0.6 (–2.1, 1.0) CI: –9.8, –1.4) and PFNA (–4.7% change; –1.1 (–5.3, 3.4) –0.1 (–1.7, 1.4) 95% CI: –8.9, –0.4).
Measured serum PFOA concentrations Associations between PFOS or PFNA and TT4 were found in children 1–17 years of age 1.0 (–1.9, 4.0) 0.2 (–0.8, 1.2) (Tables 3 and 4). Interquartile contrasts of 15 1.0 (–2.0, 4.1) 0.8 (–0.3, 1.9) to 28 ng/mL in PFOS and 1.2 to 2.0 ng/mL 2.4 (–0.6, 5.5) 0.3 (–0.8, 1.3) in PFNA were both associated with a 1.1% Measured serum PFOS concentrations increase in TT4 (95% CIs: 0.6, 1.5 and 0.7, 0.3 (–2.6, 3.2) 0.8 (–0.3, 1.8) 1.5, respectively). The association was evident –1.3 (–4.2, 1.7) 0.9 (–0.2, 1.9) in both girls and boys 10–17 years of age in the case of PFOS and for PFNA associations Measured serum PFNA concentrations overall were significant for both boys and girls (Table 4). In addition, associations between 0.4 (–2.6, 3.5) 0.8 (–0.3, 1.8) PFOS or PFNA and TT4 were similar after –0.3 (–3.2, 2.6) adjustment by other PFAAs percent change 1.5 (–1.6, 4.6) for PFOS adjusted by PFNA: 0.7, 95% CI: TSH was natural log-transformed. Adjusted differences in thyroid hormone levels between quartile (Q) groups of PFAA exposure were expressed as percentages relative to the lowest exposure quartile, calculated from the exponentiated 0.2, 1.2; or PFOA: 1.1, 95% CI: 0.6, 1.6; regression coefficient for TSH and from the ratio of beta to the mean for TT4.
percent change for PFNA adjusted by PFOS: Table 4. Change in thyroid hormone levels associated with IQR shifts in PFAAs in children 1–17 years of age, Mid-Ohio Valley, 2005–2006 [percent change (95%CI)].
All childrenb Modeled in utero PFOA concentrations –3.4 (–8.8, 2.4) –1.0 (–9.0, 7.6) 1.7 (–1.2, 4.6) –5.8 (–13.4, 2.5) 2.1 (–0.5, 4.8) –1.5 (–4.9, 2.1) 0.9 (–0.3, 2.1) –2.6 (–7.4, 2.4) 0.5 (–1.3, 2.3) 0.2 (–5.1, 4.9) 1.3 (–0.4, 3.0) 0.1 (–2.2, 2.5) –0.7 (–1.5, 0.2) 0.2 (–2.8, 3.3) –0.7 (–1.8, 0.4) –0.1 (–3.7, 3.7) –0.8 (–2.2, 0.5) –0.5 (–2.4, 1.5) –0.1 (–0.8, 0.6) –0.3 (–3.0, 2.5) –0.3 (–1.3, 0.7) –0.5 (–3.4, 2.5) –0.1 (–1.1, 1.0) Measured serum PFOA concentrations –4.3 (–8.2, –0.3) 0.7 (–0.7, 2.1) –1.1 (–6.6, 4.7) 1.3 (–0.7, 3.3) –7.7 (–13.2, –1.7) –0.1 (–2.2, 2.0) 0.5 (–2.0, 3.1) –1.1 (–4.4, 2.3) 0.1 (–1.1, 1.3) 2.2 (–1.7, 6.3) 2.0 (–0.1, 4.1) –0.3 (–1.1, 0.4) 1.6 (–1.1, 4.3) 0.5 (–0.5, 1.4) 2.4 (–0.7, 5.7) –0.9 (–2.0, 0.2) 1.0 (–0.5, 2.7) 0.1 (–0.5, 0.6) 0.7 (–1.3, 2.7) 0.4 (–0.3, 1.1) 1.3 (–1.0, 3.8) 0.0 (–0.8, 0.7) Measured serum PFOS concentrations 3.1 (–0.9, 7.3) 0.8 (–0.6, 2.2) 1.4 (–4.3, 7.5) 0.4 (–1.7, 2.5) 4.7 (–0.9, 10.5) 1.2 (–0.6, 3.0) 0.0 (–2.2, 2.3) –1.7 (–4.5, 1.2) 0.4 (–0.7, 1.4) 2.1 (–1.7, 5.7) 0.9 (–0.8, 2.7) 1.1 (–1.0, 3.2) 0.8 (–1.9, 3.5) 1.0 (–0.3, 2.3) 0.4 (–1.2, 2.1) 1.6 (–0.5, 3.6) Measured serum PFNA concentrations 0.2 (–3.5, 4.1) 1.1 (–0.2, 2.4) –0.7 (–6.0, 4.8) 1.1 (–0.8, 3.0) 1.5 (–3.8, 7.1) 1.1 (–0.7, 2.9) 0.0 (–2.1, 2.1) –0.9 (–3.3, 1.6) 0.5 (–0.4, 1.4) 1.0 (–2.4, 4.4) 1.1 (–0.5, 2.8) 0.2 (–2.0, 2.4) 0.5 (–0.3, 1.3) 0.8 (–0.4, 2.0) 1.0 (–0.7, 2.6) 0.5 (–1.4, 2.5) PFAAs and TSH were natural log-transformed. Change in TSH calculated from the exponentiated regression coefficient and change in TT4 as a percent of the mean. aNumber of children with PFAA measurements after excluding those who reported thyroid disease and/or thyroid medication (also excluded from models): boys, n = 5,526; girls,
n = 5,199. Models adjusted by sexb, ageb,c, and month of samplingb,c.
Environmental Health Perspectives • volume 120 number 7 July 2012 Lopez-Espinosa et al.
0.8, 95% CI: 0.4, 1.3; or PFOA: 1.1, 95% association between maternal serum PFOA exposure did not alter TT4 levels in zebrafish CI: 0.6, 1.5). We did not find evidence of (median = 1.46 ng/mL) concentrations and juveniles treated with PFNA until maturity associations between serum PFOS or PFNA cord serum TSH levels. No association was (Liu et al. 2011). In adult monkeys, PFOA found between PFOA, PFOS, or PFNA and exposure during 6 months, which led to The OR for thyroid disease (n = 61) was T4 (Kim et al. 2011). Another small study serum levels up to 158 μg/mL, did not alter 1.44 (95% CI: 1.02, 2.03) (Table 5). Most of 15 Japanese mother–child pairs reported TT4 or TSH (Butenhoff et al. 2002).
of the children with thyroid disease were no apparent correlation between maternal We found higher odds of reporting thy­ reported to have hypothyroidism (n = 39; blood PFOS (median = 8.1 ng/mL) concen­ roid disease (mostly hypothyroidism) with OR = 1.54; 95% CI: 1.00, 2.37). The asso­ trations and neonatal blood TSH or FT4 increased measured PFOA concentrations, ciation was similar for the strictest definition (Inoue et al. 2004). In agreement with our even when we restricted cases to children with of reported thyroid disease plus use of thy­ results, a recently published study of 52,296 reported disease plus use of thyroid medica­ roid medication (OR = 1.61; 95% CI: 1.07, adults from the C8 Health Project found a tion. However, PFOA concentrations were 2.51). Associations were similar for modeled positive association between serum PFOS and not associated with subclinical hypo/hyper­ estimates of in utero PFOA concentrations, TT4. They also found a positive association thyroidism based on individual hormone although CIs were a little wider (Table 5). between serum PFOA and TT4 in women levels or thyroid hormone levels (as continu­ We also performed analyses including both of all ages, and men > 50 years of age (Knox ous variables) in children 1–17 years of age. modeled in utero and measured PFOA in et al. 2011). In addition, a positive associ­ Therefore, the association between reported the same model, and in both cases ORs were ation was reported between plasma PFOS thyroid disease and PFOA exposure should attenuated and CIs were wider (OR = 1.29; (GM = 18.3 ng/mL) and FT4 levels and be considered with caution. Nevertheless, 95% CI: 0.87, 1.92; and OR = 1.27; 95% inverse with TSH in environmentally exposed these results are comparable to a cross­ CI: 0.74, 2.19 for thyroid disease vs. PFOA adults (n = 621) from Nunavik, Quebec, sectional analysis of PFOA/PFOS concentra­ modeled in utero or at survey, respectively). Canada (Dallaire et al. 2009). On the con­ tions and reported thyroid disease in adults in We did not find associations between concen­ trary, a modest inverse association between NHANES for 1999–2000, 2003–2004, and trations of any of the PFAAs and subclinical serum PFOA (median = 1.1 μg/mL) and FT4 2005–2006 (n = 3,966). An OR of 2.2 (95% hypo/hyperthyroidism (Table 5).
but not TT4 or TSH levels was reported in CI: 1.4, 3.7) was estimated for thyroid disease an occupational study among 506 employees in association with the highest versus first and in one Belgian and two American factories second quartiles of serum PFOA in females To the best of our knowledge, this is the first (Olsen and Zobel 2007). Some adult studies (mean = 3.77 ng/mL), and a similar associa­ large­scale report of an association between have not found associations between PFAA tion with serum PFOS (mean = 25.1 ng/mL) PFAAs in serum and thyroid function impair­ exposures and thyroid level alteration, includ­ was reported for males (OR = 2.7; 95% CI: ment in children 1–17 years of age. In a ing a study of Canadian pregnant women 1.0, 7.0) (Melzer et al. 2010).
group of 10,725 children from the Mid­Ohio with hypothyroxinemia (n = 96; PFOA and The main strengths of the present study Valley, measured serum PFOA concentra­ PFOS medians = 3.9 and 15.5 nmol/L) are the large sample size and the data for both tions in 2005–2006 were positively associated whose serum PFAA concentrations were com­ measured and modeled in utero PFOA con­ with thyroid disease (mostly hypothyroidism). parable to matched controls (n = 175; PFOA centrations. A further strength is the high In addition, serum concentrations of PFOS and PFOS medians = 3.6 and 16.4 nmol/L) rate of participation, diminishing concern and PFNA, but not PFOA, were positively (Chan et al. 2011). There was no evidence about potential selection biases. It is believed associated with TT4 levels in children 1–17 of an association between elevated serum that this population is representative, given years of age.
PFOA (median = 354 ng/mL) and TSH lev­ the high participation rates in the C8 Health Serum PFOS and PFNA concentrations els in residents (n = 371) from the same area Project, of all those children who drank con­ were associated with slightly higher levels as the present study (Emmett et al. 2006). taminated water in the Mid­Ohio Valley. of TT4 in children 1–17 years of age, but In a small study (n = 31) of anglers from Moreover, we were able to adjust for a num­ were not positively associated with subclinical New York State, no association was reported ber of potential confounders.
hyperthyroidism. PFOA was not associated between PFOA, PFOS, or PFNA concentra­ The mostly cross­sectional design of the with TSH or TT4 in all children combined, tions (GM = 1.3, 19.6, and 0.79 ng/mL) and present study is a major limitation because the though subgroup analyses suggested possible serum TSH or FT4 levels (Bloom et al. 2010). single measurements preclude determination of associations with PFOA measured at survey Altered thyroid hormone levels follow­ the time sequence between PFAA exposure and and modeled in utero, in children ≤ 5 years. ing exposure to PFAAs have also been found outcome, and some associations may have been However, given the lack of effect in the other in experimental animal studies where pre­ attributable to chance or uncontrolled sources age groups, this may be a chance finding. and postnatal long­term exposure to PFOS of bias. One further limitation is the absence Previous literature on child thyroid func­ decreased serum levels of TT4 and FT4 in of measurements of child triiodothyronine and tion and PFAA exposure is limited. A recent pregnant dams and pups, without a concomi­ FT4 levels, which would have yielded more study in Korea (n = 29) reported a positive tant rise in TSH (Lau et al. 2007). PFNA comprehensive information concerning the Table 5. ORs (95% CIs) of thyroid disease for IQR shift in PFAA concentrations in children 1–17 years of age, Mid-Ohio Valley, 2005–2006.
Modeled in utero PFOA 1.47 (0.95, 2.27) 1.61 (0.96, 2. 63) 0.94 (0.76, 1.16) 1.10 (0. 69, 1.74) Measured serum PFOA 1.44 (1.02, 2.03) 1.54 (1.00, 2.37) 0.98 (0.86, 1.15) 0.81 (0.58, 1.15) Measured serum PFOS 0.91 (0.63, 1,31) 0.99 (0.86, 1.13) 0.80 (0.62, 1.02) Measured serum PFNA 1.05 (0.78, 1.41) 1.11 (0.77, 1.60) 0.99 (0.88, 1.12) 0.78 (0.61, 1.01) PFAAs were natural log-transformed. Models were adjusted by age and sex. aBased on hormonal levels at survey after excluding people who self-reported thyroid disease and/or thyroid medication.
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Environmental Health Perspectives • volume 120 number 7 July 2012



An evidence-based, Latin-American consensus ongastro-oesophageal reflux diseaseHenry Cohena, Joaquim Prado P. Moraes-Filhob, Maria Luisa Cafferatac,Giselle Tomassoc, Graciela Salisd, Oscar Gonza´leze, Jorge Valenzuelaf,Prateek Sharmag, Peter Malfertheinerh, David Armstrongi, Lars Lundellj,Rodolfo Cortik, Paulo Sakaib, Ivan Ceconellob and the Latin-AmericanGORD Consensus Group*

MisiÓn de la universidad autÓnoma de yucatÁn