A critical review of perfluorooctanoate and perfluorooctanesulfonate exposure and immunological health conditions in humans

Figures & data

Table 1. Results of epidemiologic studies of the association between exposure to perfluorooctanoic acid (PFOA) and/or perfluorooctanesulfonate (PFOS) and immune biomarkers or gene expression profiles.

Reference	Outcome	Number (%) with outcome	Estimate of association (95% confidence interval)	Adjustment factors
Olsen et al. 2003	White blood cell count	n = 518	“There were no significant mean differences between quartiles [of PFOA or PFOS] for … hematology … (data not shown)”	Age, body mass index, current daily alcohol consumption, current daily cigarette use, years worked at Antwerp or Decatur, and type of job (production vs. non-production)
Emmett et al. 2006b	White blood cell count	n = 18 (5%) abnormal	PFOA coefficient = 0.00039608, r = 0.09, p = 0.08No significant correlation in adults aged ≥19 years or children aged <18 yearst test p = 0.64 for PFOA in normal vs. abnormal	None
Emmett et al. 2006b	Neutrophils, percent	n = 35 (9%) abnormal	PFOA coefficient = 0.0004305, r = 0.02, p = 0.71No significant correlation in adults aged ≥19 years or children aged <18 yearst test p = 0.02 for PFOA in normal vs. abnormal (more abnormal with lower serum PFOA)	None
Emmett et al. 2006b	Neutrophils, absolute	n = 12 (3%) abnormal	PFOA coefficient = 0.00025301, r = 0.07, p = 0.17No significant correlation in adults aged ≥19 years or children aged <18 yearst test p = 0.23 for PFOA in normal vs. abnormal	None
Emmett et al. 2006b	Lymphocytes, percent	n = 18 (5%) abnormal	PFOA coefficient = −0.0006401, r = 0.03, p = 0.54No significant correlation in adults aged ≥19 years or children aged <18 yearst test p = 0.01 for PFOA in normal vs. abnormal (more abnormal with lower serum PFOA)	None
Emmett et al. 2006b	Lymphocytes, absolute	n = 3 (1%) abnormal	PFOA coefficient = 0.00009406, r = 0.05, p = 0.29No significant correlation in adults aged ≥19 years or children aged <18 yearst test p = 0.59 for PFOA in normal vs. abnormal	None
Emmett et al. 2006b	Monocytes, percent	n = 39 (11%) abnormal	PFOA coefficient = 0.00023119, r = 0.04, p = 0.44No significant correlation in adults aged ≥19 years or children aged <18 yearst test p = 0.09 for PFOA in normal vs. abnormal	None
Emmett et al. 2006b	Monocytes, absolute	n = 7 (2%) abnormal	PFOA coefficient = 0.00005008, r= 0.13, p = 0.01No significant correlation in adults aged ≥19 years or children aged <18 yearst test p = 0.85 for PFOA in normal vs. abnormal	None
Emmett et al. 2006b	Eosinophils, percent	n = 19 (5%) abnormal	PFOA coefficient = −0.0000652, r = 0.01, p = 0.82No significant correlation in adults aged ≥19 years or children aged <18 yearst test p = 0.10 for PFOA in normal vs. abnormal	None
Emmett et al. 2006b	Eosinophils, absolute	n = 22 (6%) abnormal	PFOA coefficient = 0.00000252, r = 0.00, p = 0.90No significant correlation in adults aged ≥19 years or children aged <18 yearst test p = 0.85 for PFOA in normal vs. abnormal	None
Emmett et al. 2006b	Basophils, percent	n = 0 (0%) abnormal	PFOA coefficient = 0.00003319, r = 0.03, p = 0.59No significant correlation in adults aged ≥19 years or children aged <18 years	None
Emmett et al. 2006b	Basophils, absolute	n = 0 (0%) abnormal	PFOA coefficient = 0.00000586, r = 0.05, p = 0.30No significant correlation in adults aged ≥19 years or children aged <18 years	None
Costa et al. 2009	White blood cells (×10^9/L)	% outside reference range:Exposed: 2.6%Non-exposed: 5.6%	t statistic = 0.10, p ≥ 0.05 vs. matched non-exposed workersExposed vs. non-exposed coefficient = 0.58 (−0.19, 1.35)PFOA coefficient = 0.029 (−0.011, 0.071)	Currently exposed and non-exposed pairs matched by age, job seniority, working hours, residential area, and housing and living conditionsRegression analysis controlled for age, job seniority, body mass index, and alcohol consumption (+ smoking for comparison of currently vs. never exposed workers; + year of observation for comparison by PFOA level in workers with concurrent PFOA and outcomes)
Costa et al. 2009	C-reactive protein (mg/L)	% outside reference range:Exposed: 5.1%Non-exposed: NR	PFOA coefficient = −0.020 (−0.268, 0.228)	Age, job seniority, body mass index, alcohol consumption, and year of observation
Costa et al. 2009	α1 globulins (%)	% outside reference range:Exposed: 0%Non-exposed: 0.9%	t statistic = 0.59, p ≥ 0.05 vs. matched non-exposed workersExposed vs. non-exposed coefficient = −1.82 (−8.18, 4.54)PFOA coefficient = 0.026 (−0.001, 0.053)	Currently exposed and non-exposed pairs matched by age, job seniority, working hours, residential area, and housing and living conditionsRegression analysis controlled for age, job seniority, body mass index, and alcohol consumption (+ smoking for comparison of currently vs. never exposed workers; + year of observation for comparison by PFOA level in workers with concurrent PFOA and outcomes)
Costa et al. 2009	α2 globulins (%)	% outside reference range:Exposed: 12.8%Non-exposed: 14.0%	t statistic = 0.20, p ≥ 0.05 vs. matched non-exposed workersExposed vs. non-exposed coefficient = 0.27 (−0.75, 1.28)PFOA coefficient = 0.026 (0.007, 0.045)	Currently exposed and non-exposed pairs matched by age, job seniority, working hours, residential area, and housing and living conditionsRegression analysis controlled for age, job seniority, body mass index, and alcohol consumption (+ smoking for comparison of currently vs. never exposed workers; + year of observation for comparison by PFOA level in workers with concurrent PFOA and outcomes)
Costa et al. 2009	β globulins (%)	% outside reference range:Exposed: 0%Non-exposed: 0%	t statistic = 0.49, p ≥ 0.05 vs. matched non-exposed workersExposed vs. non-exposed coefficient = −0.003 (−0.37, 0.36)PFOA coefficient = 0.011 (−0.008, 0.030)	Currently exposed and non-exposed pairs matched by age, job seniority, working hours, residential area, and housing and living conditionsRegression analysis controlled for age, job seniority, body mass index, and alcohol consumption (+ smoking for comparison of currently vs. never exposed workers; + year of observation for comparison by PFOA level in workers with concurrent PFOA and outcomes)
Costa et al. 2009	γ globulins (%)	% outside reference range:Exposed: 0%Non-exposed: 0%	t statistic = 0.10, p ≥ 0.05 vs. matched non-exposed workersExposed vs. non-exposed coefficient = −0.53 (−2.29, 1.24)PFOA coefficient = 0.013 (−0.005, 0.031)	Currently exposed and non-exposed pairs matched by age, job seniority, working hours, residential area, and housing and living conditionsRegression analysis controlled for age, job seniority, body mass index, and alcohol consumption (+ smoking for comparison of currently vs. never exposed workers; + year of observation for comparison by PFOA level in workers with concurrent PFOA and outcomes)
Costa et al. 2009	IgG (g/L)	% outside reference range:Exposed: 2.6%Non-exposed: NR	PFOA coefficient = −0.017 (−0.115, −0.080)[As reported, 95% confidence interval excludes −0.017; upper 95% confidence limit may be 0.080, since p-value is reported as non-significant.]	Age, job seniority, body mass index, alcohol consumption, and year of observation
Costa et al. 2009	IgA (g/L)	% outside reference range:Exposed: 12.8%Non-exposed: NR	NR	Age, job seniority, body mass index, alcohol consumption, and year of observation
Costa et al. 2009	IgM (g/L)	% outside reference range:Exposed: 5.1%Non-exposed: NR	PFOA coefficient = 0.048 (−0.093, 0.190)	Age, job seniority, body mass index, alcohol consumption, and year of observation
Lin et al. 2011	Serum C-reactive protein (log mg/L)	NR	PFOA percentile:<50th (0.75–2.37 ng/mL): mean (SE) = 1.38 (0.14)50th–74th (2.39–5.92 ng/mL): mean (SE) = 1.43 (0.14)75th–89th (6.01–9.62 ng/mL): mean (SE) = 1.48 (0.18)≥90th (9.64–28.13 ng/mL): mean (SE) = 1.41 (0.21)P-trend = 0.932PFOS percentile:<50th (0.11–8.92 ng/mL): mean (SE) = 1.41 (0.13)50th–74th (8.95–14.35 ng/mL): mean (SE) = 1.41 (0.16)75th–89th (14.92–19.14 ng/mL): mean (SE) = 1.48 (0.17)≥90th (19.98–67.26 ng/mL): mean (SE) = 1.36 (0.21)P - trend=0.957	Age, gender, smoking status, drinking status, household income, systolic blood pressure, waist circumference, homeostasis model assessment of insulin resistance index, total cholesterol, and creatinine
Wang et al. 2011	Serum total IgE at age 2 years (kU/L, log-transformed)	n = 244 overalln = 133 malesn = 111 females	Log PFOA (ng/mL):Overall coefficient = 0.027 (SE = 0.244), p = 0.870Boys coefficient = 0.097 (SE = 0.345), p = 0.710Girls coefficient = 0.001 (SE = 0.452), p = 0.998Log PFOS (ng/mL):Overall coefficient = 0.251 (SE = 0.179), p = 0.147Boys coefficient = 0.359 (SE = 0.255), p = 0.238Girls coefficient = 0.095 (SE = 0.325), p = 0.723	Gender, gestational age, parity, maternal age, and prenatal environmental tobacco smoke exposure
Wang et al. 2011	Cord serum total IgE (kU/L, log-transformed)	n = 244 overalln = 133 malesn = 111 females	Log PFOA (ng/mL):Overall coefficient = 0.134 (0.003, 0.458)Boys coefficient = 0.206 (0.047, 0.702)Girls coefficient = 0.067 (SE = 0.231), p = 0.823Log PFOS (ng/mL):Overall coefficient = 0.161 (0.064, 0.642)Boys coefficient = 0.175 (0.004, 0.704)Girls coefficient = 0.151 (SE = 0.165), p = 0.616	Gender, gestational age, parity, maternal age, and prenatal environmental tobacco smoke exposure
Okada et al. 2012	Cord serum IgE (IU/mL)	n = 231 overalln = 103 malesn = 128 females	Log10 maternal PFOA (ng/mL):Overall:Linear coefficient = 0.282 (−0.229, 0.792)Quadratic coefficient = −1.009 (−1.918, −0.101)Cubic coefficient = −1.430 (−3.384, 0.524)Males:Linear coefficient = −0.315 (−1.114, 0.485)Quadratic coefficient = 0.227 (−1.584, 2.037)Cubic coefficient = 1.277 (−2.191, 4.744)Females:Linear coefficient = 0.766 (0.104, 1.428)Quadratic coefficient = −1.429 (−2.416, −0.422)Cubic coefficient = −3.078 (−5.431, −0.726)Log10 maternal PFOS (ng/mL):Overall:Linear coefficient = −0.240 (−0.891, 0.412)Quadratic coefficient = 0.145 (−1.150, 1.440)Cubic coefficient = 0.851 (−3.729, 5.432)Males:Linear coefficient = −0.047 (−1.051, 0.957)Quadratic coefficient = 0.911 (−1.101, 2.922)Cubic coefficient = −0.101 (−6.625, 6.422)Females:Linear coefficient = −0.342 (−1.230, 0.546)Quadratic coefficient = −0.681 (−2.500, 1.137)Cubic coefficient = 1.464 (−5.354, 8.282)	Maternal age, maternal allergic history, distance from home to highway, infant gender, parity, birth season, and blood sampling period
Ashley-Martin et al. 2015	Cord plasma thymic stromal lymphopoietin and interleukin-33 ≥ 80th percentile	n = 1242 overalln = 664 malesn = 578 females	Log10 maternal PFOA (μg/L):Overall OR = 1.1 (95% credible interval = 0.6, 1.8)Boys OR = 1.1 (0.5, 2.0)Girls OR = 1.1 (0.5, 2.1)Log10 maternal PFOS (μg/L):Overall OR = 1.1 (95% credible interval = 0.6, 1.9)Boys OR = 1.1 (0.4, 2.0)Girls OR = 1.1 (0.7, 2.1)	Maternal age, infant sex
Ashley-Martin et al. 2015	Cord plasma IgE ≥ 0.5 kU/L	n = 1242 overalln = 664 malesn = 578 females	Log10 maternal PFOA (μg/L):Overall OR = 1.1 (95% credible interval = 0.6, 1.9)Boys OR = 1.2 (0.6, 2.3)Girls OR = 1.0 (0.5, 1.9)Log10 maternal PFOS (μg/L):Overall OR = 1.1 (95% credible interval = 0.6, 1.9)Boys OR = 1.2 (0.7, 2.3)Girls OR = 1.0 (0.4, 1.9)	Maternal age, infant sex
Pennings et al. 2015	Gene expression	NR	Number of correlated genes (p < 0.05):PFOA: 453 positively correlated, 490 negatively correlatedPFOS: 636 positively correlated, 671 negatively correlated2 or more PFAS: 294 positive correlated, 284 negatively correlatedCommon cold episodes: 330 positively correlated, 250 negatively correlatedRubella antibody: 522 positively correlated, 709 negatively correlatedPFAS and common cold: 27 correlated (3 immunological and/or hematopoietic functions, 6 development and/or morphogenesis)PFAS and rubella: 26 correlated (2 regulation of T-cell activation, 1 immunological function, 7 development and/or morphogenesis)PFAS and common cold and rubella: 1 correlated (cytokine-like 1, CYTL1)	None“Adjustments for potentially confounding factors with regard to statistical analyses on the associations between PFAS exposure and the health outcomes common cold and rubella titers have been performed previously (Granum et al. 2013). Since we are including only exposure–health outcomes found to be statistically significant after adjustment for confounding factors in Granum et al. adjustments for confounding factors are not repeated in the statistical analyses in the present study.”

Columns show first author and year of study reference, outcome of interest, number and proportion of subjects with the outcome, estimates of association with PFOA and/or PFOS levels, and covariates adjusted in multivariable models.

Ig: immunoglobulin; IU: international unit; kU: kilo units; NR: not reported; OR: odds ratio; PFAS: perfluoroalkyl and polyfluoroalkyl substances; PFOA: perfluorooctanoic acid; PFOS: perfluorooctanesulfonate; Q: quartile; SE: standard error.

Table 2. Results of epidemiologic studies of the association between exposure to perfluorooctanoic acid (PFOA) and/or perfluorooctanesulfonate (PFOS) and atopic or allergic health conditions.

Reference	Outcome	Number (%) with outcome	Estimate of association (95% confidence interval)	Adjustment factors
Anderson-Mahoney et al. 2008	Asthma(All ages, 18–34 years, 35–49 years, 50–64 years, or 65 + years)	All ages: n = 105	All ages: standardized prevalence ratio (SPR) = 1.82 (1.47, 2.25)18–34 years: SPR = 2.97 (p < 0.0001) in males, 1.97 (p < 0.0001) in females35–49 years: SPR = 1.85 (p = 0.0005) in males, 1.39 (p = 0.0003) in females50–64 years: SPR = 1.38 (p = 0.002) in males, 1.65 (p < 0.0001) in females65 + years: SPR = 3.35 (p < 0.0001) in males, 1.69 (p = 0.01) in females	Age and sex
Leonard et al. 2008	Asthma mortality	Observed: 0 deathsExpected in U.S.: 2.1 deathsExpected in West Virginia: 1.8 deathsExpected in DuPont workers: 0.7 deaths	SMR vs. U.S. = 0 (0, 1.76)SMR vs. West Virginia = 0 (0, 2.05)SMR vs. DuPont workers = 0 (0, 5.27)	Age, sex, and calendar period
Wang et al. 2011	Atopic dermatitis	n = 43 (17.6%)	Cord serum PFOA:Q1 (<0.085 ng/mL): referentQ2 (0.085–0.57 ng/mL): OR = 0.84 (0.28, 2.48)Q3 (0.57–1.085 ng/mL): OR = 1.03 (0.42, 2.56)Q4 (>1.085 ng/mL): OR = 0.58 (0.22, 1.58)Cord serum PFOS:Q1 (<1.25 ng/mL): referentQ2 (1.25–1.835 ng/mL): OR = 0.68 (0.20, 2.30)Q3 (1.835–2.775 ng/mL): OR = 2.34 (0.86, 6.41)Q4 (>2.775 ng/mL): OR = 2.19 (0.78, 6.17)	Gender, gestational age, maternal age, maternal history of atopy, duration of breastfeeding, and prenatal environmental tobacco smoke exposure
Okada et al. 2012	Food allergy	n = 57 (16.6%)	Per 10-fold increase in PFOA:Overall OR = 1.67 (0.52, 5.37)Males OR = 0.87 (0.16, 4.89)Females OR = 2.37 (0.50, 17.10)Per 10-fold increase in maternal PFOS:Overall OR = 3.72 (0.81, 17.10)Males OR = 5.42 (0.62, 47.20)Females OR = 2.75 (0.31, 24.80)No significant differences by blood sampling period (data not reported)	Maternal age, maternal educational level, pre-pregnancy body mass index, parental allergy, parity, infant gender, breastfeeding duration, environmental tobacco smoke exposure, day care attendance, and blood sampling period“When total dioxins and total [polychlorinated biphenyls] were evaluated as potential confounders, no significant association remained between [perfluorinated compound] concentrations and infant allergies and infectious diseases during the first 18 months of life (data not shown).”
Okada et al. 2012	Eczema	n = 37 (10.8%)	Per 10-fold increase in PFOA:Overall OR = 0.96 (0.23, 4.02)Males OR = 1.12 (0.15, 8.42)Females OR = 0.88 (0.09, 7.70)Per 10-fold increase in maternal PFOS:Overall OR = 0.87 (0.15, 5.08)Males OR = 0.62 (0.06, 6.67)Females OR = 1.24 (0.08, 19.30)No significant differences by blood sampling period (data not reported)	Maternal age, maternal educational level, pre-pregnancy body mass index, parental allergy, parity, infant gender, breastfeeding duration, environmental tobacco smoke exposure, day care attendance, and blood sampling period“When total dioxins and total [polychlorinated biphenyls] were evaluated as potential confounders, no significant association remained between [perfluorinated compound] concentrations and infant allergies and infectious diseases during the first 18 months of life (data not shown).”
Okada et al. 2012	Wheezing	n = 33 (9.6%)	Per 10-fold increase in PFOA:Overall OR = 1.27 (0.27, 6.05)Males OR = 2.72 (0.25, 29.90)Females OR = 1.31 (0.10, 18.00)Per 10-fold increase in PFOS:Overall OR = 2.68 (0.39, 18.30)Males OR = 12.98 (0.80, 212.00)Females OR = 0.61 (0.03, 11.50)No significant differences by blood sampling period (data not reported)	Maternal age, maternal educational level, pre-pregnancy body mass index, parental allergy, parity, infant gender, breastfeeding duration, environmental tobacco smoke exposure, day care attendance, and blood sampling period“When total dioxins and total [polychlorinated biphenyls] were evaluated as potential confounders, no significant association remained between [perfluorinated compound] concentrations and infant allergies and infectious diseases during the first 18 months of life (data not shown).”
Dong et al. 2013	Asthma	PFOA quartiles:Q1: n = 43 cases, 71 controlsQ2: n = 50 cases, 64 controlsQ3: n = 61 cases, 53 controlsQ4: n = 77 cases, 37 controlsPFOS quartiles:Q1 (<19.64 ng/mL): n = 47 cases, 67 controlsQ2 (19.64–33.85 ng/mL): n = 60 cases, 54 controlsQ3 (33.85–61.08 ng/mL): n = 50 cases, 64 controlsQ4 (≥61.08 ng/mL): n = 74 cases, 40 controls	PFOA:Q1: ReferentQ2: OR = 1.58 (0.89, 2.80)Q3: OR = 2.67 (1.49, 4.79)Q4: OR = 4.05 (2.21, 7.42)P-trend < 0.001PFOS:Q1: ReferentQ2: OR = 1.96 (1.11, 3.47)Q3: OR = 1.32 (0.75, 2.32)Q4: OR = 2.63 (1.48, 4.69)P-trend = 0.003	Age, sex, body mass index, parental education, environmental tobacco smoke exposure, and month of survey
Dong et al. 2013	Asthma severity score	n = 231 asthma cases	PFOA:Q1: mean = 3.63 (2.66, 4.60)Q2: mean = 3.99 (3.02, 4.96)Q3: mean = 4.39 (3.40, 5.38)Q4: mean = 4.57 (3.59, 5.55)P-trend = 0.119PFOS:Q1: mean = 3.33 (2.36, 4.31)Q2: mean = 4.18 (3.19, 5.17)Q3: mean = 4.49 (3.52, 5.45)Q4: mean = 4.57 (3.61, 5.54)P-trend = 0.045	Age, sex, body mass index, parental education, environmental tobacco smoke exposure, and month of survey
Dong et al. 2013	Asthma control in previous 4 weeks	n = 231 asthma cases	PFOA:Q1: mean = 22.02 (21.22, 22.82)Q2: mean = 22.14 (21.33, 22.96)Q3: mean = 22.76 (21.96, 23.56)Q4: mean = 22.65 (21.84, 23.45)P-trend = 0.168PFOS:Q1: mean = 22.51 (21.71, 23.32)Q2: mean = 22.72 (21.92, 23.52)Q3: mean = 22.13 (21.30, 22.94)Q4: mean = 22.21 (21.41, 23.02)P-trend = 0.450	Age, sex, body mass index, parental education, environmental tobacco smoke exposure, and month of survey
Granum et al. 2013	Eczema and itchiness	n = 21 (25.9%) in 3rd year; 16 (30.2%) with bloodn = 32 (45.7%) in all 3 years	Per 1-ng/mL increase in PFOA:3rd year OR = 0.56 (0.17, 1.87)All 3 years OR = 0.42 (0.13, 1.30)Per 1-ng/mL increase in PFOS:3rd year OR = 0.93 (0.72, 1.18)All 3 years OR = 0.94 (0.75, 1.19)	None
Granum et al. 2013	Wheezing	n = 18 (21.2%) in 3rd year; 11 (19.6%) with bloodn = 29 (38.2%) in all 3 years	Per 1-ng/mL increase in PFOA:3rd year OR = 1.07 (0.33, 3.49)All 3 years OR = 1.92 (0.66, 5.58)Per 1-ng/mL increase in PFOS:3rd year OR = 0.99 (0.77, 1.26)All 3 years OR = 1.10 (0.88, 1.37)	None
Granum et al. 2013	Asthma	n = 11 (14.5%) in all 3 years	Per 1-ng/mL increase in PFOA:All 3 years OR = 3.56 (0.84, 15.02)Per 1-ng/mL increase in PFOS:All 3 years OR = 1.22 (0.89, 1.66)	None
Granum et al. 2013	Atopic eczema	n = 14 (18.4%) in all 3 years	Per 1-ng/mL increase in PFOA:3rd year OR = 1.31 (0.37, 4.68)Per 1-ng/mL increase in PFOS:All 3 years OR = 0.96 (0.73, 1.27)	None
Humblet et al. 2014	Asthma, ever	n = 318	Per 2-fold increase in PFOA:OR = 1.18 (1.08, 1.39)OR = 1.11 (0.87, 1.42) using survey weightsOR = 1.13 (0.99, 1.29) imputing missing dataPer 1-ng/mL increase in PFOA:OR = 1.06 (1.00, 1.11)PFOA:Tertile 1: referentTertile 2: OR = 1.06 (0.89, 1.27)Tertile 3: OR = 1.11 (0.94, 1.31)	Age, sex, smoking, race/ethnicity, survey cycle, poverty-income ratio, and health insurance type
Humblet et al. 2014	Asthma, ever	n = 318	Per 2-fold increase in PFOS:OR = 0.88 (0.74, 1.04)OR = 0.84 (0.66, 1.08) using survey weightsOR = 0.86 (0.75, 0.98) imputing missing dataPer 1-ng/mL increase in PFOS:OR = 0.99 (0.98, 1.00)PFOS:Tertile 1: referentTertile 2: OR = 0.96 (0.77, 1.19)Tertile 3: OR = 1.01 (0.80, 1.27)	Age, sex, smoking, race/ethnicity, survey cycle, poverty-income ratio, and health insurance type
Humblet et al. 2014	Asthma, current	n = 191	Per 2-fold increase in PFOA:OR = 1.12 (0.92, 1.36)OR = 1.15 (0.86, 1.55) using survey weightsOR = 1.06 (0.91, 1.25) imputing missing dataPer 1-ng/mL increase in PFOA:OR = 1.03 (0.97, 1.10)PFOA:Tertile 1: referentTertile 2: OR = 0.89 (0.70, 1.12)Tertile 3: OR = 1.18 (0.90, 1.53)	Age, sex, smoking, race/ethnicity, survey cycle, poverty-income ratio, and health insurance type
Humblet et al. 2014	Asthma, current	n = 191	Per 2-fold increase in PFOS:OR = 0.88 (0.72, 1.09)OR = 0.91 (0.68, 1.21) using survey weightsOR = 0.89 (0.75, 1.05) imputing missing dataPer 1-ng/mL increase in PFOS:OR = 0.99 (0.98, 1.01)PFOS:Tertile 1: referentTertile 2: OR = 0.88 (0.69, 1.13)Tertile 3: OR = 1.06 (0.80, 1.41)	Age, sex, smoking, race/ethnicity, survey cycle, poverty-income ratio, and health insurance type
Humblet et al. 2014	Wheezing in last 12 months	n = 217	Per 2-fold increase in PFOA:OR = 1.00 (0.80, 1.23)OR = 1.14 (0.82, 1.58) using survey weightsOR = 1.01 (0.85, 1.20) imputing missing dataPer 1-ng/mL increase in PFOA:OR = 1.01 (0.94, 1.07)PFOA:Tertile 1: referentTertile 2: OR = 0.95 (0.76, 1.19)Tertile 3: OR = 1.08 (0.86, 1.36)	Age, sex, smoking, race/ethnicity, survey cycle, poverty-income ratio, and health insurance type
Humblet et al. 2014	Wheezing in last 12 months	n = 217	Per 2-fold increase in PFOS:OR = 0.83 (0.67, 1.02)OR = 0.87 (0.67, 1.13) using survey weightsOR = 0.87 (0.73, 1.03) imputing missing dataPer 1-ng/mL increase in PFOS:OR = 0.99 (0.98, 1.01)PFOS:Tertile 1: referentTertile 2: OR = 0.93 (0.73, 1.18)Tertile 3: OR = 0.93 (0.70, 1.24)	Age, sex, smoking, race/ethnicity, survey cycle, poverty-income ratio, and health insurance type
Okada et al. 2014	Total allergic diseases (eczema, wheezing, and/or allergic rhinoconjunctivitis symptoms; at 24 months)	PFOA quartiles, overall:Q1 (≤1.31 ng/mL): n = 197Q2 (1.32–2.01 ng/mL): n = 199Q3 (2.02–3.26 ng/mL): n = 162Q4 (3.27–24.9 ng/mL): n = 156PFOA quartiles, males:Q1: n = 102Q2: n = 110Q3: n = 87Q4: n = 92PFOA quartiles, females:Q1: n = 95Q2: n = 89Q3: n = 75Q4: n = 64	PFOA, overall:Q1: referentQ2: OR = 1.05 (0.81, 1.37)Q3: OR = 0.80 (0.61, 1.06)Q4: OR = 0.79 (0.59, 1.04)P-trend = 0.030PFOA, males:Q1: referentQ2: OR = 1.11 (0.77, 1.60)Q3: OR = 0.82 (0.56, 1.20)Q4: OR = 0.93 (0.63, 1.37)P-trend = 0.402PFOA, females:Q1: referentQ2: OR = 1.01 (0.69, 1.47)Q3: OR = 0.77 (0.52, 1.15)Q4: OR = 0.64 (0.42, 0.97)P-trend = 0.017	Maternal age, maternal education level, parental allergic history, infant gender, breastfeeding duration, number of siblings, day care attendance, and environmental tobacco smoke exposure in infancy at 24 months
Okada et al. 2014	Total allergic diseases (eczema, wheezing, and/or allergic rhinoconjunctivitis symptoms; at 24 months)	PFOS quartiles, overall:Q1 (≤3.71 ng/mL): n = 195Q2 (3.72–5.02 ng/mL): n = 185Q3 (5.03–6.83 ng/mL): n = 171Q4 (6.84–30.3 ng/mL): n = 163PFOS quartiles, males:Q1: n = 102Q2: n = 96Q3: n = 106Q4: n = 87PFOS quartiles, females:Q1: n = 93Q2: n = 89Q3: n = 65Q4: n = 76	PFOS, overall:Q1: referentQ2: OR = 0.97 (0.75, 1.26)Q3: OR = 0.80 (0.61, 1.04)Q4: OR = 0.86 (0.66, 1.13)P-trend = 0.139PFOS, males:Q1: referentQ2: OR = 1.12 (0.78, 1.61)Q3: OR = 0.91 (0.64, 1.30)Q4: OR = 0.95 (0.65, 1.37)P-trend = 0.535PFOS, females:Q1: referentQ2: OR = 0.81 (0.55, 1.18)Q3: OR = 0.68 (0.46, 1.01)Q4: OR = 0.79 (0.53, 1.17)P-trend = 0.183	Maternal age, maternal education level, parental allergic history, infant gender, breastfeeding duration, number of siblings, day care attendance, and environmental tobacco smoke exposure in infancy at 24 months
Okada et al. 2014	Eczema (at 24 months)	PFOA quartiles, overall:Q1 (≤1.31 ng/mL): n = 100Q2 (1.32–2.01 ng/mL): n = 102Q3 (2.02–3.26 ng/mL): n = 90Q4 (3.27–24.9 ng/mL): n = 75PFOA quartiles, males:Q1: n = 50Q2: n = 58Q3: n = 50Q4: n = 54PFOA quartiles, females:Q1: n = 42Q2: n = 40Q3: n = 43Q4: n = 30(Males and females do not sum to total)	PFOA, overall:Q1: referentQ2: OR = 1.03 (0.75, 1.41)Q3: OR = 0.86 (0.62, 1.19)Q4: OR = 0.72 (0.51, 0.98)P-trend = 0.025PFOA, males:Q1: referentQ2: OR = 1.11 (0.73, 1.69)Q3: OR = 0.76 (0.49, 1.19)Q4: OR = 0.75 (0.48, 1.18)P-trend = 0.092PFOA, females:Q1: referentQ2: OR = 0.98 (0.60, 1.58)Q3: OR = 0.99 (0.61, 1.61)Q4: OR = 0.65 (0.39, 1.09)P-trend = 0.144“At 12 months, no significant association was observed between eczema and [perfluoroalkyl acids], although similar patterns of a decreased risk of eczema were seen (data not shown).”	Maternal age, maternal education level, parental allergic history, infant gender, breastfeeding duration, number of siblings, and environmental tobacco smoke exposure in infancy at 24 months
Okada et al. 2014	Eczema (at 24 months)	PFOS quartiles, overall:Q1 (≤3.71 ng/mL): n = 94Q2 (3.72–5.02 ng/mL): n = 99Q3 (5.03–6.83 ng/mL): n = 90Q4 (6.84–30.3 ng/mL): n = 84PFOS quartiles, males:Q1: n = 59Q2: n = 53Q3: n = 56Q4: n = 44PFOS quartiles, females:Q1: n = 41Q2: n = 50Q3: n = 27Q4: n = 37(Males and females do not sum to total)	PFOS, overall:Q1: referentQ2: OR = 1.06 (0.77, 1.46)Q3: OR = 0.93 (0.67, 1.29)Q4: OR = 0.89 (0.64, 1.24)P-trend = 0.372PFOS, males:Q1: referentQ2: OR = 1.00 (0.64, 1.55)Q3: OR = 1.33 (0.87, 2.04)Q4: OR = 0.98 (0.63, 1.53)P-trend = 0.706PFOS, females:Q1: referentQ2: OR = 1.13 (0.71, 1.81)Q3: OR = 0.56 (0.32, 0.94)Q4: OR = 0.84 (0.51, 1.38)P-trend = 0.124“At 12 months, no significant association was observed between eczema and [perfluoroalkyl acids], although similar patterns of a decreased risk of eczema were seen (data not shown).”	Maternal age, maternal education level, parental allergic history, infant gender, breastfeeding duration, number of siblings, and environmental tobacco smoke exposure in infancy at 24 months
Okada et al. 2014	Wheezing	n = 397 (19.3%)	“No significant associations were observed with any maternal [perfluoroalkyl acid] levels at 12 or 24 months (data not shown).”	NR
Smit et al. 2015	Asthma, ever	Greenland: n = 62 (12.4%)Ukraine: n = 8 (1.6%)	Per 1-SD increase in PFOA:Greenland OR = 0.79 (0.60, 1.03)Ukraine OR = 0.93 (0.47, 1.84)Combined OR = 0.80 (0.62, 1.04)Per 1-SD increase in PFOS:Greenland OR = 0.88 (0.67, 1.15)Ukraine OR = 0.75 (0.39, 1.42)Combined OR = 0.86 (0.67, 1.10)	None
Smit et al. 2015	Eczema, ever	Greenland: n = 59 (12.3%)Ukraine: n = 73 (14.8%)	Per 1-SD increase in PFOA:Greenland OR = 1.04 (0.78, 1.38)Ukraine OR = 0.93 (0.73, 1.19)Combined OR = 0.97 (0.81, 1.17)Per 1-SD increase in PFOS:Greenland OR = 1.02 (0.77, 1.34)Ukraine OR = 0.95 (0.74, 1.22)Combined OR = 0.98 (0.82, 1.18)	None
Smit et al. 2015	Wheeze, ever	Greenland: n = 97 (19.4%)Ukraine: n = 33 (6.8%)	Per 1-SD increase in PFOA:Greenland OR = 0.88 (0.70, 1.11)Ukraine OR = 0.98 (0.70, 1.38)Combined OR = 0.91 (0.76, 1.10)Per 1-SD increase in PFOS:Greenland OR = 0.86 (0.69, 1.08)Ukraine OR = 0.77 (0.55, 1.08)Combined OR = 0.83 (0.69, 1.00)	None
Smit et al. 2015	Eczema, current	Greenland: n = 53 (10.2%)Ukraine: n = 21 (4.3%)	Per 1-SD increase in PFOA:Greenland OR = 1.04 (0.77, 1.41)Ukraine OR = 0.94 (0.62, 1.44)Combined OR = 1.01 (0.79, 1.29)Per 1-SD increase in PFOS:Greenland OR = 0.98 (0.74, 1.30)Ukraine OR = 1.23 (0.78, 1.94)Combined OR = 1.05 (0.82, 1.33)	None
Smit et al. 2015	Wheeze, current	Greenland: n = 27 (5.4%)Ukraine: n = 16 (3.3%)	Per 1-SD increase in PFOA:Greenland OR = 1.12 (0.74, 1.70)Ukraine OR = 0.78 (0.47, 1.29)Combined OR = 0.97 (0.71, 1.33)Per 1-SD increase in PFOS:Greenland OR = 0.91 (0.62, 1.36)Ukraine OR = 0.60 (0.38, 0.92)Combined OR = 0.76 (0.56, 1.01)	None
Steenland et al. 2015	Asthma currently treated with medication	n = 82 validated(n = 138 self-reported)	PFOA quartiles, unlagged:Q1: referentQ2: OR = 0.76 (0.28, 2.04)Q3: OR = 0.50 (0.17, 1.49)Q4: OR = 0.53 (0.16, 1.69)P-trend, log cumulative PFOA = 0.27P-trend, categorical PFOA = 0.05PFOA quartiles, 10-year lag:Q1: referentQ2: OR = 0.48 (0.10, 2.29)Q3: OR = 0.57 (0.11, 2.93)Q4: OR = 0.52 (0.09, 2.84)P-trend, log cumulative PFOA = 0.53P-trend, categorical PFOA = 0.17	Age as time scale, sex, race, education, body mass index, time-dependent smoking, and time-dependent alcohol consumption

Columns show first author and year of study reference, outcome of interest, number and proportion of subjects with the outcome, estimates of association with PFOA and/or PFOS levels, and covariates adjusted in multivariable models.

NR: not reported; OR: odds ratio; PFOA: perfluorooctanoic acid; PFOS: perfluorooctanesulfonate; Q: quartile; SD: standard deviation; SMR: standardized mortality ratio; SPR: standardized prevalence ratio.

Table 3. Results of epidemiologic studies of the association between exposure to perfluorooctanoic acid (PFOA) and/or perfluorooctanesulfonate (PFOS) and infectious conditions.

Reference	Outcome	Number (%) with outcome	Estimate of association (95% confidence interval)	Adjustment factors
Leonard et al. 2008	Mortality from infectious and parasitic diseases	Observed: 1 deathExpected in U.S.: 15.0 deathsExpected in West Virginia: 3.4 deathsExpected in DuPont workers: 1.1 deaths	SMR vs. U.S. = 0.067 (0.002, 0.372)SMR vs. West Virginia = 0.295 (0.007, 1.646)SMR vs. DuPont workers = 0.946 (0.024, 5.269)	Age, sex, and calendar period
Leonard et al. 2008	Mortality from influenza and pneumonia	Observed: 14 deathsExpected in U.S.: 26.5 deathsExpected in West Virginia: 28.2 deathsExpected in DuPont workers: 15.7 deaths	SMR vs. U.S. = 0.529 (0.289, 0.887)SMR vs. West Virginia = 0.497 (0.272, 0.834)SMR vs. DuPont workers = 0.890 (0.487, 1.494)	Age, sex, and calendar period
Fei et al. 2010	Hospitalization for infectious diseases	PFOA quartiles:Q1 (≤ 3.90 ng/mL): n = 169Q2 (3.91–5.20 ng/mL): n = 120Q3 (5.21–6.96 ng/mL): n = 137Q4 (≥ 6.97 ng/mL): n = 151	Overall:Q1: referentQ2: RR = 0.71 (0.53, 0.94)Q3: RR = 0.77 (0.59, 1.03)Q4: RR = 0.84 (0.62, 1.13)Per quartile: RR = 0.96 (0.87, 1.06)Girls:Q1: referentQ2: RR = 1.20 (0.76, 1.89)Q3: RR = 1.63 (1.03, 2.58)Q4: RR = 1.74 (1.06, 2.87)Per quartile: RR = 1.21 (1.04, 1.42)Boys:Q1: referentQ2: RR = 0.58 (0.40, 0.83)Q3: RR = 0.53 (0.36, 0.76)Q4: RR = 0.57 (0.38, 0.86)Per quartile: RR = 0.83 (0.73, 0.95)Ages 0–<1 year: Per-quartile RR = 0.97 (0.86, 1.10)Ages 1–<2 years: Per-quartile RR = 0.96 (0.85, 1.08)Ages 2–<4 years: Per-quartile RR = 0.96 (0.85, 1.09)Ages ≥4 years: Per-quartile RR = 0.96 (0.85, 1.10)First-born: Per-quartile RR = 1.11 (0.95, 1.30)Later-born: Per-quartile RR = 0.87 (0.76, 1.00)(Quartile-specific RRs by age or birth order are not shown here)	Parity, maternal age, pre-pregnancy body mass index, breastfeeding, smoking during pregnancy, socio-occupational status, home density, child age, child gender, sibling age difference, gestational age at blood drawing, birth year, and birth season
Fei et al. 2010	Hospitalization for infectious diseases	PFOS quartiles:Q1 (6.4–26.0 ng/mL): n = 147Q2 (26.1–33.3 ng/mL): n = 142Q3 (33.4–43.2 ng/mL): n = 136Q4 (≥ 43.3 ng/mL): n = 152	Overall:Q1: referentQ2: RR = 0.93 (0.71, 1.21)Q3: RR = 0.90 (0.68, 1.18)Q4: RR = 1.00 (0.76, 1.32)Per quartile: RR = 1.00 (0.91, 1.09)Girls:Q1: referentQ2: RR = 1.14 (0.73, 1.79)Q3: RR = 1.61 (1.05, 2.47)Q4: RR = 1.59 (1.02, 2.49)Per quartile: RR = 1.18 (1.03, 1.36)Boys:Q1: referentQ2: RR = 0.80 (0.57, 1.13)Q3: RR = 0.61 (0.42, 0.89)Q4: RR = 0.77 (0.54, 1.12)Per quartile: RR = 0.90 (0.80, 1.02)Ages 0–<1 year: Per-quartile RR = 0.90 (0.80, 1.00)Ages 1–<2 years: Per-quartile RR = 0.98 (0.88, 1.09)Ages 2–<4 years: Per-quartile RR = 1.13 (1.00, 1.27)Ages ≥4 years: Per-quartile RR = 1.05 (0.94, 1.18)First-born: Per-quartile RR = 1.10 (0.96, 1.27)Later-born: Per-quartile RR = 0.93 (0.83, 1.05)(Quartile-specific RRs by age or birth order are not shown here)	Parity, maternal age, pre-pregnancy body mass index, breastfeeding, smoking during pregnancy, socio-occupational status, home density, child age, child gender, sibling age difference, gestational age at blood drawing, birth year, and birth season
Okada et al. 2012	Otitis media	n = 61 (17.8%)	Per 10-fold increase in maternal PFOA:Overall OR = 1.51 (0.45, 5.12)Males OR = 1.92 (0.35, 10.40)Females OR = 0.95 (0.16, 5.69)Per 10-fold increase in maternal PFOS:Overall OR = 1.40 (0.33, 6.00)Males OR = 1.38 (0.18, 10.60)Females OR = 1.43 (0.17, 12.30)No significant differences by blood sampling period (data not reported)	Maternal age, maternal educational level, parity, infant gender, breastfeeding duration, environmental tobacco smoke exposure, day care attendance, and blood sampling period“When total dioxins and total [polychlorinated biphenyls] were evaluated as potential confounders, no significant association remained between [perfluorinated compound] concentrations and infant allergies and infectious diseases during the first 18 months of life (data not shown).”
Granum et al. 2013	Common cold, number of episodes	Mean ± SD = 3.0 ± 3.1 in 3rd year; 3.2 ± 3.5 with bloodMean ± SD = 10.9 ± 6.4 in all 3 years	Per unit increase in PFOA:3rd year coefficient = 0.42 (0.16, 0.72)All 3 years coefficient = 0.42 (0.21, 0.62)Per unit increase in PFOS:3rd year coefficient = 0.03 (−0.03, 0.10)All 3 years coefficient = 0.01 (−0.02, 0.05)	PFOA models: previous breastfeeding, older siblings, maternal allergy, maternal education, child's gender, child's birth season, and gross household income (included in backward deletion model); previous breastfeeding and birth season included in final model for PFOA and common cold episodes over all 3 yearsPFOS models: none
Granum et al. 2013	Common cold in 3rd year (yes vs. no)	n = 70 (82.4%) in 3rd year; 45 (83.3%) with bloodn = 94 (98.9%) in all 3 years	Per 1-ng/mL increase in PFOA:3rd year OR = 1.24 (0.32, 4.83)Per 1-ng/mL increase in PFOS:3rd year OR = 1.13 (0.85, 1.51)	None
Granum et al. 2013	Gastroenteritis, number of episodes	Mean ± SD = 1.3 ± 1.1 in 3rd year; 1.37 ± 1.1 with bloodMean ± SD = 3.1 ± 2.3 in all 3 years	Per 1-ng/mL increase in PFOA:3rd year coefficient = 0.21 (−0.21, 0.64)All 3 years coefficient = 0.31 (0.002, 0.61)Per 1-ng/mL increase in PFOS:3rd year coefficient = 0.06 (−0.03, 0.14)All 3 years coefficient = 0.03 (−0.04, 0.10)	PFOA model for all 3 years: previous breastfeeding, older siblings, maternal allergy, maternal education, and gross household income (included in backward deletion model)PFOA model for 3rd year and PFOS models: none
Granum et al. 2013	Gastroenteritis in 3rd year (yes vs. no)	n = 64 (76.2%) in 3rd year; 47 (83.9%) with bloodn = 87 (93.5%) in all 3 years	Per 1-ng/mL increase in PFOA:3rd year OR = 1.16 (0.37, 3.65)All 3 years OR = 3.13 (0.37, 26.2)Per 1-ng/mL increase in PFOS:3rd year OR = 1.11 (0.87, 1.42)All 3 years OR = 1.07 (0.72, 1.58)	None
Granum et al. 2013	Otitis media (yes vs. no)	n = 16 (18.8%) in 3rd year; 10 (17.9%) with bloodn = 27 (37.0%) in all 3 years	Per 1-ng/mL increase in PFOA:3rd year OR = 0.78 (0.22, 2.77)All 3 years OR = 0.76 (0.25, 2.33)Per 1-ng/mL increase in PFOS:3rd year OR = 1.12 (0.85, 1.44)All 3 years OR = 1.02 (0.81, 1.29)	None
Looker et al. 2014	Any “flu” infection in last 12 months	PFOA quartiles:Q1 (0.25–13.7 ng/mL): n = 45Q2 (13.8–31.5 ng/mL): n = 37Q3 (31.6–90 ng/mL): n = 44Q4 (90.4–2140 ng/mL): n = 37PFOS quartiles:Q1 (0.1–5.8 ng/mL): n = 51Q2 (5.9–9.2 ng/mL): n = 39Q3 (9.3–14.5 ng/mL): n = 33Q4 (14.7–42.3 ng/mL): n = 40	PFOA quartiles:Q1: referentQ2: OR = 0.91 (0.55, 1.51)Q3: OR = 1.30 (0.79, 2.13)Q4: OR = 1.09 (0.65, 1.83); p = 0.57Per unit increase in log10 PFOA: OR = 0.98 (0.70, 1.38)PFOS quartiles:Q1: referentQ2: OR = 0.83 (0.51, 1.35)Q3: OR = 0.74 (0.44, 1.24)Q4: OR = 1.20 (0.70, 2.04); p = 0.29Per unit increase in log10 PFOS: OR = 0.97 (0.58, 1.63)	Age and gender
Looker et al. 2014	Any cold in last 12 months	PFOA quartiles:Q1 (0.25–13.7 ng/mL): n = 145Q2 (13.8–31.5 ng/mL): n = 141Q3 (31.6–90 ng/mL): n = 131Q4 (90.4–2140 ng/mL): n = 121PFOS quartiles:Q1 (0.1–5.8 ng/mL): n = 140Q2 (5.9–9.2 ng/mL): n = 146Q3 (9.3–14.5 ng/mL): n = 134Q4 (14.7–42.3 ng/mL): n = 118	PFOA quartiles:Q1: referentQ2: OR = 1.13 (0.69, 1.83)Q3: OR = 0.97 (0.60, 1.57)Q4: OR = 0.80 (0.50, 1.29); p = 0.53Per unit increase in log10 PFOA: OR = 0.83 (0.61, 1.13)PFOS quartiles:Q1: referentQ2: OR = 1.60 (0.99, 2.60)Q3: OR = 1.20 (0.75, 1.92)Q4: OR = 1.09 (0.67, 1.78); p = 0.24Per unit increase in log10 PFOS: OR = 0.83 (0.51, 1.34)	Age and gender
Looker et al. 2014	Any cold or “flu” in last 12 months	PFOA quartiles:Q1 (0.25–13.7 ng/mL): n = 148Q2 (13.8–31.5 ng/mL): n = 145Q3 (31.6–90 ng/mL): n = 137Q4 (90.4–2140 ng/mL): n = 124PFOS quartiles:Q1 (0.1–5.8 ng/mL): n = 145Q2 (5.9–9.2 ng/mL): n = 150Q3 (9.3–14.5 ng/mL): n = 137Q4 (14.7–42.3 ng/mL): n = 122	PFOA quartiles:Q1: referentQ2: OR = 1.21 (0.73, 2.00)Q3: OR = 1.10 (0.67, 1.81)Q4: OR = 0.84 (0.52, 1.36); p = 0.46Per unit increase in log10 PFOA: OR = 0.85 (0.62, 1.16)PFOS quartiles:Q1: referentQ2: OR = 1.66 (1.00, 2.75)Q3: OR = 1.19 (0.74, 1.94)Q4: OR = 1.15 (0.69, 1.91); p = 0.24Per unit increase in log10 PFOS: OR = 0.90 (0.55, 1.48)	Age and gender
Looker et al. 2014	Frequency of colds in last 12 months	0 colds: n = 217 (28.7%)1 cold: n = 404 (53.5%)2 colds: n = 122 (16.2%)3 colds: n = 9 (1.2%)4 colds: n = 3 (0.4%)	PFOA quartiles:Q1: referentQ2: OR = 0.93 (0.63, 1.38)Q3: OR = 0.95 (0.63, 1.41)Q4: OR = 0.90 (0.60, 1.36); p = 0.97Per unit increase in log10 PFOA: OR = 0.91 (0.70, 1.19)PFOS quartiles:Q1: referentQ2: OR = 1.56 (1.05, 2.31)Q3: OR = 1.05 (0.70, 1.56)Q4: OR = 1.10 (0.71, 1.69); p = 0.10Per unit increase in log10 PFOS: OR = 0.89 (0.60, 1.33)	Age and gender

Columns show first author and year of study reference, outcome of interest, number and proportion of subjects with the outcome, estimates of association with PFOA and/or PFOS levels, and covariates adjusted in multivariable models.

OR: odds ratio; PFOA: perfluorooctanoic acid; PFOS: perfluorooctanesulfonate; Q: quartile; RR: relative risk; SD: standard deviation; SMR: standardized mortality ratio.

Table 4. Results of epidemiologic studies of the association between exposure to perfluorooctanoic acid (PFOA) and/or perfluorooctanesulfonate (PFOS) and vaccine response.

Reference	Outcome	Number (%) with outcome	Estimate of association (95% confidence interval)	Adjustment factors
Grandjean et al. 2012	Serum anti-tetanus toxoid antibody concentration, % difference or % with inadequate concentration (≤0.1 IU/mL)	Maternal PFOA:Prebooster: n = 509Postbooster: n = 419Year 7: n = 424Year 7, adjusted for age 5: n = 380Age 5 PFOA:Prebooster: n = 537Postbooster: n = 440Year 7: n = 408Year 7, adjusted for age 5: n = 401	Per 2-fold increase in maternal PFOA:Prebooster: −10.5 (−28.2, 11.7)Postbooster: 14.5 (−10.4, 46.4)Year 7: 7.4 (−17.1, 39.0)Year 7, adjusted for age 5: 12.3 (−8.6, 38.1)Year 5: OR = 1.21 (0.82, 1.78)Year 7: OR = 0.73 (0.27, 1.95)Per 2-fold increase in age 5 PFOA:Prebooster: −13.3 (−31.6, 9.9)Postbooster: −9.7 (−30.7, 17.7)Year 7: −35.8 (−51.9, −14.2)Year 7, adjusted for age 5: −28.2 (−42.7, −10.1)Year 5: OR = 1.38 (0.91, 2.10)Year 7: OR = 4.20 (1.54, 11.44)	Prebooster adjusted for age and sexPostbooster adjusted for age, sex, time since vaccination, and booster typeYear 7 adjusted for age, sex, and booster type, with or without additional adjustment for child's specific antibody concentration at age 5 yearsNo substantial change after additional adjustment for polychlorinated biphenyls in breast milk and age 5 serum
Grandjean et al. 2012	Serum anti-tetanus toxoid antibody concentration, % difference or % with inadequate concentration (≤0.1 IU/mL)	Maternal PFOS:Prebooster: n = 509Postbooster: n = 419Year 7: n = 424Year 7, adjusted for age 5: n = 380Age 5 PFOS:Prebooster: n = 537Postbooster: n = 440Year 7: n = 408Year 7, adjusted for age 5: n = 401	Per 2-fold increase in maternal PFOS:Prebooster: −10.1 (−31.9, 18.7)Postbooster: −2.3 (−28.6, 33.6)Year 7: 35.3 (−3.9, 90.6)Year 7, adjusted for age 5: 33.1 (1.5, 74.6)Year 5: OR = 1.16 (0.71, 1.89)Year 7: OR = 0.53 (0.16, 1.79)Per 2-fold increase in age 5 PFOS:Prebooster: −11.9 (−30.0, 10.9)Postbooster: −28.5 (−45.5, −6.1)Year 7: −23.8 (−44.3, 4.2)Year 7, adjusted for age 5: −11.4 (−30.5, 12.8)Year 5: OR = 1.16 (0.77, 1.74)Year 7: OR = 2.61 (0.77, 8.92)	Prebooster adjusted for age and sexPostbooster adjusted for age, sex, time since vaccination, and booster typeYear 7 adjusted for age, sex, and booster type, with or without additional adjustment for child's specific antibody concentration at age 5 yearsNo substantial change after additional adjustment for polychlorinated biphenyls in breast milk and age 5 serum
Grandjean et al. 2012	Serum anti-tetanus toxoid antibody concentration, % difference or % with inadequate concentration (≤0.1 IU/mL)	Maternal PFOS isomers:Prebooster: n = 509Postbooster: n = 419Year 7: n = 424Year 7, adjusted for age 5: n = 380Age 5 PFOS isomers:Prebooster: n = 537Postbooster: n = 440Year 7: n = 408Year 7, adjusted for age 5: n = 401	Per 2-fold increase in maternal n-PFOS (linear):Prebooster: −14.7 (−35.0, 12.0)Postbooster: −4.5 (−29.7, 29.9)Year 7: 36.1 (−2.7, 90.6)Year 7, adjusted for age 5: 37.1 (5.1, 78.9)Per 2-fold increase in maternal br-PFOS (branched)Prebooster: 6.5 (−15.7, 34.5)Postbooster: 2.8 (−21.7, 34.9)Year 7: 22.2 (−7.8, 62.0)Year 7, adjusted for age 5: 11.2 (−11.0, 38.8)Per 2-fold increase in age 5 n-PFOS (linear):Prebooster: −11.7 (−29.0, 9.9)Postbooster: −29.9 (−45.8, −9.2)Year 7: −19.3 (−39.7, 8.0)Year 7, adjusted for age 5: −7.8 (−26.3, 15.5)Per 2-fold increase in age 5 br-PFOS (branched):Prebooster: −10.4 (−28.3, 12.0)Postbooster: −22.0 (−40.0, 1.3)Year 7: −24.7 (−44.6, 2.5)Year 7, adjusted for age 5: −13.1 (−31.5, 10.3)	Prebooster adjusted for age and sexPostbooster adjusted for age, sex, time since vaccination, and booster typeYear 7 adjusted for age, sex, and booster type, with or without additional adjustment for child's specific antibody concentration at age 5 years
Grandjean et al. 2012	Serum anti-diphtheria toxoid antibody concentration, % difference or % with inadequate concentration (≤0.1 IU/mL)	Maternal PFOA:Prebooster: n = 510Postbooster: n = 419Year 7: n = 424Year 7, adjusted for age 5: n = 382Age 5 PFOA:Prebooster: n = 537Postbooster: n = 440Year 7: n = 408Year 7, adjusted for age 5: n = 403	Per 2-fold increase in maternal PFOA:Prebooster: −16.2 (−34.2, 6.7)Postbooster: −6.2 (−22.4, 13.3)Year 7: −22.8 (−39.4, −1.7)Year 7, adjusted for age 5: −16.8 (−32.9, 3.3)Year 5: OR = 1.44 (1.01, 2.06)Year 7: OR = 2.11 (0.89, 4.99)Per 2-fold increase in age 5 PFOA:Prebooster: −6.8 (−28.3, 21.0)Postbooster: −6.1 (−23.6, 15.5)Year 7: −25.2 (−42.9, −2.0)Year 7, adjusted for age 5: −23.4 (−39.3, −3.4)Year 5: OR = 1.19 (0.81, 1.73)Year 7: OR = 3.27 (1.43, 7.51)	Prebooster adjusted for age and sexPostbooster adjusted for age, sex, time since vaccination, and booster typeYear 7 adjusted for age, sex, and booster type, with or without additional adjustment for child's specific antibody concentration at age 5 yearsNo substantial change after additional adjustment for polychlorinated biphenyls in breast milk and age 5 serum
Grandjean et al. 2012	Serum anti-diphtheria toxoid antibody concentration, % difference or % with inadequate concentration (≤0.1 IU/mL)	Maternal PFOS:Prebooster: n = 510Postbooster: n = 419Year 7: n = 424Year 7, adjusted for age 5: n = 382Age 5 PFOS:Prebooster: n = 537Postbooster: n = 440Year 7: n = 408Year 7, adjusted for age 5: n = 403	Per 2-fold increase in maternal PFOS:Prebooster: −38.6 (−54.7, −16.9)Postbooster: −20.6 (−37.5, 0.9)Year 7: −19.7 (−41.8, 10.7)Year 7, adjusted for age 5: −10.0 (−32.6, 20.0)Year 5: OR = 2.48 (1.55, 3.97)Year 7: OR = 2.33 (0.88, 6.14)Per 2-fold increase in age 5 PFOS:Prebooster: −16.0 (−34.9, 8.3)Postbooster: −15.5 (−31.5, 4.3)Year 7: −27.6 (−45.8, −3.3)Year 7, adjusted for age 5: −20.6 (−38.2, 2.1)Year 5: OR = 1.60 (1.10, 2.34)Year 7: OR = 2.38 (0.89, 6.35)	Prebooster adjusted for age and sexPostbooster adjusted for age, sex, time since vaccination, and booster typeYear 7 adjusted for age, sex, and booster type, with or without additional adjustment for child's specific antibody concentration at age 5 yearsNo substantial change after additional adjustment for polychlorinated biphenyls in breast milk and age 5 serum
Grandjean et al. 2012	Serum anti-diphtheria toxoid antibody concentration, % difference or % with inadequate concentration (≤0.1 IU/mL)	Maternal PFOS isomers:Prebooster: n = 510Postbooster: n = 419Year 7: n = 424Year 7, adjusted for age 5: n = 382Age 5 PFOS isomers:Prebooster: n = 537Postbooster: n = 440Year 7: n = 408Year 7, adjusted for age 5: n = 403	Per 2-fold increase in maternal n-PFOS (linear):Prebooster: −42.6 (−57.3, −22.7)Postbooster: −22.6 (−38.3, −2.2)Year 7: −22.9 (−43.8, 5.8)Year 7, adjusted for age 5: −10.6 (−32.7, 18.8)Per 2-fold increase in maternal br − PFOS (branched)Prebooster: −16.8 (−35.6, 7.5)Postbooster: −11.8 (−28.4, 8.7)Year 7: −5.7 (−27.7, 22.9)Year 7, adjusted for age 5: −5.8 (−25.3, 18.9)Per 2-fold increase in age 5 n-PFOS (linear):Prebooster: −17.5 (−35.2, 5.1)Postbooster: −16.1 (−31.3, 2.4)Year 7: −24.2 (−42.1, −0.8)Year 7, adjusted for age 5: −16.4 (−33.8, 5.5)Per 2-fold increase in age 5 br-PFOS (branched):Prebooster: −8.1 (−28.2, 17.7)Postbooster: −10.9 (−27.3, 9.2)Year 7: −21.1 (−40.6, 4.9)Year 7, adjusted for age 5: −18.3 (−36.1, 4.5)	Prebooster adjusted for age and sexPostbooster adjusted for age, sex, time since vaccination, and booster typeYear 7 adjusted for age, sex, and booster type, with or without additional adjustment for child's specific antibody concentration at age 5 years
Granum et al. 2013	Serum anti-rubella antibody concentration (optical density)	n = 50	Per 1-ng/mL increase in PFOA:coefficient = −0.40 (−0.64, −0.17)Per 1-ng/mL increase in PFOS:coefficient = −0.08 (−0.14, −0.02)	Maternal allergy, paternal allergy, maternal education, child's gender, and age at 3-year follow-up (included in backward deletion model)
Granum et al. 2013	Serum anti-measles antibody concentration (optical density)	n = 50	Per 1-ng/mL increase in PFOA:coefficient = −0.13 (−0.35, 0.09)Per 1-ng/mL increase in PFOS:coefficient = −0.05 (−0.10, 0.01)	None
Granum et al. 2013	Serum anti-Haemophilus influenza type b antibody concentration (μg/mL)	n = 51	Per 1-ng/mL increase in PFOA:coefficient = −0.05 (−3.85, 3.74)Per 1-ng/mL increase in PFOS:coefficient = −0.16 (−1.02, 0.70)	None
Granum et al. 2013	Serum anti-tetanus toxoid antibody concentration (IU/mL)	n = 49	Per 1-ng/mL increase in PFOA:coefficient = 0.01 (−0.09, 0.10)Per 1-ng/mL increase in PFOS:coefficient = −0.002 (−0.03, 0.02)	None
Looker et al. 2014	Serum anti-influenza type B antibody: GMT increase, log10 titer increase, log10 titer ratio, seroconversion, or seroprotection	PFOA quartiles:Q1 (0.25–13.7 ng/mL): n = 103Q2 (13.8–31.5 ng/mL): n = 103Q3 (31.6–90 ng/mL): n = 103Q4 (90.4–2140 ng/mL): n = 102Seroconversion:Q1: n = 61/100Q2: n = 71/102Q3: n = 66/100Q4: n = 52/101Seroprotection:Q1: n = 72/100Q2: n = 66/102Q3: n = 68/100Q4: n = 60/101	PFOA quartiles:Q1: GMT rise = 49.46 (38.14, 64.12)Q2: GMT rise = 46.00 (35.28, 59.97)Q3: GMT rise = 43.55 (33.08, 57.33)Q4: GMT rise = 20.90 (16.58, 28.24); P < 0.05Q2 (vs. Q1): log10 titer rise = −0.03 (−0.19, 0.13)Q3: log10 titer rise = −0.02 (−0.19, 0.15)Q4: log10 titer rise = −0.07 (−0.24, 0.10)Q2 (vs. Q1): log10 titer ratio = 0.05 (−0.09, 0.19)Q3: log10 titer ratio = 0.07 (−0.07, 0.22)Q4: log10 titer ratio = −0.03 (−0.17, 0.12)Q2 (vs. Q1): seroconversion OR = 1.43 (0.76, 2.70)Q3: seroconversion OR = 1.39 (0.73, 2.66)Q4: seroconversion OR = 0.71 (0.38, 1.36)Q2 (vs. Q1): seroprotection OR = 0.76 (0.40, 1.45)Q3: seroprotection OR = 1.13 (0.57, 2.23)Q4: seroprotection OR = 0.77 (0.39, 1.50)Per unit increase in log10 PFOA:Log10 titer rise: coefficient = −0.02 (−0.13, 0.09)Log10 titer ratio: coefficient = −0.02 (−0.11, 0.08)Seroconversion OR = 0.80 (0.53, 1.21)Seroprotection OR = 1.04 (0.68, 1.60)	Log10 models adjusted for age, gender, residential mobility, and history of previous influenza vaccinationResults stratified by demographic characteristics, comorbidity, or medication use are not shown here
Looker et al. 2014	Serum anti-influenza type B antibody: GMT increase, log10 titer increase, log10 titer ratio, seroconversion, or seroprotection	PFOS quartiles:Q1 (0.1–5.8 ng/mL): n = 106Q2 (5.9–9.2 ng/mL): n = 101Q3 (9.3–14.5 ng/mL): n = 102Q4 (14.7–42.3 ng/mL): n = 102Seroconversion:Q1: n = 67/104Q2: n = 54/97Q3: n = 61/100Q4: n = 68/102Seroprotection:Q1: n = 75/104Q2: n = 59/97Q3: n = 66/100Q4: n = 66/102	PFOS quartiles:Q1: GMT rise = 42.25 (33.41, 53.42)Q2: GMT rise = 41.48 (30.73, 55.99)Q3: GMT rise = 41.13 (31.65, 53.44)Q4: GMT rise = 52.83 (38.92, 71.71)Q2 (vs. Q1): log10 titer rise = 0.02 (−0.13, 0.18)Q3: log10 titer rise = −0.03 (−0.19, 0.14)Q4: log10 titer rise = 0.04 (−0.14, 0.21)Q2 (vs. Q1): log10 titer ratio = 0.004 (−0.14, 0.14)Q3: log10 titer ratio = −0.02 (−0.16, 0.12)Q4: log10 titer ratio = 0.03 (−0.12, 0.18)Q2 (vs. Q1): seroconversion OR = 0.72 (0.39, 1.33)Q3: seroconversion OR = 0.81 (0.42, 1.53)Q4: seroconversion OR = 0.87 (0.43, 1.74)Q2 (vs. Q1): seroprotection OR = 0.67 (0.35, 1.25)Q3: seroprotection OR = 0.82 (0.42, 1.59)Q4: seroprotection OR = 0.73 (0.36, 1.47)Per unit increase in log10 PFOS:Log10 titer rise: coefficient = 0.05 (−0.11, 0.21)Log10 titer ratio: coefficient = 0.05 (−0.09, 0.18)Seroconversion OR = 1.17 (0.63, 2.17)Seroprotection OR = 0.85 (0.44, 1.64)	Log10 models adjusted for age, gender, residential mobility, and history of previous influenza vaccinationResults stratified by demographic characteristics, comorbidity, or medication use are not shown here
Looker et al. 2014	Serum anti-influenza type A/H1N1 antibody: GMT increase, log10 titer increase, log10 titer ratio, seroconversion, or seroprotection	PFOA quartiles:Q1 (0.25–13.7 ng/mL): n = 103Q2 (13.8–31.5 ng/mL): n = 103Q3 (31.6–90 ng/mL): n = 103Q4 (90.4–2140 ng/mL): n = 102Seroconversion:Q1: n = 83/100Q2: n = 82/102Q3: n = 83/100Q4: n = 91/101Seroprotection:Q1: n = 97/100Q2: n = 95/102Q3: n = 94/100Q4: n = 99/101	PFOA quartiles:Q1: GMT rise = 476.23 (360.77, 628.65)Q2: GMT rise = 352.22 (255.33, 485.88)Q3: GMT rise = 306.32 (232.58, 403.44)Q4: GMT rise = 274.79 (202.85, 372.23)Q2 (vs. Q1): log10 titer rise = −0.09 (−0.27, 0.08)Q3: log10 titer rise = −0.10 (−0.28, 0.09)Q4: log10 titer rise = −0.12 (−0.30, 0.06)Q2 (vs. Q1): log10 titer ratio = −0.08 (−0.29, 0.12)Q3: log10 titer ratio = −0.04 (−0.25, 0.18)Q4: log10 titer ratio = 0.07 (−0.14, 0.29)Q2 (vs. Q1): seroconversion OR = 0.74 (0.34, 1.59)Q3: seroconversion OR = 1.11 (0.49, 2.50)Q4: seroconversion OR = 2.23 (0.90, 5.53)Q2 (vs. Q1): seroprotection OR = 0.74 (0.17, 3.28)Q3: seroprotection OR = 1.59 (0.33, 7.70)Q4: seroprotection OR = 6.47 (0.91, 45.85)Per unit increase in log10 PFOA:Log10 titer rise: coefficient = −0.03 (−0.14, 0.09)Log10 titer ratio: coefficient = 0.07 (−0.06, 0.21)Seroconversion OR = 1.51 (0.89, 2.56)Seroprotection OR = 2.34 (0.91, 6.07)	Log10 models adjusted for age, gender, residential mobility, and history of previous influenza vaccinationResults stratified by demographic characteristics, comorbidity, or medication use are not shown here
Looker et al. 2014	Serum anti-influenza type A/H1N1 antibody: GMT increase, log10 titer increase, log10 titer ratio, seroconversion, or seroprotection	PFOS quartiles:Q1 (0.1–5.8 ng/mL): n = 106Q2 (5.9–9.2 ng/mL): n = 101Q3 (9.3–14.5 ng/mL): n = 102Q4 (14.7–42.3 ng/mL): n = 102Seroconversion:Q1: n = 88/104Q2: n = 81/97Q3: n = 82/100Q4: n = 88/102Seroprotection:Q1: n = 101/104Q2: n = 90/97Q3: n = 97/100Q4: n = 97/102	PFOS quartiles:Q1: GMT rise = 342.31 (256.04, 457.65)Q2: GMT rise = 280.44 (197.64, 397.92)Q3: GMT rise = 417.74 (318.99, 547.07)Q4: GMT rise = 341.82 (258.03, 452.81); p ≥ 0.05Q2 (vs. Q1): log10 titer rise = −0.04 (−0.21, 0.14)Q3: log10 titer rise = 0.13 (−0.04, 0.31)Q4: log10 titer rise = 0.10 (−0.09, 0.29)Q2 (vs. Q1): log10 titer ratio = −0.07 (−0.28, 0.13)Q3: log10 titer ratio = 0.03 (−0.18, 0.24)Q4: log10 titer ratio = 0.03 (−0.19, 0.26)Q2 (vs. Q1): seroconversion OR = 0.97 (0.44, 2.14)Q3: seroconversion OR = 0.78 (0.35, 1.75)Q4: seroconversion OR = 0.94 (0.38, 2.31)Q2 (vs. Q1): seroprotection OR = 0.55 (0.13, 2.37)Q3: seroprotection OR = 1.81 (0.32, 10.22)Q4: seroprotection OR = 1.26 (0.24, 6.61)Per unit increase in log10 PFOS:Log10 titer rise: coefficient = 0.15 (−0.02, 0.32)Log10 titer ratio: coefficient = 0.10 (−0.11, 0.30)Seroconversion OR = 1.10 (0.51, 2.37)Seroprotection OR = 0.93 (0.23, 3.71)	Log10 models adjusted for age, gender, residential mobility, and history of previous influenza vaccinationResults stratified by demographic characteristics, comorbidity, or medication use are not shown here
Looker et al. 2014	Serum anti-influenza type A/H3N2 antibody: GMT increase, log10 titer increase, log10 titer ratio, seroconversion, or seroprotection	PFOA quartiles:Q1 (0.25–13.7 ng/mL): n = 103Q2 (13.8–31.5 ng/mL): n = 103Q3 (31.6–90 ng/mL): n = 103Q4 (90.4–2140 ng/mL): n = 102Seroconversion:Q1: n = 68/100Q2: n = 68/102Q3: n = 69/100Q4: n = 56/101Seroprotection:Q1: n = 91/100Q2: n = 82/102Q3: n = 80/100Q4: n = 85/101	PFOA quartiles:Q1: GMT rise = 228.86 (161.53, 324.27)Q2: GMT rise = 125.36 (86.01, 182.73)Q3: GMT rise = 104.13 (72.47, 149.64)Q4: GMT rise = 183.73 (127.28, 265.23); p ≥ 0.05Q2 (vs. Q1): log10 titer rise = −0.28 (−0.51, −0.06)Q3: log10 titer rise = −0.37 (−0.60, −0.13)Q4: log10 titer rise = −0.12 (−0.36, 0.13)Q2 (vs. Q1): log10 titer ratio = −0.10 (−0.30, 0.10)Q3: log10 titer ratio = −0.07 (−0.28, 0.14)Q4: log10 titer ratio = −0.22 (−0.43, −0.01)Q2 (vs. Q1): seroconversion OR = 0.90 (0.48, 1.68)Q3: seroconversion OR = 1.13 (0.59, 2.17)Q4: seroconversion OR = 0.62 (0.33, 1.16)Q2 (vs. Q1): seroprotection OR = 0.34 (0.14, 0.83)Q3: seroprotection OR = 0.28 (0.11, 0.70)Q4: seroprotection OR = 0.39 (0.15, 0.99)Per unit increase in log10 PFOA:Log10 titer rise: coefficient = −0.01 (−0.17, 0.14)Log10 titer ratio: coefficient = −0.12 (−0.25, 0.02)Seroconversion OR = 0.76 (0.51, 1.15)Seroprotection OR = 0.66 (0.39, 1.12)	Log10 models adjusted for age, gender, residential mobility, and history of previous influenza vaccinationResults stratified by demographic characteristics, comorbidity, or medication use are not shown here
Looker et al. 2014	Serum anti-influenza type A/H3N2 antibody: GMT increase, log10 titer increase, log10 titer ratio, seroconversion, or seroprotection	PFOS quartiles:Q1 (0.1–5.8 ng/mL): n = 106Q2 (5.9–9.2 ng/mL): n = 101Q3 (9.3–14.5 ng/mL): n = 102Q4 (14.7–42.3 ng/mL): n = 102Seroconversion:Q1: n = 65/104Q2: n = 60/97Q3: n = 64/100Q4: n = 72/102Seroprotection:Q1: n = 89/104Q2: n = 82/97Q3: n = 87/100Q4: n = 80/102	PFOS quartiles:Q1: GMT rise = 137.69 (98.70, 192.09)Q2: GMT rise = 147.27 (99.27, 218.47)Q3: GMT rise = 211.02 (141.24, 315.27)Q4: GMT rise = 126.69 (88.85, 180.65)Q2 (vs. Q1): log10 titer rise = 0.03 (−0.19, 0.26)Q3: log10 titer rise = 0.13 (−0.06, 0.41)Q4: log10 titer rise = −0.04 (−0.28, 0.21)Q2 (vs. Q1): log10 titer ratio = −0.06 (−0.26, 0.14)Q3: log10 titer ratio = 0.02 (−0.18, 0.23)Q4: log10 titer ratio = −0.03 (−0.24, 0.19)Q2 (vs. Q1): seroconversion OR = 1.08 (0.59, 1.97)Q3: seroconversion OR = 1.10 (0.59, 2.06)Q4: seroconversion OR = 1.41 (0.72, 2.78)Q2 (vs. Q1): seroprotection OR = 0.85 (0.38, 1.88)Q3: seroprotection OR = 1.09 (0.47, 2.56)Q4: seroprotection OR = 0.56 (0.24, 1.28)Per unit increase in log10 PFOS:Log10 titer rise: coefficient = 0.09 (−0.13, 0.32)Log10 titer ratio: coefficient = −0.005 (−0.20, 0.19)Seroconversion OR = 1.17 (0.63, 2.15)Seroprotection OR = 0.63 (0.26, 1.49)	Log10 models adjusted for age, gender, residential mobility, and history of previous influenza vaccinationResults stratified by demographic characteristics, comorbidity, or medication use are not shown here
Kielsen et al. 2015	Serum anti-diphtheria toxoid antibody, log10 titer % change	n = 12	Per 2-fold increase in serum PFOA:% change = −8.22 (−20.85, 6.44)Per 2-fold increase in serum PFOS:% change = −11.90 (−21.92, −0.33)	NoneAdjustment for age and sex showed “similar results”
Kielsen et al. 2015	Serum anti-tetanus toxoid antibody, log10 titer % change	n = 12	Per 2-fold increase in serum PFOA:% change = 0.23 (−10.40, 12.1)Per 2-fold increase in serum PFOS:% change = −3.59 (−11.91, 5.51)	NoneAdjustment for age and sex showed “similar results”

Columns show first author and year of study reference, outcome of interest, number and proportion of subjects with the outcome, estimates of association with PFOA and/or PFOS levels, and covariates adjusted in multivariable models.

GMT: geometric mean titer; IU: international unit; OR: odds ratio; PFOA: perfluorooctanoic acid; PFOS: perfluorooctanesulfonate; Q: quartile.

Table 5. Results of epidemiologic studies of the association between exposure to perfluorooctanoic acid (PFOA) and/or perfluorooctanesulfonate (PFOS) and autoimmune or chronic inflammatory conditions.

Reference	Outcome	Number (%) with outcome	Estimate of association (95% confidence interval)	Adjustment factors
Innes et al. 2011	Osteoarthritis	PFOA quartiles:Q1 (0.25–13.5 ng/mL): n = 737Q2 (13.6–28.0 ng/mL): n = 838Q3 (28.1–71.9 ng/mL): n = 994Q4 (≥72.0 ng/mL): n = 1162	PFOA quartiles:Q1: referentQ2: OR = 1.16 (1.03, 1.31)Q3: OR = 1.21 (1.07, 1.36)Q4: OR = 1.42 (1.26, 1.59)P-trend = 0.00001Per unit increase in log PFOA: OR = 1.07 (1.04, 1.11)P-interaction with age <0.00001P-trend for ages <55 years = 0.00001P-trend for ages ≥55 years = 0.11P-interaction with obesity = 0.0005P-trend for non − obese <0.00001P-trend for obese = 0.25Results not appreciably changed after restriction to PFOA levels <90th percentile (<193 ng/mL)Association “largely eliminated” after restriction to PFOA levels ≤20 ng/mL (n = 17 885, including 1167 cases)	Age, body mass index, race/ethnicity, gender, socioeconomic status, marital status, menopausal status, hormone replacement therapy, smoking status, current alcohol consumption, vegetarian diet, regular exercise program, years of education, annual household income, employment status/disability, comorbidityOverall (non-stratified) ORs also adjusted for military service, harmful chemical exposure, sleep impairment, frequent mood disturbance, frequent recent memory loss, and serum estradiol, cholesterol, uric acid, and C-reactive protein levelsFurther adjustment for other PFAS did not substantially change estimates
Innes et al. 2011	Osteoarthritis	PFOS quartiles:Q1 (0.25–13.6 ng/mL): n = 861Q2 (13.7–20.2 ng/mL): n = 868Q3 (20.3–29.3 ng/mL): n = 964Q4 (≥29.4 ng/mL): n = 1038	PFOS quartiles:Q1: referentQ2: OR = 0.91 (0.81, 1.01)Q3: OR = 0.94 (0.84, 1.06)Q4: OR = 0.76 (0.68, 0.85)P-trend = 0.00001Per unit increase in log PFOS: OR = 0.88 (0.84, 0.93)Results not appreciably changed after stratification by age group or obesity status or restriction to relatively low PFOS levels	Age, body mass index, race/ethnicity, gender, socioeconomic status, marital status, menopausal status, hormone replacement therapy, smoking status, current alcohol consumption, vegetarian diet, regular exercise program, years of education, annual household income, employment status/disability, comorbidityOverall (non-stratified) ORs also adjusted for military service, harmful chemical exposure, sleep impairment, frequent mood disturbance, frequent recent memory loss, and serum estradiol, cholesterol, uric acid, and C-reactive protein levelsFurther adjustment for other PFAS did not substantially change estimates
Steenland et al. 2013	Ulcerative colitis, lifetime	n = 151 validated(n = 596 self-reported)	PFOA quartiles, unlagged:Q1 (≤159 ng/mL/year): referentQ2 (18–586 ng/mL/year): OR = 1.76 (1.04, 2.99)Q3 (587–3500 ng/mL/year): OR = 2.63 (1.56, 4.43)Q4 (≥3501 ng/mL/year): OR = 2.86 (1.65, 4.96)P-trend <0.0001PFOA quartiles, 10-year lag:Q1: referentQ2: OR = 1.71 (0.89, 3.27)Q3: OR = 2.05 (1.07, 3.91)Q4: OR = 3.05 (1.56, 5.96)P-trend <0.0001PFOA quartiles, follow-up started at first residence in study area or first employment at plant:Q1: referentQ2: OR = 1.59 (0.95, 2.65)Q3: OR = 2.40 (1.44, 3.99)Q4: OR = 2.33 (1.37, 3.97)P-trend < 0.0001PFOA quartiles, excluding background exposures:Q1: referentQ2: OR = 1.27 (0.78, 2.08)Q3: OR = 2.08 (1.26, 3.44)Q4: OR = 2.30 (1.36, 3.91)P-trend <0.0001	Age as time scale, sex, race/ethnicity, time-dependent smoking, time-dependent body mass index, and time-dependent alcohol consumption
Steenland et al. 2013	Ulcerative colitis, incident	n = 30 validated	PFOA quartiles, unlagged:Q1 (≤159 ng/mL/year): referentQ2 (18–586 ng/mL/year): OR = 1.68 (0.62, 4.66)Q3 (587–3500 ng/mL/year): OR = 2.10 (0.75, 5.85)Q4 (≥3501 ng/mL/year): OR = 1.62 (0.57, 4.61)P-trend = 0.21PFOA quartiles, 10-year lag:Q1: referentQ2: OR = 1.21 (0.43, 3.34)Q3: OR = 2.16 (0.80, 5.81)Q4: OR = 1.51 (0.43, 4.30)P-trend = 0.12	Age as time scale, sex, race/ethnicity, time-dependent smoking, time-dependent body mass index, and time-dependent alcohol consumption
Steenland et al. 2013	Crohn's disease, lifetime	n = 95 validated(n = 178 self-reported)	PFOA quartiles, unlagged:Q1: referentQ2: OR = 1.25 (0.61, 2.58)Q3: OR = 1.15 (0.55, 2.41)Q4: OR = 1.00 (0.48, 2.09)P-trend = 0.73PFOA quartiles, 10-year lag:Q1: referentQ2: OR = 0.80 (0.32,1.99)Q3: OR = 0.97 (0.36, 2.60)Q4: OR = 0.69 (0.26, 1.82)P-trend = 0.79Results were similar when follow-up started at the time of first residence in the study area or first employment at the plant, or when only cumulative exposures above background levels were considered (results not published)	Age as time scale, sex, race/ethnicity, time-dependent smoking, time-dependent body mass index, and time-dependent alcohol consumption
Steenland et al. 2013	Rheumatoid arthritis, lifetime	n = 346 validated(n = 1292 self-reported)	PFOA quartiles, unlagged:Q1: referentQ2: OR = 1.24 (0.85, 1.79)Q3: OR = 1.40 (0.96, 2.03)Q4: OR = 0.99 (0.68, 1.43)P-trend = 0.84PFOA quartiles, 10-year lag:Q1: referentQ2: OR = 1.53 (0.61, 2.58)Q3: OR = 1.73 (1.10, 2.71)Q4: OR = 1.35 (0.87, 2.11)P-trend = 0.73Results were similar when follow-up started at the time of first residence in the study area or first employment at the plant, or when only cumulative exposures above background levels were considered (results not published)	Age as time scale, sex, race/ethnicity, time-dependent smoking, time-dependent body mass index, and time-dependent alcohol consumption
Steenland et al. 2013	Rheumatoid arthritis, incident	n = 56 validated	PFOA quartiles, unlagged:Q1: referentQ2: OR = 0.81 (0.39, 1.68)Q3: OR = 2.07 (1.00, 4.27)Q4: OR = 0.52 (0.25, 1.09)P-trend = 0.89PFOA quartiles, 10-year lag:Q1: referentQ2: OR = 0.31 (0.14, 0.71)Q3: OR = 0.90 (0.41, 2.00)Q4: OR = 0.32 (0.14, 0.72)P-trend = 0.89	Age as time scale, sex, race/ethnicity, time-dependent smoking, time-dependent body mass index, and time-dependent alcohol consumption
Steenland et al. 2013	Insulin-dependent diabetes, broad definition, lifetime	n = 160 validated(n = 342 self-reported)	PFOA quartiles, unlagged:Q1: referentQ2: OR = 0.68 (0.29, 1.58)Q3: OR = 0.53 (0.22, 1.30)Q4: OR = 0.54 (0.22, 1.33)P-trend = 0.84PFOA quartiles, 10-year lag:Q1: referentQ2: OR = 0.42 (0.09, 2.00)Q3: OR = 0.70 (0.14, 0.35)Q4: OR = 0.38 (0.08, 1.93)P-trend = 0.84Results were similar when follow-up started at the time of first residence in the study area or first employment at the plant, or when only cumulative exposures above background levels were considered (results not published)	Age as time scale, sex, race/ethnicity, time-dependent smoking, time-dependent body mass index, and time-dependent alcohol consumption
Steenland et al. 2013	Type I diabetes, narrow definition, lifetime	n = 85 validated	PFOA quartiles, unlagged:Q1: referentQ2: OR = 0.83 (0.25, 2.78)Q3: OR = 1.41 (0.40, 4.95)Q4: OR = 0.88 (0.25, 3.06)P-trend = 0.68PFOA quartiles, 10-year lag:Q1: referentQ2: OR = 0.50 (0.05, 4.90)Q3: OR = 1.32 (0.14, 12.40)Q4: OR = 0.71 (0.07, 7.14)P-trend = 0.65Results were similar when follow-up started at the time of first residence in the study area or first employment at the plant, or when only cumulative exposures above background levels were considered (results not published)	Age as time scale, sex, race/ethnicity, time-dependent smoking, time-dependent body mass index, and time-dependent alcohol consumption
Steenland et al. 2013	Lupus, lifetime	n = 72 validated(n = 187 self-reported)	PFOA quartiles, unlagged:Q1: referentQ2: OR = 1.49 (0.68, 3.34)Q3: OR = 1.01 (0.44, 2.30)Q4: OR = 0.71 (0.31, 1.65)P-trend = 0.94PFOA quartiles, 10-year lag:Q1: referentQ2: OR = 0.79 (0.27, 2.34)Q3: OR = 1.26 (0.40, 4.03)Q4: OR = 0.61 (0.19, 1.91)P-trend = 0.93Results were similar when follow-up started at the time of first residence in the study area or first employment at the plant, or when only cumulative exposures above background levels were considered (results not published)	Age as time scale, sex, race/ethnicity, time-dependent smoking, time-dependent body mass index, and time-dependent alcohol consumption
Steenland et al. 2013	Multiple sclerosis, lifetime	n = 99 validated(n = 150 self-reported)	PFOA quartiles, unlagged:Q1: referentQ2: OR = 0.85 (0.44, 1.63)Q3: OR = 1.56 (0.81, 3.00)Q4: OR = 1.26 (0.65, 2.42)P-trend = 0.22PFOA quartiles, 10-year lag:Q1: referentQ2: OR = 1.16 (0.54, 2.47)Q3: OR = 1.62 (0.75, 3.52)Q4: OR = 1.32 (0.61, 2.84)P-trend = 0.59Results were similar when follow-up started at the time of first residence in the study area or first employment at the plant, or when only cumulative exposures above background levels were considered (results not published)	Age as time scale, sex, race/ethnicity, time-dependent smoking, time-dependent body mass index, and time-dependent alcohol consumption
Steenland et al. 2015	Ulcerative colitis	n = 28 validated	PFOA quartiles, unlagged:Q1: referentQ2: OR = 1.57 (0.52, 4.76)Q3: OR = 0.57 (0.10, 3.11)Q4: OR = 2.74 (0.78, 9.65)P-trend, log cumulative PFOA = 0.05P-trend, categorical PFOA = 0.26PFOA quartiles, 10-year lag:Q1: referentQ2: OR = 3.00 (0.82, 11.0)Q3: OR = 3.26 (0.70, 15.10)Q4: OR = 6.57 (1.47, 29.40)P-trend, log cumulative PFOA = 0.05P-trend, categorical PFOA = 0.05	Age as time scale, sex, race, education, body mass index, time-dependent smoking, and time-dependent alcohol consumption
Steenland et al. 2015	Rheumatoid arthritis	n = 23 validated	PFOA quartiles, unlagged:Q1: referentQ2: OR = 2.11 (0.49, 8.98)Q3: OR = 4.08 (0.96, 17.2)Q4: OR = 4.45 (0.99, 19.9)P-trend, log cumulative PFOA = 0.54P-trend, categorical PFOA = 0.04PFOA quartiles, 10-year lag:Q1: referentQ2: OR = 1.74 (0.45, 6.77)Q3: OR = 2.12 (0.4, 11.1)Q4: OR = 2.62 (0.47, 14.7)P-trend, log cumulative PFOA = 0.75P-trend, categorical PFOA = 0.06	Age as time scale, sex, race, education, body mass index, time-dependent smoking, and time-dependent alcohol consumption
Steenland et al. 2015	Osteoarthritis	n = 196 self-reported	PFOA quartiles, unlagged:Q1: referentQ2: OR = 0.88 (0.58, 1.34)Q3: OR = 0.97 (0.71, 1.54)Q4: OR = 0.97 (0.59, 1.59)P-trend, log cumulative PFOA = 0.92P-trend, categorical PFOA = 0.48PFOA quartiles, 10-year lag:Q1: referentQ2: OR = 0.74 (0.49, 1.10)Q3: OR = 0.56 (0.34, 0.93)Q4: OR = 0.67 (0.39, 1.14)P-trend, log cumulative PFOA = 0.13P-trend, categorical PFOA = 0.15	Age as time scale, sex, race, education, body mass index, time-dependent smoking, and time-dependent alcohol consumption

Columns show first author and year of study reference, outcome of interest, number and proportion of subjects with the outcome, estimates of association with PFOA and/or PFOS levels, and covariates adjusted in multivariable models.

OR: odds ratio; PFAS: perfluoroalkyl and polyfluoroalkyl substances; PFOA: perfluorooctanoic acid; PFOS: perfluorooctanesulfonate; Q: quartile.

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