Abstract
Background
Per- and polyfluoroalkyl substances (PFAS) are a class of chemicals widely used in manufacturing and are highly resistant to degradation, so they accumulate in the environment. Serum concentrations of these so-called forever chemicals have been associated with impairment of innate and adaptive immune responses. The relationship between serum PFAS levels and asthma morbidity has not been studied.
Objective
We tested the association between serum PFAS concentration and asthma exacerbations.
Methods
We performed secondary analysis of data from the National Health and Nutrition Examination Survey (NHANES, 2003-18). We fit multivariable logistic regression models to estimate odds ratios and 95% CIs for asthma exacerbation in the prior 12 months, given serum concentrations of PFAS. Models were adjusted for relevant covariates.
Results
Of 1101 participants with self-reported current asthma and available serum PFAS data, we observed that higher serum perfluorooctanoic and perfluorodecanoic acids were associated with greater odds of asthma attacks in the previous 12 months (respectively, adjusted odds ratio 1.16, 95% CI 1.01, 1.33; and adjusted odds ratio 1.21, 95% CI 1.03, 1.43). After stratification by age, the association between perfluorooctanoic acid and asthma attacks was significant in the 12-18-year-old group only (adjusted odds ratio 1.56, 95% CI 1.06, 2.31). No significant relationships were observed between PFAS and asthma-related emergency department visits. After correction for multiple comparison testing, none of the associations reached the threshold of significance.
Conclusion
The role of these bioaccumulative forever chemicals in susceptibility to asthma attacks warrants further examination in longitudinal studies.
Key words: PFAS, infection, asthma, viral
Introduction
Asthma is influenced by a complex interaction of genetic and environmental factors. Viral respiratory infections are the most common trigger for acute exacerbations of asthma, and modulation of the immune response to infection has been associated with increased frequency and severity of exacerbations.1 There is increasing interest in the health risks of per- and polyfluoroalkyl substances (PFAS), a class of >4000 synthetic compounds used in manufacturing of items like nonstick cookware, water-repellant fabrics, and fire extinguisher foams that contaminate food and drinking water sources. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are known immunotoxins in humans with effects on the innate and adaptive immune responses.2 The US National Toxicology Program concluded that PFOS and PFOA were associated with reduced antibody responses to vaccines,3,4 impaired nuclear factor kappa–light-chain enhancer of activated B cells (aka NF-κB) signaling,5,6 and suppression of natural killer cell activity.2,7 Despite being phased out of production, such legacy PFAS remain relevant to human health because of their extreme stability in the environment and persistence in the human body. Other PFAS types, including perfluorononanoic acid and perfluorodecanoic acid (PFDA), have been reported to be associated with similar impaired immune responses3,8 and higher rates of lower respiratory tract infections in children.9 The relationship between PFAS exposure and asthma prevalence is inconsistent, with some reporting a significant positive association10, 11, 12, 13 and others finding no association.9,14, 15, 16 It is unknown whether a relationship exists between PFAS exposure and worsened asthma severity or control. Given the role of acute respiratory infections in triggering exacerbations of asthma, we hypothesized that PFAS exposure was associated with increased asthma morbidity.
To test our hypothesis, we performed an analysis of data from 8 cycles (2003-18) of the National Health and Nutrition Examination Survey (NHANES). Serum PFAS measurement was obtained from a random one-third subsample of participants 12 years and older during each cycle. Current asthma, asthma attacks, and asthma-related emergency room or urgent care visits in the prior 12 months were assessed by self-report. Those reporting a history of emphysema, chronic bronchitis, or chronic obstructive pulmonary disease were excluded from the analysis. All analyses were conducted by Stata v17.0 (StataCorp, College Station, Tex). We fit multivariable logistic regression models to estimate odds ratios and 95% CIs for asthma exacerbation in the prior 12 months, given serum concentrations of PFAS. Seven PFAS types were collected in all NHANES cycles between 2003 and 2018. Of these, 6 types were found in concentrations at or above the limit of detection in ≥50% of samples and were included in the analysis. Separate models were generated for each PFAS type: PFOS, PFOA, perfluorohexane sulfonic acid, perfluorononanoic acid, 2-(N-methyl-PFOSA) acetic acid, and PFDA. Serum PFAS data were log2 transformed to approximate a normal distribution. Models were adjusted for age, sex, race, ethnicity, family income-to-poverty ratio, body mass index, and serum cotinine concentration. A correction for multiple comparison testing was added, calculated as 0.05 divided by 6, the number of PFAS types tested. Detailed information is available in this article’s Methods section in the Online Repository at www.jaci-global.org.
Results and discussion
A total of 1101 individuals were identified as having current asthma and available serum PFAS data, although as a result of sample limitations in the 2013-14 cycle, PFOS and PFOA data were available for only 935 participants. Forty-nine percent of this population reported having an asthma attack in the prior 12 months, and 15% reported an asthma-related emergency department/urgent care visit in the prior 12 months. Demographic characteristics and mean serum PFAS concentrations are presented in Table I. Serum PFOS, PFOA, and perfluorohexane sulfonic acid concentrations were higher in male participants than in female participants. Non-Hispanic White participants and those with higher family income-to-poverty ratio had higher serum levels of PFOS and PFOA compared to other race/ethnicity and income groups. We observed high correlation between PFOA and PFOS (r = 0.79) and low to moderate correlations between other PFAS types, with correlation coefficients ranging from 0.11 to 0.66 (Table II).
Table I.
Serum PFAS concentrations and demographic characteristics
| Characteristic | Legacy PFAS (ng/mL) |
Other PFAS types (ng/mL) |
||||||
|---|---|---|---|---|---|---|---|---|
| No. (%) | PFOS | PFOA | No. (%) | PHs | PFNA | Me-PFOSA-AcOH | PFDA | |
| Overall | 935 | 8.0 (11.5) | 2.5 (2.7) | 1101 | 1.3 (1.8) | 0.8 (0.7) | 0.2 (0.2) | 0.2 (0.1) |
| Sex | ||||||||
| Male | 397 | 10.7 (13.9) | 3.1 (3) | 453 | 1.8 (1.9) | 0.9 (0.8) | 0.3 (0.3) | 0.2 (0.2) |
| Female | 538 | 6.5 (9.5) | 2.2 (2) | 648 | 1.0 (1.3) | 0.7 (0.6) | 0.2 (0.2) | 0.2 (0.2) |
| Race/ethnicity | ||||||||
| Non-Hispanic White | 378 | 9.2 (11.4) | 2.9 (2.7) | 446 | 1.4 (1.9) | 0.8 (0.7) | 0.3 (0.3) | 0.2 (0.2) |
| Non-Hispanic Black | 271 | 8.5 (11.8) | 2.3 (2.4) | 321 | 1.3 (1.7) | 0.8 (0.8) | 0.2 (0.2) | 0.2 (0.2) |
| Mexican American | 130 | 6.6 (12.9) | 2.3 (2.6) | 146 | 1.2 (1.7) | 0.7 (0.6) | 0.2 (0.2) | 0.2 (0.1) |
| Other Hispanic | 83 | 7 (9.7) | 2.7 (2.8) | 98 | 1.2 (1.5) | 0.9 (0.7) | 0.1 (0.2) | 0.2 (0.2) |
| Other race, or multiracial | 73 | 4.4 (8) | 1.8 (2) | 90 | 0.9 (1.4) | 0.7 (0.6) | 0.1 (0.2) | 0.2 (0.2) |
| Age | ||||||||
| ≤18 years | 302 | 8.1 (11.5) | 2.5 (2.9) | 338 | 1.4 (2.0) | 0.8 (0.7) | 0.2 (0.2) | 0.2 (0.2) |
| >18 years | 633 | 8.0 (11.6) | 2.5 (2.6) | 763 | 1.2 (1.6) | 0.8 (0.7) | 0.2 (0.2) | 0.2 (0.2) |
| Body mass index | ||||||||
| <30 kg/m2 | 540 | 8.8 (14.1) | 2.7 (2.8) | 633 | 1.4 (1.8) | 0.8 (0.7) | 0.2 (0.2) | 0.2 (0.2) |
| ≥ 30 kg/m2 | 395 | 7.1 (10.2) | 2.2 (2.1) | 468 | 1.2 (1.5) | 0.7 (0.7) | 0.2 (0.2) | 0.2 (0.2) |
| Family income-to-poverty ratio | ||||||||
| <1 | 238 | 6.8 (9.9) | 2.1 (1.9) | 281 | 1.2 (1.4) | 0.7 (0.7) | 0.2 (0.2) | 0.2 (0.2) |
| ≥1 to <3 | 353 | 7.5 (12.2) | 2.4 (2.7) | 405 | 1.2 (1.6) | 0.7 (0.8) | 0.2 (0.2) | 0.2 (0.2) |
| ≥3 | 344 | 9.6 (11.7) | 2.9 (2.8) | 415 | 1.4 (1.9) | 0.9 (0.7) | 0.2 (0.2) | 0.2 (0.2) |
| Serum cotinine (ng/mL) | ||||||||
| Below LOD | 219 | 7.7 (10.8) | 2.4 (2.4) | 276 | 1.3 (1.9) | 0.7 (0.8) | 0.1 (0.2) | 0.2 (0.2) |
| Above LOD | 716 | 8.3 (11.9) | 2.6 (2.7) | 825 | 1.3 (1.7) | 0.8 (0.8) | 0.2 (0.2) | 0.2 (0.2) |
Data are presented as medians (interquartile ranges).
LOD, Level of detection; Me-PFOSA-AcOH, 2-(N-methyl-PFOSA) acetic acid; PFHxS, perfluorohexane sulfonic acid; PFNA, perfluorononanoic acid.
Table II.
Weighted Pearson correlation coefficients for PFAS types (N = 1101)
| PFOS∗ | PFOA∗ | PFHxS | PFNA | PFDA | Me-PFOSA-AcOH | |
|---|---|---|---|---|---|---|
| PFOS∗ | 1.0 | |||||
| PFOA∗ | .79 | 1.0 | ||||
| PFHxS | .31 | .31 | 1.0 | |||
| PFNA | .35 | .49 | .21 | 1.0 | ||
| PFDA | .31 | .38 | .11 | .66 | 1.0 | |
| Me-PFOSA-AcOH | .29 | .32 | .17 | .24 | .20 | 1.0 |
Me-PFOSA-AcOH, 2-(N-methyl-PFOSA) acetic acid; PFHxS, perfluorohexane sulfonic acid; PFNA, perfluorononanoic acid.
Sample size 935.
We observed positive associations between asthma attacks in the past 12 months and serum PFAS concentrations in the adjusted models, with the strongest associations observed with PFOA and PFDA (Table III). After stratification by age, PFDA remained statistically significant among those >18 years of age but not in those ≤18 years. In the overall population and the adolescent group, PFOA was positively associated with odds of asthma attacks. Stratification by sex revealed that the association between PFDA and higher odds of asthma attacks remained significant only for male subjects (Table IV). However, no associations passed the significance threshold when corrected for multiple testing. No significant associations were observed between PFAS concentrations and emergency department/urgent care visits in the adjusted models.
Table III.
Adjusted odds ratios (aORs) with 95% CIs for asthma attacks and emergency care visits for asthma in the past 12 months by serum log2 PFAS concentrations (ng/mL), overall and stratified by age group
| Type of PFAS | Overall |
Age ≤18 years |
Age >18 years |
||||||
|---|---|---|---|---|---|---|---|---|---|
| No. | aOR (95% CI), overall | P | No. | aOR (95% CI) | P | No. | aOR (95% CI) | P | |
| Asthma attack in past 12 months | |||||||||
| PFOS | 859 | 1.08 (0.95, 1.22) | .22 | 279 | 1.21 (0.91, 1.59) | .18 | 580 | 1.07 (0.93, 1.23) | .33 |
| PFOA | 859 | 1.16 (1.01, 1.33) | .04 | 279 | 1.56 (1.06, 2.31) | .03 | 580 | 1.12 (0.95, 1.32) | .16 |
| PFHxS | 1010 | 1.05 (0.93, 1.17) | .43 | 312 | 1.11 (0.90, 1.37) | .35 | 698 | 1.05 (0.91, 1.21) | .52 |
| PFNA | 1010 | 1.11 (0.96, 1.28) | .17 | 312 | 1.05 (0.79, 1.41) | .73 | 698 | 1.13 (0.95, 1.34) | .17 |
| Me-PFOSA-AcOH | 1010 | 1.10 (0.99, 1.23) | .08 | 312 | 1.24 (0.95, 1.61) | .11 | 698 | 1.09 (0.96, 1.23) | .17 |
| PFDA | 1010 | 1.21 (1.03, 1.43) | .02 | 312 | 1.24 (0.86, 1.79) | .24 | 698 | 1.23 (1.02, 1.48) | .03 |
| Emergency care visit for asthma in past 12 months | |||||||||
| PFOS | 859 | 0.99 (0.79, 1.23) | .90 | 262 | 0.91 (0.61, 1.34) | .61 | 580 | 1.03 (0.79, 1.33) | .85 |
| PFOA | 859 | 1.03 (0.77, 1.38) | .85 | 262 | 0.76 (0.46, 1.26) | .29 | 580 | 1.10 (0.78, 1.55) | .58 |
| PFHxS | 1010 | 1.02 (0.86, 1.20) | .85 | 292 | 0.97 (0.71, 1.33) | .85 | 698 | 1.06 (0.85, 1.33) | .59 |
| PFNA | 1010 | 1.00 (0.78, 1.28) | .99 | 292 | 0.65 (0.41, 1.04) | .07 | 698 | 1.06 (0.78, 1.44) | .70 |
| Me-PFOSA-AcOH | 1010 | 0.96 (0.78, 1.18) | .70 | 292 | 1.01 (0.67, 1.52) | .96 | 698 | 0.96 (0.75, 1.23) | .76 |
| PFDA | 1010 | 1.09 (0.86, 1.39) | .48 | 292 | 0.91 (0.58, 1.47) | .70 | 698 | 1.10 (0.82, 1.48) | .51 |
Adjusted for age, sex, race, ethnicity, body mass index, income-to-poverty ratio, and serum cotinine.
Me-PFOSA-AcOH, 2-(N-methyl-PFOSA) acetic acid; PFHxS, perfluorohexane sulfonic acid; PFNA, perfluorononanoic acid.
Table IV.
Adjusted odds ratios (ORs) with 95% CIs for asthma attacks and emergency care visits for asthma in the past 12 months by serum log2 PFAS concentrations (ng/mL), overall and stratified by sex
| Type of PFAS | Overall |
Male |
Female |
||||||
|---|---|---|---|---|---|---|---|---|---|
| No. | Adjusted OR (95% CI) | P | No. | Adjusted OR (95% CI) | P | No. | Adjusted OR (95% CI) | P | |
| Asthma attack in past 12 months | |||||||||
| PFOS | 859 | 1.08 (0.95, 1.22) | .22 | 371 | 1.18 (0.95, 1.48) | .13 | 488 | 1.01 (0.85, 1.19) | .93 |
| PFOA | 859 | 1.16 (1.01, 1.33) | .04 | 371 | 1.23 (0.94, 1.61) | .13 | 488 | 1.10 (0.90, 1.34) | .35 |
| PFHxS | 1010 | 1.05 (0.93, 1.17) | .43 | 421 | 1.00 (0.80, 1.25) | .99 | 589 | 1.06 (0.92, 1.23) | .41 |
| PFNA | 1010 | 1.11 (0.96, 1.28) | .17 | 421 | 1.17 (0.91, 1.52) | .22 | 589 | 1.07 (0.87, 1.32) | .51 |
| Me-PFOSA-AcOH | 1010 | 1.10 (0.99, 1.23) | .08 | 421 | 1.21 (0.99, 1.49) | .07 | 589 | 1.03 (0.90, 1.18) | .68 |
| PFDA | 1010 | 1.21 (1.03, 1.43) | .02 | 421 | 1.36 (1.05, 1.75) | .02 | 589 | 1.14 (0.92, 1.43) | .23 |
| Emergency care visit for asthma in past 12 months | |||||||||
| PFOS | 859 | 0.99 (0.79, 1.23) | .90 | 371 | 1.14 (0.70, 1.86) | .59 | 488 | 0.91 (0.67, 1.24) | .54 |
| PFOA | 859 | 1.03 (0.77, 1.38) | .85 | 371 | 1.45 (0.64, 3.30) | .37 | 488 | 0.88 (0.62, 1.25) | .47 |
| PFHxS | 1010 | 1.02 (0.86, 1.20) | .85 | 421 | 1.15 (0.69, 1.93) | .59 | 589 | 0.97 (0.81, 1.15) | .70 |
| PFNA | 1010 | 1.00 (0.78, 1.28) | .99 | 421 | 1.12 (0.64, 1.97) | .69 | 589 | 0.98 (0.74, 1.28) | .86 |
| Me-PFOSA-AcOH | 1010 | 0.96 (0.78, 1.18) | .70 | 421 | 1.37 (0.90, 2.10) | .14 | 589 | 0.82 (0.63, 1.06) | .13 |
| PFDA | 1010 | 1.09 (0.86, 1.39) | .48 | 421 | 1.39 (0.86, 2.25) | .18 | 589 | 0.99 (0.74, 1.34) | .97 |
Adjusted for age, sex, race, ethnicity, body mass index, income-to-poverty ratio, and serum cotinine.
Me-PFOSA-AcOH, 2-(N-methyl-PFOSA) acetic acid; PFHxS, perfluorohexane sulfonic acid; PFNA, perfluorononanoic acid.
In this analysis of a representative sample of the US population, we observed that serum concentrations of PFDA and PFOA were positively associated with asthma attacks in individuals 12 years and older after adjustment for covariates. Among adolescents, but not adults, every doubling of serum PFOA concentration was associated with a 1.6-fold increase in the odds of having had an asthma attack in the previous 12 months. Among adults, but not adolescents, every doubling of serum PFDA concentration was associated with a 1.2-fold increase in the odds of asthma attacks. However, no associations remained statistically significant after correction for multiple testing.
PFOA and PFDA have been associated with immune suppression in previous studies,2,3,8,9 and PFOA is also linked to increased frequency of lower respiratory tract infections,9,17 the most common trigger for acute asthma exacerbations. These findings support the biological plausibility of PFAS as a potential environmental risk factor for asthma exacerbation. Susceptibility to exposure-related health effects may be dependent on PFAS type as well as age, biological sex, and other individual-level factors. Previous studies have observed that children are particularly vulnerable to the health effects of PFAS,18, 19, 20 which is in line with our findings showing a significant association between PFOA and asthma attacks among adolescents but not adults. Biological sex may also mediate the relationship between some PFAS and asthma morbidity. Consistent with our observations, multiple studies have reported higher serum PFAS concentrations in male compared to female subjects, suggesting potential sex-based differences in exposure or clearance of PFAS from the body.21,22
Our analysis is limited by the cross-sectional nature of the data and by potential recall bias inherent to survey data. As a result of limitations in the data collected in the survey, we were unable to control for some relevant covariates, including asthma severity, allergic sensitization, and air pollution exposure. Despite the large size of the NHANES data set, a relatively small number of participants had both current asthma (9%) and serum PFAS measurements (random one-third subsample). Further, the prevalence of asthma-related emergency department/urgent care visits in the prior 12 months was only 15%; the low number of events may have limited our ability to detect an association with serum PFAS levels. Different results may have been observed in a larger or more severe asthma population. It is possible that PFAS could be a marker for other unmeasured risk factors for poorly controlled asthma, though our analysis adjusted for most of the well-described potentially confounding variables. Our analysis was limited to only the PFAS types measured in the NHANES study; it is unknown whether an association exists between asthma morbidity and unmeasured PFAS types, including newer compounds like the ammonium salt of hexafluoropropylene oxide dimer acid, or GenX, which was created to replace legacy PFAS types. Finally, our study outcome was based on self-reported asthma attacks and emergency department visits, but we cannot definitively conclude that these events were triggered by infection. However, given that most asthma exacerbations are mediated by respiratory infection, we interpret our findings as supporting a potential relationship between PFAS-induced immune suppression and increased likelihood of asthma exacerbation.
In conclusion, we found that higher serum concentrations of PFOA and PFDA were associated with higher odds of asthma attacks in the previous 12 months in a nationally representative sample. Further mechanistic studies and prospective cohort studies are needed to determine whether and how PFAS exposure contributes to increased susceptibility to asthma exacerbations.
Clinical implications.
Self-reported asthma attacks were associated with serum concentrations of the persistent environmental chemicals called PFAS in a US representative sample. The role of these bioaccumulative forever chemicals in susceptibility to asthma attacks warrants further study.
Footnotes
Supported by the National Institutes of Health (NIH) under awards NCATS UL1TR002489 and KL2TR002490. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.
Supplementary data
References
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