OVERVIEW OF EVIDENCE REVIEW APPROACH

Appendix D provides full details of the methods used for the committee’s review. Briefly, the committee aimed to build upon existing decisions from other authoritative bodies. The focus was on more recent studies, both high-quality systematic reviews and published epidemiologic research articles, which could inform updates to authoritative conclusions regarding PFAS exposure and any human health effects. The review approach improved efficiency while minimizing the risk of excluding scientific findings that could inform the committee’s recommendations.

Review of Recent Epidemiologic Studies

As detailed in Appendix D, the committee’s review of original literature consisted of the following steps: a literature search, screening of abstracts, a full-text review of studies identified in the abstract screening, evaluation of a final set of studies identified as relevant after the full-text review, data abstraction, and an evidence synthesis step.

The literature search identified 5,172 potentially relevant studies. After removal of duplicates (112 articles), 5,060 articles were subject to title and abstract screening by two independent reviewers. After 4,434 articles had been excluded because the titles and abstracts did not meet the committee’s inclusion criteria, 626 articles were subjected to full-text review, during which additional articles were excluded if they had been published before 2018 or were listed among the references in ATSDR’s Toxicological Profile for Perfluoroalkyls (n = 320); were cross-sectional in design (n = 160); were not published in English (n = 1); did not provide risk estimates associated with PFAS exposure (n = 3); or documented studies not conducted in humans (n = 3). Cross-sectional studies were excluded largely because this study design measures exposure and disease at the same time, and so cannot determine cause and effect. The remaining 139 articles were categorized according to the human health outcomes studied, as shown in Figure 3-1.

Figure 3-1

Evidence map describing the number of studies found, by PFAS, for each health outcome category. NOTES: MeFOSAA = methylperfluorooctane sulfonamidoacetic acid; PFDA = perfluorodecanoic acid; PFHxS = perfluorohexanesulfonic acid; PFNA = perfluorononanoic (more...)

The committee’s review of the recent literature focused mainly on those health effect categories for which additional evidence might have changed the committee’s understanding of the association between PFAS exposure and health outcomes. The committee formally evaluated the individual studies for internal validity or “risk of bias,” using a tool adapted from the Navigation Guide of Woodruff and Sutton (2014), assigning to each an overall assessment of its risk of bias (low, probably low, probably high, or high risk of bias). Effect estimates from the individual studies included in the review were extracted into a database and uploaded to a public website (Tableau Public) to allow for visualizations such as evidence maps and forest plots.¹ The effect estimates in the Tableau represent those from the model most adjusted for confounders. Appendix D provides the critical domains used by the committee to assess risk of bias, as well as the data abstraction procedure.

Evidence Synthesis

To assess the strength of evidence regarding the potential for PFAS to cause a particular health effect, the committee integrated the evidence reviewed in ATSDR’s Toxicological Profile for Perfluoroalkyls with the evidence from its review of the original epidemiologic studies. A framework based on the Hill considerations, which help determine whether associations are causal, guided the synthesis of available evidence (Fedak et al., 2015; Hill, 1965; NASEM, 2018a). The committee considered the animal studies discussed in ATSDR’s Toxicological Profile for Perfluoroalkyls and in the systematic reviews examined by the committee in making its determinations, as an aid to interpretation of the human studies. Toxicologic evidence, whether it supports or conflicts with evidence from epidemiologic studies, provides insights about biologic processes and informs how an observed association might be interpreted (NASEM, 2018a).

The committee’s strength-of-evidence conclusions reflect one of the four categories described below (see Figure 3-2).

Figure 3-2

Categories of association used in this report. NOTES: The categories of association only describe how strong the evidence is between PFAS and the health outcome. The risk of developing an outcome from exposure to PFAS for things in the same category can (more...)

Sufficient Evidence of an Association

For effects in this category, a positive association between PFAS and the outcome must be observed in studies in which chance, bias, and confounding can be ruled out with reasonable confidence. For example, the committee might regard as sufficient evidence of an association evidence from several small studies that is unlikely to be due to confounding or to otherwise be biased and that shows an association that is consistent in magnitude and direction. Experimental data supporting biologic plausibility strengthen the evidence of an association but are not a prerequisite, nor are they sufficient to establish an association without corresponding epidemiologic findings.

Limited or Suggestive Evidence of an Association

In this category, the evidence must suggest an association between exposure to PFAS and the outcome in studies of humans, but the evidence can be limited by an inability to rule out chance, bias, or confounding with confidence. One high-quality study may indicate a positive association, but the results of other studies of lower quality may be inconsistent.

Inadequate or Insufficient Evidence to Determine an Association

If there was not enough reliable scientific data to categorize the potential association with a health effect as “sufficient evidence of an association,” “limited or suggestive evidence of an association,” or on the other end of the spectrum, “limited or suggestive evidence of no association,” the health outcome was placed in the category of “inadequate or insufficient evidence to determine an association” by default. In this category, the available human studies may have inconsistent findings or be of insufficient quality, validity, consistency, or statistical power to support a conclusion regarding the presence of an association. Such studies may have failed to control for confounding factors or may have had inadequate assessment of exposure.

Limited or Suggestive Evidence of No Association

A conclusion of “no association” is inevitably limited to the conditions, exposures, and observation periods covered by the available studies, and the possibility of a small increase in risk related to the magnitude of exposure studied can never be excluded. However, a change in classification from inadequate or insufficient evidence of an association to limited or suggestive evidence of no association would require new studies that corrected for the methodologic problems of previous studies and that had samples large enough to limit the possible study results attributable to chance.

COMMITTEE’S CONCLUSIONS

Annex Table 3-1 at the end of the chapter summarizes the health outcomes considered by the committee, the relevant conclusions from authoritative reviews, and the committee’s overall conclusions for endpoints relevant to each outcome. The committee’s conclusions reflect its integration of evidence reviewed in ATSDR’s Toxicological Profile for Perfluoroalkyls and other authoritative reviews with the evidence garnered from the review of recent epidemiologic studies.

ANNEX Table 3-1

Health Effects of PFAS by Category.

The committee found sufficient evidence of an association for the following diseases and health outcomes:

• decreased antibody response (in adults and children),
• dyslipidemia (in adults and children),
• decreased infant and fetal growth, and
• increased risk of kidney cancer (in adults).

The committee found limited or suggestive evidence of an association for the following diseases and health outcomes:

• increased risk of breast cancer (in adults),
• liver enzyme alterations (in adults and children),
• increased risk of pregnancy-induced hypertension (gestational hypertension and preeclampsia),
• increased risk of testicular cancer (in adults),
• increased risk of thyroid disease and dysfunction (in adults), and
• increased risk of ulcerative colitis (in adults).

For a range of other health effects, the evidence was inadequate or insufficient. These include type 1 and gestational diabetes; cardiovascular disease; metabolic syndrome; obesity; infertility; male and female reproductive effects; reproductive hormone levels; and cancers other than kidney, breast, and testicular.

The committee’s rationale for these conclusions is provided in the sections that follow, organized by human health outcomes. For effects with limited or sufficient evidence, the range of effect size estimates considered by the committee is indicated. Additional information, including an evidence map of recent studies, information about the quality of individual studies, and forest plots showing effect size estimates in a searchable format, can also be accessed from the committee’s public Tableau.

With one exception (decreased infant and fetal growth), the committee provided forest plots for all outcomes with sufficient evidence of an association to display effect estimates from the studies with low or probably low risk of bias. Specifically, forest plots based on the data in the Tableau are displayed in this chapter for the following outcomes: changes in antibody response (a measure of immune function), total cholesterol (a marker of dyslipidemia), and hypertensive disorders of pregnancy. For these outcomes, the committee chose to display the effect estimate that was the most common across studies if more than one was available in the Tableau. For cancer, forest plots were created based on studies included in ATSDR’s Toxicological Profile and Polyfluoroalkyls and the more recent epidemiologic studies. The committee handled cancer in this way because it was upgrading the previously observed association between PFAS and kidney cancer and drawing a new conclusion on breast cancer. Each cancer figure displays the PFAS with the strongest effect. For birthweight, there were many studies with probably or definitely low risk of bias, and those with definitely low risk of bias are displayed in a table rather than a forest plot. In addition to the outcomes with sufficient evidence of an association, one outcome with limited or suggestive evidence, hypertensive disorders of pregnancy, is displayed in a forest plot. This was an important outcome category to speakers at the committee’s town halls.

SUMMARY AND RATIONALE FOR THE COMMITTEE’S CONCLUSIONS BY HUMAN HEALTH OUTCOMES

Immune System Effects

The committee’s evaluation of the impact of PFAS on immune function considered evidence relevant to the three basic functions of the immune system: response to infection, response to foreign substances (allergy), and response to self (autoimmunity). The committee found sufficient evidence for an association of PFAS exposure with decreased antibody response to vaccination or infection, and limited or suggestive evidence of an association with ulcerative colitis (relevant to autoimmunity). There was inadequate evidence for other immune system endpoints, including infectious disease (response to infection) and response to allergens.

Response to Infection

ATSDR concluded that there is suggestive evidence for an association between serum levels of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexanesulfonic acid (PFHxS), and perfluorodecanoic acid (PFDA) and decreased antibody response to vaccines, and limited evidence of an association for perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnDA), and perfluorododecanoic acid (PFDoDA). Other authoritative reviews (including those of EFSA, EPA, NTP, and OECD) also found associations between PFAS and decreased antibody response to vaccines. Three more recent papers focus on antibody response early in life. Huang and colleagues (2020) conducted a study, with probably low risk of bias, which found that immunoglobulin G (IgG) levels were slightly lower among children with higher PFAS serum levels. The regression coefficient per 1-log10 nanograms per milliliter (ng/mL) increase in PFAS ranged from −0.04 (95% confidence interval [CI]: −0.11–0.04) for PFHxS to 0.00 for PFUnDA (95% CI: −0.06–0.05) (see Figure 3-3). In another study with probably low risk of bias, Timmermann and colleagues (2020) evaluated measles antibodies at three time points: before first vaccination (measuring antibodies passed from the mother) and after first and second vaccination; for most PFAS, no strong associations with antibody levels were found. For PFOS, there was an inverse association between PFAS levels in blood and antibody levels before first vaccination in boys (see Figure 3-4). In a study of bias of antibodies to hand, foot, and mouth disease (CA 16 and EV71 antibody), with probably high risk of bias, Zeng and colleagues (2019) observed that 3-month-old infants with higher PFAS cord blood levels were two to four times more likely to have levels of antibodies to hand, foot, and mouth disease that were below the clinically protective level (see Figure 3-5). This finding suggests that higher PFAS blood levels may contribute to lower antibody levels over time. Taken together, these three recent studies add support for the conclusion of sufficient evidence of an association between PFAS exposure and decreased antibody response.

Figure 3-3

Regression coefficients for changes in immunoglobulin (IgG) concentrations per 1-log10 nanograms per milliliter (ng /mL) increase in PFAS serum level. DATA SOURCE: Huang et al., 2020.

Figure 3-4

Regression coefficients for percent difference in measles antibody response per doubling of log10 nanograms per milliliter (ng /mL) serum PFOS. DATA SOURCE: Timmerman et al., 2020.

Figure 3-5

Regression coefficients for percent change in hand, foot, and mouth disease antibody response per doubling of natural logarithm (ln)-nanograms per milliliter (ng /mL) sum of PFAS. DATA SOURCE: Zeng et al., 2019.

The committee reviewed four papers focused on specific infectious diseases (chicken pox, common cold, otitis media, pneumonia, and respiratory tract infection) in children (Ait Bamai et al., 2020; Huang et al., 2020; Kvalem et al., 2020; Manzano-Salgado et al., 2019). All four studies were rated as having a probably low risk of bias; however, three of the studies used parental reports of infection to ascertain outcomes, which could result in information bias, leading in turn to null findings. The fourth study, by Huang and colleagues (2020), collected data on infections from medical records. These four studies did not provide strong evidence of an association of PFAS with these common illnesses, although there was some suggestion that for children without siblings, PFAS may be associated with respiratory syncytial virus (Ait Bamai et al., 2020). There was no evidence for fever among children with higher PFAS blood levels (Timmermann et al., 2020). The committee concluded there is inadequate or insufficient evidence of an association between PFAS exposure and risk of infection, although this is an area worthy of future research, including the relationship of PFAS to novel infections such as SARS-CoV-2 (see Box 3-1).

BOX 3-1

PFAS Exposure and Risk of SARS-CoV-2 Infection.

Response to Foreign Substances (Allergy)

The committee reviewed several studies evaluating the impact of PFAS exposure on allergic symptoms and disease, all with a probably low risk of bias. The specific outcomes studied included allergies to food and inhaled substances, atopic dermatitis, dermatitis, changes in serum immunoglobulin E (IgE) levels, rhinitis, rhinoconjunctivitis, and results of skin prick tests. Six studies (Ait Bamai et al., 2020; Chen et al., 2018; Huang et al., 2020; Impinen et al., 2019; Kvalem et al., 2020; Wen et al., 2019) evaluated some aspect of allergic response, with most not providing strong evidence of an association with PFAS. The one exception is the study by Wen and colleagues (2019), which showed increased atopic dermatitis among those in the highest tertile of PFOA levels, but not for other PFAS. One study included in ATSDR’s Toxicological Profile for Perfluoroalkyls found that PFAS exposure was associated with increased odds of asthma diagnosis among children at ages 5 and 13, but only those children who had not received measles, mumps, and rubella vaccination (Timmerman et al., 2020). Overall, the evidence for an association between PFAS and allergy response is inadequate or insufficient, a finding consistent with the authoritative review by EFSA.

Response to Self (Autoimmunity)

As noted in authoritative reviews by the EPA and OECD, the C-8 Science Panel identified an association between PFAS and ulcerative colitis, a rare autoimmune condition of the gastrointestinal (GI) tract. In a follow-up to that study, Steenland and colleagues (2018) further evaluated the exposure–response relationship between PFAS and ulcerative colitis, examining Crohn’s disease as well. They found that ulcerative colitis was positively associated with PFOA but not with other PFAS. The odds ratio for ulcerative colitis per 1 unit of log PFOA was 1.60 (95% CI: 1.14–2.24), but the trend by quintiles was not monotonic (1, 0.84, 40.98, 33.36, 2.86) (Steenland et al., 2018). The only other analysis of the association of PFAS with ulcerative colitis is a 2022 case-control study from the Nurses’ Health Study using blood specimens collected between 1989 and 1999 (Lochead et al., 2022), identified after the committee had completed its review. This study did not find an association between ulcerative colitis and any PFAS measured; the median concentration of PFOA among the 80 cases was 3.97 ng/mL, higher than the median value of 2.93 ng/mL for the 114 ulcerative colitis cases in the Steenland study. Given the low incidence of ulcerative colitis, it will be difficult to replicate the findings from either of these studies in other populations. The Nurses’ Health Study also observed a statistically significant decreased risk of Crohn’s disease with PFAS; the Steenland study found no association with Crohn’s disease. To assess the relationship between PFAS and inflammatory bowel disease, Xu and colleagues (2020b) measured two proteins (calprotectin and Zonulin) in feces and saw no association with PFAS.

Given the difficulty of evaluating these diseases, future studies are needed to characterize the impact of PFAS on autoimmunity. Although there is more recent inconsistent evidence, it is not strong enough to override the previous conclusion from the C-8 study. Overall, the committee concluded that there is limited or suggestive evidence of an association of PFAS with ulcerative colitis. The committee did not review studies that considered other autoimmune endpoints.

Cardiometabolic Outcomes

The committee’s evaluation of the impact of PFAS on cardiometabolic outcomes considered evidence relevant to four disorders of the three basic functions of the cardiometabolic system: dyslipidemia, high blood pressure or hypertension, metabolic syndrome, and elevated body mass index (BMI) or obesity. The committee did not identify any studies that evaluated the association between PFAS and cardiovascular disease, a group of disorders involving the heart and blood vessels (coronary [ischemic] heart disease, cerebrovascular disease [stroke], peripheral arterial disease, rheumatic heart disease, congenital heart disease, and deep vein thrombosis and pulmonary embolism).² The committee concluded that there is sufficient evidence of an association of PFAS exposure with dyslipidemia in adults and children. This conclusion builds on those of the authoritative reviews considered by the committee, all of which (including those of ATSDR, EFSA, EPA, OECD, and the C-8 Science Panel) found associations between PFAS and dyslipidemia. The committee concluded that the evidence is insufficient for other findings related to cardiovascular risk factors and nonpregnancy clinical cardiovascular diseases. This conclusion is consistent with those of the authoritative reviews, which concluded that there was mixed to limited evidence supporting associations between PFAS and cardiovascular risk factors and diseases other than the four discussed above because of inconsistencies in measurement, differences in study designs and populations, and differences in adjustment for potential confounding factors.

Dyslipidemia

The studies identified by the committee that evaluated dyslipidemia used several types of study designs, including cohort and nested case-control approaches, and the studies encompassed both children and adults. Some of the major challenges to interpretation of their findings were that outcome definitions were inconsistent across studies (total triglycerides, total cholesterol, and low-density lipoprotein [LDL], and high-density lipoprotein [HDL], sometimes measured in a variety of different units). In addition, the study populations included were very broad with respect to age range, sex, and race or ethnicity representation, making it difficult to interpret and generalize the results across studies. In addition, the timing of exposure to PFAS was often unclear, particularly in the studies of adults, in which confounding could be an issue. The study designs and sample sizes varied; there were six cohort studies and one nested case-control study, most of which were rated as having probably low risk of bias. Figures 3-6 and 3-7 display effect estimates from those studies of low or probably low risk of bias that evaluated the impact of PFAS exposure on total cholesterol (the most consistent effect measured across studies) in adults (Donat-Vargas et al., 2019b; Lin et al., 2019; Tian et al., 2021) and children (Mora et al., 2018). The effects documented across studies were heterogenous, possibly because of the timing of the exposures and outcome measurements. Overall, the committee concluded that there is sufficient evidence of an association between PFAS and dyslipidemia, as the recent epidemiologic literature provides additional confidence in the conclusions of authoritative reviews regarding this association.

Figure 3-6

Regression coefficients for changes in total cholesterol in adults. DATA SOURCES: Donat-Vargas et al., 2019b; Lin et al., 2019; Tian et al., 2021.

Figure 3-7

Regression coefficients for total cholesterol per interquartile range (IQR) increase in PFAS exposure in children. DATA SOURCE: Mora et al., 2018.

High Blood Pressure or Hypertension

The authoritative reviews do not identify an association between PFAS and high blood pressure or hypertension. The committee identified four studies rated as having probably low or definitely low risk of bias that evaluated the impact of PFAS exposure on hypertension, blood pressure, systolic blood pressure, and diastolic blood pressure (Donat-Vargas et al., 2019b; Lin et al., 2020b; Mitro et al., 2020a). The populations and designs varied greatly across these studies: Donat-Vargus and colleagues (2019b) was a nested case-control study of middle-aged women and men; Lin and colleagues (2020b) was a randomized, controlled clinical trial conducted at 27 clinical centers around the United States from 1996 to 2001; and Mitro and colleagues (2020a) was a cohort study among postpartum females. Donat-Vargus and colleagues (2019b observed that the effect estimates for the impact of exposure to PFAS and hypertension were inconsistent. Lin and colleagues (2020b) observed modest and mostly null associations of plasma PFAS concentrations with high blood pressure and hypertension. Mitro and colleagues (2020a) observed higher systolic blood pressure (e.g., 1.2 mm Hg [95% CI: 0.3, 2.2] per doubling of PFOS) at 3 years postpartum. Given the inconsistency of the evidence, the committee concluded that the evidence is inadequate or insufficient to determine an association between PFAS and high blood pressure or hypertension.

Metabolic Syndrome

The authoritative reviews do not identify an association between PFAS and metabolic syndrome. Metabolic syndrome is a group of risk factors that increases the risk of heart disease and stroke. Diagnosis requires that an individual have three of the following risk factors: (1) a large waist circumference (males: >102 cm, females: >88 cm); (2) high triglyceride levels (≥1.7 mmol/L); (3) low HDL cholesterol (males <1.04 mmol/L, females <1.30 mmol/L); (4) high blood pressure (≥130 over ≥85 mm Hg); and (5) high fasting glucose levels (≥6.1 mmol/L) (Beilby, 2004). The committee did not identify any new epidemiologic studies reporting associations between exposure to PFAS and a diagnosis of metabolic syndrome. The committee concluded that the evidence is inadequate or insufficient to determine such an association, although the relationship is plausible given the association between PFAS and dyslipidemia.

Elevated Body Mass Index or Obesity

The authoritative reviews do not identify an association between PFAS and elevated BMI or obesity. Epidemiologic studies have assessed associations between exposure to PFAS and anthropometric outcomes because some PFAS may activate peroxisome proliferator-activated receptor (PPAR) gamma, which promotes adipogenesis (Liu et al., 2018; Takacs and Abbott, 2007). Sex differences in obesity, coupled with differences in exposures within certain subpopulations, may place certain groups at increased risk of overweight and obesity (Fenton et al., 2021; Mitro et al., 2020b; Starling et al., 2019). In addition, exposure during certain periods of growth and development may have short- and long-term consequences for overweight and obesity among children and adolescents, with later-life health consequences (Araújo and Ramos, 2017; Fenton et al., 2021; Gross et al., 2020; Hruby and Hu, 2015; Yeung et al., 2019). Co-exposures to psychosocial factors and other chemicals that also promote fat cell development may work synergistically with PFAS chemicals to impact fat growth and development, with impacts on body weight and growth measures (Araújo and Ramos, 2017; Braun et al., 2021; Chen et al., 2019; Fenton et al., 2021; Jensen et al., 2020a; Liu et al., 2018, 2020; Mitro et al., 2020b; Rahman et al., 2019; Romano et al., 2021; Shoaff et al., 2018; Starling et al., 2019, 2020).

The committee identified several studies that evaluated the impact of exposure to PFAS on obesity, four being rated as having a definitely low risk of bias (Braun et al., 2021; Chen et al., 2019; Mitro et al., 2020a,b; Shoaff et al., 2018). These four studies varied greatly in the ages of the populations assessed. Two of the studies used data from the Health Outcomes and Measures of the Environment (HOME) study cohort (Braun et al., 2021; Shoaff et al., 2018), and one was a study of children in Shanghai, China (Chen et al., 2019). The fourth investigated the impact of PFAS exposure on adiposity among postpartum women (Mitro et al., 2020b). The study by Braun and colleagues (2020) (which largely updates Shoaff et al., 2018)—assessed exposure to PFAS (PFOA, PFOS, and PFHxS) at 16 weeks’ gestation and delivery, and measured weight and length or height and calculated child BMI at several time points across the life course (4 weeks to 12 years). The authors observed some suggestive evidence of an impact on BMI trajectory (age × PFOA interaction p value = 0.03) for PFOA, but not for PFOS and PFHxS. The study in Shanghai, China, was a prospective birth cohort study that measured 10 PFAS in cord blood plasma and assessed child adiposity measures at 5 years of age. The authors observed no association for the PFAS considered in this review, but did observe that, among girls, perfluorobutane sulfonic acid (PFBS) exposure had a significant positive association with waist circumference and waist-to-height ratio (p values <0.05). Mitro and colleagues (2020b) observed that PFOS and PFOA were associated with greater adiposity at 3 years’ postpartum. The heterogeneity of the effects found across studies is the reason the committee concluded that the evidence for an association between PFAS exposure and elevated BMI or obesity is inadequate or insufficient in adults and children, although this is an area worthy of future study.

Developmental Outcomes

The committee’s evaluation of the impact of PFAS on developmental outcomes considered evidence relevant to fetal growth, development of genitalia, and neurodevelopment. The committee concluded that there is sufficient evidence of an association between PFAS exposure and reductions in birthweight. This conclusion builds on those of the authoritative reviews (including ATSDR, EFSA, and OECD). ATSDR concluded that the evidence is suggestive of association between serum PFOA and PFOS and small decreases in birthweight. The committee concluded that there is insufficient evidence of an association between PFAS exposure and either development of the external genitalia or neurodevelopmental outcomes.

Birthweight

The committee identified numerous studies with low or probably low risk of bias that examined the relationship between exposure to PFAS and birthweight (Buck Louis et al., 2018; Chu et al., 2020; Gao et al., 2019; Kashino et al., 2020; Marks et al., 2019; Wikstrom et al., 2020; Workman et al., 2019). The magnitude and precision of the estimates of the impacts of PFAS exposure on birthweight varied across and within studies, but the direction of the effect was consistent. None of the studies found a statistically significant effect of PFAS exposure on an increase in birthweight. Table 3-3 presents the estimated impact of PFAS on birthweight from the two studies reviewed by the committee that were rated as having low risk of bias. Overall, these studies strengthened conclusions and supported the committee’s assessment that there is sufficient evidence of an association of PFAS exposure with small reductions in birthweight.

TABLE 3-3

Effect Estimates Change in Birthweight Per Change in PFAS, from Studies Rated as Having Low Risk of Bias.

Development of Genitalia

Authoritative reviews have yet to associate PFAS exposure with the development of genitalia, a possible indicator of reproductive disorders (Bonde et al., 2016). The committee identified one study that evaluated PFAS exposure and hypospadias and cryptorchidism, potential manifestations of testicular dysgenesis syndrome at birth (Anand-Ivell et al., 2018). Two studies (Arbuckle et al., 2020; Tian et al., 2019) evaluated PFAS and measures of anogenital distance (distance from the anus to the penis or scrotum in males or to the clitoris in females).

Anand-Ivell and colleagues (2018) conducted a case-control study within a large national biobank of amniotic fluid samples, which was rated as having a probably high risk of bias due to the high potential for confounding. The study found no influence of PFOS on cryptorchid or hypospadias (comparison of mean PFOS in amniotic fluid: control versus cryptorchid versus hypospadias). Arbuckle and colleagues (2020) conducted a cohort study with probably low risk of bias and reported inconsistent findings regarding PFAS and anogenital distance. Although the authors observed an association between PFOA (measured in first-trimester maternal plasma) and increased anoscrotal distance (adjusted for active smoking status during pregnancy and gestational age), when they examined the data by quartiles, they found no consistent patterns of association, and the effect estimates were imprecise with wide confidence intervals. Tian and colleagues (2019) conducted a cohort study with probably low risk of bias to evaluate the impacts of a PFAS on anogenital distance measures. They observed that maternal plasma concentrations (ln-transformed) of PFOS, PFDA, and PFUnDA were inversely associated with anoscrotal distance and anopenile distance measures at birth. For anoscrotal distance, they found per ln unit increase in PFAS concentrations −0.65 (−1.27 to −0.02) mm for PFOS; −0.58 (−1.11 to −0.06) mm for PFDA; and −0.57 (−1.09 to −0.06) mm for PFUnDA. For anopenile distance, they found per ln unit increase in PFAS concentrations −0.63 (−1.24 to −0.01) mm for PFDA and −0.76 (−1.36 to −0.16) mm for PFUnDA. The committee determined that, taken together, the evidence is inadequate or insufficient to determine an association between PFAS exposure and the development of external genitalia, largely because effects were inconsistent across studies.

Neurodevelopmental Effects

The committee divided the literature on neurodevelopmental effects of PFAS into studies of learning and behavior and of autism spectrum disorder.

Learning and behavior The committee identified 12 studies with low or possibly low risk of bias that examined learning and behavior using psychometrically valid tools to evaluate the impact of PFAS on neurodevelopment in children. The ages of the children varied greatly across studies, as did the timing of the exposure measurement used in the analysis, making it difficult to generalize the findings. For example, Hoyer and colleagues (2018) observed weak effects on child behavior of prenatal exposure to some PFAS. In analysis that combined results from birth cohorts in Greenland and Ukraine, the odds ratio (OR) for hyperactivity was 1.8 (CI: 1.0–3.2) for one nanoliter-unit (nL-unit) increase in prenatal PFNA and 1.7 (CI: 1.0–3.1) for one nL-unit increase in prenatal PFDA exposure. Using the Ages and Stages Questionnaire, Niu and colleagues (2019) found that prenatal plasma concentrations of most PFAS, including PFHxS, PFOS, PFOA, PFNA, and PFDA tended to be associated with an increased risk of developmental problems in personal/social skills, and the associations for PFNA and PFDA were significant (per nL-unit increase). The committee concluded that the evidence is inadequate or insufficient to determine an association of PFAS exposure with neurodevelopmental effects, largely because of the heterogeneity of both the effects measured and the results observed.

Autism spectrum disorder The committee identified four studies with low or probably low risk of bias evaluating the impacts of PFAS exposure on autism spectrum disorder (Long et al., 2019; Lyall et al., 2018; Oh et al., 2021; Shin et al., 2020). Lyall and colleagues (2018) conducted a population-based, nested case-control study of children born from 2000 to 2003 in southern California and did not observe an association between exposure to PFAS and autism. Long and colleagues (2019) conducted a case-control study that compared exposure to PFAS in amniotic fluid between cases and controls, and observed a negative association between PFAS in amniotic fluid and autism spectrum disorder diagnosis (OR: 0.410; 95% CI: 0.174–0.967). Shin and colleagues (2020) conducted a case-control study of autism spectrum disorder and observed that PFHxS and PFOS were borderline associated with increased odds of child diagnosis of autism spectrum disorder (per ng/mL increase: OR = 1.46; 95% CI: 0.98–2.18 for PFHxS, OR = 1.03; 95% CI: 0.99–1.08 for PFOS). Oh and colleagues (2021) conducted an analysis of the impacts of PFAS exposure on the risk of developing autism spectrum disorder and found that increased PFOA exposures were associated with negative trend Early Learning Composite scores and all four subscales. When they compared trajectories of the scores between low- and high-scoring groups, PFOA was associated with having lower or decreasing Early Learning Composite scores (risk ratio [RR] = 1.49; 95% CI: 1.09–2.03). The committee determined that the evidence is inadequate or insufficient to determine an association between exposure to PFAS and neurodevelopment, largely because effects were inconsistent across studies.

Cancers

Authoritative reviews have considered the carcinogenic potential of PFAS, and IARC has classified PFOA as possibly carcinogenic to humans (Benbrahim-Tallaa et al., 2014). The committee concluded that there is sufficient evidence for an association between PFAS and kidney cancer. This conclusion builds on those of the authoritative reviews (C-8 Science Panel, EPA, ATSDR), which concluded that the evidence for an association between PFAS and cancer in humans is limited, and takes into account robust findings from more recent epidemiological studies. The committee concluded that there is limited or suggestive evidence for cancers of the testis and breast. The conclusion on testicular cancer is consistent with the authoritative reviews, and the finding on breast cancer is based on the more recent epidemiological studies considered by the committee. The committee found that the existing body of literature on other cancers constituted inadequate or insufficient evidence to determine an association with PFAS.

Kidney Cancer

The committee’s assessment that there is sufficient evidence of an association between PFAS exposure and kidney cancer was motivated in large part by the study with low risk of bias conducted by Shearer and colleagues (2021). These investigators conducted a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial with a large sample size, appropriate controls, and validated endpoints (renal cell carcinoma diagnosis [C64.9 in the International Classification of Diseases for Oncology, Second Edition]). The statistical analyses conducted by the authors were robust and adjusted for relevant confounders, and sensitivity analysis was performed to assess whether effects were still observed regardless of kidney function. The study clearly showed that ORs for kidney cancer were significantly elevated among individuals in the highest PFOA exposure category, with a strong exposure-response trend. This study and earlier studies (Barry et al., 2013; Vieira et al., 2013) demonstrating a consistency in the direction and magnitude of this effect among those with the highest exposure form a body of literature that the committee concluded constitutes sufficient evidence of an association. Effect estimates for associations between PFOA exposure and kidney cancer are summarized by study in Figure 3-8.

Figure 3-8

Kidney cancer adjusted rate ratios and 95% confidence intervals by study and PFOA exposure category. DATA SOURCES: Barry et al., 2013; Raleigh et al., 2014; Shearer et al., 2021; Steenland and Woskie, 2012; Vieira et al., 2013.

Testicular Cancer

The committee’s conclusion of limited or suggestive evidence of an association between PFAS exposure and testicular cancer is consistent with the conclusions of the authoritative reviews. ATSDR does not draw a clear conclusion with respect to PFAS and testicular cancer, but the C-8 Science Panel identified a probable link with incident testicular cancer based on evidence from studies by Barry and colleagues (2013) and Vieira and colleagues (2013). These two studies were also included in the EPA review (2016), which noted the positive associations they found with PFOA and their overlap in cases. IARC (2016) stated that the evidence for an association with testicular cancer was credible and unlikely to be explained by bias and confounding, but limited by small sample numbers. EFSA (2020) found that there was insufficient support for the carcinogenicity of PFOA and PFOS in humans. Given a lack of new studies on this association, the committee found the existing evidence to be supportive of a conclusion of limited or suggestive evidence of an association between PFAS exposure and testicular cancer (see Figure 3-9).

Figure 3-9

Testicular cancer adjusted rate ratios and 95% confidence intervals by study and PFOA exposure category. DATA SOURCES: Barry et al., 2013; Vieira et al., 2013.

Breast Cancer

ATSDR did not draw a clear conclusion with respect to PFAS and breast cancer. Studies included in the ATSDR review found inconsistent associations, with Bonefeld-Jørgensen and colleagues (2014) finding an inverse association with PFHxS and null association for PFOS and PFNA, while Wielsøe and colleagues (2017) found positive associations with all these chemicals. Wielsøe and colleagues (2017) also found positive associations between PFDA, PFUnDA, and PFHpA (not statistically significant), and no association for PFDoDA. Bonefeld-Jorgensen and colleagues (2014) found a positive association with FOSA. IARC (2016) also reviewed the null study of Bonefeld-Jorgensen and colleagues (2014), as did EPA (2016), which stated that no associations were found in the general community. Recent studies, however, found more associations suggestive of a relationship between PFAS and breast cancer. A nested case-control study with low risk of bias found an association between estrogen receptor–positive breast cancer and PFOS (Mancini et al., 2020). An additional study with probably low risk of bias found no evidence of associations between PFAS and breast cancer (Cohn et al., 2020). Two additional recent studies had high risk of bias because the exposure was measured after the cancer diagnosis had been made (Hurley et al., 2018; Tsai et al., 2020). Hurley and colleagues (2018) found no evidence of associations between PFAS exposure and breast cancer, whereas Tsai and colleagues (2020) found evidence of associations among women aged ≤50. Those associations were stronger among women with estrogen receptor–positive tumors. Figure 3-10 summarizes the effect estimates for associations between PFOS exposure and breast cancer by study. The committee found that this body of literature constitutes limited or suggestive evidence of an association of PFAS exposure with breast cancer.

Figure 3-10

Breast cancer adjusted rate ratios and 95% confidence intervals by study and PFOS exposure category. NOTE: ER = estrogen receptor; PR = progesterone receptor. DATA SOURCES: Bonefeld-Jorgensen et al., 2011; Cohn et al., 2020; Hurley et al., 2018; Mancini (more...)

Reproductive Outcomes

In its review of reproductive outcomes, the committee considered evidence on hypertensive disorders of pregnancy, female reproductive effects, reproductive hormone levels, infertility and subfecundity, and gestational diabetes. The committee concluded that there is limited or suggestive evidence of an association between PFAS exposure and hypertensive disorders of pregnancy, preeclampsia, and gestational hypertension without preeclampsia. This conclusion is consistent with that of the C-8 Science Panel and subsequent authoritative reviews by ATSDR, EPA, and OECD. Consistent with ATSDR, the committee concluded that there is insufficient evidence of an association between PFAS exposure and other reproductive outcomes.

Hypertensive Disorders of Pregnancy (Gestational Hypertension and Preeclampsia)

The committee identified five recent studies examining PFAS exposure and preeclampsia, all having probably low risk of bias (see Figures 3-11–3-15). The four cohort studies (Birukov et al., 2021; Borghese et al., 2020; Huang et al., 2019; Wikstrom et al., 2019) supported the conclusions from the authoritative reviews. Wikstrom and colleagues (2019) observed modestly elevated risk for preeclampsia, but not necessarily a consistent exposure-response trend, and Borghese and colleagues (2020) observed no association with gestational hypertension without preeclampsia. Birukov and colleagues (2021) evaluated exposure to PFAS in early pregnancy and maternal blood pressure trajectories in pregnancy, gestational hypertension, and preeclampsia. No clear associations were observed with gestational hypertension (de novo blood pressure >140/90 mm Hg after 20 weeks’ gestation on two or more episodes with at least 4 h in between or significant aggravation of preexisting hypertension) or preeclampsia (gestational hypertension with proteinuria [>0.3 g/24 h or at least +1 on sterile urine dipstick]). Birukov and colleagues (2021) did observe modest but not statistically significant increases in blood pressure for PFOS and PFOA. Another cohort study measuring PFAS in cord blood found an association with preeclampsia but not gestational hypertension (Huang et al., 2019). A case-control study of preeclampsia and PFAS measured in maternal serum categorized PFAS into quartiles; the women in the highest quartiles had no significant increased risks of developing preeclampsia compared with the women in the lowest quartile in adjusted analyses (Rylander et al., 2020). Given that the studies showed a tendency toward an association between PFAS and hypertensive disorders of pregnancy, the committee concluded that there is limited or suggestive evidence of an association.

Figure 3-11

Adjusted risk estimates for preeclampsia, gestational hypertension (hypertension without preeclampsia), and hypertensive disorders of pregnancy and 95% confidence intervals by study and PFOS exposure category. NOTE: All studies present odds ratios except (more...)

Figure 3-15

Adjusted risk estimates for preeclampsia, gestational hypertension (hypertension without preeclampsia), and hypertensive disorders of pregnancy and 95% confidence intervals by study and PFNA exposure category. NOTE: All studies present odds ratios except (more...)

Fertility and Fecundity

A conclusion in ATSDR’s Toxicological Profile for Perfluoroalkyls is that “epidemiological studies provided mixed evidence of impaired fertility (increased risks of longer time to pregnancy and infertility) for PFOA, PFOS, PFHxS PFNA, PFHpA, and PFBS: the results are not consistent across studies or were only based on a single study. The small number of studies evaluating fertility for PFDA, PFUnDA, PFDoDA, and FOSA did not find associations and no study has evaluated reproductive outcomes and PFBA” (ATSDR, 2021, p. 359). The committee identified a few more recent studies to update that authoritative review.

Figure 3-12

Adjusted risk estimates for preeclampsia, gestational hypertension (hypertension without preeclampsia), and hypertensive disorders of pregnancy and 95% confidence intervals by study and PFOA exposure category. NOTE: All studies present odds ratios except (more...)

Figure 3-13

Adjusted risk estimates for preeclampsia, gestational hypertension (hypertension without preeclampsia), and hypertensive disorders of pregnancy and 95% confidence intervals by study and PFuDA and PFDA exposure category. NOTE: All studies present odds (more...)

Zhang and colleagues (2018) conducted a case-control study to evaluate the impact of PFAS on risks of premature ovarian insufficiency, and observed positive associations with PFOA, PFOS, and PFHxS (highest versus lowest tertile, PFOA: OR, 3.80; 95% CI: 1.92–7.49; PFOS: OR, 2.81; 95% CI: 1.46–5.41; PFHxS: OR, 6.63; 95% CI: 3.22–13.65). The study was rated as having high risk of bias for a potential for reverse causality (Zhang et al., 2018). Ma and colleagues (2021) conducted a small cohort study in a fertility clinic in Zhejiang, China, that evaluated the association between PFAS exposure and fertility measures (numbers of retrieved oocytes, mature oocytes, two-pronuclei (2 PN) zygotes, good-quality embryos, and semen parameters). The authors found that maternal plasma concentrations of PFOA were negatively associated with the numbers of retrieved oocytes (p-trend 0.023), mature oocytes (p-trend 0.015), 2 PN zygotes (p-trend 0.014), and good-quality embryos (p-trend 0.012). Higher paternal plasma PFOA concentrations were found to be significantly associated with reduced numbers of 2 PN zygotes (p-trend 0.047), but no associations were found between maternal or paternal PFAS levels and the probability of implantation, clinical pregnancy, or live birth. Given the mixed evidence, the committee concluded that there is insufficient evidence of an association between PFAS exposure and fertility or fecundity.

Figure 3-14

Adjusted risk estimates for preeclampsia, gestational hypertension (hypertension without preeclampsia), and hypertensive disorders of pregnancy and 95% confidence intervals by study and PFHxS exposure category. NOTE: All studies present odds ratios except (more...)

Male Reproductive Effects

For its authoritative review, ATSDR looked at articles examining the relationship between PFAS and sperm quality and concluded that while some associations with serum perfluoroalkyl levels were observed for some markers of sperm quality, the markers measured were not consistent across studies. The committee identified only one new study evaluating the effect on PFAS on male reproduction (Ma et al., 2021 ). This study found no significant association between PFAS and sperm progressive motility rate, but did find associations of some PFAS with decreased sperm concentration. Given that this study has some potential for bias, the committee concluded that the evidence is inadequate or insufficient to determine an association.

Female Reproductive Effects

Female reproductive effects discussed here include menopause, age at menarche, and duration of breastfeeding. The authoritative reviews did not find associations for other female reproductive outcomes (polycystic ovary syndrome, endometriosis), and the committee identified no new studies of these effects.

In its Toxicological Profile for Perfluoroalkyls, ATSDR concludes that there is some suggestive evidence of an association between serum PFAS levels and an increased risk of early menopause; however, this finding may be due to reverse causation since an earlier onset of menopause would result in a decrease in the removal of perfluoroalkyls in menstrual blood. One more recent cohort study (Ding et al., 2020), with low risk of bias, found an association of PFAS with earlier onset of menopause. Mixed results were observed in a study of age at menarche (Ernst et al., 2019) and a study of cycle irregularity (Singer et al., 2018) (rated as probably having and having low risk of bias, respectively).

ATDSR’s Toxicological Profile does not offer conclusions on the impact of PFAS exposure on duration of breastfeeding. The committee identified one more recent study, with probably low risk of bias, that observed mostly null associations but also a decreased hazard of breastfeeding cessation by 3 and 6 months with increasing maternal serum concentrations of PFNA, PFDA, and PFUnDA during pregnancy (Rosen et al., 2018). The committee concluded that there is insufficient human evidence of an association of PFAS with female reproductive effects, including breastfeeding duration.

Reproductive Hormone Levels

ATSDR’s Toxicology Profile reviews the literature on associations between PFAS concentrations and reproductive hormones. The conclusion of this review is that while some studies examining reproductive hormone levels have observed associations with PFAS, the findings are inconsistent across studies, and there are too few studies to enable interpretation of the results.

The committee found several more recent studies evaluating the relationship between PFAS and reproductive hormone levels, but these studies varied in the populations they included and the hormones measured, among other factors, making it difficult to synthesize the evidence. For example, three studies evaluated the impact of PFAS on estradiol levels (Ma et al., 2021; Yao et al., 2019; Zhang et al., 2018). The study by Ma and colleagues (2021) was conducted among couples visiting a fertility clinic in China; the study by Zhang and colleagues (2018) was a case-control study of adult women in China; and Yao and colleagues (2019) analyzed PFAS and hormone levels in infant cord blood. The studies that measured testosterone were also distinct; two were analyses of data from birth cohorts (Jensen et al., 2020b; Nian et al., 2020); two were studies in pregnant women (Anand-Ivell et al., 2018; Yao et al., 2019); and two were studies in Chinese adults (Ma et al., 2021; Zhang et al., 2018). The committee concluded that the evidence is too heterogeneous to support drawing conclusions and therefore inadequate or insufficient to determine an association.

Gestational Diabetes

ATSDR’s Toxicology Profile reviews the evidence for an association between PFAS and gestational diabetes and concludes that the results of the studies reviewed do not suggest an association. The committee identified four more recent studies evaluating the impact of PFAS on gestational diabetes. These studies had varying designs, including case-control, cohort, and nested case-control (Preston et al., 2020a; Rahman et al., 2019; Wang et al., 2018; Xu et al., 2020a) and had somewhat inconsistent results. Xu and colleagues (2020a) and Rahman and colleagues (2019) observed an effect on gestational diabetes, whereas Preston and colleagues (2020a) and Wang and colleagues (2018) observed an effect on glucose homeostasis. Given the inconsistent effects reported, the committee concluded the evidence is inadequate or insufficient to determine an association.

EVIDENCE GAPS

The committee found several conditions to be associated with exposure to PFAS. The effects of PFAS span many different organ systems and disease states. The human populations most at risk of these health effects include those with a family history of or other risk factors for associated health effects and those who are in vulnerable life stages, including pregnancy, fetal development or early childhood, and the elderly. The committee did not complete a meta-analysis of the impact of each individual PFAS on each health outcome or provide an overall estimate of risk because the data from the studies are highly heterogeneous, limiting the applicability of meta-analytic techniques. The committee also observed gaps in the evidence for many health effects, whereby the evidence was inadequate or insufficient to determine associations. These gaps include

• immune effects other than reduced antibody response, and ulcerative colitis;
• cardiovascular outcomes other than dyslipidemia;
• developmental outcomes other than small reductions in birthweight;
• cancers other than kidney, breast, and testicular;
• reproductive effects other than hypertensive disorders of pregnancy;
• endocrine disorders other than thyroid hormone levels;
• hepatic effects other than liver enzyme levels;
• respiratory effects;
• hematological effects;
• musculoskeletal effects, such as effects on bone mineral density;
• renal effects, such as renal disease; and
• neurological effects.

It is critical to recognize that an assessment of inadequate or insufficient evidence does not mean there is no significant and important association between PFAS exposure and the outcome under consideration. It is quite possible that further research into the association of PFAS exposure with these outcomes would provide the evidence necessary to change the assessment to the category of either limited or suggestive or sufficient evidence. The committee believes that ongoing research on and review of these associations will be important in updating its clinical recommendations. A gap also remains in determining which developmental effects are the most clinically meaningful. For some outcome categories, the available research spans many different tests, all of which assessed slightly different effects, making the evidence difficult to synthesize and support strong conclusions. An authoritative organization needs to determine which endpoints are the most critical to evaluate to support clinical follow-up recommendations.

Additionally, most studies reviewed by the committee were not conducted among people known to have high exposures to PFAS. As a result, there is a gap in understanding of the effects of PFAS among those highly exposed, and the evidence presented in this report may therefore underestimate the effects of PFAS.

Although the committee aimed to assess the available scientific evidence as carefully and systematically as possible, it was sensitive to the fact that value judgments are unavoidable when performing an assessment of this kind (Elliott, 2017; Elliott and Richards, 2017; Jasanoff, 1998). These judgments include decisions about what forms of evidence to include, how to weigh and categorize different pieces of evidence, and what standards of evidence to demand before drawing conclusions. Literature from the sociology of science and medicine emphasizes not only that different expert communities may disagree about how to make these decisions (Cetina, 1999) but also that lay communities may make these decisions in ways that differ from those of expert communities (Epstein, 1996; Ottinger, 2010; Suryanarayanan and Kleinman, 2016). For example, because lay communities are often particularly concerned about addressing urgent health issues or informing time-sensitive policy decisions, they may accept lower standards of evidence than experts typically do (Brown, 1992). These differing evidential approaches across different communities raise the potential for differing rates of positive and negative errors (Douglas, 2009; Elliott, 2017; Elliott and Richards, 2017). Different communities also have varying background disease risk, which may lead to differing associations with PFAS and differing needs for risk assessment as it relates to these associations.

With these observations in mind, the committee acknowledges that other expert and lay communities might draw different conclusions about PFAS health risks, either by including different lines of evidence or by making alternative judgments when assessing the available evidence. This is one of the reasons that the committee emphasizes the importance of patient autonomy and shared decision making in subsequent chapters. Although the committee’s evaluation of the evidence can provide an important starting point for decision making by clinicians and their patients, some individuals and groups could employ different evidential standards. Therefore, the committee encourages ongoing efforts to make scientific information about PFAS publicly available and understandable so that patients and clinicians can make informed decisions that respect individual patient values.

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