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Perfluorinated Compounds (PFCs)


PFCs and diabetes/obesity

Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) have been used in the manufacturing of Teflon, Gore-Tex, and Scotchguard. They are perfluorinated compound (PFCs), also known as perfluoroalkyl substances (PFAS). Low levels of exposure are ubiquitous in the blood of essentially all residents of industrialized countries, via food, drinking water, house dust, and air (Steenland et al. 2013).

While initially assumed to be inert and non-toxic, these substances are now thought to have the ability to affect the immune system (and carcinogenicity) at exposure levels found in the general population. Existing drinking water limits may be 100-fold too high (Grandjean and Clapp 2015).

Type 1 diabetes

A small study from Italy found that PFOS levels were higher in children and adolescents with new-onset type 1 diabetes than in controls without diabetes. PFOA levels were not associated (Predieri et al. 2015). A study from Denmark found that PFOA levels in childhood were associated with lower beta cell function in adolescence (Domazet et al. 2016).

In an area with high PFC exposure levels (see Mid-Ohio Valley Studies section below), a study of community members looked for autoimmune diseases, including type 1 diabetes. They did find an association between the autoimmune disease ulcerative colitis, but not type 1 diabetes (Steenland et al. 2013). A furthers study also found no increased risk of type 1 diabetes with PFC exposure-- in fact there was a decreased risk (Conway et al. 2016). PFCs are potentially immunotoxic, which could favor the development of autoimmune diseases (or suppress the immune system) (Corsini et al. 2014).

A report on immunotoxicity of PFOA and PFOS by the National Toxicology Program (NTP) finds that, "PFOA is presumed to be an immune hazard to humans based on a high level of evidence that PFOA suppressed the antibody response from animal studies and a moderate level of evidence from studies in humans. Although the strongest evidence for an effect of PFOA on the immune system is for suppression of the antibody response, there is additional, although weaker, evidence that is primarily from epidemiological studies that PFOA reduced infectious disease resistance, increased hypersensitivity-related outcomes, and increased autoimmune disease incidence" (NTP 2016). The report also finds that PFOS "is presumed to be an immune hazard to humans."

Type 2 diabetes and body weight

Lower exposures in humans

A cross-sectional study of Danish children found that in overweight children, higher PFC levels were associated with higher insulin levels, higher beta cell activity, higher insulin resistance, and higher triglycerides. There was no association between these and PFCs in normal-weight children (Timmermann et al. 2014).

A cross-sectional study of elderly Swedes found that the PFCs perfluorononanoic acid (PFNA) and PFOA were significantly related to diabetes in a non-linear manner. PFOA was also related to insulin secretion, but none of the PFCs were associated with insulin resistance. The exposures encountered in this study were typical of the general population (Lind et al. 2014).

A cross-sectional study of Canadian adults found associations between some PFCs and cholesterol levels, but not glucose levels or metabolic syndrome (Fisher et al. 2013). And, a cross-sectional study of Americans also found associations between some PFCs and cholesterol levels, but not insulin resistance or body size (Nelson et al. 2010). (It seems like associations between PFCs and higher cholesterol levels are pretty consistent across studies, especially in studies of more highly exposed people, but also among less exposed, e.g., Eriksen et al. 2013). Despite using in part some of the same dataset as Nelson et al., (NHANES), Lin et al. (2009) found links between PFCs and various measures of blood glucose in Americans. For example, they found that in adolescents, higher PFNA levels were associated with higher blood sugar levels and cholesterol levels. In adults, higher PFNA levels were associated with higher beta cell function, and higher PFOS levels were associated with higher insulin levels, higher beta cell function, and insulin resistance.

A study of working-aged Taiwanese adults found that those with higher PFOS levels had a higher risk of impaired glucose homeostasis and diabetes. However, those with PFOA, PFNA, and PFUA had a lower risk (Su et al. 2015).

A trial of elderly adults from Korea found that while PFC levels were associated with insulin resistance, supplementation with vitamin C reversed these effects (Kim et al. 2015).
Factsheet on PFCs from the National Institute of Environmental Health Sciences (NIEHS)

Exposures during development

Evidence is growing that exposure to pollution during critical developmental periods, such as in utero or during childhood, may have effects later in life.

In a study from Denmark, in utero exposure to PFOA was associated with higher weight, overweight/obesity, higher waist circumference, and higher insulin levels in female offspring at age 20 (with similar results in males but fewer data points). Other PFCs, including PFOS and PFNA did not show any associations (Halldorsson et al. 2012).

In British girls, exposure to PFOS in the womb is associated with lower birth weight, but then higher weight at age 20 months (Maisonet et al. 2012). Other studies have also found associations between PFCs and birth weight as well (Apelberg et al. 2007; de Cock et al. 2015Fei et al. 2007; Lenters et al. 2015Washino et al. 2009). Further study of the British girls at age 9 found that prenatal PFOA and PFOS levels were associated with percent body fat in different ways, depending on the mother's level of education. PFHxS and PFNA were not associated (Hartman et al. 2017).

A Danish study, however, did not find an association between PFOA or PFOS levels in mothers during pregnancy, and body mass index, waist circumference, or risk of overweight in their children at 7 years of age (if anything, the more highly exposed children were thinner than the others, although the difference was not statistically significant) (Andersen et al. 2013). These same authors had also found that maternal PFC levels were associated with lower body weight in the first year of life (Andersen et al. 2010). A different study from Denmark found that childhood levels of PFOS was associated with higher waist circumference at ages 15 and 21. PFOA levels in childhood were associated with lower beta cell function in adolescence (Domazet et al. 2016).

A study from Boston found that PFC levels in mothers were not associated with metabolic changes in children, although children with higher PFAS levels had lower insulin resistance (Fleisch et al. 2016). However, another study of the same cohort by the same authors found that maternal PFAS levels were associated with small increases in weight-related measurements in girls in mid-childhood (Mora et al. 2016).

A study from Greenland and the Ukraine found that neither PFOA nor PFOS levels in mothers during pregnancy were associated with their children being overweight at ages 5-9. However, the children did have higher waist-to-height ratios (Høyer et al. 2015). A study from the Faroe Islands found that maternal PFOS and PFOA (but not PFHxS, PFNA or PFDA) levels after childbirth were associated with higher BMI in the offspring at 18 months and 5 years of age (Karlsen et al. 2016).

A Japanese study found that PFOS levels were associated with reduced fatty acid levels in pregnant women. These polyunsaturated fatty acids are essential for fetal growth. The female babies also had a lower birth weight if exposed to higher levels of PFOS (these associations were not found with PFOA or in male babies) (Kishi et al. 2015). A Taiwanese study also found that PFC levels were associated with lower birth weight in girls. Levels were not associated with weight through age 11 in either sex, but were associated with lower height (Wang et al. 2016). A Canadian study found that maternal PFOA levels were associated with a lower birth weight (Ashley-Martin et al. 2017/Ashley-Martin et al. 2017).

Mid-Ohio Valley studies: High exposures in humans

An area of the Mid-Ohio Valley has been contaminated by high levels of PFOA. Research suggests an increased risk of mortality due to type 2 diabetes in workers occupationally exposed to PFOA, as compared to other DuPont workers (Steenland and Woskie, 2012). Previous research suggest an association between diabetes and PFOA exposure in workers as well (Lundin et al. 2009). Workers in the Mid-Ohio Valley were exposed to PFOA in a chemical plant that produced Teflon. Emissions from this plant polluted the drinking water of the nearby community. Recent studies of these community members have looked for diabetes risk, as well as other health issues. These studies are known as the C8 Health Project (C8 is another term for PFOA) (see Frisbee et al. 2009 for a description of study design).

A cross-sectional study of the exposed Mid-Ohio Valley community members did not find an association between PFOA and type 2 diabetes or fasting glucose levels (MacNeil et al. 2009), nor did a long-term study of this population (Karnes et al. 2014). A more detailed study found that those with diabetes (especially type 1) had lower levels of PFCs than those without diabetes (Conway et al. 2016). Early-life PFOA levels were not associated with obesity or overweight in adulthood (Barry et al. 2014). However they did find associations between PFOA levels and high cholesterol (Winquist and Steenland 2014). For an article describing this findins, see PFOA and High Cholesterol: Basis for the Finding of a Probable Link, published in Environmental Health Perspectives (Betts 2014).

A long-term study from Cincinnati looked at associations in the offspring of women living downstream from a PFC manufacturing plant. They found that higher maternal PFOA levels were associated with higher weight and waist circumference in their children, as well as greater BMI gains from ages 2-8 (Braun et al. 2015). 

Gestational diabetes

Preconception levels of PFOA were associated with gestational diabetes in a prospective U.S. study of women with background levels of PFC exposure. Six other PFCs were also associated with an increased risk, although not statistically significant (Zhang et al. 2014). In Canadian women, first-trimester levels of most PFCs were not associated with gestational diabetes. However, a Canadian study found a higher risk of impaired glucose tolerance during pregnancy in women with moderate (second-quartile) levels of perfluorohexane sulfonate (PFHxS) (Shapiro et al. 2016). The Canadian women with higher PFOS levels also had higher gestational weight gain (Ashley-Martin et al. 2016).

The Madrid Statement

In 2015, fourteen experts published the Madrid Statement on Poly- and Perfluoroalkyl Substances (PFASs), subsequently signed by 206 scientists and professionals from 40 countries (Blum et al. 2015; Birnbaum and Grandjean 2015). 

The Statement documents the scientific consensus about the environmental persistence, bioaccumulation, and potential toxicity of these substances.

Laboratory studies

Adult male rats exposed to PFNA experienced high blood sugar by increasing the release of glucose from the liver (Fang et al. 2012).

PFOA exposure reduced the production of glycogen in the liver of mice, and actually increased insulin sensitivity and glucose tolerance. While these effects may appear to be beneficial, the mechanism by which they occurred may have harmful effects in the long run-- several protein levels were also affected, and these proteins are potentially involved in diabetes and liver disease (Yan et al. 2015).

Mice fed high doses of PFCs show reduced body weight and lower fat mass, via reduced food intake (Shabalina et al. 2015). (While high doses of some chemicals can cause lower weight, it may be that lower doses have opposite effects).

PFOS causes changes in the liver and the intestine in zebrafish, an animal model used to study the effects of toxic chemical exposures (Cui et al. 2016).

Cell culture studies

Laboratory studies show that PFCs may have effects on the immune system that are consistent with autoimmune diseases. Human cells exposed to PFOS had these effects at exposures at the high end of human exposure range (Midgett et al. 2014).

PFOA increases the development of fat cells, which then accumulate triglycerides (Yamamoto et al. 2014). PFOS also increases fat cell development, and fat accumulation as well (Xu et al. 2016).

PFOS essentially causes insulin resistance in cells; scientists are working to identify the exact mechanisms involved (Qui et al. 2016).

Exposures during development

Pregnant/mother rats were exposed to PFOS, to see the effects on the offspring (exposed in the womb and while nursing). The offspring had low body weight from birth to weaning, and had impaired glucose tolerance, and higher insulin levels, resembling pre-diabetes (Lv et al. 2013). A study of mice showed that when pregnant mice were exposed to low doses of PFOA, their offspring had metabolic effects that differed by sex (van Esterik et al. 2015). 

Mice exposed to low doses of PFOA in the womb had reduced body weight at birth followed by excess body weight at mid-life, as well as higher insulin levels at mid-life. There was no effect of PFOA on these parameters from exposure during adulthood, showing that developmental exposures may be most critical (Hines et al. 2009).

When mother mice were exposed to PFOS during pregnancy, they had higher insulin resistance than untreated controls, suggesting a gestational-diabetes-like pattern. Early in life, their male offspring had higher insulin levels, although the female offspring had normal levels. Later in life, as adults, both groups of offspring had higher fasting glucose and insulin levels than controls. The pups fed a high-fat diet showed even greater effects than those fed a normal diet (Wan et al. 2014).

PFOS exposure in the womb appears to affect oxidative stress more in the fetus than the pregnant mother, and this could affect fetal development (Lee et al. 2015).

PFOS exposure during development also affects the development of the pancreas in ways that may predispose to diabetes (Sant et al. 2016).

Diabetes complications

Some cross-sectional human studies show associations between PFCs and heart disease, but a longitudinal study from Sweden found no associations for seven of eight PFCs measured (Mattsson et al. 2015). Another study finds an association between PFC levels and reduced kidney function in healthy adolescents (Kataria et al. 2015).

I have not yet seen any studies of complications and PFCs in people with diabetes. However, a laboratory study exposed rats with (type 1) diabetes to PFCs and found that the exposure caused the accumulation of triglycerides and total cholesterol in the liver, not a good thing (Fang et al. 2015).

The bottom line

In a combined analysis of the human and animal evidence, "developmental exposure to PFOA adversely affects human health based on sufficient evidence of decreased fetal growth in both human and non-human mammalian species" (Lam et al. 2014). That is, there is evidence that PFOA exposure in the womb reduces the growth of the fetus. Whether there are other related effects later in life is not yet clear.

PFCs are only beginning to be studied in relation to diabetes. Results may vary by exposure level, timing of exposure, and other factors.

References

To download or see a list of all the references cited on this page, see the collection Perfluorinated compounds and diabetes/obesity in PubMed.