Synopsis by Dr. Abby Benninghoff and Wendy Hessler

Exposure through the skin to perfluorooctanoid acid (PFOA), a chemical commonly used to make fabric protectors, stain repellants and non-stick surfaces, increases the allergic response in mice when they are subsequently exposed to an allergen.

The results suggest one possible explanation for the rising incidence of asthma in children. Over the past 5 decades PFOA has become so widespread a contaminant that almost everyone tested has measurable amounts in their bodies. Indeed a recent study by scientists at Johns Hopkins University found that 100% of Baltimore newborns were contaminated by PFOA. The levels used in this experiment, however, were much higher than those commonly detected in people.

Context: PFOA. Containing the element fluorine, PFOA belongs to a family of chemicals called 'perfluorinated compounds,' or PFCs. PFCs are useful industrial chemicals due to their oil- and water-repelling chemical properties and have many commercial applications as: surfactants and surface protectors (e.g., Teflon™ by DuPont), paper and textile coatings, polishes, food packaging (e.g., microwave popcorn bags) and fire-retardant foams. PFOA is commonly used in and can be a byproduct of the manufacture of these commercial PFCs.

Researchers have become increasingly alarmed in the past decade, as numerous studies have shown that PFOA and related chemicals are found in nearly all Americans and commonly found in people from other nations. On average, levels of these chemicals in human blood are relatively low ranging from about 4 to 7 parts per billion (ppb) on average. PFOA can be absorbed rapidly by eating and drinking, breathing and touching. The half-life of PFOA in humans is estimated to be about 4 years, although in some laboratory animal models it is considerably less (hours to days).

Widespread PFC contamination of humans raises concerns about the potential harmful health effects of these chemicals. In particular, there is concern that children may be especially susceptible to PFC exposure, particularly due to their intimate contact with many surfaces treated with PFCs, such as chemically-treated stain-resistant carpet, clothes and food packaging.

The very persistant PFOAs can contribute to thyroid problems, immune changes and cancer (testicular, liver and pancreatic) in laboratory animals. People exposed to PFOA at work may be at higher risk for pancreas, testis and prostate cancers.

In early 2006, the eight PFOA manufacturers agreed to work to end emissions and take the chemical out of products by 2015. Even if intentional manufacturing is phased out, PFOAs will be around for a long time. The chemical is persistent - it does not break down; it is a byproduct of PFC manufacturing; and it is produced in animals and people during metabolism of PFCs.

What did they do? The authors compared three major immune responses in mice subjected to an allergen alone, the environmental chemical PFOA alone and the two together. They measured antibody response (immunoglobulin E or IgE) levels, airway hypersensitivity response, and lung and immune system tissue structure.

Mice were treated on the skin on the back of their ears with PFOA for 4 days then exposed to the foreign antigen ovalbumin or a control. The PFOA doses, ranging from 12.5 to 50 milligrams per kilogram (mg/kg), are comparable to those used in similar studies , but are considerably higher than those to which humans are likely exposed.

After the skin exposure, the researchers measured blood levels of the immunoglobulin IgE to assess the allergic response to ovalbumin. IgE triggers a more powerful immune reaction than other immunoglobulins involved in allergy and asthma responses. Both total IgE and ovalbumin-specific IgE were measured.

The airway hyperreactivity response was also measured to gauge how the lungs of PFOA-exposed mice responded to the allergen ovalbumin. Mice breathed an ovalbumin air mixture after being exposed to PFOA on their ears and injected twice with the allergen. Lung, spleen and thymus tissue samples were preserved and stained to identify any abnormal changes in response to the PFOA treatment.

What did they find? Skin exposure to PFOA induced the same toxicity markers observed in other rodent experiments with this chemical, including increased liver weight, decreased spleen and thymus weight and decreased numbers of cells in the spleen and thymus.

Results show that mice exposed to PFOA through the skin mount a stronger than normal allergic response to the foreign allergen (in this case the chicken egg protein ovalbumin). Both total and antigen-specific IgE levels were increased in ovalbumin-challenged animals exposed to PFOA compared to controls.

However, PFOA treatment alone, without the ovalbumin challenge, did not affect IgE blood levels. Similarly, the airway hyperreactivity response was also elevated in mice co-treated with ovalbumin and PFOA, whereas PFOA alone did not affect this response.

Interestingly, the IgE and airway hyperreactivity response to PFOA was not always dose-dependent, as the highest dose (50 mg/kg) was less effective or completely ineffective.

In mice exposed to ovalbumin alone, a typical inflammatory response in lung cells was observed. This normal response is characterized by moderate infiltration of the lung tissue with different types of inflammatory cells (macrophages, neutrophils, lymphocytes, etc.) and white blood cells of the immune system.

However, a more severe allergic response was noted in animals exposed to both PFOA and ovalbumin; many more of these inflammatory cells and white blood cells were found in the lung tissue. Tissue analysis further confirmed that co-treatment (PFOA and ovalbumin) altered lung cell shape compared to ovalbumin exposure alone. In PFOA-exposed lung tissue, airway secretory cells were enlarged and some cell death was observed.

What does it mean? In general, while PFOA alone was ineffective in altering any of the immune responses evaluated (IgE levels, airway hypersensitivity response and tissue structure), PFOA exposure exacerbated the allergic response to the antigen ovalbumin. In other words, PFOA could cause adverse health effects by intensifying the normal allergic responses to foreign particles.

Previous studies in mice have shown that dietary exposure to PFOA can lead to immune toxicity by decreasing the total number of spleen and thymus cells (Yang et al. 2000). Subsequently, these researchers observed that PFOA decreased blood levels of two immunoglobulins, IgM and IgG, important for the adaptive immune response. However, it was known until the current study whether the allergic response involved in asthma was affected by PFOA.

As stated by the authors, “the persistence of PFOA in the environment in combination with these findings suggest that exposure to PFOA, although not allergenic itself, may enhance an individual’s response to commonly encountered environmental allergens.”

However, the authors observed that in some cases, the enhanced immune response to co-treatment with ovalbumin and PFOA was diminished at the highest dose of PFOA tested. In other words, ever-increasing doses of PFOA exposure did not always lead to ever-increasing immune responses. This pattern is termed a “non-monotonic” dose response, a surprisingly common observation in toxicological and environmental science. The importance of this non-monotonic response to PFOA is unclear at this time. Further studies will be needed to address the question, why is the allergic/asthmatic response to high doses of PFOA different than the response to moderate or low PFOA levels?

Resources:

American Lung Association. 2006. Asthma and Children Fact Sheet.

Asthma and Allergy Foundation of America. 2005. What you should know about childhood asthma.

Burris JM, JL Lundberg, GW Olsen, C Simpson and J Mandel. 2002. Determination of serum half-lives of several fluorochemicals. 3M Medical Department, Interim Report #2.

Clark, NM, RW Brown, E Parker, TG Robins, DG Remick, Jr., MA Philbert, GJ Keeler and BA Israel. 1999. Childhood asthma. Environmental Health Perspectives. 107(Suppl 3):421-429.

Environmental Working Group. 2003. PFCs: a family of chemicals that contaminate the planet.

US EPA. 2006. 100 percent Participation and Commitment in EPA's PFOA Stewardship Program. Press release, March 2, 2006.

US EPA. 2007. Perfluorooctanoic Acid (PFOA).

Yang, Q, Y Xie, and JW Depierre. 2000. Effects of peroxisome proliferators on the thymus and spleen of mice. Clinical and Experimental Immunology 122: 219-226.

Yang, Q, M Abedi-Valugerdi, Y Xie, XY Zhao, G Moller, BD Nelson and JW DePierre. 2002. Potent suppression of the adaptive immune response in mice upon dietary exposure to the potent peroxisome proliferator, perfluorooctanoic acid. International Immunopharmacology. 2:389-397.