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Manufacturing

NORA Manufacturing Sector Strategic Goals

927ZJFV - Evaluation of Perfluoralkyl acids (PFAAs) immunotoxicity

Start Date: 10/1/2009
End Date: 9/30/2012

Principal Investigator (PI)
Name: Jennifer Franko
Organization: NIOSH
Sub-Unit: HELD
Funded By: NIOSH

Primary Goal Addressed
5.0

Secondary Goal Addressed
None


Attributed to Manufacturing
75%

Project Description

Short Summary

The purpose of this project is to evaluate the immunotoxic effects associated with PFAAs exposures. PFAAs are synthetic chemical substances whose unique chemical properties, such as high stabilities and extremely low surface tensions, lend them to be valuable in a wide range of consumer and industrial applications. Exposure to one specific PFAA, PFOA, although no longer used in manufacturing, but still persistent in the environment, has been shown in a murine model to be both immunosuppressive and to have a potential role in asthma and allergy. Studies investigating the mechanisms underlying the immune modulation mediated by exposure to PFOA are limited. Due to the potential health effects linked to PFOA exposure, replacement PFAAs are now being used in the manufacturing process. Little is known about what effects of these compounds will have on immune function. The overall goal of this project is to evaluate the immunotoxic effects associated with individual PFAAs that are still used in the manufacturing process, and to investigate the mechanism mediating the identified immunological alterations associated with PFOA exposure. This project should result in peer reviewed journal articles which will provide scientific data regarding the immunotoxic effect of PFAAs. The knowledge gained from this study will address specific NIOSH research goals for reducing respiratory disease and occupational skin disease and hazard identification of occupational chemicals/allergens.



Description

In animal models, PFOA and PFOS exposure has been linked to the development of cancer, physical developmental delays, endocrine disruption, neonatal mortality, and shown to impact both the body's hormone and immune systems. Specific alterations in immune function include: reduction of thymocyte and splenocyte numbers, alterations in T lymphocyte populations, and inhibition of T-cell-dependent IgM and IgG responses. In addition, although not allergenic itself, PFOA has been shown capable of augmenting OVA-induced IgE production and airway hyperreactivity (AHR). These results suggest that PFOA may alter or prime an immune response by skewing the Th1/Th2 balance. While the immunosuppressive effects of PFOA may increase susceptibility to cancer and infection, its adjuvant-like effects may increase the susceptibility to occupational asthma and allergic respiratory diseases.



We have previously demonstrated using a murine model of asthma that dermal exposure to PFOA, along with its immune suppressive characteristics, has the potential to enhance IgE mediated hypersensitivity suggesting that exposure to PFOA, although not allergenic itself, may enhance an individual's response to commonly encountered environmental allergens. The mechanisms governing these two independent immune events are currently undefined. Several mechanisms could be involved, including regulation by regulatory T cells which have been shown to play a critical role in controlling asthma and allergy. Due to the specific lung cytokine expression profiles identified in preliminary studies, induction of a specific type of regulatory T-cell, natural killer T-cells (NKT), has been hypothesized as a contributing factor to the immune modulation induced by PFOA exposure. The specific contribution of NKT cells in PFOA immune modulation will be evaluated using mice deficient in this particular T cell subset (CD1d-/-). Absolute numbers and total percentages of NKT cells localized to the lung will be evaluated by flow cytometric analysis using CD1d tetramers and intracellular cytokine staining will be utilized to analyze NKT cell specific cytokine production.



Little is known about the immunotoxic effects associated with exposure to other PFAAs currently being used in the manufacturing process. About 20 compounds have been introduced as PFOA and PFOS replacements. These compounds include PFAAs containing fewer carbons, which are thought to have shorter half–lives in humans, and flurotelomeric alcohols. These compounds may also pose a threat to human health due to their potential to transform into PFOA or PFOA as the result of metabolism or environmental biodegradation. This study proposes to investigate the immunotoxicity of other PFAAs currently being used in manufacturing and which have been detected in human blood and the environment. These compounds include perfluorobutane sulfonate (PFBS) and perfluorohexane sulfonate (PFHxS). The effect of PFAA exposure on immune suppression will be evaluated by investigating alterations in immune system organ weights and immune cell phenotypes following dermal PFAA exposure. Effects on humoral immunity will be evaluated in response to T-cell dependent antigens using the sheep red blood cell (SRBC) primary response assay (plaque assay), and spleen cell proliferation will be analyzed in response to both T and B cell activators in attempt to identify cells specifically affected by PFAA exposure. Cells responsible for any noted immunosuppressive effects will be further identified through the use separation/reconstitution assays and their cytokine profiles evaluated using both real-time PCR analysis and ELISA. Because of the potential role of PFOA in allergy and asthma, further investigations will be conducted on PFAAs identified as immunotoxic in an attempt to define potential respiratory effects caused by exposure and their associated mechanism of action.


Despite the potential for dermal exposure during the manufacturing process, as well as in end use products, such as firefighting foams and carpet and fabric protectants, most research has focused on oral and inhalation routes of PFAA exposure due to the assumption that PFAAs are less well absorbed via the dermal route. However, to our knowledge, no previous studies have been published in the peer review literature, which have investigated the potential for PFOA dermal absorption. This is in spite of the fact that the chemical properties of these compounds suggest that the rate of dermal absorption could be potentially significant. PFAA serum concentration following dermal dosing with increasing PFAA concentrations will be determined. Any correlations between serum concentration, dermal dose, and PFAA immunotoxicity will be noted. Skin penetration potential in both mouse and human skin will also examined.

This project has the following Specific Aims:
1. Evaluate the immunotoxicity effects associated with individual PFAAs used as PFOA substitutes in the manufacturing process.
a. Investigate PFAA-mediated changes in spleen, thymus, and draining lymph node weights and immune cell phenotypes.
b. Analyze alterations in IgM and IgG antibody production in response to sheep red blood cells (SRBCs) following PFAA exposure.
c. If identified as immunotoxic, examine changes in OVA induced serum IgE production and AHR following PFOA exposure.

2. Characterize the mechanism mediating PFOA immunotoxicity.
a. Analyze alterations in cytokine profiles in the lung and spleen following PFOA exposure.
b. Investigate the involvement of NKT cells in the enhancement of OVA specific IgE and airway hyperreactivity (AHR) responses induced by PFOA exposure.

3. Determine the extent by which individual PFAAs are dermally absorbed in and how serum PFAAs concentrations correspond to noted immunotoxic effects.



Objectives

Methods that will be used to substantiate the expansion of the immunological database for human exposure to chemicals in the workplace include routine Internet searches to ensure the information has been made public and continued publication and communication of new findings and results throughout the duration of the project. Feedback from stakeholders in terms of literature citations and requests for research papers or collaborations will be monitored. These practices will help to promote the transfer and translation of these research findings into prevention practices.



Mission Relevance

Perfluoroalkyl acids (PFAAs) are synthetic chemical substances whose unique chemical properties, such as high stabilities and extremely low surface tensions, lend them to be valuable in a wide range of consumer and industrial applications, including the manufacturing of flame retardants, firefighting foams, surfactants, wax and gloss finish enhancers, as well as carpet and fabric protectants. However, these same properties have also led to their environmental persistence. The environmental hydrolytic half -life of the most widely studied PFAA, perfluorooctanoic acid (PFOA), is estimated to be more than 97 years. Following several decades of commercial use, PFAAs are now being recognized as one of the most notorious global pollutants of the air, water, and soil and have been detected in blood and liver samples collected from a variety of animal species. In humans, PFOA, as well as related PFAAs, perfluoroctanesulfonate (PFOS) and perfluorohexanesulfonate (PFHxS), have been detected not only in the blood of occupationally exposed individuals, but also in the blood of everyone in the general population. The extremely long halflives of PFAAs (3.8, 5.4, and 8.5 years respectively for PFOA, PFOS, and PFHxS in humans) have raised concerns about potential health effects associated with PFAA bioaccumulation. Increased concerns have focused specifically on occupationally exposed individuals due to the fact that their serum PFAA concentrations have been found to be up to 1000 times higher than that of the general population.

In animal models, PFOA and PFOS exposure has been linked to the development of cancer, physical developmental delays, endocrine disruption and neonatal mortality, as well as to impact both the bodys hormone and immune systems. Our lab has previously shown that dermal exposure to PFOA suppresses the IgM response to SRBC and augments the IgE response to the protein allergen ovalbumin (OVA). Due to the health concerns related to PFOA and PFOS exposure specifically, 3M, the dominant global producer of PFAA related chemicals, no longer manufactures PFOS and all 8 companies currently using PFOA have agreed to reduce PFOA releases and levels in products by 95% by 2010 and to eliminate their use completely by 2015.

Despite the expected halt in PFOA and PFOS manufacturing, both compounds will still remain health concerns due to their persistence in household goods and commercial products manufactured before production was stopped. The new compounds being introduced as replacements for PFOA and PFOS are currently being built around PFAAs with smaller carbon length chains due to their shorter human half-lives, but they have also been identified in the environment and blood samples of the general public and it is suspected that they can be transformed into PFOS and PFOA once in the environment. The immunotoxicological effects of these new compounds remain to be investigated and the mechanism mediating the known immunotoxic effects identified following PFOA exposure remains to be defined. The overall goal of this project is to evaluate the immunotoxic effects associated with the individual PFAAs that are still used in the manufacturing process, and to investigate the mechanism mediating the identified immunological alterations associated with PFOA exposure. The knowledge gained from this study will address specific NIOSH research goals for reducing respiratory disease and occupational skin disease particularly in the manufacturing and service sectors.

The effect of PFAA exposure on immune suppression will be evaluated by investigating alterations in immune system organ weights and immune cell phenotypes following dermal PFAA exposure. Effects on humoral immunity will be evaluated in response to T-cell dependent antigens using the sheep red blood cell (SRBC) primary response assay (plaque assay), and spleen cell proliferation will be analyzed in response to both T and B cell activators in attempt to identify cells specifically affected by PFAA exposure. Cells responsible for any noted immunosuppressive effects will be further identified through the use separation/reconstitution assays and their cytokine profiles evaluated using both real-time PCR analysis and ELISA. Because of the potential role of PFOA in allergy and asthma, further investigations will be conducted on PFAAs identified as immunotoxic in an attempt to define potential respiratory effects caused by exposure and their associated mechanism of action.



Page last updated: June 3, 2011
Page last reviewed: May 23, 2011
Content Source: National Institute for Occupational Safety and Health (NIOSH) Office of the Director

 

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