Research Grants/Fellowships/SBIR

Mechanism(s) of Chloroethylene-Induced Autoimmunity

EPA Grant Number: R826409
Title: Mechanism(s) of Chloroethylene-Induced Autoimmunity
Investigators: Pumford, Neil R. , Gilbert, Kathleen M.
Institution: University of Arkansas for Medical Sciences
Current Institution: University of Arkansas for Medical Sciences , University of Arkansas at Fayetteville
EPA Project Officer: Saint, Chris
Project Period: March 25, 1998 through March 24, 2001
Project Amount: $374,384
RFA: Exploratory Research - Human Health (1997) Recipients Lists
Research Category: Health Effects , Human Health , Health


The development of autoimmune diseases (e.g. rheumatoid arthritis, systemic lupus erythematosus, and systemic scleroderma) is believed to be multifactorial, involving both genetic and environmental components. Chemical exposures may be a major environmental influence on the development of autoimmune diseases. Chloroethylenes are industrial chemicals with widespread occupational exposure and are major environmental contaminants. Furthermore, these chemicals are present at many hazardous waste sites at levels from hundreds of thousands of times higher in ground water to millions of times higher in soils and sediment than EPA's maximum regulatory levels in drinking water. There is good evidence for an association of chlorinated ethylenes such as vinyl chloride, trichloroethylene, and tetrachloroethylene in the causation of a life-threatening autoimmune disorder known as systemic sclerosis-like syndrome, or scleroderma; the mechanism by which chlorinated ethylenes cause this sclerosis-like syndrome is unknown. It is our hypothesis that the development of an autoimmune response in certain susceptible individuals may be precipitated by the metabolic activation of chloroethylene's to reactive intermediates that covalently modify proteins, such as cytochrome P450 2E1, in hepatocytes, clara cells, leukocytes, lymphocytes, and keratinocytes. Covalent binding damages the cells causing the release of chemotactic factors that recruit macrophages, leukocytes, and lymphocytes. The damaged cells also release chloroethylene-modified proteins that are phagocytized, processed and presented by macrophages to T cells specific for the chemical modification. In addition, recruited macrophages and lymphocytes may directly metabolize chlorinated ethylenes to reactive intermediates that covalently bind to the proteins that promote T-cell and macrophage interactions, thereby leading to the release of cytokines that stimulate fibroblasts and lead to the fibrosis and vascular damage observed in chloroethylene-induced scleroderma-like disease.


Utilizing antisera specific for proteins covalently modified by chlorinated ethylenes we will investigate the metabolic activation in hepatocytes, clara cells, keratinocytes, macrophages, and CD4+ T cells. Immunohistochemical localization of the adducts within the liver, lung, and skin in MRL/++ mice treated with chloroethylenes will help determine the cells involved in metabolic activation and Western blot analysis of tissue will determine the protein targets. The mechanism of immune-cell activation leading to autoimmunity and fibrosis will be determined in autoimmune-prone MRL/++ mice. Chloroethylene-exposed scleroderma patients will be tested for chloroethylene-modified proteins and/or antibodies directed against modified proteins.

Expected Results:

The results should provide insights into the mechanism(s) involved in chemical-induced autoimmunity and may lead to the development of new treatments for patients with autoimmune diseases, such as the development of new drugs to reduce a critical toxification pathway or to induce a detoxification pathway. Investigation of a non-carcinogen endpoint for chlorinated ethylenes will provide an additional endpoint for evaluating potential human risk. The utilization of biomarkers for chloroethylene exposure will help identify susceptible individuals or populations and is important for risk management. Additionally, the identification of a similar mechanism(s) involved in humans is important for a more precise species extrapolation.

Publications and Presentations:

Publications have been submitted on this project: View all 21 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 6 journal articles for this project

Supplemental Keywords:

Volatile organic compounds (VOC), intermediates, metabolism, human health, genetic pre-disposition, sensitive populations, susceptibility., RFA, Health, Scientific Discipline, Toxics, Waste, Genetics, Environmental Chemistry, Health Risk Assessment, VOCs, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Environmental Microbiology, Disease & Cumulative Effects, Hazardous Waste, Biochemistry, genetic susceptability, Hazardous, 33/50, health effects, sensitive populations, biomarkers, chloroethylene autoimmunity, effects assessment, cytokines, cytochrome P450, lupus erythematosus, scleroderma, chlorinated ethylenes, exposure, gene-environment interaction, genetic predisposition, Tetrachloroethylene, Lymphocytes, Trichloroethylene, human exposure, chemical releases, metabolism, hazardous chemicals, rheumatoid arthritis, environmentally caused disease, human susceptibility, chloroethylenes, Vinyl chloride, air emissions, autoimmunity, exposure assessment, groundwater, immune response, autoimmune diseases, occupational exposure, environmental hazard exposures

Progress and Final Reports:
1999 Progress Report
2000 Progress Report
2001 Progress Report
Final Report