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Prediction of irritation based on exposure duration.

McDougal JN

NIOSH 2003 Feb; :1-7

20023735

Dermatitis is an extremely important occupational disease that can make the life of a worker miserable and cost the economy millions of dollars a year in medical treatment and lost time. Dermatitis is the second most frequent occupational disease. Appropriate identification of the contact time required for chemicals to cause irritancy would help ameliorate problems from dermal exposures. The broad, long-term objectives of this project are to develop a biologically-based mathematical modeling approach that can be used to derive duration-based standards for chemical irritancy. The specific objectives of this research were to mechanistically model the relationship between the duration of solvent exposure on the skin and the degree of irritation produced by chemicals representative of solvents and surfactants. Our approach was to use a rodent model to address the phannacokinetics and phannacodynamics of three known irritants. We exposed skin on the back of rats and guinea pigs to xylene, limonene and sodium lauryl sulfate for one hour and quantified the responses for up to 6 hours. We developed biologically-based models that can be used for distribution of chemicals in the skin. We measured temporal changes in IL-l and iNOS proteins in the skin. We found histological changes in guinea pigs were more severe than in rats, but the molecular responses in guinea pigs were much more variable, so we focused on rats. We quantified oxidative species and low molecular weight DNA due to chemical exposure. We measured baseline gene expression and changes in gene transcripts due to exposure to the three chemicals. We found that the skin responded rapidly to chemical contact as evidenced by gene transcript and inflammatory cytokine changes. Gene responses and histological responses suggest that these chemicals may cause irritation by different mechanisms. We developed methods to expose dermal fibroblasts in a collagen matrix to a volatile chemical and quantify toxicity based on target tissue dose. Our conclusions are that our approach is an excellent model to study chemical irritation, but the temporal responses of proteins related to changes in mRNA we found need to be studied before the long-term objectives can be achieved.

Dermatitis; Dermatosis; Occupational-exposure; Exposure-levels; Occupational-diseases; Medical-treatment; Mathematical-models; Skin-exposure; Skin-irritants; Pharmacodynamics; Xylenes; Laboratory-animals; Animal-studies; Animals

Wright State University School of Medicine, 3640 Colonel Glenn Hwy, Dayton, OH 45435-0001

1330-20-7; 5989-27-5; 151-21-3

20030211

Final Grant Report

777420

Grant

2003

Grant-Number-R01-OH-003654

OEP

Disease and Injury: Allergic and Irritant Dermatitis

National Institute for Occupational Safety and Health

OH

Wright State University, Dayton, Ohio