This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Hatch, G. Articles by Costa, D Search for Related Content PubMed PubMed Citation Articles by Hatch, G. Articles by Costa, D Social Bookmarking                         What's this?

An ‘injury-time integral’ model for extrapolating from acute to chronic effects of phosgene

Pulmonary Toxicology Branch, Experimental Toxicology Division, National Health and Ecological Effects Research Laboratory, US EPA, Research Triangle Park, North Carolina 27711, USA, hatch.gary{at}epa.gov

U Kodavanti

Pulmonary Toxicology Branch, Experimental Toxicology Division, National Health and Ecological Effects Research Laboratory, US EPA, Research Triangle Park, North Carolina 27711, USA

K Crissman

Pulmonary Toxicology Branch, Experimental Toxicology Division, National Health and Ecological Effects Research Laboratory, US EPA, Research Triangle Park, North Carolina 27711, USA

R Slade

Pulmonary Toxicology Branch, Experimental Toxicology Division, National Health and Ecological Effects Research Laboratory, US EPA, Research Triangle Park, North Carolina 27711, USA

D Costa

Pulmonary Toxicology Branch, Experimental Toxicology Division, National Health and Ecological Effects Research Laboratory, US EPA, Research Triangle Park, North Carolina 27711, USA

The present study compares acute and subchronic episodic exposures to phosgene to test the applicability of the `concentrationxtime’ (CxT) product as a measure of exposure dose, and to relate acute toxicity and adaptive responses to chronic toxicity. Rats (male Fischer 344) were exposed (six hours/day) to air or 0.1, 0.2, 0.5 and 1.0 ppm of phosgene one time or on a repeated regimen for up to 12 weeks as follows: 0.1 ppm (five days/week), 0.2 ppm (five days/week), 0.5 ppm (two days/week), or 1.0 ppm (one day/week) (note that the CxT for the three highest exposures was the same). Animals were sacrificed at 4, 8, and 12 weeks during the exposure and after four weeks recovery. Bronchoalveolar lavage (BAL) was performed 18 hours after the last exposure for each time period and the BAL supernatant assayed for protein. Elevated BAL fluid protein was defined as `acute injury’, diminished response after repeated exposure was defined as `adaptation’, and increased lung hydroxyproline or trichrome staining for collagen was defined as `chronic injury’. Results indicated that exposures that cause maximal chronic injury involve high exposure concentrations and longer times between exposures, not high CxT products. A conceptual model is presented that explains the lack of CxT correlation by the fact that adaptation reduces an `injury-time integral’ as phosgene exposure is lengthened from acute to subchronic. At high exposure concentrations, the adaptive response appears to be overwhelmed, causing a continued injury-time integral, which appears to be related to appearance of chronic injury. The adaptive response is predicted to disappear if the time between exposures is lengthened, leading to a continued high injury-time integral and chronic injury. It has generally been assumed that long, continuous exposures of rodents is a conservative approach for detecting possible chronic effects. The present study suggests that such an approach my not be conservative, but might actually mask effects that could occur under intermittent exposure conditions.

Key Words: chronic lung injury • dose response models • extrapolation • phosgene toxicity • risk assessment

Toxicology and Industrial Health, Vol. 17, No. 5-10, 285-293 (2001)
DOI: 10.1191/0748233701th123oa


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?