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Toxicant-inflicted injury and stimulated tissue repair are opposing toxicodynamic forces in predictive toxicology.
- Source :
-
Regulatory toxicology and pharmacology : RTP [Regul Toxicol Pharmacol] 1999 Apr; Vol. 29 (2 Pt 1), pp. 165-74. - Publication Year :
- 1999
-
Abstract
- These studies were designed to investigate the dose response for liver injury and tissue repair induced by exposure to four structurally and mechanistically dissimilar hepatotoxicants, individually and as mixtures. The objective was to illuminate the impact of the extent and timeliness of tissue repair on the ultimate outcome of toxicity. Dose-response relationships for trichloroethylene (TCE), allyl alcohol (AA), thioacetamide (TA), and chloroform alone or as mixtures were studied. Male Sprague-Dawley rats (200-250 g) received a single intraperitoneal injection of individual toxicants as well as mixtures of these toxicants. Liver injury was monitored by plasma enzyme (ALT and SDH) levels and histopathology. Tissue regeneration was measured by [3H]thymidine incorporation into hepatic nuclear DNA. Individually, TCE, TA, and AA administration, over a 10- to 12-fold dose range, revealed a dose-related increase in injury as well as tissue repair up to a threshold dose. Beyond this threshold, tissue repair was delayed and attenuated, and liver injury progressed. Mixtures of the four chemicals at the higher doses used in individual dose-response studies resulted in 100% mortality. Hence, mixtures at the lower two doses were selected for further study. Additional lower doses were also included to better understand the dose-response relationship of mixtures. Results of these studies support the observations of individual chemicals. Higher and sustained repair was observed at low dose levels. These studies show that the extent of injury at early time points correlates well with the maximal stimulation of the opposing response of tissue repair. It appears that the toxicity of the mixture employed in these studies is roughly additive and correlates well with tissue repair response. These initial studies suggest that a biologically based mathematical model can be constructed and tested to extrapolate the outcome of toxicity from a given dose of individual compounds as well as their mixtures, where the responses measured are injury on the one hand and compensatory tissue repair on the other.<br /> (Copyright 1999 Academic Press.)
- Subjects :
- Animals
Cell Division drug effects
Chloroform pharmacology
Chloroform toxicity
Dose-Response Relationship, Drug
Drug Interactions
Humans
Liver pathology
Liver physiopathology
Male
Propanols pharmacology
Propanols toxicity
Rats
Rats, Sprague-Dawley
Risk Assessment
Thioacetamide pharmacology
Thioacetamide toxicity
Toxicology methods
Toxins, Biological toxicity
Trichloroethylene pharmacology
Trichloroethylene toxicity
United States
United States Public Health Service
Liver drug effects
Toxins, Biological pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0273-2300
- Volume :
- 29
- Issue :
- 2 Pt 1
- Database :
- MEDLINE
- Journal :
- Regulatory toxicology and pharmacology : RTP
- Publication Type :
- Academic Journal
- Accession number :
- 10341147
- Full Text :
- https://doi.org/10.1006/rtph.1998.1280