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AGING AND SUSCEPTIBILITY TO TOLUENE IN RATS: A PHARMACOKINETIC, BIOMARKER, AND PHYSIOLOGICAL APPROACH.
Citation:
GORDON, C. J., R. R. GOTTIPOLU, E. M. KENYON, R. THOMAS, M. SCHLADWEILER, C. M. MACK, J. H. SHANNAHAN, G. WALLENBORN, A. NYSKA, R. C. MACPHAIL, J. E. RICHARDS, M. J. DEVITO, AND U. P. KODAVANTI. AGING AND SUSCEPTIBILITY TO TOLUENE IN RATS: A PHARMACOKINETIC, BIOMARKER, AND PHYSIOLOGICAL APPROACH. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH - PART A: CURRENT ISSUES. Taylor & Francis, Inc., Philadelphia, PA, 73(4):301-318, (2010).
Impact/Purpose:
This paper represents a cross-divisional effort to assess the susceptibility of the aged to an environmental toxicant. Toluene was selected as the toxicant to study because of its relevance in air pollution studies and its well characterized toxicity in younger animals. The Brown Norway rat was used as a model of aging. Its susceptibility to toluene was assessed using a pharmacokinetic, molecular, and physiological approach. This is one of the first multidisciplinary approaches to study the susceptibility of an aged animal model to an environmental toxicant. The results of these studies indicate that the aged exhibit increased susceptibility to toluene exposure.
Description:
Aging adults are a growing segment of the U.S. population and are likely to exhibit increased susceptibility to many environmental toxicants. However, there is little information on the susceptibility of the aged to toxicants. The toxicity of toluene has been well characterized in young adult rodents but there is little information in the aged. We used three approaches: pharmacokinetic (PK), cardiac biomarkers, and whole-animal physiology to assess if aging increases susceptibility to toluene in the Brown Norway (BN) rat. Three life stages, young adult, middle age, and aged (4, 12, and 24 months, respectively) were administered toluene orally at doses of 0, 0.3, 0.65, or 1.0 g/kg and subjected to the following: Terminated at 45 min or 4 hours post dosing and blood and brain toluene concentration measured; terminated at 4 hours post dosing and biomarkers of cardiac function measured; or monitor heart rate (HR), core temperature (Tc), and motor activity (MA) by radiotelemetry before and after dosing. Brain toluene concentration was significantly elevated in aged rats at 4 hours after dosing with either 0.3 or 1.0 g/kg. Blood toluene concentrations were unaffected by age. There were a variety of interactions between aging and toluene-induced effects on cardiac biomarkers. Most notably, toluene exposure led to reductions in mRNA markers for oxidative stress in aged but not younger animals. Toluene also elicited reduction in cardiac endothelin-1 in aged rats. Higher doses of toluene led to tachycardia, hypothermia, and a transient elevation in MA. Aged rats were less sensitive to the tachycardic effects of toluene but showed a prolonged hypothermic response. Elevated brain levels of toluene in aged rats may be attributed to their suppressed cardiovascular and respiratory responses. The expression of several cardiac biochemical markers of toluene exposure in the aged may also reflect differential susceptibility to this toxicant.
