title: Aging and susceptibility to toluene in rats: a pharmacokinetic, biomarker, and physiological approach.
abstract: 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. Three approaches were used: (1) pharmacokinetic (PK), (2) cardiac biomarkers, and (3) whole-animal physiology to assess whether aging increases susceptibility to toluene in the Brown Norway (BN) rat. Three life stages, young adult, middle aged, and aged (4, 12, and 24 mo, respectively), were administered toluene orally at doses of 0, 0.3, 0.65, or 1 g/kg and subjected to the following: terminated at 45 min or 4 h post dosing, and blood and brain toluene concentration were measured; terminated at 4 h post dosing, and biomarkers of cardiac function were 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 h after dosing with either 0.3 or 1 g/kg. Blood toluene concentrations were unaffected by age. There were various 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 produced a 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.
authors.affiliation: National Health and Environmental Effects Research Laboratory, ORD, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA. Gordon.christopher@epa.gov
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Gordon
authors.forename: Reddy R
authors.initials: RR
authors.lastname: Gottipolu
authors.forename: Elaina M
authors.initials: EM
authors.lastname: Kenyon
authors.forename: Ronald
authors.initials: R
authors.lastname: Thomas
authors.forename: Mette C
authors.initials: MC
authors.lastname: Schladweiler
authors.forename: Cina M
authors.initials: CM
authors.lastname: Mack
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Shannahan
authors.forename: J Grace
authors.initials: JG
authors.lastname: Wallenborn
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.forename: Robert C
authors.initials: RC
authors.lastname: MacPhail
authors.forename: Judy E
authors.initials: JE
authors.lastname: Richards
authors.forename: Mike
authors.initials: M
authors.lastname: Devito
authors.forename: Urmila P
authors.initials: UP
authors.lastname: Kodavanti
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014050:Toluene / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D015415:Biomarkers; D014050:Toluene; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005982:Glutathione Transferase