Duke Integrated Toxicology Program
Philip J. Bushnell, Ph.D.
Toxicologist, Neurotoxicology Division
National Health and Environmental Effects Laboratory
U.S. Environmental Protection Agency
Research Areas:
Neurotoxicology
Cognitive Processes
Pharmacokinetics
Chemical Tolerance
Education:
B.A., Chemistry, Univ. of California, Santa Cruz, 1969
M.S., Psychology, Univ. of Wisconsin, Madison, 1973
Ph.D., Psychology, Univ. of Wisconsin, Madison, 1978
Research Description:
Many of the neurotoxic chemicals released into the environment affect cognitive processes such as attention, learning, and memory. The broad objective of this research is to model human cognitive processes with quantitative, analytic behavioral tests in laboratory animals. These animal models may then be used experimentally to characterize cognitive dysfunction caused by exposure to neurotoxic environmental chemicals and to predict potential effects in humans exposed to those chemicals.
We base our animal models upon known neurobiological systems, to enhance understanding of the interactions of the chemicals with the nervous system and to facilitate extrapolation of effects in the animals to those in humans. Our experiments with Long-Evans rats are designed to maximize specificity for the cognitive process of interest and sensitivity to positive control compounds. We prefer a baseline approach, in which repeated assessments can be made in the same animals before, during and after exposure. The same approach permits repeated assessments after exposure to neurotoxic chemicals. The tasks are designed to assess the three major classes of cognition: attention, memory and learning.
We assess sustained and selective attention using signal detection tasks with auditory or visual stimuli, which rats must detect and report to earn food. We assess working and reference memory using a delayed matching-to-position/visual discrimination (DMTP/VD) procedure. Learning is quantified in the course of training the animals to perform the responses and discriminations required for performing the attention and memory tasks. We use these tasks to evaluate the functional neurotoxic effects of inhaled solvents, pesticides, endocrine-disrupting compounds, and heavy metals. At present we are focusing on the acute neurotoxicity of inhaled organic solvents.
Our solvent project involves collaboration with pharmacokineticists and physiologists, and seeks to develop an exposure-dose-response model to characterize the several processes by which these ubiquitous chemicals affect the nervous system. These processes include dosimetry [i.e., the relationship between external (inhaled concentration) and internal (tissue concentration) dose]; interactions with neurotransmitter systems in the CNS; modeling of those interactions in vitro; predicting functional deficits in vivo based upon changes in receptor function in vitro; comparing the relative sensitivities of rats and humans to the acute functional effects of inhaled solvents; and accounting for physiological factors (e.g., physical activity and body composition) that modify the kinetics and toxicity of the solvents. The behavioral tasks are also ideal for exploring tolerance to these solvents and potential functional consequences of tolerance.
Selected publications:
Bushnell, P.J. Overt orienting in the rat: Parametric studies of cued detection of visual targets. Behavioral Neuroscience 109:1095-1105, 1995.
Bushnell, P.J. and W.M. Oshiro. 2,4-Dithiobiuret in Rats: Cognitive facilitation after acute injection precedes motor impairment after repeated daily injections. Psychopharmacology 123:267-279, 1996.
Bushnell, P.J. Concentration-time relationships for the effects of inhaled trichloroethylene on detection of visual signals in rats. Fundam. Appl. Toxicol. 36:30-38, 1997.
Bushnell, P.J., W.M. Oshiro and B.K. Padnos. Effects of chlordiazepoxide and cholinergic and adrenergic drugs on sustained attention in rats. Psychopharmacology 134:242-257, 1997.
Bushnell, P.J., A.A. Chiba and W.M. Oshiro. Effects of unilateral lesions of basal forebrain cholinergic neurons on cued target detection in rats. Behavioural Brain Research 90:57-71, 1998.
Bushnell, P.J. Behavioral approaches to the assessment of attention in animals. Psychopharmacology 138:231-259, 1998.
Benignus, V.A., Boyes, W.K., and Bushnell, P.J. A dosimetric analysis of behavioral effects of acute toluene exposure in rats and humans. Toxicol. Sci. 43:186-195, 1998.
Bushnell, P.J. Detection of visual signals by rats: Effects of signal intensity, event rate and task type. Behavioural Processes 46:141-150, 1999.
Chiba, A.A., P.J. Bushnell, W.M. Oshiro and M. Gallagher. Changes in attention after bilateral cholinergic lesions of the substantia innominata in rats performing a cued target detection task. NeuroReport 10:3119-3123, 1999.
Bushnell, P.J. and K.M. Crofton, Organic solvents. In: R.J.M. Niesink, R.M.A. Jaspers, L.M.W. Kornet, J.M. van Ree and H.A. Tilson, Eds., Introduction to Neurobehavioral Toxicology: Food and Environment, pp. 394-429. CRC Press, Boca Raton, FL, 1999.
Bushnell, P.J. Advanced behavioral testing in rodents. In: Current Protocols in Toxicology, Unit 12.4, Wiley, New York, 1999.
Oshiro, W.M., P.J. Bushnell and A.A. Chiba. A comparison of the effects of bilateral and unilateral infusions of muscimol into the basal forebrain on cued detection of visual targets in rats. Behavioral Neuroscience 114(1):137-149, 2000.
Bushnell, P.J. and W.M. Oshiro. Behavioral components of tolerance to repeated inhalation of trichloroethylene (TCE) in rats. Neurotoxicol. Teratol. 22(2):221-229, 2000.
Boyes, W. K., P. Bushnell, K. Crofton, M. Evans, and J. E. Simmons. Neurotoxic and pharmacokinetic responses to trichloroethylene as a function of exposure scenario. In: Trichloroethylene Health Risks, Environmental Health Perspectives 108(Suppl. 2):317-322, 2000.
Bushnell, P.J., E.D. Levin, R.T. Marrocco, B.J. Strupp, M. Sarter and D.M. Warburton. Symposium Overview: "Attention as a Target of Intoxication: Insights and Methods from Studies of Drug Abuse". Neurotoxicology & Teratology 24:487-502, 2000.
Bushnell, P.J. Assessing attention in rats. In: Methods of Behavior Analysis in Neuroscience, pp. 111-122. J.J. Buccafusco, Ed. CRC Press, Boca Raton, FL, 2001.
Contact information
(919) 541-7747