Lead exposure and fear-potentiated startle in the VA Normative Aging Study: a pilot study of a novel physiological approach to investigating neurotoxicant effects

Neurotoxicol Teratol. Jul-Aug 2013;38:21-8. doi: 10.1016/j.ntt.2013.04.003. Epub 2013 Apr 17.


Background: Physiologically-based indicators of neural plasticity in humans could provide mechanistic insights into toxicant actions on learning in the brain, and perhaps prove more objective and sensitive measures of such effects than other methods.

Objectives: We explored the association between lead exposure and classical conditioning of the acoustic startle reflex (ASR)-a simple form of associative learning in the brain-in a population of elderly men. Fifty-one men from the VA Normative Aging Study with cumulative bone lead exposure measurements made with K-X-Ray-Fluorescence participated in a fear-conditioning protocol.

Results: The mean age of the men was 75.5years (standard deviation [sd]=5.9) and mean patella lead concentration was 22.7μg/g bone (sd=15.9). Baseline ASR eyeblink response decreased with age, but was not associated with subsequent conditioning. Among 37 men with valid responses at the end of the protocol, higher patella lead was associated with decreased awareness of the conditioning contingency (declarative learning; adjusted odds ratio [OR] per 20μg/g patella lead=0.91, 95% confidence interval [CI]: 0.84, 0.99, p=0.03). Eyeblink conditioning (non-declarative learning) was 0.44sd less (95% CI: -0.91, 0.02; p=0.06) per 20μg/g patella lead after adjustment. Each result was stronger when correcting for the interval between lead measurement and startle testing (awareness: OR=0.88, 95% CI: 0.78, 0.99, p=0.04; conditioning: -0.79sd less, 95% CI: -1.56, 0.03, p=0.04).

Conclusions: This initial exploration suggests that lead exposure interferes with specific neural mechanisms of learning and offers the possibility that the ASR may provide a new approach to physiologically explore the effects of neurotoxicant exposures on neural mechanisms of learning in humans with a paradigm that is directly comparable to animal models.

Keywords: ASR; Acoustic startle reflex; Acoustic startle response; Aging; Behavioral toxicology; CI; CS; Conditioned stimulus; Confidence interval; DSA; Differential startle amplitude; EMG; Electromyography; IQR; Interquartile range; K-X-Ray-Fluorescence; KXRF; Lead; N-methyl-D-aspartate; NAS; NMDA; Normative Aging Study; OR; Odds ratio; Psychophysiology; US; Unconditioned stimulus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acoustic Stimulation
  • Aged
  • Aged, 80 and over
  • Aging / drug effects*
  • Animals
  • Awareness / drug effects
  • Bone and Bones / chemistry
  • Conditioning, Classical / drug effects
  • Disease Models, Animal
  • Environmental Exposure / adverse effects*
  • Fear / drug effects*
  • Humans
  • Hydrocortisone / metabolism
  • Lead / analysis
  • Lead / toxicity*
  • Male
  • Pilot Projects
  • Reflex, Startle / drug effects*
  • Saliva / metabolism


  • Lead
  • Hydrocortisone