Combined Effects of Metals and Stress on Central Nervous System Function

EPA Grant Number: R834578
Title: Combined Effects of Metals and Stress on Central Nervous System Function
Investigators: Cory-Slechta, Deborah , Korfmacher Smith, Katrina
Institution: University of Rochester School of Medicine and Dentistry
EPA Project Officer: Breville, Maggie
Project Period: October 1, 2010 through September 30, 2014 (Extended to September 30, 2015)
Project Amount: $1,250,000
RFA: Understanding the Role of Nonchemical Stressors and Developing Analytic Methods for Cumulative Risk Assessments (2009) RFA Text |  Recipients Lists
Research Category: Health Effects , Human Health Risk Assessment , Health


Chemical exposures do not occur in isolation but concurrently with other risk factors for human diseases and disorders, including host, genetic and lifestyle risk factors. This application asks two crucial questions in relation to the inclusion of non-chemical stressors in cumulative risk assessment: 1) How general is the ability of one such risk factor, i.e., stress, to enhance effects of chemical exposures? 2) Under what conditions would such synergies be expected, i.e., can a biological framework be proposed to assist in defining such conditions, thereby circumscribing the agenda required for protecting human health?


This project tests the hypothesis that non-chemical and chemical stressors that act on the same biological systems or substrates, or that produce common adverse outcomes will have the potential to produce additive or greater effects when they co-occur as risk factors. It is based on our prior studies demonstrating synergistic and potentiated central nervous system effects in response to combined exposures to (Pb) and stress, co-occurring risk factors that both act on the HPA axis and on brain dopamine and glutamate systems and produce common adverse outcomes, including cognitive deficits.


The proposed studies extend our observations of Pb and stress to two other neurotoxic metals (methylmercury (MeHg) and arsenic (As)) that also interact with the HPA axis and brain dopamine and glutamate systems and affect similar behaviors using rat and mouse models. Two experiments examine whether dopamine and glutamate-mediated effects of developmental MeHg will be further enhanced by prenatal stress. A third experiment similarly examines the combined impacts of arsenic (As) and prenatal stress. A fourth study will examine the extent to which the enhanced toxicity of combined Pb and prenatal stress generalizes to other Pb-disrupted, dopamine-mediated behaviors in addition to those observed on schedule-controlled behavior, in this case to a measure of attention deficit disorder. With the relationship of such research to health disparities, our Community Based Participatory Research Plan focuses on how to best communicate findings to our community partner groups and to enhance community capacity based on the findings.

Expected Results:

The proposed experiments the extent to which a non-chemical stressor can modulate the toxicity of metals with which it shares biological properties. Positive outcomes would have significant implications for human health protection: failure to consider pertinent non-chemical stressors could yield underestimates of the risks to human health from exposures to these chemicals, as NOAELs (no observed adverse effect levels) determined from chemical exposures evaluated in isolation may be adverse effect levels (AELs) when exposures occur in contexts with other pertinent risk factors, a situation that typifies the human environment.

Publications and Presentations:

Publications have been submitted on this project: View all 42 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 6 journal articles for this project

Supplemental Keywords:

cumulative risk, health effects, heavy metals, susceptible populations, brain, behavioral toxicology, neurotoxicology, environmental stressors;

Progress and Final Reports:

  • 2011 Progress Report
  • 2012 Progress Report
  • 2013 Progress Report
  • 2014
  • Final Report