Combined exposure to lead, inorganic mercury and methylmercury shows deviation from additivity for cardiovascular toxicity in rats

J Appl Toxicol. 2015 Aug;35(8):918-26. doi: 10.1002/jat.3092. Epub 2014 Dec 18.


Environmental exposure to metal mixtures in the human population is common. Mixture risk assessments are often challenging because of a lack of suitable data on the relevant mixture. A growing number of studies show an association between lead or mercury exposure and cardiovascular effects. We investigated the cardiovascular effects of single metal exposure or co-exposure to methylmercury [MeHg(I)], inorganic mercury [Hg(II)] and lead [Pb(II)]. Male Wistar rats received four different metal mixtures for 28 days through the drinking water. The ratios of the metals were based on reference and environmental exposure values. Blood and pulse pressure, cardiac output and electrical activity of the heart were selected as end-points. While exposure to only MeHg(I) increased the systolic blood pressure and decreased cardiac output, the effects were reversed with combined exposures (antagonism). In contrast to these effects, combined exposures negatively affected the electrical activity of the heart (synergism). Thus, it appears that estimates of blood total Hg levels need to be paired with estimates of what species of mercury dominate exposure as well as whether lead co-exposure is present to link total blood Hg levels to cardiovascular effects. Based on current human exposure data and our results, there may be an increased risk of cardiac events as a result of combined exposures to Hg(II), MeHg(I) and Pb(II). This increased risk needs to be clarified by analyzing lead and Hg exposure data in relation to cardiac electrical activity in epidemiological studies.

Keywords: Hg(II); Pb(II); antagonism; cardiovascular; combined exposure; mixture; rats; synergism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Blood Pressure / drug effects
  • Cardiac Output / drug effects
  • Cardiovascular Diseases / chemically induced*
  • Cardiovascular Diseases / diagnostic imaging
  • Drug Synergism
  • Electric Conductivity
  • Electrocardiography / drug effects
  • Environmental Pollutants / pharmacokinetics
  • Environmental Pollutants / toxicity*
  • Heart / drug effects
  • Heart / growth & development
  • Lead / pharmacokinetics
  • Lead / toxicity*
  • Male
  • Mercury / pharmacokinetics
  • Mercury / toxicity*
  • Methylmercury Compounds / pharmacokinetics
  • Methylmercury Compounds / toxicity*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Rats
  • Rats, Wistar
  • Ultrasonography


  • Environmental Pollutants
  • Methylmercury Compounds
  • Lead
  • Mercury