Setting safer exposure limits for toxic substance combinations

Ronald N. Kostoff, Michael Aschner, Marina Goumenou, Aristidis Tsatsakis

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Toxic stimuli (stressors) exposure limits are typically based on single toxic stimuli experiments, but are presently used for both toxic stimuli in isolation and in combination with other toxic stimuli (simultaneous co-exposure or exposures separated in time). In the combination case, typically less of each constituent of the combination is required to cause damage compared to the amount determined from single stressor experiments. Thus, exposure limits based on single toxic stimulus experiments are inadequate for setting limits for stressor combinations. This article presents a recommended simplified approach to improving regulatory exposure limits for toxic stimuli combinations, and a more expansive and expensive alternative to the recommended simplified approach. The recommended approach will partially compensate for the enhanced adverse effects of toxic stimuli combinations relative to adverse effects of toxic stimuli in isolation. The approach covers myriad categories of toxic stimuli reflective of real-life exposures due to lifestyle, iatrogenic, biotoxin, occupational/environmental, and psychosocial/socioeconomic conditions. The proposed approach 1) assumes that all potential toxic stimuli to which an individual might be exposed have the same mechanisms/modes of action on biological mechanisms, and are, thus, indistinguishable by the impacted organism; 2) normalizes the myriad stimuli by converting the doses of toxic stimuli exposures to the respective toxicity reference values (TRV) fractions; 3) sums all the TRVs fractions from these toxic stimuli exposures; and 4) divides all the single substance TRVs by the sum of fractions. While it is an additive approach conceptually, it differs from other additive approaches in the breadth of its inter-category coverage, in order to reflect true inter-category real-life simulation. The newly posited approach does not account for hormetic, antagonistic, or synergistic effects of toxic stimuli in combination. It does not adjust for 1) low-dose toxicants with adverse effects that have been under-reported, or 2) exposure limits like the Occupational Safety and Health Administration - Permissible Exposure Limits (OSHA PELs) that are orders of magnitude above levels shown by published single toxic stimuli studies to have caused adverse effects. Practical considerations for the application of this approach are presented.

Original languageEnglish (US)
Article number111346
JournalFood and Chemical Toxicology
StatePublished - Jun 2020


  • Combined effects
  • Cumulative risk assessment
  • Exposure limits
  • Mixtures
  • New approach
  • Synergistic effects
  • Toxic stimuli
  • Toxicity reference values

ASJC Scopus subject areas

  • Food Science
  • Toxicology


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