Use of human data for the derivation of a reference dose for chlorpyrifos

Regul Toxicol Pharmacol. 2001 Apr;33(2):110-6. doi: 10.1006/rtph.2000.1447.


In 1998 a panel of experts met to discuss the data available on chlorpyrifos, both human and animal, and to determine the most appropriate endpoints to be used for the derivation of the reference dose (RfD). Since that time, additional data have become available on chlorpyrifos from an experimental study involving humans. Moreover, Food Quality Protection Act (FQPA) considerations need to be addressed, and the appropriate cholinesterase endpoint, whether plasma, red blood cell, peripheral nerve, or brain, has become highly debated. Therefore, Dow AgroSciences, one of the manufacturers of chlorpyrifos, convened a second panel of toxicology and medical experts on June 21, 1999, to consider the presently available scientific literature both published and unpublished on chlorpyrifos and to determine the acute and chronic toxicological RfDs for chlorpyrifos. Four questions were posed to this second panel of experts concerning the available data on chlorpyrifos. (1) Should the RfD for chlorpyrifos be based on acetylcholinesterase (AChE) inhibition or butyrylcholinesterase (BuChE) inhibition as an endpoint for adverse effect? (2) Should the RfDs for chlorpyrifos be based on the data set from three human studies, which are supported by animal data? (3) Should the FQPA safety factor be reduced to 1xbased on animal studies of pre- or postnatal toxicity? (4) If an RfD for chlorpyrifos were to be based on animal data, then is a 10-fold interspecies uncertainty factor necessary? The panel of experts concluded that: (1) inhibition of BuChE is not an adverse effect, and the RfD for chlorpyrifos should be based on AChE inhibition; (2) the RfD for chlorpyrifos should be based on the three available human studies, which are also supported by animal data; (3) the extra FQPA safety factor should be reduced to 1x, because chlorpyrifos shows no pre- or postnatal toxicity of concern at relevant human exposure conditions; and (4) the extra 10-fold safety factor for interspecies variation appears overly conservative because no differences in species sensitivity to chlorpyrifos is evident.

MeSH terms

  • Acetylcholinesterase / drug effects
  • Acetylcholinesterase / metabolism*
  • Animals
  • Butyrylcholinesterase / drug effects
  • Butyrylcholinesterase / metabolism*
  • Chlorpyrifos / toxicity*
  • Endpoint Determination
  • Female
  • Humans
  • Insecticides / toxicity*
  • Male
  • Mice
  • Pregnancy
  • Public Health
  • Reference Values
  • Risk Assessment


  • Insecticides
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Chlorpyrifos