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

In 1998 a panel of experts met to discuss the data available on chlorpyrifo s, both human and animal, and to determine the most appropriate endpoints t o 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) consid erations need to be addressed, and the appropriate cholinesterase endpoint, whether plasma, red blood cell, peripheral nerve, or brain, has become hig hly debated. Therefore, Dow AgroSciences, one of the manufacturers of chlor pyrifos, convened a second panel of toxicology and medical experts on June 21, 1999, to consider the presently available scientific literature both pu blished and unpublished on chlorpyrifos and to determine the acute and chro nic toxicological RfDs for chlorpyrifos.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) inh ibition or butyrylcholinesterase (BuChE) inhibition as an endpoint for adve rse effect? (2) Should the RfDs for chlorpyrifos be based on the data set f rom three human studies, which are supported by animal data? (3) Should the FQPA safety factor be reduced to 1x based on animal studies of pre- or pos tnatal toxicity? (4) If an RfD for chlorpyrifos were to be based on animal data, then is a 10-fold interspecies uncertainty factor necessary? The pane l of experts concluded that: (1) inhibition of BuChE: is not an adverse eff ect, and the RfD for chlorpyrifos should be based on AChE inhibition; (2) t he RfD for chlorpyrifos should be based on the three available human studie s, which are also supported by animal data; (3) the extra FQPA safety facto r should be reduced to 1x, because chlorpyrifos shows no pre- or postnatal toxicity of concern at relevant human exposure conditions; and (4) the extr a 10-fold safety factor for interspecies variation appears overly conservat ive because no differences in species sensitivity to chlorpyrifos is eviden t. (C) 2001 Academic Press.