Use of the local lymph node assay in the evaluation of the sensitizing potential of pharmaceutical process intermediates.

Abstract

The murine local lymph node assay (LLNA) has recently been developed to determine the contact sensitization potential of chemicals. Since its original development, the LLNA results have been the subject of extensive comparisons with guinea pig and human data. The investigations described here were designed to explore the ability of the LLNA to identify accurately, pharmaceutical process intermediates (PIs) known to cause contact allergy in humans. To that end, 16 PIs previously tested in the guinea-pig maximization test (GPMT) were tested in the LLNA. Another PI known to be a contact sensitizer in humans was tested only in the LLNA. Cases of contact sensitization in humans were reported only for PIs that were extreme sensitizers in the GPMT and had low EC3 values (concentration of the test substance required to generate a threefold increase in lymph node cell proliferation) in the LLNA. These data provide additional evidence that the LLNA is able to discriminate skin sensitizers from chemicals that do not possess a significant skin sensitization potential and is thus a useful method for hazard identification. In addition, this method also offers important animal welfare benefits and may also be useful for risk assessment purposes.