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.

Setting surface wipe limits for skin sensitizers

“…The current recommendations rely on the literature values for LLNA EC3 s and HRIPT NOELs. Industrial experience indicates that when the skin sensitization potential of the compounds evaluated by Durand et al (2003) became known, and appropriate control measures were implemented, no new cases were reported. The effectiveness of using the LLNA to establish surface wipe limits and potency-based control strategies, with possible future adjustments resulting from further research, should be adequately investigated over time.…”

Inter-laboratory validation of the modified murine local lymph node assay based on 5-bromo-2′-deoxyuridine incorporation

“…The assay is not intended to facilitate the detection of low molecular weight chemicals associated with systemic sensitization or drug allergies (Kimber, 2001). However, an investigation, which was designed to explore the ability of LLNA to identify pharmaceutical process intermediates known to cause contact allergy in humans, provided evidence that the assay is a useful method for hazard identification (Durand et al ., 2003). Furthermore, the use of the method, along with the use of GPMT and BT, is recommended for the determination of the skin sensitization potential of new drugs (FDA, 2002).…”