Evidence for the efficacy of the emetic PP796 in paraquat SL20 formulations - a narrative review of published and unpublished evidence.

BACKGROUND

The bipyridyl herbicide paraquat was first introduced into agriculture in the 1960s by Imperial Chemical Industries. Due to issues with unintentional poisoning, the centrally acting emetic PP796 was added in 1976 to the company's 20% paraquat ion soluble liquid (SL20) formulations (Gramoxone) at a concentration of 0.5 g/L or 0.05% (equivalent to 0.071 mg/kg in a 70 kg adult ingesting a minimum lethal dose of 10 mL) to induce early vomiting (within 30 min), reduce paraquat absorption from the gut, and prevent deaths. Its presence in paraquat products was subsequently mandated by the Food and Agriculture Organization Committee of Experts on Pesticides in Agriculture (predecessor to the current FAO/WHO Joint Meeting on Pesticide Specifications). However, no primary pre-clinical or clinical data have been published regarding the effectiveness of PP796. We reviewed the published literature and unpublished company reports for data on the effectiveness of PP796.

METHODS

PubMed and Google were searched for published studies on the emetic using the search terms "paraquat" and ["emetic" or "PP796"]. Company documents reporting pre-clinical and clinical studies were accessed at the website of (https://usrtk.org/pesticides/paraquat-papers/). Primary study reports were sought as well as overviews written by company toxicologists.

RESULTS

Pre-clinical dog and monkey studies indicated that the PP796 EC50 dose for vomiting was around 0.5-2 mg/kg. Further increasing the PP796 concentration speeded up the time to first vomit and reduced the amount of paraquat absorbed (as assessed by the 0-24 h plasma area-under-the-curve) 100-fold compared to a control group receiving no PP796. However, the dose selected for paraquat SL20 formulations by the company (0.5 g/L or 0.05%) was based exclusively on a phase II study in the early 1970s involving five volunteers receiving 3 different doses, with only two individuals actually vomiting, supplemented by data from 37 patients taking 2 mg in clinical trials. A UK-mandated toxicovigilance study in the 1980s identified only 21 patients ingesting paraquat SL20 with PP796 for whom data on time to vomit was available; of these patients, 11 vomited within 30 min (52.4%, 95%CI 31-73.7%). No effect on mortality could be identified from any study of paraquat SL containing 0.05% PP796. A clinical study in Sri Lanka 30 years after the emetic was first introduced, of a revised formulation (Gramoxone Inteon) containing a three-fold higher amount of PP796, as well as MgSO4 and an alginate, showed increased rates of early vomiting and modestly reduced mortality for patients ingesting up to 100 mL.

CONCLUSION

Pre-clinical studies showed a clear dose response for PP796 to cause early vomiting, with effective doses in the 0.5-20 mg/kg range. A too low concentration of PP796 was selected for paraquat formulations based on an inadequate phase II study. Currently, evidence that PP796 at 0.05% in paraquat SL20 causes more rapid vomiting after ingestion is weak or unpublished; no evidence of clinical benefit or fewer deaths has been identified. There is no evidence to support the FAO/WHO Joint Meeting on Pesticide Specifications mandate to include PP796 or any other emetic in paraquat products. Products with higher emetic concentrations have been developed but are not widely used; it is possible they may prevent deaths.