Safety assessment of β-nitropropionic acid: a monograph in support of an acceptable daily intake in humans

Abstract

Abstract Several molds, Aspergillus, Penicillium and to a lesser extent, Arthrinium can produce β-nitropropionic acid (NPA). The presence of NPA has been detected in at least four families of higher plants. Use of Aspergillus as an economic mould in the production of foods and the accidental contamination of foods provides for an historically lengthy and widespread exposure of humans to NPA. Despite widespread consumption of foods containing NPA, human poisoning by NPA is rare and confined to circumstances involving gross mishandling of the food products. NPA is absorbed in the gastrointestinal tract, enters the circulation and is metabolized to nitrite, although some may bind succinate dehydrogenase upon oxidation. The primary mechanism of toxicity of NPA is as a “suicide” substrate (non-competitive inhibitor) of succinate dehydrogenase, an enzyme of the mitochondrial membrane (part of Complex II) that catalyzes the oxidation of succinate to fumarate, which is manifested as pathological change in striatal areas of the brain. The physiological damage caused by NPA metabolic compromise resembles the genetic disorder, Huntington's disease. This resemblance has been extensively exploited in recent years to understand the mechanisms of neurodegeneration. There are no irreversible effects resulting from ingestion of subthreshold doses of NPA, nor is there any accumulation of NPA in the body. The LD 50 dose of NPA for mice and rats is between 60 and 120 mg/kg. In long-term studies, NPA did not exhibit carcinogenicity or chronic toxicity. The reported no observed adverse effect level (NOAEL) for NPA is 2.5 and 3.75 mg/kg/day for male and female rats, respectively. Results of mutagenicity tests are mixed, but positive assays can be traced back to the use of a single impure sample of NPA. Based on the NOAEL of the chronic rodent bioassay, an ADI of 25 μg/kg/day or 1.750 mg/day for a 70 kg human is appropriate.