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

Several molds, Aspergillus, Penicillium and to a lesser extent, Arthrinium can produce beta -nitropropionic acid (NPA). The presence of NPA has been d etected in at least four families of higher plants. Use of Aspergillus as a n economic mould in the production of foods and the accidental contaminatio n of foods provides for an historically lengthy and widespread exposure of humans to NPA. Despite widespread consumption of foods containing NPA, huma n poisoning by NPA is rare and confined to circumstances involving gross mi shandling of the food products. NPA is absorbed in the gastrointestinal tra ct, enters the circulation and is metabolized to nitrite, although some may bind succinate dehydrogenase upon oxidation, The primary mechanism of toxi city of NPA is as a "suicide" substrate (non-competitive inhibitor) of succ inate dehydrogenase, an enzyme of the mitochondrial membrane (part of Compl ex II) that catalyzes the oxidation of succinate to fumarate, which is mani fested as pathological change in striatal areas of the brain. The physiolog ical damage caused by NPA metabolic compromise resembles the genetic disord er, Huntington's disease. This resemblance has been extensively exploited i n recent years to, understand the mechanisms of neurodegeneration. There ar e no irreversible effects resulting from ingestion of subthreshold doses of NPA, nor is there any accumulation of NPA in the body. The LD50 dose of NP A 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 observ ed 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 mug/k g/day or 1.750 mg/day for a 70 kg human is appropriate. (C) 2001 Elsevier S cience Ltd. All rights reserved.