Review Article: Safety Assessment of the Mycotoxin Cyclopiazonic Acid

Abstract

Cyclopiazonic acid (CPA) is an indol-tetramic acid mycotoxin and is produced by the nearly ubiquitous molds, Aspergillus and Penicillium. CPA produced by these molds has been identified in a number of food sources (including, but not limited to, grain, legumes, meat, milk, and cheese) and from parasitic infections of man and other animals. Few incidents of CPA mycotoxicoses have been reported because of the benign nature of the intoxication, the small amounts present, and its effects may be disguised with concurrent aflatoxicosis (some toxicity data may have been generated using aflatoxin-contaminated CPA). CPA is absorbed in the gastrointestinal tract and following oral administration; it has a half-life of approximately 30 hours and is excreted largely unchanged in the urine and feces. Cyclopiazonic acid is not considered to be a potent acute toxin as its oral LD50 in rodents is in the range of 30 to 70 mg/kg. Multiple dose studies also show a range of effects in several species and among mammalian models, the pig appears to be the most sensitive with a no-observable-effect level (NOEL) in the range of 1.0 mg/kg/day. The preponderance of evidence from the rat and other test animals supports this dose as a defensible estimate of a no effect level. The target organs of CPA toxicity appear to be muscle, hepatic tissue, and spleen, with a localization in the former, although a more apparent toxic change in the latter two. The toxicity and symptoms of CPA poisoning can be attributed to its ability to alter normal intracellular calcium flux through its inhibition of the reticular form of the Ca2+-ATPase pump. CPA was not teratogenic in mice. CPA is not considered a carcinogen and the weight of evidence militates against its characterization as a mutagen. Despite CPA-induced pathological changes ascribed to the spleen or bursa of Fabricius, there does not appear to be an effect on the immune system. In vitro studies imply a potential immunomodulatory effect of CPA, but in all of those reports very high concentrations of CPA were required and none of these findings have been supported with in vivo studies. Therefore, based on a NOEL of 1 mg/kg/day and accounting for species variation, an appropriate acceptable daily intake (ADI) would be approximately 10 μg/kg/day or 700 μg/day. In the context of human exposure, if the uppermost limit of CPA found in cheese is 4 μg/g and the average individual consumes 50 g of cheese daily, this allows an intake of 200 μg, less than one third of a traditionally established ADI.

Peanut and peanut products: A food safety perspective

“…The compound is not considered to be a potent toxin in humans due to low oral LD 50 values, in the range of 30e70 mg/kg in rodents (Antony, Shukla, & Janardhanan, 2003;Nishie, Cole, & Dorner, 1987). On peanuts, the natural level of contamination by this toxin is only 6.5 ppm (Lansden & Davidson, 1983), thus, the compound is toxic to humans only when it is consumed at levels that exceed the natural level of intake of the toxin (Burdock & Flamm, 2000;Van Rensburg, 1984). Further, in most cases, both cyclopiazonic acid and aflatoxin, both produced by Aspergillus flavus, are present concurrently (Urano et al, 1992), and this effectively disguises the presence of cyclopiazonic acid.…”

Clustered genes involved in cyclopiazonic acid production are next to the aflatoxin biosynthesis gene cluster in Aspergillus flavus

“…It was first isolated from Penicillium cyclopium (Holzapfel, 1968). Several species of Penicillium (P. griseofulvum, P. camemberti, P. urticae, and P. commune) and Aspergillus (A. versicolor, A. flavus, A. oryzae, A. tamarii, A. fumigatus and A. phoenicis) were subsequently found to produce CPA (Burdock and Flamm, 2000;Vinokurova et al, 2007). CPA-producing fungi can grow on many substrates, including cheese, meat products, and various grains and seeds.…”

Management and prevention of mycotoxins in peanuts

“…Although not as acutely toxic as aflatoxins (the oral LD 50 in rodents is approximately 30-70 mg kg -1 ), CPA is a potent inhibitor of the reticular form of the Ca 2þ -ATPase pump. A thorough review of the toxicology and a safety assessment of CPA has been published recently (Burdock & Flamm 2000). CPA has been found as a natural contaminant of a variety of commodities and foods, and it was implicated in a human poisoning associated with kodo millet (Rao & Husain 1985).…”