Pulegone is found in the essential oil of several mints, including Pennyroyal. These mints are used in flavoring food and beverages. The use of Pennyroyal oil, which contains about 85% pulegone, as an abortifacient has resulted in serious toxicity and death. Pulegone has been nominated to the NTP for toxicity and carcinogenicity studies. Pulegone is metabolized by rats by three major pathways: 1) hydroxylation followed by glucuronidation; 2) reduction to menthone/isomenthone followed by hydroxylation; 3) Michael addition of glutathione. Metabolism of pulegone in mice differs from rats in that several mercapturic acid and aromatic metabolites identified in rat urine are not present in mouse urine. The lack of mercapturic acid metabolites which result from reactive intermediates correlates with the observation that pulegone is less toxic to mice in the NTP studies. However, there are literature reports that high doses of pulegone deplete GSH in mice. Bile duct cannulation studies in mice revealed the presence of metabolites formed from direct addition of GSH to pulegone. Probably due to differences in transport, GSH adducts in rats are converted in liver and kidney to mercapturic acids, while in mice the adducts are excreted in bile. In both rats and mice the GSH adducts and /or the corresponding mercapturic acids are derived from direct conjugation via Michael addition with pulegone. The accepted mechanism for pulegone toxicity is metabolism first to menthofuran followed by further oxidation of the furan ring to an enonal. Interestingly none of the nearly 20 pulegone metabolites we have identified are unambiguously required to be formed via the menthofuran enonal pathway. Metabolism studies of menthofuran in male rats revealed 4 urinary metabolites common to both chemicals supporting the intermediacy of menthofuran in pulegone metabolism. Other menthofuran metabolites were clearly derived from oxidation of the furan ring followed by reaction with nucleophiles such as GSH, water, sulfite, and taurine, verifying the postulated reactive intermediate. The identification of the latter metabolites are the first in vivo metabolites of a furan that unambiguously arise from reaction of biological nucleophiles with the enonal intermediate since the first evidence for the intermediate was presented over 20 years ago. The focus of research now and in the near future will be on a class of flame retardants, polybrominated diphenyl ethers (PBDE). PBDE?s are produced commercially as mixtures based on bromine content. For instance, Great Lakes DE-71? (DE-71) is a commercial mixture containing 71% bromine used primarily as a flame retardant in polyurethane foams. DE-71 contains penta-, tetra- , and hexa-brominated diphenyl ethers. PBDE?s came into use in the 1970?s and as a consequence of their highly lipophilic nature have accumulated over time in soil, sediment, air, and biota. PBDE?s are found in mammalian tissues and fluids, including human adipose, serum, and milk. The most prevalent congeners in human samples are BDE-47 (a tetraBDE), BDE-99, and BDE-100 (both pentaBDE?s). These are also the main congeners in the DE-71 commercial mixture. Little toxicological characterization, including carcinogenic potential, has been made for these and other DE-71 congener components. Therefore the NTP is currently designing a 2-year bioassay for the DE-71 mixture. PBDE?s have relatively low acute toxicity and appear to be non-mutagenic. However, PBDE congeners are structurally similar to TCDD and PCB?s and may have mechanisms of toxicity in common with those chemicals. Additionally, BDE-47 and some other congeners are structurally similarity to thyroxin and may interfere with thyroid hormone controlled pathways. In rodents, there is evidence of endocrine disruptor activity as well as developmental neurotoxicity following exposure to DE-71. BDE-47 makes up 24-38% of commercial DE-71 is a major PBDE congener found in the environment. The distribution of BDE-47 in tissues of male F344 rats following single and repeated exposure to the compound at doses closer to human exposure than those of published studies has been determined. Rats received either 1, 5, or 10 consecutive daily doses of 0.1 ?mol 14C BDE-47/kg by gavage in corn oil. Tissue distribution of 14C was determined 24 hr following the last daily dose. Adipose tissue was the major depot of 14C, containing up to 50% of each daily dose. BDE-47-derived 14C accumulated extensively in skin, thymus, adrenal, and thyroid and to a lesser extent in liver, brain, blood, and muscle. The disposition of BDE-47 was further investigated following oral administration of single doses from 1-1000 ?mol/kg in corn oil. Analysis of major tissues and excreta indicated that both absorption of BDE-47 and tissue distribution of 14C were dose-proportional in this range. Cumulative 24 hr excretion was ca. 0.5 and 35% total dose in urine and feces, respectively. A comparison of oral and iv excretion data indicated that ca. 70% of an orally administered BDE-47 dose was absorbed from the gut. The disposition of 14C-BDE-99, the major congener in DE-71, was studied in male F344 rats in single dose studies at 0.1 to 100 umoles/kg. Animals were dosed orally and iv. Based on the radioactivity excreted in feces (and present in the large intestine at termination) after oral and iv administration 80-90% of the single oral dose is absorbed. After a single oral dose, BDE-99 concentrates in fat (17-23% of the total dose after 24 hours) and is excreted in the feces (35-38%), with less than 2% in urine. There is no dose effect on tissue distribution between 0.1 and 10 umol/kg. The liver/fat ratio is about 0.2 indicating that sequestration in liver, typical of dioxin-like chemicals is not occurring (for example, 3, 3?, 4, 4?, 5-PCB, has a liver/fat ratio of about 20 after 24 hr). BDE-99 concentration (after oral dose) was higher in all tissues than in blood, with tissue/blood ratios over 10 in liver, kidney, skin, fat, thymus, and adrenal glands. The amount of BDE-99-derived radioactivity in thyroid is not significantly different from other tissues, such as muscle and lung, and is about an order magnitude less than the amount of PBE-47-derived radioactivity found in thyroid following the same molar dose of PBE-47.
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