Human variability in mercury toxicokinetics and steady state biomarker ratios

Regulatory guidelines regarding methylmercury exposure depend on dose-response models relating observed mercury concentrations in maternal blood, cord blood, and maternal hair to developmental neurobehavioral endpoints. Generalized estimates of the maternal blood-to-hair, blood-to-intake, or hair-to-intake ratios are necessary for linking exposure to biomarker-based dose-response models. Most assessments have used point estimates for these ratios; however, significant interindividual and interstudy variability has been reported. For example, a maternal ratio of 250 ppm in hair per mg/L in blood is commonly used in models, but a 1990 WHO review reports mean ratios ranging from 140 to 370 ppm per mg/L. To account for interindividual and interstudy variation in applying these ratios to risk and safety assessment, some researchers have proposed representing the ratios with probability distributions and conducting probabilistic assessments. Such assessments would allow regulators to consider the range and like-lihood of mercury exposures in a population, rather than limiting the evaluation to an estimate of the average exposure or a single conservative exposure estimate. However, no consensus exists on the most appropriate distributions for representing these parameters. We discuss published reviews of blood-to-hair and blood-to-intake steady state ratios for mercury and suggest statistical approaches for combining existing datasets to form generalized probability distributions for mercury distribution ratios. Although generalized distributions may not be applicable to all populations, they allow a more informative assessment than point estimates where individual biokinetic information is unavailable. Whereas development and use of these distributions will improve existing exposure and risk models, additional efforts in data generation and model development are required.     

In vivo tissue distribution and kinetics of a pseudorabies virus plasmid DNA vaccine after intramuscular injection in swine

Previous biodistribution studies of plasmids following intramuscular or intradermal injections of DNA vaccines have been performed in mice, rats or rabbits, but not in large mammals. The aim of the present study was to determine the biodistribution of plasmids in swine using the PRV-specific DNA vaccination model consisting of a single intramuscular (i.m.) injection of three plasmids individually encoding glycoproteins gB, gC and gD. The weak bioavailability of the plasmids (less than 10%) after i.m. injection was consistent with the tissue distribution study. Plasmids remained in the injected muscle for at least 4 weeks and were also detected in liver, spleen, kidney, lung, remote muscle, lymph nodes and ovaries for shorter periods. Differences in persistence, apparent elimination half-lives and clearance in blood were observed between the three plasmids. In conclusion, the three plasmids behaved differently and were transiently detected in most of the organs tested. The exact persistence in the injected muscle was not determined but exceeded 4 weeks. To date this is the first published DNA vaccine tissue distribution study in large animals.     

Daily intakes of 232Th and 238U in Japanese males.

Diet samples were collected by a duplicate portion method from 31 locations in Japan and were analyzed by inductively coupled plasma mass spectrometry. Average daily intakes per adult male were estimated at 1.7 mBq for 232Th and 8.8 mBq for 238U.     

Radium-226, 232Th, and 40K distribution in the environment of Kaiga of south west coast of India

Systematic studies on gamma radiation level and the distribution of natural radionuclides were carried out under a pre-operational survey for the establishment of baseline data on background radiation level and the distribution of radio-nuclides in the environment of Kaiga, in the south west coast of India, where a nuclear power reactor of 235 MWe has just been commissioned. The external gamma absorbed dose rates prevailing in the region were measured using a portable plastic scintillometer. Soil samples from 18 stations were collected from depth intervals of 0-5, 5-10, and 10-25 cm and analyzed for their 226Ra, 232Th, and 40K activity concentrations by gamma spectrometry employing a 90 cc PGT HpGe detector coupled to an EG&G ORTEC 8K multichannel analyzer. The activity of 226Ra was found to vary between 15.5-61.2 Bq kg(-1) with a mean value of 31.3 Bq kg(-1), that of 232Th varies between 11.4-41.9 Bq kg(-1) with a mean value of 27.5 Bq kg(-1) and of 40K between 78.3-254.8 Bq kg(-1) with a mean value of 159.9 Bq kg(-1) in 0-5 cm soil profiles of the region. The contributions of 238U, 232Th, and 40K to the total gamma absorbed dose rate were 39.9%, 40.7%, and 16.0%, respectively. The gamma absorbed dose rate in air estimated using the results of activity concentration of 226Ra, 232Th, and 40K are found to compare well with that of the direct measurement. The results of the study were compared with the literature values reported for other environs of the country as well as the world, and conclusions are drawn.     

Absorption, tissue distribution and excretion of pelargonidin and its metabolites following oral administration to rats

Recent reports have demonstrated various cardiovascular and neurological benefits associated with the consumption of foods rich in anthocyanidins. However, information regarding absorption, metabolism, and especially, tissue distribution are only beginning to accumulate. In the present study, we investigated the occurrence and the kinetics of various circulating pelargonidin metabolites, and we aimed at providing initial information with regard to tissue distribution. Based on HPLC and LC-MS analyses we demonstrate that pelargonidin is absorbed and present in plasma following oral gavage to rats. In addition, the main structurally related pelargonidin metabolite identified in plasma and urine was pelargonidin glucuronide. Furthermore, p-hydroxybenzoic acid, a ring fission product of pelargonidin, was detected in plasma and urine samples obtained at 2 and 18 h after ingestion. At 2 h post-gavage, pelargonidin glucuronide was the major metabolite detected in kidney and liver, with levels reaching 0.5 and 0.15 nmol pelargonidin equivalents/g tissue, respectively. Brain and lung tissues contained detectable levels of the aglycone, with the glucuronide also present in the lungs. Other tissues, including spleen and heart, did not contain detectable levels of pelargonidin or ensuing metabolites. At 18 h post-gavage, tissue analyses did not reveal detectable levels of the aglycone nor of pelargonidin glucuronides. Taken together, our results demonstrate that the overall uptake of the administered pelargonidin was 18 % after 2 h, with the majority of the detected levels located in the stomach. However, the amounts recovered dropped to 1.2 % only 18 h post-gavage, with the urine and faecal content constituting almost 90 % of the total recovered pelargonidin.     

Lack of ifenprodil anxiolytic activity after its multiple treatment in chronically ethanol-treated rats

AIMS: The purpose of this study was to assess the anxiolytic activity of ifenprodil in Warsaw high-preferring (WHP) and low-preferring (WLP) rats after chronic ethanol treatment. METHODS: WHP and WLP animals, their paired-ethanol-naive groups and control Wistar rats were treated with ifenprodil (1.0 mg/kg, intraperitoneally) for 21 consecutive days. Anxiolytic activity was evaluated by using the two-compartment exploratory test. In addition, the locomotor activity paradigm was also assessed. RESULTS: Ifenprodil did not affect this paradigm in all investigated groups. The ethanol treatment led to lowering of anxiolytic scores in WHP rats. Multiple ifenprodil administration showed an anxiogenic-like activity in both WHP- and WLP-ethanol-treated groups. CONCLUSIONS: Our results suggest that, under some conditions, the role of ifenprodil in the treatment of alcoholism may be insufficient to support its use.     

反高效液相色谱法研究芹菜素在大鼠体内的药代动力学及组织分布

目的建立一个检测大鼠血浆及组织中芹菜素的RP—HPLC分析方法,并对其大鼠体内过程特性进行分析研究。方法生物样品经甲醇沉淀蛋白质,采用RP—HPLC法,色谱柱为Phenomenex C18柱（250×4．6mm,4μm）,流动相为甲醇-0．1％磷酸水溶液-乙腈（25：40：35）,流速1．0ml／min,柱温为30℃,检测波长为339nm。结果测得芹菜素在血浆和组织中的线性范围分别为：0．10～2．00μg／ml（r〉0．999）和0．05～2．00μg／g（r〉0．999）,最低检出限分别为0．03μg／ml和0．02μg／g,日内和日间精密度（RSD）均小于8％。大鼠一次性灌胃给予芹菜素后血芹菜素浓度-时间曲线呈一室模型,半衰期t1／2（116．53±22．55）min。在主要组织脏器分布特点是C肝〉C肾〉C肺〉C卵〉C脂肪〉C脾〉C脑〉C心〉C睾。结论本法准确、灵敏度较高,可用于芹菜素在大鼠体内代谢过程的研究。     

Contributions of 18 food categories to intakes of 232Th and 238U in Japan

Daily intakes of 232Th and 238U and contributions of food categories to those nuclide intakes in Japanese were estimated using a market basket study for 18 food categories. Food categories having higher 238U contents (per g-fresh) were found to be as follows: seaweeds 1,140 microBq; fishes and shellfishes 37 microBq; nuts and seeds 11 microBq; bean products 8.6 microBq; and cooked meals 7.3 microBq. Big contributors to the daily 238U intake in Japan were as follows: seaweeds (50%); fishes and shellfishes (26%); and bean products (4.3%). For 232Th, higher contents (per g-fresh) were found as follows: seaweeds 28 microBq; fishes and shellfishes 13 microBq; nuts and seeds 8.2 microBq; green vegetables 3.9 microBq; cooked meals 3.5 microBq; and bean products 2.9 microBq. Big contributors to the daily 232Th intake were as follows: fishes and shellfishes (44%); green vegetables (11%); bean products (7.4%); and seaweeds (6.0%). For both nuclides, marine food products were big contributors, while minor contributors were oil and fats, eggs, and cooked meals. Daily intakes of 232Th and 238U in Japan were estimated to be 2.7 mBq and 14 mBq per person from the intakes of the 18 categories, respectively. Annual effective doses were estimated to be 232Th, 2.2 x 10(-7) Sv, and 238U, 2.2 x 10(-7) Sv.     

The effects of Thorotrast and quartz on the induction of lung tumors in rats.

In a long-term animal study, the combined and separate effects of Thorotrast (colloidal 232ThO2) and silica dust on the induction of lung tumors were investigated. Female Wistar rats were exposed for 29 d to aerosol concentrations of quartz of either 6 mg m-3, 30 mg m-3, or 0 mg m-3 (6 h d-1, 5 d wk-1). After inhalation, one-half of all exposed animals received a single intravenous injection of enriched Thorotrast (600 microL, 2960 Bq 228 Th mL-1). In all quartz-exposed groups the incidence of benign and malignant lung tumors turned out to be more than 40%. The additional Thorotrast treatment (lifelong exhalation of 220Rn) led to a marked shortening of latency times (first lung tumor was found 1 y after treatment) and to a higher total incidence in the animals exposed to 30 mg m-3 quartz (57 of 87 animals with lung tumors = 65.5%). In the group treated only with Thorotrast, three of 87 animals developed lung tumors. Statistical methods that correct for intercurrent mortality showed a significant increase of the lung tumor risk with respect to Thorotrast treatment, even for the low quartz groups with nearly similar incidences of lung tumors (in the group with ThO2, 39 out of 87 = 44.8%; in the group without ThO2, 37 out of 82 = 45.1%). The tumors were found predominantly in the peripheral regions of the lung and were preceded by proliferation and hyperplasia of the alveolar and bronchiolar epithelium. The results demonstrate a pronounced interactive effect of quartz and Thorotrast on carcinogenesis of the lung. The underlying possible mechanisms are discussed.