Toxicokinetics of 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA) in the European corn borer,Ostrinia nubilalis (Hübner)

2,4-Dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA), the major hydroxamic acid present in corn, and its tritiated derivative, were prepared synthetically for use in the determination of the toxicokinetics of this insect deterrent in the European corn borer (ECB),Ostrinia nubilalis. In growth studies with DIMBOA (0, 0.05, 0.2, and 0.5 mg/g diet), the mean time to pupation and adult emergence were significantly lengthened by an increase in concentration. Pupal and adult weights, for both female and male, decreased with an increase in concentration. Increased larval and pupal mortality occurred at the highest concentration of DIMBOA. DIMBOA, at concentrations of 0.2 and 0.5 mg/g diet, resulted in a decrease in the number of egg masses produced per female, and at 0.5 mg/g diet, in a decrease in the number of eggs per egg mass. Larvae fed from the neonate stage on a diet containing 0.2 mg [³H]- + [¹H]DIMBOA/g diet showed an increase in the content of label from fourth to fifth instar, but levels declined at pupation and emergence. A large amount of the labeled compounds was excreted by the insect in the pupal case. In dose-related studies, both uptake and excretion increased with an increase in concentration of DIMBOA (0.05, 0.2, 0.4 mg/g diet), while a body burden (concentration in the tissues/concentration in the frass) of approximately 0.25 was maintained for all concentrations. At the highest dose of DIMBOA (0.4 mg/g), the ECB increased consumption, possibly to compensate for the toxic effects of the compound. In topical application studies, elimination of the labeled compound in the frass was rapid, reaching 65% by 4 hr and 88% by 48 hr. Accumulation of label in tissues other than hemolymph was low. The results show that the ECB does possess adaptive mechanisms to deal with the effects of this host-derived compound.     

TOXICOKINETICS OF POLYCYCLIC AROMATIC HYDROCARBONS FROM CONTAMINATED SEDIMENT BY THE AMPHIBIAN LARVAE (PLEURODELES WALTL)

The molecular phototransformation mechanism of nitroarenes, genotoxic and ubiquitous pollutants in the atmosphere, is still under debate. With increasing exposure to radiation 1,6- and 1,8-dinitropyrene (DNP) in acetonitrile showed a decrease in their characteristic absorption bands (396 and 411 nm, respectively) in the presence of O ₂ , N ₂ and H ₂ O, and an increase in the 220–390 nm region and above 450 nm, indicating their photodegradation and transformation. The resulting photoproducts were highly fluorescent, presenting a broad emission band around 520–540 nm. Oxygen reactive species did not seem to be produced in the principal photodegradation pathways, since photodegradation rates were similar to those in anaerobic samples. In the presence of O ₂ or N ₂ 1,6-DNP photodegraded 4 times faster than 1,8-DNP, while in the presence of water is 1.5 times faster. Two chromatographic fractions were separated, and identified as pyrenediones using authentic samples and reported spectral data for hydroxy-nitropyrenes. Other chromatographic fractions are still to be identified. The properties of the identified products suggested that these were formed through a nitro-nitrite rearrangement.     

Toxicokinetics and recovery studies of dicamba dimethyl amine salt in goats following single oral administration

BACKGROUND: Toxicokinetics and recovery studies of dicamba dimethyl amine salt (DDAS) were conducted to obtain more information about its toxicity and tissue retention in farm animals. RESULTS: The minimum oral toxic dose level of DDAS was determined as 1400 mg kg^?1 body weight. In the toxicokinetic study, blood DDAS concentration of 55.6 ± 0.59 µg mL^?1 (mean ± standard error) was detected at 0.08 h, which peaked to 102.3 ± 5.03 µg mL^?1 at 0.25 h, and declined to a minimum of 4.1 ± 0.06 µg mL^?1 at 36 h. In recovery studies, DDAS concentration in urine began to increase significantly (P < 0.05) from 12 h, peaked at 24 h and declined from 48 h onwards. Maximum excretion through faeces was at 24 h and was complete by 144 h. The residual level in tissues decreased significantly (P < 0.05) on day 7 as compared to day 4. In histopathological studies, cellular alterations in lungs, liver, kidney, adrenal gland and spleen were found. CONCLUSION: DDAS persists in the body for a shorter period and its major excretory route is through urine. DDAS has lower affinity to accumulate in tissues, and intensity of cellular alterations is not severe after single‐dose oral administration. Copyright © 2009 Society of Chemical Industry     

HPLC 法测定马兜铃酸Ⅰ在大鼠体内的浓度及其毒代动力学

目的:建立大鼠血浆中马兜铃酸Ⅰ的HPLC测定方法, 采用单次灌胃给药毒性研究的3种剂量对马兜铃酸Ⅰ进行毒代动力学的初步研究, 了解在毒性实验条件下马兜铃酸Ⅰ所达到的全身暴露与毒性之间的内在联系。方法:大鼠分别灌胃给予马兜铃酸Ⅰ 100、30、10 mg/kg, 测定不同时间点的血浆药物浓度, 应用统计矩的方法对血药浓度-时间数据进行拟合并计算毒代动力学参数。结果:测定方法的最低定量浓度为0.02 mg/L, 线性范围为0.02 ~ 40.00 mg/L, 回收率在82.4 %~101.2 %之间, 日内、日间RSD 小于1.0 %。100、30、10 mg/kg 3 个剂量组的主要毒代动力学参数如下:t_1/2α分别为(0.8 ±0.4)、(0.9 ±0.7)、(1.0 ±0.8) h ;t_1/2β分别为(34 ±19)、(133 ±64)、(114 ±50) h ;t_max 分别为(0.31 ±0.12)、(0.25 ±0.00)、(0.38 ±0.19) h ;C_max 分别为(3.0 ±1.7)、(1.1 ±0.7)、(1.0 ±0.7) mg/L ;AUC_(0-48) 分别为(18 ±3) 、(18 ±2) 、(21 ±5) mg^。L^{-1 。}h。结论:该方法重现性好、灵敏度高, 适用于大鼠血浆中马兜铃酸Ⅰ的测定。马兜铃酸Ⅰ能迅速吸收入血, 随后快速分布、缓慢消除。在毒性剂量下, 马兜铃酸Ⅰ在大鼠体内的毒代动力学过程具有非线性动力学性质。     

Oral Toxicokinetics,Tissue Distribution,and 28-Day Oral Toxicity of Two Differently Manufactured Food Additive Silicon Dioxides

(1) Background: Synthetic amorphous silica (SAS) is widely used as a food additive and contains nano-sized particles. SAS can be produced by fumed and precipitated methods, which may possess different physiochemical properties, toxicokinetics, and oral toxicity. (2) Methods: The toxicokinetics of fumed SAS and precipitated SAS were evaluated following a single-dose oral administration in rats. The tissue distribution and fate of both SAS particles were assessed after repeated oral administration in rats for 28 d, followed by recovery period for 90 d. Their 28-d repeated oral toxicity was also evaluated. (3) Results: Precipitated SAS showed higher oral absorption than fumed SAS, but the oral absorption of both SAS particles was low (<4%), even at 2000 mg/kg. Our tissue-distribution study revealed that both SAS particles, at a high dose (2000 mg/kg), were accumulated in the liver after repeated administration for 28 d, but the increased concentrations returned to normal levels at 29 d, the first day of the recovery period. A higher distribution level of precipitated SAS than fumed SAS and decomposed particle fates of both SAS particles were found in the liver at 28 d. No significant toxicological findings were observed after 28-d oral administration, suggesting their low oral toxicity. (4) Conclusions: Different manufacturing methods of SAS can, therefore, affect its oral toxicokinetics and tissue distribution, but not oral toxicity.     

Short communication: Toxicokinetics of ochratoxin A in dairy ewes and carryover to milk following a single or long-term ingestion of contaminated feed

Ruminal microbes have the capacity to inactivate ochratoxins, rendering ruminants less sensitive to this fungal contaminant found in cereal feeds. However, ochratoxin A has been reported in milk surveys. The objective of this study was to assess the toxicokinetics, excretion, and transmission into milk of ochratoxin A using doses similar to those of naturally occurring field contaminations. Six Lacaune dairy ewes in late lactation were separated into 2 groups that received a single dose of contaminated wheat containing 5 or 30 μg of ochratoxin A/kg of body weight. After administration, toxicokinetics and excretion were monitored for 48 h. Subsequently, ewes were administered the corresponding toxin dose daily for 24 d followed by a second toxicokinetics and excretion monitoring period for this long-term exposure. The doses used did not affect production or health of ewes. After a single dose, ochratoxin A and its main metabolite, ochratoxin α, were found in blood 1 h postexposure. The maximum blood concentrations of ochratoxin A and α, respectively, were dose dependent and were observed, on average, 6 and 8 h after exposure. Long-term exposure increased the maximum concentration of ochratoxin A detected in blood, whereas ochratoxin α was not affected. In contrast, the time to reach the maximum concentration was reduced to 3 h for both molecules. Ochratoxins, essentially ochratoxin α, were mainly excreted in feces. Ochratoxin A and α were detected in milk at concentrations that were dose dependent but with a low carryover rate (<0.02%). Chronic administration did not increase the concentration of toxin in milk. Even though ochratoxin A can escape ruminal degradation and traces were found in milk of experimentally exposed ewes, the low carryover of ochratoxin A in milk minimizes the risk to consumers.     

Pharmacokinetic,toxicokinetic, and bioavailability studies of epigallocatechin-3-gallate loaded solid lipid nanoparticle in rat model

Epigallocatechin-3-gallate (EGCG), derived from green tea, is an active phytochemical against many types of cancer, cardiovascular, neurological and inflammatory diseases. However, its pharmaceutical activity is limited due to low bioavailability and chemical instability. To overcome these limitations, we fabricated spherical, EGCG loaded solid lipid nanoparticles (SLN-EGCG) as an oral delivery system. The SLN-EGCG showed a hydrodynamic diameter of 300.2?±?3.8?nm with the drug encapsulation efficiency of 81?±?1.4%. Additionally, a slow and sustained release of EGCG was noted. Mathematical modeling of release kinetic data suggested that the SLN-EGCG followed the Higuchi model and released EGCG via fickian diffusion method. The data on pharmacokinetic parameters indicated significantly improved bioavailability and protection of EGCG from degradation due to encapsulation into SLN. The SLN-EGCG did not show any acute or sub-chronic toxicity when compared with free EGCG in the rat model. Together these data supported the hypothesis that SLN-EGCG is capable of enhancing the bioavailability and stability of EGCG and can be used as an alternative system for oral administration of EGCG.     

Effects of live yeast cell supplementation to high concentrate diets on the toxicokinetics of ochratoxin A in sheep

Previous studies have indicated that high concentrate feeding reduces the ruminal degradation of the mycotoxin ochratoxin A (OA) to the less-toxic ochratoxin α (Oα) in ruminants. This is due to a pH-induced decrease in ruminal protozoa and subsequent increasing transfer of OA into the systemic circulation. The present study investigated whether stabilization of rumen pH by the live yeast cell supplementation to high concentrate diets affects the toxicokinetics of OA in sheep. Sheep were fed diets consisting of 70% concentrates and 30% grass silage (dry matter basis) supplemented without or with live yeast cells (Saccharomyces cerevisiae CNCM I-1077). After an adaptation period of 3 weeks, animals were given a single dose of OA (2.46 mg) in the form of contaminated wheat. Even though live yeast cells accelerated the recovery of ruminal pH from the decrease in pH induced by feeding, no effect on ruminal degradability and systemic availability of OA was recorded. Based on in vitro studies, live yeast cells and extracts of live yeast cell walls have been suggested as a mycotoxin-binding agent. However, supplementation with live yeast cells had no effect on the excretion pattern of OA in sheep, indicating that binding of OA to yeast components may be limited in ruminants. With respect to the toxicokinetics of OA, our results are in agreement with earlier results demonstrating that the hydrolysis of OA in the gastrointestinal tract of sheep is substantially less than previously described, especially if OA is ingested in combination with concentrate-rich diets. Our study demonstrates that feeding a live yeast cells product, registered as a feed additive for improving zootechnical performance, had no impact on the toxicokinetics of OA under the chosen conditions.     

Toxicity and toxicokinetics of 6-methoxybenzoxazolinone (MBOA) in the european corn borer,Ostrinia nubilalis (Hübner)

The maize-derived secondary chemical 6-methyoxybenzoxazoii-none (MBOA) and a tritiated derivative were prepared synthetically for a detailed examination of their toxicity and toxicokinetics in the European corn borer (ECB),Ostrinia nubilalis. During feeding trials with MBOA incorporated into meridic diets (at 0, 0.5, 1.5, 2.5, and 4.0 mg/g diet), the mean time to pupation and adult emergence was significantly lengthened at concentrations of 1.5 mg MBOA/g diet and above. Increased mortality occurred at concentrations at 1.5 mg/g and above. A decrease in the sex ratio (female/ total) and fecundity was observed at concentrations of 0.5 mg/g and above. The latter observations represent new biological effects related to MBOA. In tracer studies, both uptake and excretion of MBOA administered in diets to larvae increased linearly with concentration. Body burden values indicated that the ECB larvae were capable of excreting enough compound to maintain total tissue levels at approximately 50% of the dietary concentration. Total amount of label increased with larval stage, but decreased in adults due to a large amount of label eliminated in the pupal case. In topical application studies, elimination of the label in the frass was rapid, reaching 60% by 6 hr and 82% of applied dose by 24 hr. Accumulation of label in tissues other than hemolymph was small. The results show that MBOA is toxic to ECB, but the insect has efficient methods for minimizing these effects.