Comparative Toxicokinetics of Inhaled Methanol in the Female CD-1 Mouse and Sprague-Dawley Rat

Female CD-1 mice were exposed for 8 hr, both individually andin groups of eight to nine, to 2500, 5000, and 10,000 ppm methanolvapor in a flowthrough exposure chamber. The ventilation ofindividually exposed mice and the absorption of methanol fromthe chamber airstream were measured. The extraction of methanolfrom the airstream and the blood methanol concentration at varioustime points during and following exposure were determined forthe group-exposed mice. The similarity of systemic kinetic parameters(volume of distribution; Michaelis-Menten elimination parameters,V_max and K_M) between inhalation exposure and iv and po routesof administration was verified. Total 8-hr ventilation decreasedslightly with increasing exposure concentration. The fractionof inhaled methanol absorbed (0.85 0.14) did not vary statisticallywith exposure concentration. Measured ventilation, fractionalabsorption, and systemic kinetic parameters were combined ina semiphysiologic pharmacokinetic model that yielded accuratepredictions of blood methanol concentrations during and afteran 8-hr exposure. Model predictions for the mouse were comparedto a previously developed inhalation toxicokinetic model forthe rat. The comparison demonstrated that at similar methanolvapor concentrations, mice evidenced a two- to threefold higherblood methanol concentration than rats, despite the fact thatthe apparent V_max for methanol elimination in the mouse is twofoldlarger than that in the rat. These data may have significantimplications in understanding species differences in methanol-inducedteratogenic effects.     

Toxicokinetics of Intravenous Methanol in the Female Rat

The toxicokinetics of intravenously administered methanol wereexamined in female Sprague-Dawley rats. Animals received a singleadministration of 100, 500, or 2500 mg methanol/kg; the twolower doses were administered as a bolus, while the high dosewas administered over 1.5 min. A small (approximately 3%) butstatistically insignificant (p>0.1) degree of transpulmonarymethanol extraction, expressed as the fractional arterial-venousdifference in concentration, was observed after administrationof 250 mg methanol/kg. The elimination of methanol from thesystemic circulation was markedly nonlinear, suggestive of asignificant capacity-limited route of elimination. A singleset of kinetic parameters (apparent distributional volume ofthe central compartment [V_c], intercompartmental transfer rateconstants [k₁₂ and k₂₁], and V_max and K_m for elimination) describedthe blood methanol concentration-time data from rats receivingthe 100 and 500 mg/kg doses. Blood methanol concentrations declinedmuch more rapidly in animals receiving the 2500 mg/kg dose thanwould be predicted from the kinetic parameters derived fromthe other two experimental groups. The data from the 2500 mg/kggroup could be described adequately by a kinetic model incorporatingparallel first-order and saturable elimination processes. Aportion of this apparent linear elimination pathway was dueto renal excretion of the unchanged alcohol. The presence ofboth linear and nonlinear elimination pathways for methanolmay have implications regarding high-dose to low-dose toxicologicextrapolations.     

毒物动力学及与毒效动力学的联接

本文简要报告了肼、甲基肼、偏二甲基肼、苯乙烯、芥氧氮丙烷、丙二醇二硝酸酯、1-和2-位的丙二醇一硝酸酯、甲基丙烯酸甲酯、甲基丙烯酸环氧丙酯、硫膦、甲胺磷的毒物力动学研究结果。结合我们的实际经验,本文讨论了毒物动力学研究的主要目的、对象、内容和范围、经皮接触和吸入接触的毒物动力学研究、毒物动力学与毒效动力学的联接和在毒理学研究中毒物动力学与毒效动力学同步模型的应用。     

Perinatal Methanol Exposure in the Rat: I. Blood Methanol Concentration and Neural Cell Adhesion Molecules

Although the acute toxicity of methanol is well documented,few studies have addressed the consequences of perinatal exposuresto the low concentrations that are expected to arise from itsproposed use as a component of automobile fuel. This reportdescribes the general research design of a series of studies,the effects of methanol exposures on blood concentrations indams and neonates, and indices of brain development. Four cohortsof Long-Evans pregnant rats, each cohort consisting of an exposure(n=12) and a control (n=12) group, were exposed whole-body to4500 ppm methanol vapor or air for 6 hr daily beginning on GestationDay 6. Both dams and pups were then exposed through PostnatalDay 21 (PND 21). Blood methanol concentrations determined bygas chromatography from samples obtained immediately followinga 6-hr exposure reached approximately 500–800 µg/mlin the dams during gestation and lactation. Average concentrationsfor pups attained levels about twice those of the dams. Selectedoffspring from Cohort 4 were exposed for one additional 6-hrsession at ages that extended out to PND 52. Regression analysesshowed that the blood methanol concentrations of the pups declineduntil about PND 48, at which time their levels approximatedthose of their dams. Such pharmacokinetic differences mightincrease the risks posed to developing organisms. Light-microscopicanalysis showed no significant abnormalities in the brains ofthe methanol-treated animals. However, assays of neural celladhesion molecules (NCAMs) in brains of pups sacrificed on PND4 showed staining for both the 140 and the 180 kDa isoformsto be less intense in the cerebellum of exposed animals. NCAMdifferences were not apparent in animals sacrificed 15 monthsafter their final exposure.     

The Metabolism of 5,7-Dinitroindazole in the Mouse and the Rat

Abstract

1. 5,7-Dinitroindazole was extensively metabolized in both rats and mice. The principal biotransformations were nitro group reduction and aromatic hydroxylation.

2. Selective reduction of the 7-nitro group to yield the 7-amino derivative occurred in both species in vivo. The same specificity of reduction was evident when dinitroindazole was incubated with a mixed culture of rat faecal microorganisms.

3. A species difference in conjugation was found. In the mouse the major urinary excretion product was the N-glucuronide of the 7-amino derivative but this was not found in rat urine, acetylation of the 7-amino group being the preferred biosynthetic reaction.

4. This 7-acetamido derivative is the probable precursor of two other metabolites in the rat. One of these has been identified as 3-hydroxy-5-nitro-7-acetamidoindazole and the other may be an N-hydroxylated derivative.     

Toxicokinetics of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Female Sprague-Dawley Rats Including Placental and Lactational Transfer to Fetuses and Neonates

The toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)in virgin female Sprague-Dawley (S-D) rats, the effects of pregnancy,parturition, and lactation on the distribution and/or redistributionof TCDD, and placental and lactational transfer to fetuses andneonates were investigated. Doses of 5.6 µg/kg of ¹⁴C-labeledTCDD were given iv either to virgin rats or to pregnant ratson Day 18 of gestation and 1 day postparturition,, respectively.Virgin females were terminated on Day 1, 2, 4, 8, 16, or 32,pregnant rats on Day 1, 2, 4, or 8, after dosing to collecttissues. Two groups of neonates, which were born either to TCDD-treatedor nontreated dams were crossfostered beginning on the firstday after birth to simulate exposure to TCDD either by lactationaltransfer only or by both placental and lactatlonal transfer.Serum and 18 different tissues were collected from virgin ratsto evaluate the kinetic profile of TCDD. Serum and tissue samplesfrom liver, kidney, brown, and white adipose tissue were collectedfrom pregnant and postparturition rats. Liver samples from fetusesand neonates were obtained on Gestational Days 19 and 20, orpostnatally on Days 1 and 5. TCDD equivalents were caku latedfrom measurement of radioactivity. The results show that theprofile of TCDD distribution in virgin female rats similar tothat in male rats but that the concentration of TCDD in mosttissues was higher in females than in males. The ratios of tissueand serum areas under the curve and the ratio of half-livesbetween females and males were very similar to the ratio ofthe LD50s between male and female S-D rats, suggesting thatthe small gender difference in the acute toxicity of TCDD wasprobably due to the difference in toxicokinetics alone. Pregnancyand parturition as well as lactation significantly altered thetoxicokinetic profile of TCDD probably due to changing bodycomposition during pregnancy and nursing. The results also indicatedthat TCDD was predominantly transferred to the offspring bylactation rather than via the placenta. This highly efficientlactational transfer of TCDD in rats implied that breast feedingof children by mothers can result in effective transfer of TCDDvia mother's milk.     

Perinatal Methanol Exposure in the Rat II Behavioral Effects in Neonates and Adults

The use of methanol as a component of automobile fuel will increaseperinatal exposures in the general population. Few studies haveaddressed questions concerning neurotoxicity stemming from suchexposures. In the current study, four cohorts of pregnant Long-Evansrats, each cohort consisting of an exposure and a control group,were exposed to 4500 ppm methanol vapor in Rochester-type inhalationchambers for 6 hr daily beginning on Gestation Day 6. Exposurecontinued for both dams and pups through Postnatal Day 21 (PND21) to model gestational and neonatal toxicity in humans. Severalbehavioral procedures were used to assess exposure effects inthe offspring. Male-female littermates were studied wheneverpossible to examine sex differences, with one pair from a litterfor each procedure. Exposure to methanol did not affect sucklinglatency and nipple attachment on PND 5 or performance on anaversive olfactory conditioning procedure on PND 10. Exposureto methanol did alter performances in a motor activity procedure.Methanol-exposed neonates were less active on PND 18, but moreactive on PND 25 than the equivalent control group pups. Twooperant conditioning procedures, not used previously in thiscontext, assayed other littermates as adults. A fixed ratioschedule required the rat to rotate a running wheel a specifiednumber of revolutions to obtain food-pellet reinforcers. Whenthe fixed ratio requirement changed, number of responses (revolutions)per 1-hr session displayed a complex interaction with treatment.Changes in performance over the course of training differedbetween males and females depending on exposure to methanol.Compared to initial baseline performances, methanol-exposedmales showed decreases, and methanol-exposed females increases,in the rate of running. A stochastic spatial discriminationprocedure permitted subjects to respond on any three levers,with the probabilities of food-pellet delivery determined bythe location of the preceding response. A reinforcement matrixdefined the response sequence required to maximize reinforcements.When the matrix was changed, the methanol-exposed subjects respondedless efficiently at asymptotic levels of performance than controls.Across procedures, developmental exposure to 4500 ppm methanolvapor was associated with subtle behavioral changes in bothneonates and adults.     

Toxicokinetics of parathion in the rabbit

The plasma kinetics of parathion were studied in rabbits after i.v. administration of a dose of 1.5 mg/kg and oral administration of 3 mg/kg. The time course of parathion plasma levels administered intravenously followed a three-compartment kinetic model statistically, whereas when administration was oral, the optimum kinetic model proved to be two-compartmental. The process of the absorption of parathion is very fast with a mean value for the absorption constant (k_a) of 33±15.41 h^–1. The slow disposition half-lives for i.v. and oral administration had mean values of 5.08±3.08 and 1.08±0.27h, respectively. From the values established for the parameters defining the distribution process the wide accessibility of parathion to the different body organs and tissues may be seen. Although the compound has a high elimination constant, this process is not limiting to distribution.     

Toxicokinetics of permethrin in the rat

The toxicokinetics of permethrin after single 460 mg/kg oral and 46 mg/kg intravenous doses were studied in male Sprague-Dawley rats. Serial blood samples after oral and intravenous dosage, and brain, medulla oblongata, sciatic nerve, and liver samples after oral administration were collected. Plasma, hypothalamus, cerebellum, frontal cortex, caudate putamen, hippocampus, medulla oblongata, sciatic nerve, and liver concentrations of permethrin and its metabolites, m-phenoxybenzyl alcohol and m-phenoxybenzoic acid, were determined by a high-performance liquid chromatographic assay. The permethrin plasma profile could be adequately described by a two-compartment open model. For permethrin, the elimination half-life (t1/2 beta) and the mean residence time from plasma were 8.67 and 11.19 hr after i.v. and 12.37 and 17.77 hr after po administration. The total plasma clearance was not influenced by dose concentration or route and reached a value of 0.058 liter/hr. After the single oral dose, permethrin was absorbed slowly with a Tmax of 3.52 hr. The maximum plasma concentration was 49.46 micrograms/ml. The oral bioavailability of permethrin was found to be 60.69%. The plasma concentration-time data for permethrin metabolites as well as the tissue concentration-time data for permethrin and its metabolites after an oral dose of permethrin were found to fit a one-compartment open model. The elimination half-life (t1/2el) of permethrin was greater for the hippocampus, medulla oblongata, frontal cortex, and sciatic nerve (23.10, 22.36, 13.86, and 16.27 hr, respectively) than for plasma (t1/2 beta, 12.37 hr). The maximum amounts of permethrin in cerebellum, hippocampus, caudate putamen, frontal cortex, hypothalamus, and sciatic nerve were about 1.5, 2, 2, 2.7, 4.8, and 7.5 times higher than in plasma, respectively, indicating an accumulation of pyrethroid by nervous tissue itself. Nervous tissue accumulation of permethrin was also reflected by the area under the concentration curve ratios of tissue/plasma (1.16, 3.71, 1.57, 4.27, 3.48, and 8.77, respectively). The metabolites of permethrin, m-phenoxy-benzyl alcohol and m-phenoxybenzoic acid, were detected in plasma and in all selected tissues for 48 hr after dosing, suggesting that a combination of metabolism by the tissues and diffusion into it from the blood may be present.     

Effects of Hepatic Inducers on Testicular Epoxide-Metabolizing Enzymes in the Rat and Mouse

Effects of Hepatic Inducers on Testicular Epoxide-MetabolizingEnzymes in the Rat and Mouse. DIBIASIO, K. W., SILVA, M. H.,HAMMOCK B. D., AND SHULL, L. R. (1989). Fundam. Appl. Toxicol.12, 449–459. Testicular toxicants have become of increasingimportance, necessitating a better understanding of the possiblerole of testicular xenobiotic metabolism. The responsivenessof testicular microsomal epoxide hydrolase (mEH), cytosolicepoxide hydrolase (cEH), and cytosolic glutathione S-transferase(cGST to hepatic inducers was studied in sexually mature maleF344 rats and CD-1 mice. The hepatic inducers employed werephenobarbital (PB), ß-naphthoflavone (BNF), and butylatedhydcoxyanisole (BHA) which are known to induce cytochrome P-450,cytochrome P-448, and cGST, respectively. Hepatic mEH, cEH,and cGST activities were assessed as positive controls. Measurableactivities of all enzymes studied were present in the testesof both rats and mice. PB, BNF, and BHA produced the expectedeffects on mEH, cEH, and cGST in rat and mouse livers, whereasthe testes were generally nonresponsive to the inducers. Inductionof testicular cGST by PB occurred in mice but not rats and wasthe only testicular effect produced by the hepatic inducersin this study.     

Comparison of the Hepatic and Renal Effects of 1,4-Dichlorobenzene in the Rat and Mouse

The effects of 1,4-dichlorobenzene (DCB) have been comparedin male F344 rats given 0 (corn oil control), 25, 75, 150, and300 mg/kg DCB and male B6C3F₁ mice given 0 (corn oil control),300, and 600 mg/kg DCB by daily oral gavage five days per weekfor 1, 4, and 13 weeks. The two highest rat and both mouse doselevels were the same as those employed In a NTP bioassay, whereDCB produced kidney tumors in male rats and liver tumors inmice. DCB produced significant dose-related increases in relativeliver weight in both the rat and the mouse which was associatedwith, respectively, mild and marked centrilobular hypertrophy.Administration of DCB also produced a sustained induction ofmicrosomal cytochrome P450 content and 7-pentoxyresorufin O-depentylaseactivity in both species. Western immunoblotting studies demonstratedthat DCB induced CYP2B isoenzyme(s) in both rat and mouse livermicrosomes. Replicative DNA synthesis was studied by implantingosmotic pumps containing 5-bromo-2'-deoxyuridine in study Weeks0–1, 3–4, and 12–13. In the rat hepatocytelabeling index values were only increased in animals given 300mg/kg DCB for 1 week, whereas hepatocyte labeling index valueswere significantly increased in mice given 300 and 600 mg/kgDCB for 1 and 4 weeks. DCB treatment produced significant increasesin rat renal P₁/P₂ proximal tubule cell labeling index valuesat all time points, whereas little effect was observed in mousekidney. The observed species difference in DCB-induced livertumor formation may reflect the greater sensitivity of the mouseto tumor promotion by a CYP2B inducer. For the kidney, the presentdata provides further evidence that while DCB-induced a nephropathyis associated with a sustained stimulation of cell replicationin male rat renal proximal tubule cells, this effect is notobserved in the male mouse.     

Human,Rat, and Mouse Metabolism of Resveratrol

Purpose. Resveratrol, a phenolic phytoalexin occurring in grapes, wine, peanuts, and cranberries, has been reported to have anticarcinogenic, antioxidative, phytoestrogenic, and cardioprotective activities. Because little is known about the metabolism of this potentially important compound, the in vitro and in vivo metabolism of trans-resveratrol were investigated. Methods. The in vitro experiments included incubation with human liver microsomes, human hepatocytes, and rat hepatocytes and the in vivo studies included oral or intraperitoneal administration of resveratrol to rats and mice. Methanol extracts of rat urine, mouse serum, human hepatocytes, rat hepatocytes, and human liver microsomes were analyzed for resveratrol metabolites using reversed-phase high-performance liquid chromatography with on-line ultraviolet-photodiode array detection and mass spectrometric detection (LC-DAD-MS and LC-UV-MS-MS). UV-photodiode array analysis facilitated the identification of cis- and trans-isomers of resveratrol and its metabolites. Negative ion electrospray mass spectrometric analysis provided molecular weight confirmation of resveratrol metabolites and tandem mass spectrometry allowed structural information to be obtained. Results. No resveratrol metabolites were detected in the microsomal incubations, and no phase I metabolites, such as oxidations, reductions, or hydrolyzes, were observed in any samples. However, abundant trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate were identified in rat urine, mouse serum, and incubations with rat and human hepatocytes. Incubation with -glucuronidase and sulfatase to release free resveratrol was used to confirm the structures of these conjugates. Only trace amounts of cis-resveratrol were detected, indicating that isomerization was not an important factor in the metabolism and elimination of resveratrol. Conclusion. Our results indicate that trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate are the most abundant metabolites of resveratrol. Virtually no unconjugated resveratrol was detected in urine or serum samples, which might have implications regarding the significance of in vitro studies that used only unconjugated resveratrol.     

Pregnancy Alterations Following Xenobiotic-Induced Delays in Ovulation in the Female Rat

Chlordimeform [N'-(4-chloro-o-tolyl)-N,N-dimethylformamidine]has been shown to cause a 1-day delay in the surge of luteinizinghormone (LH) in ovariectomized, steroid-primed female rats,presumably through its ability to block CNS -noradrenergic receptorsand consequently CNS regulation of anterior pituitary function.In the present study, we determined whether a chlordimeform-induceddelay in the ovulatory surge of LH would alter pregnancy outcomein intact females. Chlordimeform (50 mg/kg) or sodium pentobarbital(35 mg/kg), as a positive control, was administered in orderto delay ovulation 24 (1-day delay) or 48 hr (2-day delay).Females were then housed with proven fertile males on the eveningof proestrus (0-day delay group), the following evening (1-daydelay group), or the evening after that (2-day delay group).The number of receptive females in each group, the mean lordosisquotient, and the number of sperm-positive females in each groupwere recorded. All females were killed on Gestation Day 20.The number of pregnant females in the 1- or 2-day delay groupswas reduced with both chlordimeform and pentobarbital. Also,delaying ovulation for 1 or 2 days with either compound resultedin a significant reduction in the number of live pups presenton Gestation Day 20 and a decrease in the number of implantationsites. Litter size was not affected if the females were matedon the same day that treatment was administered (0-day delay).Pentobarbital did not alter the proportion of females showingsexual behavior or the mean lordosis quotient in the 0- and1-day delay groups, although fewer 1-day females were spermpositive. The number of sexually active and sperm-positive femaleswas reduced in the 2-day pentobarbital-delayed group. However,the lordosis quotient of those that were sexually active wasnot different than that of control. Similarly, in CDF-treatedgroups, the proportion of females showing sexual activity wasreduced in the 0- and 2-day delayed groups. In contrast, sexualbehavior was lower in the 0-day delayed females when tested2 hr after lights out. These females did eventually mate, however,as confirmed by the high incidence of sperm positive smearsthe following morning. The number of sperm positive femaleswas lower in both the 1- and 2-day chlordimeform-induced delaygroups. Thus, brief exposures to compounds such as formamidinepesticide chlordimeform will result in not only a delay in breedingbut, more importantly, a significant reduction in litter size.     

Toxicokinetics in the evaluation of toxicity data

Toxicokinetics provides a powerful tool, which is not used sufficiently in the conduct and interpretation of animal toxicity studies. In selecting doses for toxicity studies toxicokinetic data can be used effectively. The tools of toxicokinetics are limited only by the toxicologists' understanding of basic biologic mechanisms. More knowledge on mechanisms of action implicates the possibility of more detailed toxicokinetic models. Physiologically based pharmacokinetic models are valuable in the interpretation of animal toxicity studies. They provide a physiological basis for extrapolating between species and routes of administration, and the future use of these models in setting acceptable levels of exposure for non-cancer toxicity in humans deserves serious consideration.     

Toxicokinetics of methyl paraoxon in the dog

The toxicokinetics of methyl paraoxon, the active metabolite of the organophosphorus insecticide methyl parathion, were studied in non-anaesthetized dogs after intravenous (2.5 mg/kg) and oral (15 mg/kg) administration of methyl paraoxon. After intravenous administration, distribution and elimination occured very rapidly and using the data from 5 min post-injection, the plasma concentration versus time curves could be fitted to a one-compartment open model. The mean half-life of elimination was 9.7 min, the average volume of distribution 1.76 l/kg and the average plasma clearance 126 ml/kg/min. After oral administration, peak plasma concentrations were obtained within 3–16 min, and the bioavailability varied from 5 to 71%. The hepatic extraction of methyl paraoxon measured in anaesthetized dogs, was high (70–92%). Comparison of the urinary excretion after intravenous and oral administration in two dogs indicated a gastrointestinal absorption of more than 60%. The kinetics of methyl paraoxon were linear in the dose range tested.     

The Hormonal and Antifertility Activity of 2,6-cis-Diphenylhexamethylcyclotetrasiloxane in the Female Rat*

Abstract: An organosilicon compound, 2,6-cis-diphenylhexamethylcyclotetrasiloxane, cyclic 2,6-[(PhMeSiO)₂(Me₂SiO)₂], was shown to be an orally active estrogen in the mature castrate rat; about 1.0 mg/kg is equivalent to 0.005 mg/kg estradiol benzoate used as a maximum stimulatory dose in a uterotropic assay. Cyclic 2,6-cis-[(PhMeSiO)₂ (Me₂SiO)₂] is not an antiestrogen. Cyclic 2,6-cis-[(PhMeSiO)₂ (Me₂SiO)₂] is an effective oral postcoital antifertility agent when administered at 0.33 mg/kg on days 1–5 of gestation and at 3.0 mg/kg given on day 1 of gestation. The primary effect appeared to be accelerated passage of ova to the uterus and induction of ovum destruction in the oviduct. At the doses used cyclic 2,6-cis-[(PhMeSiO)₂ (Me₂SiO)₂] was similar to diethylstilbestrol in that tubal retention did not occur as shown for estradiol benzoate. Administration of cyclic 2,6-cis-[(PhMeSiO)₂ (Me₂SiO)₂] at other times during gestation terminated pregnancy during primitive streak and neurula stages (days 8–11). Gestation was less sensitive to organosiloxane treatment during implantation. Pregnancy was not terminated after day 11. Thus, this purely organosilicon compound represents a new class of moderate estrogens and may be useful in the study of estrogen structure-activity relationships.     

Assessment of Offspring Development and Behavior Following Gestational Exposure to Inhaled Methanol in the Rat

The prospect of widespread human exposure associated with itsuse as an alternative fuel has sparked concern about the toxicpotential of inhaled methanol (MeOH). Previous studies haverevealed congenital malformations in rats following inhaledMeOH (Nelson et al. (1985). Fundam. Appl. Toxicol. 5,727–736)but these studies did not include postnatal behavioral assessment.In the present study, pregnant Long–Evans rats were placedin exposure chambers containing 15,000 ppm MeOH or air for 7hr/day on Gestational Days (GD) 7–19. The total alveolardose of methanol was estimated at about 6.1 g/kg/day, for atotal dose of about 42.7 g/kg for the entire study. Maternalbody weights were recorded daily and blood methanol concentrationswere determined at the end of exposure on GD 7, 10, 14, and18. Following birth (Postnatal Day 0 [PND 0]), a number of testswere performed at various points in development, including:offspring mortality and body wt (PND 1, 3), motor activity (PND13–21, 30, 60), olfactory learning (PND 18), behavioralthermoregulation (PND 20–21), T-maze learning (PND 23–24),acoustic startle response (PND 24, 60), reflex modfficationaudiometry (PND 60), pubertal landmarks (PND 31–56), passiveavoidance (PND 72), and visual-evoked potentials (PND 160).Maternal blood MeOH levels, measured from samples taken within15 mm after removal from the exposure chamber, declined fromabout 3.8 mg/ml on the first day of exposure to 3.1 mg/ml onthe 12th day of exposure. MeOH transiently reduced maternalbody wt (4–7%) on GD 8–10, and offspring BW (5%)on PND 1. No other test revealed significant effects of MeOH.Prenatal exposure to high levels of inhaled MeOH appears tohave little effect on this broad battery of tests beyond PND1 in the rat.     

阿多拉扶正霖对老龄雌性小鼠微核和肝功能的影响

阿多拉扶正霖（ADL）是一种新开发的抗辐射药物，为了临床上的安全使用，特选用老龄雌性昆明种小鼠进行骨髓嗜多染红细胞微核率和肝功能的检测。结果表明，连续9天灌以ADL的老年雌性小鼠其微核率比相应的对照组降低，差异显著（P＜0．05）。ADL对小鼠的肝功能指标ALT、AST和GGT基本上无改变，差异不显著（P＞0．05）。实验结果提示，ADL对小鼠骨髓细胞不具有细胞遗传毒性，不影响肝功能，临床上使用基本安全。     

Toxicokinetics of labeled amatoxins in the dog

Radioactivities were measured in serum, urine, and bile of dogs at different times after intravenous injection of ¹⁴C-methyl-γ-amanitin (¹⁴C-A) and ³H-O-methyl-dehydroxy methyl-α-amanitin (³H-A). For either substance, the relation between the specific plasma activity C and the time t could be best described with the function . Therefore the linear open two-compartment system was selected as an adequate toxicokinetic model. Most important, the distribution volumes (in the steady state) were in the range of the extracellular space, and the total body clearances were in the range of the dog creatinine clearance. In accordance with former findings for 3H-A, ¹⁴C-A was not bound to plasma proteins. More than 80% of ¹⁴C-A was eliminated in the urine; less than 10% was found in the bile. From these data, two suggestions may be derived for the therapy of Amanita intoxication in man. First, detection in the urine of amatoxins 2 or 3 days after mushroom ingestion points to an ongoing amatoxin absorption or reabsorption from the intestine, and should lead to therapy with adsorbents and, in the absence of diarrhea, with laxatives. Second, hemoperfusion will remove significant amounts of amatoxins during the time of ongoing absorption or reabsorption and a few hours thereafter.     

肟硫磷的毒物代谢动力学和毒效学

采用高效液相色谱法 ,测定血清和脑组织匀浆中的肟硫磷 ,揭示其经口染毒 SD大鼠体内的毒物代谢动力学过程 ;以血清丁酰胆碱酯酶 (BCh E)和脑组织乙酰胆碱酯酶 (ACh E)的抑制率及一氧化氮合酶 (NOS)活性为毒效应指标 ,阐明肟硫磷的毒效动力学特征 .给大鼠 ig肟硫磷 2 75mg·kg-1后 ,血清毒物浓度 -时间曲线符合一级吸收一室开放模型 ,ka= 1 .87h-1,Tp=1 .2 6h,Cmax=1 .90 mg· L-1.ACh E抑制效应与血清肟硫磷浓度之间呈逆时针滞后环 .脑组织中 NOS活性随时间进程的异常波动 ,提示 NO参与产生非胆碱能神经毒作用 . BCh E抑制以后不能迅速自动恢复 ,所致酶的“老化”,可能是产生胆碱能效应的直接证据