苯乙烯吸入染毒在家兔体内的毒物动力学

家兔iv 36.4 mg/kg和inh 3.6 g/m~3苯乙烯,分别符合三室开放模型和零级吸收二室开放模型。毒物动力学基本特征是:经呼吸道的吸收率稳定为56.3％,k_0=0.79±0.20 mg·kg~(-1)·min~(-1),iv和inh染毒在家兔体内分布和消除过程相同;分布快,α=0.138±0.097min~(-1) ,t_(1/2α)=6.8± 3.6min;呈周身分布;消除快,t_(1/2β)=84±69min,Cl_t=36.8ml·kg~(-1)·min~(-1);存在肾外途径消除。inh染毒时呼出气中苯乙烯浓度的动态变化与血相平行。     

The toxicology of inhaled nitric oxide.

Inhaled nitric oxide is a targeted pulmonary vasodilator that improves clinical outcomes for newborn patients with persistent pulmonary hypertension of the newborn, and may be effective in treating some premature patients with acute respiratory distress syndrome or lung disease of prematurity. Nitric oxide is now recognized as playing an important role in the regulation of diverse physiological processes. However, the pharmacological properties of inhaled nitric oxide are not easy to separate from its toxicological effects. For example, the intended effect of inhaled nitric oxide, vasodilation in the lung, is mediated, in part, by increased cellular cyclic GMP (cGMP). However, increased cGMP can also interfere with normal cellular proliferation. Nitric oxide has also been shown to cause DNA strand breaks and/or base alterations that are potentially mutagenic. Inhaled nitric oxide can rapidly react with oxygen in the lung to form nitrogen dioxide, which is a potent pulmonary irritant. Nitric oxide also reacts with superoxide anion to form peroxynitrite, a cytotoxic oxidant that can interfere with surfactant functioning. The overall effect of inhaled nitric oxide in potentiating or attenuating inflammation and oxidative damage in diseased lung is dependent on the dose administered. Furthermore, despite rapid inactivation by circulating hemoglobin, inhaled nitric oxide exerts effects outside the lung, including blocking platelet aggregation, causing methemoglobinemia, and possibly inducing extrapulmonary vasodilation. The toxicology of inhaled nitric oxide is not completely understood and must be considered in the design of protocols for its safe and effective clinical use.     

Reproductive toxicology profile of emtricitabine in mice and rabbits

Reproductive and developmental toxicology studies were conducted with emtricitabine, a nucleoside analog in development for treatment of human immunodeficiency virus (HIV) (Phase III) and hepatitis B (HBV) (Phase III) infections. Oral doses up to 1000 mg/kg/day provided daily area under the curve (AUC(0-->24)) exposure to pregnant animals approximately 60- (mice) to 120-fold (rabbits) higher than that in humans at the recommended dose of 200 mg given once per day. In a mouse fertility study, emtricitabine had no effect on fertility, sperm count, or early embryonic development. There was no increased incidence of malformations in mouse and rabbit embryofetal toxicology studies. The average ratio for concentration of emtricitabine in fetal plasma divided by concentration in maternal plasma was approximately 0.40 in mice and 0.50 in rabbits, a finding that indicates significant exposure of the fetuses to emtricitabine. The development and fertility of F(1) progeny were unaffected by emtricitabine in a mouse pre- and post-natal study. These data demonstrate a favorable pre-clinical reproductive safety profile for emtricitabine.     

Reproductive toxicology of methyldopa in male F344/N rats

Methyldopa, a widely used antihypertensive drug, was administered to male Fischer 344/N rats by gavage 5 days/week for 65 days at dosages of 0, 50, 100, 200, or 400 mg/kg. Decreased body weight was seen in treated animals. After mating to untreated female Fischer 344/N rats on days 57-61, the male rats were necropsied (days 65-67) and reproductive toxicity was measured by sperm count, sperm motility, organ weights, hormone levels and histologic evaluation of the testis. Decreased fertility was seen in males dosed with 200 or 400 mg/kg methyldopa. Decreases were also seen in sperm count, sperm motility, apparent number of late spermatids, and plasma testosterone levels in males in the 200 and 400 mg/kg groups. This alternation of reproductive function in male rats was found to be reversible after a 13-week recovery period without dosing. The marked decrease in circulating testosterone levels following methyldopa treatment at 200 or 400 mg/kg may have contributed to the reproductive toxicity of this drug.     

The toxicology of inhaled woodsmoke

In addition to developing nations relying almost exclusively upon biomass fuels, such as wood for cooking and home heating, North Americans, particularly in Canada and the northwestern and northeastern sections of the United States, have increasingly turned to woodburning as an alternate method for domestic heating because of increasing energy costs. As a result, the number of households using woodburning devices has increased dramatically. This has resulted in an increase in public exposure to indoor and outdoor woodsmoke-associated pollutants, which has prompted widespread concern about the adverse human health consequences that may be associated with prolonged woodsmoke exposure. This mini-review article brings together many of the human and animal studies performed over the last three decades in an attempt to better define the toxicological impact of inhaled woodsmoke on exposed children and adults; particular attention is given to effects upon the immune system. General information regarding occurrence and woodsmoke chemistry is provided so as to set the stage for a better understanding of the toxicological impact. It can be concluded from this review that exposure to woodsmoke, particularly for children, represents a potential health hazard. However, despite its widespread occurrence and apparent human health risks, relatively few studies have focused upon this particular area of research. More laboratory studies aimed at understanding the effects and underlying mechanisms of woodsmoke exposure, particularly on those individuals deemed to be at greatest risk, are badly needed, so that precise human health risks can be defined, appropriate regulatory standards can be set, and accurate decisions can be made concerning the use of current and new woodburning devices.     

Reproductive and developmental toxicity of inhaled 2,3-dichloro-1,3-butadiene in rats

Inhalation developmental and reproductive toxicity studies were conducted with 2,3-dichloro-1,3-butadiene (DCBD), a monomer used in the production of synthetic rubber. In the reproductive toxicity study, Crl:CD^®(SD)IGS BR rats (24/sex/group) were exposed whole body by inhalation to 0, 1, 5, or 50 ppm DCBD (6 h/day) for approximately 10–11 weeks total, through premating (8 weeks; 5 days/week), cohabitation of mating pairs (up to 2 weeks, 7 days/week), post-cohabitation for males (7 days) and from conception to implantation (gestation days 0–7 [GD 0–7]), followed by a recovery period (GD 8–21) for presumed pregnant females. Estrous cyclicity was evaluated during premating (last 3 weeks) and cohabitation. Reproductive organs and potential target organs, sperm parameters, and GD 21 fetuses (viability, weight, external alterations) were evaluated. In the developmental study, pregnant Crl:CD^®(SD)IGS BR rats (22/group) were exposed whole body by inhalation to 0, 1, 10, or 50 ppm DCBD (6 h/day) on GD 6–20; dams were necropsied on GD 21 (gross post-mortem only) and fetuses were evaluated (viability, weight, and external, visceral and skeletal exams). During the in-life portion of the studies, body weight, food consumption, and clinical observation data were collected. At 50 ppm, gasping and labored breathing occurred in both studies during the first few exposures; body weight and food consumption parameters were affected in parental animals from both studies, but were more severely affected in the developmental study. Fetal weight was decreased in the developmental study at 50 ppm. Degeneration of the nasal olfactory epithelium was observed in the reproduction study at 50 ppm. There were no effects on reproductive function, embryo–fetal viability, or increases in fetal structural alterations in either study. The no-observed-adverse-effect level (NOAEL) for reproductive toxicity was 50 ppm. The NOAEL for systemic toxicity in the reproduction study was 5 ppm based on adverse effects on body weight and food consumption parameters and nasal olfactory epithelial toxicity at 50 ppm in parental rats. The NOAEL for maternal and developmental toxicity was 10 ppm based on reduced maternal weight gain and food consumption and reduced fetal weight at 50 ppm in the developmental toxicity study.     

Pulmonary toxicity of inhaled styrene in acetone-, phenobarbital- and 3-methylcholanthrene-treated rats

Pulmonary changes in glutathione (GSH) indicated by the concentration of non-protein sulphydryls showed a decrease of 43% in rats exposed for 5 h per day three times to 500 cm³/m³ (2100 mg/m³) styrene vapour. In these rats, only a marginal decrease was observed in the pulmonary cytochrome P450 oxidative metabolism. Following a single 24-h inhalation exposure to 500 cm³/m³ styrene, the decreases in GSH were 66% in lung but only 16% in liver. On the other hand, a multifold increase in the disposition of thioether compounds was found in urine. Pulmonary cytochrome P450-dependent metabolism was decreased, shown by low residual activities of 7-ethoxyresorufin (<20%), 7-ethoxycoumarin (53%) and 7-pentoxyresorufin O-dealkylases (76%). Epoxide hydrolase and GSH S-transferase enzyme activities which catalyze styrene detoxification were not decreased. Styrene exposure (24 h) of acetone-, phénobarbitalor 3-methylcholanthrene-pretreated rats resulted in pulmonary effects different from each other and from those of styrene alone. Acetone potentiated the lung effect and elevated 1.5-fold urine thioether output. Inducer pretreatment seemed to be a factor aggravating styrene toxicity; in effect this was clearest in acetone-induced rats. In general, GSH depletion accompanied by inhibition of cytochrome P450-dependent oxidative drug metabolism were the earliest biochemical lesions manifested in styrene-exposed lung.     

Reductive metabolism of stilbene oxide and styrene oxide to the olefins in rats

The present study provides the first evidence that stilbene oxide and styrene oxide are reductively metabolized to the corresponding olefins in rats. When cis- or trans-stilbene oxide was given orally to rats, both cis- and trans-stilbene were isolated from the urine and feces. Styrene was also isolated from the urine and feces of rats given styrene oxide. These metabolites were identified unequivocally by UV and mass spectral comparison with authentic samples, and on the basis of their TLC and HPLC behavior. However, these olefins were not detected in the urine or feces of antibiotics-treated rats dosed with cis- or trans-stilbene oxide. Cecal contents of the untreated rats exhibited olefin oxide reductase activities toward cis- and trans-stilbene oxides under anaerobic conditions. The results suggest that intestinal bacteria play an important role in the reduction of olefin oxides to the corresponding olefins in the animal body.     

Reproductive toxicology studies and immunotherapeutics

There are many ways in which immunotherapeutic agents could potentially cause developmental toxicity. According to the published data in humans and animals, however, this class of drugs does not appear to present any increased risk of reproductive toxicity by comparison with other therapeutic classes. The basic testing strategy outlined in the ICH guidelines is suitable for the preclinical reproductive toxicity assessment of these drugs (except vaccines). Particular consideration needs to be given to the choice of species when testing antibodies or human molecules. Immune-active drugs may have the potential to interfere with the development of the immune system. For this reason, it may be advisable to assess the integrity of the immune system in animals previously exposed to the test substance during development. Such tests can easily be appended to the study design of the pre- and post-natal study. In view of the lack of any provision for post-weaning exposure in the guidelines and the late maturation of the immune system, a separate post-natal study may be considered for drugs that are likely to be prescribed to children.     

Review of the toxicology of styrene

Styrene is used in the production of plastics and resins, which include polystyrene resins, acrylonitrile-butadiene-styrene resins, styrene-acrylonitrile resins, styrene-butadiene copolymer resins, styrene-butadiene rubber, and unsaturated polyester resins. In 1985, styrene ranked in the top ten of synthetic organic chemicals produced in the U.S. This review focuses on various aspects of styrene toxicology including acute and chronic toxicity, carcinogenicity, genotoxicity, pharmacokinetics, effects on hepatic and extrahepatic xenobiotic-metabolizing enzymes, pharmacokinetic modeling, and covalent interactions with macromolecules. There appear to be many similarities between the toxicity and metabolism of styrene in rodents and humans. Needed areas of future research on styrene include studies on the molecular dosimetry of styrene in terms of both hemoglobin and DNA adducts. The results of such research should improve our ability to assess the relationship between exposure to styrene and surrogate measures of "effective dose", thereby improving our ability to estimate the effects of low-level human exposures.     

Reproductive toxicity of cabergoline in mice, rats, and rabbits

Cabergoline, a new dopaminergic ergot derivative with potent long-lasting prolactin (PRL)-lowering properties, was assessed using standard reproductive studies in the mouse, rat, and rabbit with oral administration. Because of the compound's pharmacologic activity, several aspects remain incompletely explored in the rat, in which prolactin is the luteotrophic hormone. A fertility study in female rats was possible only at very low doses (0.5, 1, and 2 μg/kg/d) because higher doses completely inhibited implantation. In male rats no adverse effects were seen on male reproductive performance or on the offspring at doses up to 320 μg/kg/d given for 10 weeks prior to mating with untreated females. In a developmental toxicity study in rats treated from day 6 to day 15 of gestation at doses (6.25, 12.5, and 25 μg/kg/d) not exceeding the active dose for inhibition of egg nidation (ED₅₀ = 25 μg/kg), a high incidence of total litter loss occurred as a reflection of inhibition of egg nidation at the highest dose, but embryofetal development was not impaired in litters reaching term. An exploratory study at 30 or 1000 μg/kg/d with treatment from day 5 of gestation or later demonstrated that cabergoline did not affect the maintenance of pregnancy at 30 μg/kg/d given from day 7 or later, or at 1000 μg/kg/d given from day 9. Doses of 500, 2000, and 8000 μg/kg/d (treatment from day 6 to day 15 of gestation) did not inhibit egg nidation in mice and showed no adverse effects on intrauterine development Doses ranging from 5 to 8000 μg/kg/d administered from day 6 to day 18 of gestation in the rabbit were associated with maternal effects, including a reduction in body weight gain and food and water intake starting from 500 μg/kg/d and increased reactivity at the highest doses (4000 and 8000 μg/kg/d). Effects on intrauterine development were restricted to a reduction in mean fetal and placental weights at 4000 and 8000 μg/kg/d. In peri- and postnatal studies in rats (treatment from day 15 or 17 of gestation to weaning) cabergoline did not affect fetal development and parturition up to 100 μg/kg/d, but strongly inhibited milk secretion starting from 10 μg/kg/d, thus leaving unexplored the postnatal phase at higher doses. When neonatal rats (born from untreated dams) were treated directly with cabergoline at 10, 30, and 90 μg/kg/d from day 7 to 13 after birth, treatment was well tolerated up to the highest dose tested (90 μg/kg/d). It was concluded that cabergoline did not impair fertility in the male rat, was not teratogenic in mice and rabbits, did not affect the latter phase of gestation or parturition in the rat, and was not toxic when administered directly to neonatal rats.     

Carcinogenic and toxicologic effects of inhaled ethylene oxide and propylene oxide in F344 rats

The chronic inhalation toxicity and carcinogenicity of ethylene oxide (EO) and propylene oxide (PO) were evaluated in a 2-year inhalation bioassay. Five groups of male weanling Fischer 344 rats, 80 per group, were exposed at 0 ppm (shared control; filtered air), 50 ppm EO, 100 ppm EO, 100 ppm PO, or 300 ppm PO (7 hr/day, 5 days/week) for 104 weeks. Body weights from rats exposed to EO and PO at all exposure concentrations were significantly reduced compared to controls. A statistically significant increase in mortality was observed in all groups of exposed rats compared to controls. Skeletal muscle atrophy in the absence of any sciatic nerve neuropathology was found in rats exposed at 100 ppm EO and 300 ppm PO. Statistically significant associations between EO exposure and an increased incidence of the following rat neoplasms were observed: mononuclear cell leukemia, peritoneal mesothelioma, and mixed cell brain glioma. Among rats exposed to PO there was a dose-dependent increase in the incidence of complex epithelial hyperplasia in the nasal passages, and two adenomas were detected in the nasal passages of rats exposed at 300 ppm PO. The incidence of adrenal pheochromocytomas was elevated in both PO exposure groups, but not in a dose-related manner. All rat groups were affected by an outbreak of Mycoplasma pulmonis infection which occurred about 16 months into the study. This infection alone and in combination with the epoxide exposures affected the survival of rats in this study, and influenced the development of the proliferative lesions in the nasal mucosa of the PO-exposed rats. No treatment-related changes in any clinical chemistry or urinalysis indices were detected. PO exposure did not increase the incidence of the three neoplasms associated with EO exposure; however, adrenal pheochromocytomas and proliferative lesions of the nasal cavity were increased in rats exposed to PO.     

气道滴入肺表面活性物质和吸入一氧化氮治疗经气道肺泡灌洗诱发兔急性呼吸衰竭的效果比较

目的:比较单独或联合应用气道滴入肺表面活性物质(Surf)和吸入一氧化氮(iNO)对急性呼吸窘迫综合征的疗效。方法:成年兔反复气道生理盐水灌洗,去除内源Surf,经机械通气诱发急性肺损伤和呼吸衰竭,随机分组给予:iNO 0.8μmol·L~(-1);Surf磷脂100mg·kg~(-1);联合应用iNO和Surf;或不给药对照。结果:机械通气8小时生存率以联合治疗组为最高,Surf组及联合治疗组的氧合指数(OI)、肺顺应性、气道阻力均有所改善。联合治疗组的肺膨胀有显著改善。结论:对因Surf缺乏而萎陷和损伤的肺,单纯iNO不显治疗效果,但应用Surf或与iNO联合应用,具有提高生存率和改善血氧及肺膨胀的效果。     

Embryotoxicity and fetotoxicity of inhaled or ingested vinylidene chloride in rats and rabbits.

The teratogenic potential of inhaled or ingested vinylidene chloride was evaluated in Sprague-Dawley rats and New Zealand white rabbits. Both species were exposed to the test material by inhalation for 7 hr/day at concentrations of 20 (rats only), 80, or 160 ppm. For the ingestion study, rats were given drinking water containing 200 ppm vinylidene chloride. Rats were given vinylidene chloride from the 6th to the 15th days of gestation and rabbits on the 6th to the 18th days. A teratogenic effect was not seen in rats or rabbits inhaling concentrations of up to 160 ppm vinylidene chloride for 7 hr/day or in rats given drinking water containing 200 ppm vinylidene chloride. Toxicity to both the dams and their developing embryos was observed among the rats inhaling 80 or 160 ppm and among the rabbits inhaling 160 ppm. At exposure levels which caused little or no maternal toxicity (20 ppm in rats and 80 ppm in rabbits), there was no effect on embryonal or fetal development. Among the rats given drinking water containing 200 ppm VDC, there was no evidence of toxicity to the dams or their offspring.     

Reproductive toxicology of acephate in male mice

The reproductive toxicity of the insecticide acephate was studied in male mice. Adult male mice were treated by gavage with acephate at doses of 0, 7, 14, and 28 mg/kg/day for 4 weeks before mating with untreated females. Signs of cholinergic effects were observed in the 28 mg/kg/day group. Brain and skeletal muscle acetylcholinesterase activity was inhibited only in this group. Acephate treatment was associated with a decreased number of implantations and live fetuses, and an increased number of early resorptions at 28 mg/kg/day. The percent morphologically normal spermatozoa was unaffected in all dose groups; however, sperm motility and count were decreased in the 14 and 28 mg/kg/day groups compared to the control. Histologic examination of brain did not reveal any abnormalities. Dose related histologic changes, including degeneration of muscle fibers, were observed in the muscles of male mice treated with any of the doses of acephate. The current study demonstrated adverse effects of male acephate exposure on pregnancy outcome with effects on sperm parameters at 14 and 28 mg/kg/day.     

气道滴入肺表面活性物质和吸入一氧化氮治疗经气道肺泡灌洗诱发 …

目的：比较单独或联合应用气道滴入肺表面活性物质（Ｓｕｒｆ）和吸入一氧化氮（ｉＮＯ）对急性呼吸窘迫综合征的疗效。方法：成年兔反复气道生理盐水灌洗,去除内源Ｓｕｒｆ,经机械通气诱发急性肺损伤和呼吸衰竭,随机分组给予：ｉＮＯ０．８μｍｏｌ．Ｌ＾－１;Ｓｕｒｆ磷脂１００ｍｇ．ｋｇ＾－１;联合应用ｉＮＯ和Ｓｕｒｆ;或不约药对通气８小时生存率以联合治疗组为最高,Ｓｕｒｆ组及联合治疗组的氧合指数（ＯＩ）、肺顺应     

吸入的甲基肼在家兔体内的毒代动力学

家兔吸入111±4和162±12mg/m~3及恒速静脉输注2.1±0.1和4.1±0.1 mg·kg~(-1)·h~(-1)甲基肼(MMH),均以一室模型在体内配置,iv MMH呈二室模型。MMH经呼吸道的吸收,与恒速静脉输注一样,为表观零级速度过程。经呼吸道的滞留率高、稳定,不受吸入气中MMH浓度和动物通气量变化的影响。MMH在家兔体内分布快,呈周身分布,周室稍富集。消除较快,物质蓄积性弱;消除速度与染毒水平有一定的依赖关系,有消除饱和的趋势。肾清除只占机体总清除的50％左右,提示存在肾外消除途径。此外,对估算MMH吸入染毒的表观零级吸收速度常数k_0和实际吸收剂量Da的简化方法进行了探讨。