Fundamental and applied toxicology : official journal of the Society of Toxicology最新文献_第2页

The effects of perinatal/juvenile methoxychlor exposure on adult rat nervous, immune, and reproductive system function. 围产期/幼期甲氧氯暴露对成年大鼠神经、免疫和生殖系统功能的影响。

Fundamental and applied toxicology : official journal of the Society of Toxicology

Pub Date : 1997-11-01 DOI: 10.1093/TOXSCI/40.1.138

R. Chapin, M. Harris, B. Davis, S. Ward, Ralph E. Wilson, M. Mauney, A. Lockhart, R. Smialowicz, V. Moser, L. T. Burka, B. Collins

In order to address data gaps identified by the NAS report Pesticides in the Diets of Infants and Children, a study was performed using methoxychlor (MXC). Female rats were gavaged with MXC at 0, 5, 50, or 150 mg/kg/day for the week before and the week after birth, whereupon the pups were directly dosed with MXC from postnatal day (pnd) 7. Some dams were killed pnd7 and milk and plasma were assayed for MXC and metabolites. For one cohort of juveniles, treatment stopped at pnd21; a modified functional observational battery was used to assess neurobehavioral changes. Other cohorts of juveniles were dosed until pnd42 and evaluated for changes to the immune system and for reproductive toxicity. Dose-dependent amounts of MXC and metabolites were present in milk and plasma of dams and pups. The high dose of MXC reduced litter size by approximately 17%. Ano-genital distance was unchanged, although vaginal opening was accelerated in all treated groups, and male prepuce separation was delayed at the middle and high doses by 8 and 34 days, respectively. In the neurobehavioral evaluation, high-dose males were more excitable, but other changes were inconsistent and insubstantial. A decrease in the antibody plaque-forming cell response was seen in males only. Adult estrous cyclicity was disrupted at 50 and 150 MXC, doses which also showed reduced rates of pregnancy and delivery. Uterine weights (corrected for pregnancy) were reduced in all treated pregnant females. High-dose males impregnated fewer untreated females; epididymal sperm count and testis weight were reduced at the high, or top two, doses, respectively. All groups of treated females showed uterine dysplasias and less mammary alveolar development; estrous levels of follicle stimulating hormone were lower in all treated groups, and estrus progesterone levels were lower at 50 and 150 MXC, attributed to fewer corpora lutea secondary to ovulation defects. These data collectively show that the primary adult effects of early exposure to MXC are reproductive, show that 5 mg/kg/day is not a NO(A)EL in rats with this exposure paradigm (based on changes in day of vaginal opening, pubertal ovary weights, adult uterine and seminal vesicle weights, and female hormone data) and imply that the sites of action are both central and peripheral.

为了解决美国国家科学院报告《婴幼儿饮食中的农药》中确定的数据缺口，使用甲氧氯(MXC)进行了一项研究。雌性大鼠在出生前一周和出生后一周分别以0、5、50、150 mg/kg/天的剂量灌胃MXC，幼鼠从出生后第7天起直接灌胃MXC。处死部分奶牛，检测乳汁和血浆中MXC及其代谢物。对于一组青少年，治疗在pnd21时停止;改良的功能观察电池用于评估神经行为变化。其他组的幼鱼被给药至pnd42，并评估免疫系统的变化和生殖毒性。MXC及其代谢物存在于母鼠和幼崽的乳和血浆中，呈剂量依赖性。高剂量MXC可使产仔数减少约17%。尽管在所有治疗组中阴道口都加快了，但肛门与生殖器的距离没有变化，在中剂量和高剂量组中，男性包皮分离分别延迟了8天和34天。在神经行为评估中，高剂量的雄性更容易兴奋，但其他变化不一致且不明显。抗体斑块形成细胞反应的减少只在男性中出现。在50和150 MXC的剂量下，成虫的发情周期被打乱，这也显示出怀孕和分娩率的降低。所有接受治疗的孕妇子宫重量(经妊娠校正)均有所减轻。高剂量雄鼠使未经治疗的雌鼠受孕的数量较少;在高剂量或前两种剂量下，附睾精子数量和睾丸重量分别减少。所有治疗组女性均出现子宫发育不良和乳腺泡发育减少;在所有治疗组中，促卵泡激素的发情水平都较低，在50和150 MXC时，发情黄体酮水平较低，这是由于排卵缺陷继发的黄体较少。这些数据共同表明，早期暴露于MXC对成年的主要影响是生殖方面的，表明在这种暴露模式下(基于阴道开口天数、青春期卵巢重量、成年子宫和精囊重量以及雌性激素数据的变化)，5mg /kg/天对大鼠的NO(a) EL没有影响，并暗示作用部位包括中枢和外周。

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引用次数: 276

Two-generation reproductive toxicity study of dietary tributyl phosphate in CD rats. 膳食磷酸三丁酯对CD大鼠的两代生殖毒性研究。

Fundamental and applied toxicology : official journal of the Society of Toxicology

Pub Date : 1997-11-01 DOI: 10.1093/TOXSCI/40.1.90

R. Tyl, J. Gerhart, C. Myers, M. Marr, D. Brine, J. Seely, R. Henrich

Tributyl phosphate (TBP) was tested for reproductive toxicity in rats. Thirty weanlings/sex (F0) were exposed to TBP in the diet ad libitum at 0, 200, 700, or 3000 ppm for 10 weeks and then randomly mated within groups for 3 weeks with continued exposure. F0 parents and 10 F1 weanlings/sex/dose were necropsied, and adult reproductive organs, urinary bladders (both sexes), kidneys (males), and livers (females) were evaluated histologically. Thirty F1 weanlings/sex/dose continued exposure for 11 weeks and were bred as described above. F1 parents and F2 weanlings, 10/sex/dose, were then necropsied as described above. Adult toxicity was observed in both sexes and generations at 700 and 3000 ppm; observations included reduced body weights, weight gain and feed consumption, urinary bladder epithelial hyperplasia (both sexes), renal pelvis epithelial hyperplasia only at 3000 ppm (male kidneys), and centrilobular hypertrophy (female livers). At 200 ppm, transient reductions in body weight were observed in F0 and F1 females, with urinary bladder epithelial hyperplasia in F0 males and females and in F1 males. There was no evidence of reproductive toxicity, of reproductive organ pathology, or of effects on gestation or lactation at any dose tested. Postnatal toxicity was evidenced by consistent reductions in F1 and F2 pup body weights at 3000 ppm and by occasional weight reductions in F2 litters at 700 ppm, and was associated with maternal toxicity observed at these doses and times. Under the conditions of this study, a NOAEL was not determined for adult toxicity; the NOAEL for reproductive toxicity was at least 3000 ppm and the NOAEL for postnatal toxicity was approximately 200 ppm.

研究了磷酸三丁酯(TBP)对大鼠生殖毒性的影响。将30只断奶仔猪(F0)随意暴露于0、200、700或3000 ppm的TBP中10周，然后随机分组，持续暴露3周。对0只父母和10只断奶仔猪(性别/剂量)进行尸检，并对成年生殖器官、膀胱(两性)、肾脏(雄性)和肝脏(雌性)进行组织学评估。30只F1断奶仔猪/性别/剂量持续暴露11周，按上述方法饲养。F1父母和F2断奶仔猪，10只/性别/剂量，然后如上所述进行尸检。在700 ppm和3000 ppm浓度下，在两性和世代中均观察到成虫毒性;观察结果包括体重减轻，体重增加和饲料消耗，膀胱上皮增生(两性)，肾盂上皮增生仅在3000 PPM(男性肾脏)，小叶中心肥大(女性肝脏)。在200ppm浓度下，F0和F1雌性小鼠体重短暂下降，F0雄性和雌性以及F1雄性小鼠膀胱上皮增生。在任何剂量的试验中，没有证据表明存在生殖毒性、生殖器官病理或对妊娠或哺乳的影响。在3000 ppm的浓度下，F1和F2幼崽体重持续下降，在700 ppm的浓度下，F2幼崽体重偶尔下降，证明了出生后的毒性，并与这些剂量和时间下观察到的母体毒性有关。在本研究条件下，未测定NOAEL对成人的毒性;生殖毒性的NOAEL至少为3000 ppm，产后毒性的NOAEL约为200 ppm。

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引用次数: 8

Trimethylphosphate: a 30-month chronic toxicity/carcinogenicity study in Wistar rats with administration in drinking water. 三甲基磷酸:饮水给药Wistar大鼠30个月的慢性毒性/致癌性研究。

Fundamental and applied toxicology : official journal of the Society of Toxicology

Pub Date : 1997-11-01 DOI: 10.1093/TOXSCI/40.1.75

E. Bomhard, G. Krinke, W. Rossberg, T. Skripsky

Trimethylphosphate (TMPO) was administered to 50 male and 50 female Wistar rats through their drinking water at doses of 0, 1, 10, or 100 mg/kg body weight up to 30 months. The dosage of 100 mg/kg was reduced to 50 mg/kg in week 54 for reasons of tolerance, and the animals were euthanized in week 100. Additional 10 animals per dose and sex were treated for 12 months and then euthanized for interim analysis. Weakness of the hind limbs, increased incidences of sunken flanks, distended abdomen, and poor general condition were observed in both sexes of the 100/50 mg/kg group beginning with week 46. Food intake was reduced in high dose males. At 10 mg/kg body weights were up to 10% (males) and at 100/50 mg/kg up to 20% (males) or 15% (females) lower than in controls. Mortality was not affected in animals receiving up to 10 mg/kg. At 100/50 mg/kg it was markedly increased, reaching about 70% at week 100. Relatively slight hematologic changes (reduced hemoglobin, hematocrit, erythrocyte counts, increased reticulocyte numbers, and thrombocyte counts as well as a shift in the differential blood count) at 100/50 mg/kg are interpreted as changes most probably secondary to the other toxic effects. Increased cholesterol concentrations in plasma, shifts in the serum protein electrophoresis (males), increased organ weights (females), and an increased incidence of necroses and lymphocytic infiltrations point to a treatment-related effect on the liver at 100/50 mg/kg. Slightly increased protein excretion, increased relative kidney weights, and an increased incidence of chronic progressive nephropathy are considered treatment-related but rather secondary effects at 100/50 mg/kg. At 100/50 mg/kg an increased incidence and severity of bilateral tubular atrophy in the testes was diagnosed. The most important toxic effect was neurotoxicity, consisting of degeneration and loss of nerve fibers in the peripheral nerves and the spinal cord, associated with myopathic changes, and occurring at 100/50 mg/kg. The no-observed-adverse-effect-level, based on the suppression of body weight gain, is 1 mg/kg in males and 10 mg/kg in females. The incidence, time of occurrence, spectrum of types, and localizations of tumors provided no indication of a tumorigenic/carcinogenic effect of the test substance. TMPO is therefore considered not to be carcinogenic in Wistar rats.

将三甲基磷酸(TMPO)以0、1、10或100 mg/kg体重的剂量通过饮用水给予50只雄性和50只雌性Wistar大鼠，直至30个月。第54周因耐受原因将100 mg/kg的剂量降至50 mg/kg，第100周实施安乐死。每个剂量和性别另外10只动物治疗12个月，然后实施安乐死以进行中期分析。从第46周开始，100/50 mg/kg组男女均出现后肢无力、侧腹凹陷、腹部肿胀的发生率增加和一般状况不佳。高剂量雄性的食物摄入量减少。在10 mg/kg体重组中，男性体重比对照组低10%，在100/50 mg/kg体重组中，男性体重比对照组低20%，女性体重比对照组低15%。在接受高达10 mg/kg剂量的动物中，死亡率不受影响。在100/50 mg/kg浓度下显著升高，第100周达到70%左右。在100/50 mg/kg时，相对轻微的血液学变化(血红蛋白、红细胞压积、红细胞计数、网织红细胞数量增加、血小板计数以及差异血细胞计数的变化)被解释为最可能继发于其他毒性作用的变化。血浆中胆固醇浓度升高，血清蛋白电泳(男性)改变，器官重量增加(女性)，坏死和淋巴细胞浸润发生率增加，表明100/50 mg/kg时对肝脏的治疗相关影响。当剂量为100/50 mg/kg时，蛋白质排泄量轻微增加、相对肾脏重量增加和慢性进行性肾病发生率增加被认为是与治疗相关的，而不是次要效应。当剂量为100/50 mg/kg时，诊断为双侧睾丸小管萎缩的发生率和严重程度增加。最重要的毒性作用是神经毒性，包括周围神经和脊髓神经纤维的变性和丧失，与肌病改变相关，并在100/50 mg/kg时发生。基于对体重增加的抑制，未观察到的不良反应水平为男性1mg /kg，女性10mg /kg。肿瘤的发生率、发生时间、类型谱和肿瘤的位置没有显示试验物质有致瘤/致癌作用。因此，在Wistar大鼠中，TMPO被认为没有致癌性。

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引用次数: 10

Toxicity of divinylbenzene-55 for B6C3F1 mice in a two-week inhalation study. 二乙烯基苯55对B6C3F1小鼠为期两周的吸入毒性研究。

Fundamental and applied toxicology : official journal of the Society of Toxicology

Pub Date : 1997-10-01 DOI: 10.1093/TOXSCI/39.2.89

D. Morgan, J. Mahler, R. Wilson, M. Moorman, H. Price, R. W. O'connor

Divinylbenzene (DVB) is a crosslinking monomer used primarily for copolymerization with styrene to produce ion-exchange resins. The toxicity of inhaled DVB was investigated because of the potential for worker exposure and the structural similarity of DVB to styrene, a potential carcinogen. Male and female B6C3F1 mice were exposed to 0, 25, 50, or 75 ppm DVB for 6 hr/day, 5 days/week for up to 2 weeks. Six mice/sex/dose group were killed after 3, 5, and 10 exposures and six mice/sex in the 75 ppm group were killed 7 days after 10 exposures. The most severe effects occurred in the nasal cavity and liver, with less severe effects occurring in the kidneys. In the nasal cavity olfactory epithelium acute necrosis and inflammation were present at early time points followed by regeneration, architectural reorganization, and focal respiratory metaplasia by 7 days after the last exposure. Olfactory epithelial changes were concentration-dependent with extensive involvement at 75 ppm and peripheral sparing at 25 ppm. There was also necrosis and regeneration of olfactory-associated Bowman's glands as well as the lateral nasal (Steno's) glands. Hepatocellular centrilobular (CL) necrosis was observed only in the 75 ppm dose group and was similar to that caused by styrene. A time-dependent progression was observed, characterized by CL degeneration after 1 exposure, necrosis after 3 and 5 exposures, and chronic inflammation with CL karyomegaly after 10 exposures and 7 days after the 10th exposure. Hepatic GSH levels were decreased in a dose-dependent manner. In the kidneys, transient tubular damage was observed in some male mice exposed to 75 ppm, and appeared to be a response to DVB-induced tubular epithelial injury.

二乙烯基苯(DVB)是一种交联单体，主要用于与苯乙烯共聚生产离子交换树脂。由于工人可能接触到DVB，并且其结构与苯乙烯(一种潜在的致癌物)相似，因此对吸入DVB的毒性进行了研究。雄性和雌性B6C3F1小鼠分别暴露于0、25、50或75 ppm的DVB中，每天6小时，每周5天，持续2周。暴露于3、5、10天后，6只/性别/剂量组小鼠死亡;暴露于10天后，75 ppm组6只/性别小鼠死亡。最严重的影响发生在鼻腔和肝脏，较轻的影响发生在肾脏。鼻腔嗅上皮早期出现急性坏死和炎症，最后一次暴露后7天出现再生、结构重组和局灶性呼吸道化生。嗅觉上皮的变化是浓度依赖性的，在75 ppm时广泛受累，在25 ppm时外周保留。嗅觉相关的鲍曼腺和侧鼻腺也有坏死和再生。仅在75 ppm剂量组观察到肝细胞小叶中心(CL)坏死，与苯乙烯引起的肝细胞小叶中心坏死相似。观察到一个时间依赖性的进展，其特征是1次暴露后CL变性，3次和5次暴露后坏死，10次暴露后慢性炎症伴CL核肿大，第10次暴露后7天。肝GSH水平呈剂量依赖性降低。在肾脏中，暴露于75ppm的一些雄性小鼠观察到短暂的肾小管损伤，这似乎是对dvb诱导的肾小管上皮损伤的反应。

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引用次数: 7

Coincubation of rat renal proximal tubules with hepatic subcellular fractions potentiates the effects of para-aminophenol. 大鼠肾近端小管与肝亚细胞组分共孵育增强了对氨基酚的作用。

Fundamental and applied toxicology : official journal of the Society of Toxicology

Pub Date : 1997-10-01 DOI: 10.1093/TOXSCI/39.2.101

R. Shao, S. Ring, J. Tarloff

Treatment of rats with para-aminophenol (PAP) (300 mg/kg ip) produced decreases in renal nonprotein sulfhydryl (NPSH) content, oxygen consumption, and adenine nucleotide concentrations 2-4 hr following administration. In contrast, incubation of rat renal tubules with up to 1 mm PAP for 4 hr produced inconsistent changes in renal tubules. This discrepancy suggested that extrarenal metabolism of PAP may be involved in PAP bioactivation and nephrotoxicity. We designed the present studies to test the hypothesis that hepatic metabolism of PAP potentiates the effects of PAP on renal tubules. Incubation of renal tubules with 0.5 mm PAP and 10 mg protein from hepatic postmitochondrial supernatant (S9 fraction) in the absence of glutathione (GSH) for 4 hr did not alter renal oxygen consumption or adenine nucleotide metabolite concentrations. We observed no changes when we incubated tubules with 0.5 mm PAP and 1 mm GSH in the absence of hepatic S9 fraction. However, incubation of renal tubules with 0.5 mm PAP, 1 mm GSH, and 10 mg hepatic S9 protein for 4 hr significantly decreased renal oxygen consumption and adenosine triphosphate and total nucleotide concentrations. These data suggest that the effects of PAP in renal tubules may be potentiated by enzymatic metabolism of PAP, possibly involving oxidation and GSH conjugation. From experiments using hepatic microsomes or cytosol instead of S9 fraction, we found that changes were produced when we incubated tubules with PAP in the presence of hepatic microsomes, but not cytosol. These data suggest that hepatic microsomal metabolism of PAP may contribute to the production of changes in renal tubules in vitro. PAP-induced changes in renal proximal tubules were prevented when we included a beta-nicotinamide adenine dinucleotide phosphate (NADPH) generating system in the incubation medium. The protective effect of NADPH persisted when microsomes were inactivated by incubation with 1-aminobenzotriazole, a cytochrome P450 inhibitor. These data suggest that cytochrome P450-dependent oxidation is not involved in the production or prevention of PAP-induced changes in renal tubules. The enzyme(s) responsible for PAP bioactivation and the mechanism(s) by which NADPH protects renal tubules from PAP-induced decrements in oxygen consumption and adenine nucleotide concentrations are currently unclear.

给药后2-4小时，对氨基酚(PAP) (300 mg/kg / ip)治疗大鼠可降低肾脏非蛋白巯基(NPSH)含量、耗氧量和腺嘌呤核苷酸浓度。相比之下，大鼠肾小管与高达1mm PAP孵育4小时产生不一致的肾小管变化。这一差异提示PAP的肾外代谢可能参与了PAP的生物活化和肾毒性。我们设计了本研究来验证PAP的肝脏代谢增强PAP对肾小管的作用的假设。在不含谷胱甘肽(GSH)的情况下，用0.5 mm PAP和10 mg肝脏线粒体后上清蛋白(S9部分)孵育肾小管4小时，不会改变肾脏耗氧量或腺嘌呤核苷酸代谢物浓度。在没有肝S9组分的情况下，用0.5 mm PAP和1mm GSH孵育小管，我们没有观察到任何变化。然而，用0.5 mm PAP、1 mm GSH和10 mg肝S9蛋白孵育肾小管4小时，可显著降低肾脏耗氧量、三磷酸腺苷和总核苷酸浓度。这些数据表明，PAP在肾小管中的作用可能通过PAP的酶代谢而增强，可能涉及氧化和谷胱甘肽结合。从使用肝微粒体或细胞质而不是S9组分的实验中，我们发现当我们在肝微粒体存在的情况下用PAP孵育小管时产生了变化，而不是细胞质。这些数据表明，PAP的肝微粒体代谢可能有助于体外肾小管变化的产生。当我们在培养培养基中加入β -烟酰胺腺嘌呤二核苷酸磷酸(NADPH)生成系统时，可以防止pap诱导的肾近端小管变化。当细胞色素P450抑制剂1-氨基苯并三唑孵育使微粒体失活时，NADPH的保护作用仍然存在。这些数据表明，细胞色素p450依赖性氧化不参与产生或预防pap诱导的肾小管变化。负责PAP生物活化的酶以及NADPH保护肾小管免受PAP诱导的氧消耗和腺嘌呤核苷酸浓度下降的机制目前尚不清楚。

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引用次数: 13

Risk characterization: A bridge to informed decision making. 风险表征:通向知情决策的桥梁。

Fundamental and applied toxicology : official journal of the Society of Toxicology

Pub Date : 1997-10-01

D W North

Regulatory decisions should be made in the most expert and informed way since they are precipitated by real and perceived threats to human health, under the glare of public scrutiny. In 1994, the National Research Council (NRC) reported that the U.S. Environmental Protection Agency's (USEPA's) overall approach to assessing risks is fundamentally sound, but the Agency must more clearly establish the scientific and policy basis for risk estimates and better communicate the associated uncertainties. On March 21, 1995, USEPA issued a risk characterization policy and guidance. In this policy, an effective risk characterization must fully and clearly characterize risks and disclose the scientific analysis, uncertainties, assumptions, and science policy that underlie decisions throughout the risk assessment process. A number of regulatory reform bills which required risk characterization as part of all Federal risk assessments were introduced by the 104th Congress. The purpose of this workshop was to familiarize Society of Toxicology members with: (1) key elements to be considered in risk characterization and (2) new advances in risk characterization addressed by Federal and State agencies, industry, academia, NRC, and Presidential/Congressional Commission on Risk Assessment and Risk Management. Furthermore, the main objective was to engage the audience in discussing the proper role of science in risk assessment-risk management interface to make informed decisions in the face of scientific uncertainty.

管制决定应以最专业和最知情的方式作出，因为这些决定是在公众监督的注视下，由对人类健康的实际和感知威胁促成的。1994年，美国国家研究委员会(NRC)报告称，美国环境保护署(USEPA)评估风险的总体方法基本上是合理的，但该机构必须更清楚地建立风险评估的科学和政策基础，并更好地沟通相关的不确定性。1995年3月21日，美国环保署发布了一项风险描述政策和指南。在这一政策中，有效的风险描述必须充分而清晰地描述风险，并揭示贯穿风险评估过程的科学分析、不确定性、假设和科学政策。第104届国会提出了一系列监管改革法案，要求将风险定性作为所有联邦风险评估的一部分。本次研讨会的目的是使毒理学学会成员熟悉:(1)风险表征中需要考虑的关键因素;(2)联邦和州机构、工业界、学术界、NRC和总统/国会风险评估和风险管理委员会在风险表征方面的新进展。此外，主要目标是让听众参与讨论科学在风险评估-风险管理界面中的适当作用，以便在面对科学不确定性时做出明智的决策。

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引用次数: 0

Risk characterization: A bridge to informed decision making. 风险表征:通向知情决策的桥梁。

Fundamental and applied toxicology : official journal of the Society of Toxicology

Pub Date : 1997-10-01 DOI: 10.1093/TOXSCI/39.2.81

D. North

Regulatory decisions should be made in the most expert and informed way since they are precipitated by real and perceived threats to human health, under the glare of public scrutiny. In 1994, the National Research Council (NRC) reported that the U.S. Environmental Protection Agency's (USEPA's) overall approach to assessing risks is fundamentally sound, but the Agency must more clearly establish the scientific and policy basis for risk estimates and better communicate the associated uncertainties. On March 21, 1995, USEPA issued a risk characterization policy and guidance. In this policy, an effective risk characterization must fully and clearly characterize risks and disclose the scientific analysis, uncertainties, assumptions, and science policy that underlie decisions throughout the risk assessment process. A number of regulatory reform bills which required risk characterization as part of all Federal risk assessments were introduced by the 104th Congress. The purpose of this workshop was to familiarize Society of Toxicology members with: (1) key elements to be considered in risk characterization and (2) new advances in risk characterization addressed by Federal and State agencies, industry, academia, NRC, and Presidential/Congressional Commission on Risk Assessment and Risk Management. Furthermore, the main objective was to engage the audience in discussing the proper role of science in risk assessment-risk management interface to make informed decisions in the face of scientific uncertainty.

管制决定应以最专业和最知情的方式作出，因为这些决定是在公众监督的注视下，由对人类健康的实际和感知威胁促成的。1994年，美国国家研究委员会(NRC)报告称，美国环境保护署(USEPA)评估风险的总体方法基本上是合理的，但该机构必须更清楚地建立风险评估的科学和政策基础，并更好地沟通相关的不确定性。1995年3月21日，美国环保署发布了一项风险描述政策和指南。在这一政策中，有效的风险描述必须充分而清晰地描述风险，并揭示贯穿风险评估过程的科学分析、不确定性、假设和科学政策。第104届国会提出了一系列监管改革法案，要求将风险定性作为所有联邦风险评估的一部分。本次研讨会的目的是使毒理学学会成员熟悉:(1)风险表征中需要考虑的关键因素;(2)联邦和州机构、工业界、学术界、NRC和总统/国会风险评估和风险管理委员会在风险表征方面的新进展。此外，主要目标是让听众参与讨论科学在风险评估-风险管理界面中的适当作用，以便在面对科学不确定性时做出明智的决策。

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引用次数: 13

Assessment of the developmental toxicity, metabolism, and placental transfer of N,N-dimethylformamide administered to pregnant rats. 妊娠大鼠N,N-二甲基甲酰胺的发育毒性、代谢和胎盘转移的评估。

Fundamental and applied toxicology : official journal of the Society of Toxicology

Pub Date : 1997-09-01 DOI: 10.1093/TOXSCI/39.1.33

A. Saillenfait, J. Payan, D. Beydon, J. Fabry, I. Langonné, J. Sabaté, F. Gallissot

This study evaluates the developmental toxicity and placental and milk transfer of N,N-dimethylformamide (DMF) in rats. Sprague-Dawley rats were given 0, 50, 100, 200, and 300 mg DMF/kg/day, by gavage, on Gestational Days (GD) 6 through 20. Maternal toxicity was indicated by depressions in weight gain and food consumption at doses >/=100 mg/kg. Fetal toxicity was indicated by decreased fetal body weight at doses >/=100 mg/kg, and by increased incidences of two skeletal variations (absent or poorly ossified supraoccipital and sternebrae) at 200 and 300 mg/kg. Thus, the maternal and developmental no-observed-adverse-effect level was 50 mg/kg/day. The time course disposition of [14C]DMF was examined over a 48-hr period in GD12- and GD18-pregnant rats after a single oral dose of 100 mg [14C]DMF/kg. Peak concentrations of radiocarbon occurred within 1 hr after dosing. Embryonic (GD12) and fetal (GD18) tissues accounted for 0.15 and 6% of the administered dose, respectively. Levels of radiocarbon in embryonic and fetal tissues were equal or slightly less than in maternal plasma up to 8 and 24 hr, respectively, and higher thereafter. HPLC analysis performed at intervals from 1 to 8 hr on GD12 and 1-24 hr on GD18 indicated that unchanged DMF and metabolites were readily transferred to the embryonic and fetal tissues, where their levels were generally equal to those in maternal plasma. The parent compound accounted for most of the radioactivity until 4-8 hr and then decreased. N-Hydroxymethyl-N-methylformamide (HMMF) and N-methylformamide (NMF) were the predominent metabolites and increased with time. Much lower concentrations were found for formamide and N-acetyl-S-(N-methylcarbamoyl)cysteine. Transfer of radioactivity into milk was studied in dams given a single oral administration of 100 mg [14C]DMF on Lactation Day 14. DMF, HMMF, and NMF were found in the milk at concentrations equal to those in plasma.

本研究评价了N,N-二甲基甲酰胺(DMF)对大鼠的发育毒性及胎盘和乳汁的转移。妊娠第6 ~ 20天，sd - dawley大鼠分别灌胃0、50、100、200、300 mg DMF/kg/d。当剂量>/=100 mg/kg时，母体的体重增加和食物消耗下降表明母体毒性。当剂量>/=100 mg/kg时，胎儿体重下降，当剂量为200和300 mg/kg时，两种骨骼变异(枕骨上和胸骨缺失或骨化不良)发生率增加，表明胎儿毒性。因此，母体和发育未观察到的不良反应水平为50 mg/kg/天。在GD12和gd18妊娠大鼠单次口服100 mg [14C]DMF/kg后，在48小时内检测[14C]DMF的时间过程。放射性碳浓度峰值出现在给药后1小时内。胚胎组织(GD12)和胎儿组织(GD18)分别占给药剂量的0.15和6%。胚胎和胎儿组织中的放射性碳水平分别在8小时和24小时内等于或略低于母体血浆中的水平，此后更高。对GD12和GD18分别进行1- 8小时和1-24小时的HPLC分析表明，未改变的DMF和代谢物很容易转移到胚胎和胎儿组织中，其水平与母体血浆中的水平大致相同。母体化合物的放射性在4-8小时之前占大部分，然后下降。n -羟甲基- n -甲基甲酰胺(HMMF)和n -甲基甲酰胺(NMF)是主要代谢物，随时间增加而增加。甲酰胺和n -乙酰- s -(n -甲基氨基甲酰)半胱氨酸的浓度要低得多。研究了在哺乳期第14天给母鼠单次口服100 mg [14C]DMF的放射性转移。牛奶中发现的DMF、HMMF和NMF的浓度与血浆中的浓度相等。

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引用次数: 31

Effects of fumonisin B1 on the immune system of sprague-dawley rats following a 14-day oral (gavage) exposure. 伏马菌素B1对sprague-dawley大鼠14天后免疫系统的影响

Fundamental and applied toxicology : official journal of the Society of Toxicology

Pub Date : 1997-09-01

H Tryphonas, G Bondy, J D Miller, F Lacroix, M Hodgen, P Mcguire, S Fernie, D Miller, S Hayward

The effects of fumonisin B1 (FB1) on the immune system of Sprague-Dawley rats were investigated. Groups of male and female rats (10 rats/group) were gavaged daily for 14 days with doses of 0, 5, 15, and 25 mg/kg body wt/day and the primary (IgM) response to sheep red blood cells expressed as plaque-forming cell numbers/10(6) spleen mononuclear leukocytes (PFC/10(6) splenocytes) and PFC/spleen was determined. There was a significant dose-related linear trend toward decreased PFC/10(6) splenocytes (p = 0.003) and PFC/spleen cells (p = 0.001) in the male rats. Body weights, expressed as a percentage of the control, were significantly reduced (p = 0.002) in the male rats administered 15 and 25 mg/kg doses. The PFC numbers in female rats were not affected significantly by treatment (p > 0.05). For the remaining immunotoxicity studies, groups of male rats (10 rats/group) were gavaged with FB1 doses of 0, 1, 5, and 15 mg/kg body wt/day for 14 days. There was a weakly significant dose-related trend toward increased numbers of serum immunoglobulin class G (p = 0.04). Also a significant dose-related increase (p = 0.013) in Listeria monocytogenes numbers was observed in the spleen at 24 hr postinfection. Treatment did not have a significant effect on organ weights, hematology, mitogen-induced lymphocyte transformation, calcium mobilization, the numbers of leukocytes and T-lymphocyte subsets, the natural killer cell activity, and phagocytosis (p >/= 0. 05). These observations suggested that FB1 may have indirect consequences for human health and warrant further investigations.

研究伏马菌素B1 (FB1)对Sprague-Dawley大鼠免疫系统的影响。以0、5、15和25 mg/kg体重量/天的剂量，每天灌胃雄性和雌性大鼠组(10只/组)，连续14天，测定绵羊红细胞对血小板形成细胞数/10(6)个脾脏单核白细胞(PFC/10(6)个脾细胞)和PFC/脾脏的主要(IgM)反应。雄性大鼠PFC/10(6)脾细胞和PFC/脾细胞呈显著的剂量相关线性趋势(p = 0.003)。在15和25 mg/kg剂量的雄性大鼠中，体重(以对照的百分比表示)显著降低(p = 0.002)。治疗对雌性大鼠PFC数无显著影响(p > 0.05)。在其余免疫毒性研究中，雄性大鼠组(10只/组)分别以0、1、5和15 mg/kg体重量/天的剂量灌胃FB1，持续14天。血清免疫球蛋白G类增加呈弱显著剂量相关趋势(p = 0.04)。在感染后24小时，脾脏中单核增生李斯特菌数量也有显著的剂量相关增加(p = 0.013)。治疗对器官重量、血液学、丝裂原诱导的淋巴细胞转化、钙动员、白细胞和t淋巴细胞亚群数量、自然杀伤细胞活性和吞噬没有显著影响(p >/= 0。05）. 这些观察结果表明，FB1可能对人类健康产生间接影响，值得进一步调查。

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引用次数: 0

Effects of polychlorinated biphenyls (PCBs) on brain tyrosine hydroxylase activity and dopamine synthesis in rats. 多氯联苯对大鼠脑酪氨酸羟化酶活性和多巴胺合成的影响。

Fundamental and applied toxicology : official journal of the Society of Toxicology

Pub Date : 1997-09-01 DOI: 10.1093/TOXSCI/39.1.76

N. Choksi, P. Kodavanti, H. Tilson, R. Booth

Literature reports suggest that polychlorinated biphenyls (PCBs) may alter dopaminergic neurotransmission in mammalian forebrain. In vitro, PCBs can decrease dopamine levels in PC 12 cells and studies of the structure-activity relationship (SAR) indicate that ortho-substituted (non-coplanar) PCB congeners are more active than para-substituted (coplanar) congeners. This report tested the hypothesis that ortho-substituted PCBs can selectively (vs para-substituted congeners) decrease dopamine synthesis in mammalian forebrain by inhibiting the activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis. In vitro effects of individual PCB congeners on activity of striatal tyrosine hydroxylase from two different rat strains were assessed. It was found that certain ortho-substituted PCB congeners (e.g., 2,2'-DCB) can inhibit tyrosine hydroxylase activity and dopamine synthesis by nearly 40% in minces of corpus striatum prepared from Sprague-Dawley and Long-Evans hooded rats. Comparatively, the ortho, meta-substituted PCB congener 2,2',5,5'-TeCB inhibited tyrosine hydroxylase activity only in striatal minces obtained from Sprague-Dawley rats, suggesting that genetic factors may influence the susceptibility of mammals to effects of PCBs that compromise brain dopamine synthesis. The PCB-induced inhibition of tyrosine hydroxylase activity in mammalian forebrain observed here appears to occur through indirect and as yet unknown mechanisms.

文献报道多氯联苯(PCBs)可能改变哺乳动物前脑多巴胺能神经传递。在体外，多氯联苯可以降低pc12细胞中的多巴胺水平，结构-活性关系(SAR)研究表明，邻位取代(非共面)PCB同系物比对位取代(共面)同系物更有活性。本报告验证了邻位取代多氯联苯(相对于对位取代同族物)可以通过抑制酪氨酸羟化酶(多巴胺生物合成中的限速酶)的活性来选择性地减少哺乳动物前脑多巴胺合成的假设。在体外研究了不同多氯联苯同源物对两种大鼠纹状体酪氨酸羟化酶活性的影响。研究发现，某些邻位取代的多氯联苯同源物(如2,2′-DCB)可抑制Sprague-Dawley和lonevans大鼠纹状体肉末中酪氨酸羟化酶活性和多巴胺合成近40%。相比之下，邻位取代的多氯联苯同系物2,2'，5,5'-TeCB仅在Sprague-Dawley大鼠纹状体碎料中抑制酪氨酸羟化酶活性，这表明遗传因素可能影响哺乳动物对多氯联苯影响的易感性，从而损害脑多巴胺合成。多氯联苯诱导的哺乳动物前脑酪氨酸羟化酶活性的抑制似乎是通过间接的和未知的机制发生的。

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引用次数: 76