对居民使用液化气健康效应的初步探讨

对液化气燃烧后室内空气污染进行了流行病学调查，结果显示，液化气燃烧可造成ＳＯ＿２、ＮＯ＿２、空气总悬浮颗粒物和总烃类的室内空气污染。小鼠接触三个月出现Ｔ淋巴细胞计数降低、睡眠时间延长、骨髓嗜多染红细胞微核率增加、肺组织匀浆Ａｍｅｓ试验阳性率增高、雄性小鼠精子畸形率增加，并有明显的剂量－反应关系。对接触５年以上的人群调查发现，呼吸道、鼻和眼的自觉症状明显增加，咽炎、鼻炎、结膜炎患病率增高。人群尿液浓缩物Ａｍｅｓ试验和外周血红细胞微核率检出阳性结果，可能与液化气燃烧废气中含有致突变污染物有关。     

Toxicology of FK506 in the cynomolgus monkey: a clinical,biochemical, and histopathological study

We investigated clinical, biochemical, and histopathological parameters in FK506-treated cynomolgus monkeys. Eight monkeys given oral FK506, 1 (n = 4) or 10 (n = 4) mg/kg daily, survived the 90 days of treatment apparently in good health and without significant changes in biochemical and histopathological parameters, as did 2 control monkeys except one monkey on 10 mg/kg/day FK506 orally, who was found to have a malignant lymphoma. In contrast, monkeys given intramuscular FK506 1 mg/kg daily (n = 4) had to be sacrificed at day 20, 25, 32, and 47 because of severe illness. They showed abnormal biochemical parameters (increased serum urea and aspartate aminotransferase activity) and major histopathological changes in the kidney (mesangial cell proliferation and acute tubular necrosis), pancreas (depletion of beta cells), liver (steatosis), and heart (cardiomyopathy). Intramuscular administration of 1 mg/kg daily resulted in serum levels ranging from 10 to 15 ng/ml, while oral administration at a dose of 1 or 10 mg/kg daily resulted in equal or even higher serum levels (range 2–70 ng/ml). Thus, the height of the serum trough level of FK506 using the enzyme immunoassay is not related to the toxicity of FK506 in cynomolgus monkeys.     

Application of Animal Toxicology Data to Clinical Study of Experimental Drugs

The pharmaceutical industry performs safety studies in animals to underwrite administration of new chemical entities to man. Early clinical evaluation of drugs in volunteers is performed, generally, using highdose acute studies in rodents and 1-month repeat dose studies in one rodent species and one non-rodent species as a basis for risk assessment. Results from the 1-month toxicology studies enable a ceiling for initial clinical doses to be set and give some indication of the major target organs for toxicity. Extrapolation of these results to man helps determine the preliminary safety endpoints, including clinical chemistry parameters, for use in early clinical studies in man.Originally presented at ECCP 93.     

Six months before ICH2: An overview on the harmonisation of the guidelines in toxicology

The aim of this paper is to emphasize the necessity of an international harmonisation of the guidelines in toxicology for the safety evaluation of pharmaceutical products, and the role of the International Conference on Harmonization (ICH). The organisation of the working-groups and the choice of the topics are descibed, and an overview of the achievement and on the difficulties encountered for this purpose is presented, some months before the ICH2 meeting in Orlando (USA). Originally presented at ECCP 93.     

The morphogenesis of testicular degeneration induced in rats by orally administered 2,5-hexanedione

The neurotoxic hexacarbon 2,5-hexanedione (2,5-HD) produces testicular atrophy in experimental animals. To examine the morphogenesis of the testicular lesion, 1.0% 2,5-HD was provided in the drinking water of adult F-344 rats for up to 6 weeks. After 3 weeks of administration, there were occasional large vacuoles in the basal region of the germinal epithelium. At 4 weeks, these vacuoles were much larger and more numerous; electron microscopy demonstrated that they were derived from the smooth endoplasmic reticulum. The vacuoles were preferentially associated with stages 12, 13, 14, and 1 of the spermatogenic cycle. Additionally, at 4 weeks there was a significant decrease in the number of tubules in stages 7 and 13, and a concomitant increase in the percentage of tubules in stages 3, 5, and 6. By Week 5, most Golgi-phase and cap-phase spermatids were visibly affected, showing margination of nuclear chromatin, and were becoming dissociated from Sertoli cells. Frequent multinucleated giant cells were seen and electron microscopy of these cells suggested that they were derived from fused spermatocytes or spermatids. After 6 weeks, fewer giant cells were present, most tubules contained cellular debris, and many showed empty lumina encircled by a thin ring of cytoplasm near the basement membrane. Interstitial tissue appeared unaffected. These studies indicate that the Sertoli cell is probably an initial target for 2,5-HD action in the testis.     

Analytical studies on illicit heroin

The recovery of heroin in fumes was investigated. In the Netherlands the common mode of heroin smoking is the chasing the dragon procedure: heroin is heated on an aluminium foil by a lighter and the fumes are inhaled. The efficiency of the volatilization of heroin using this procedure was studied under laboratory conditions using thin layer chromatography, gas chromatography and high pressure liquid chromatography. A considerable influence of the form (salt or base) of the heroin was found as well as strong influences of other substances that may be present in illicit heroin samples as diluents. The danger of the inhalation of fumes containing unknown pyrolysis products is mentioned and a hypothesis is given for the phenomenon of heroin-leucoencephalopathy that was observed in heroin smokers in Amsterdam in 1981. The types of heroin encountered in the Netherlands are discussed with regard to their suitability for smoking.     

The hydroxylation, dechlorination, and glucuronidation of 4,4'-dichlorobiphenyl (4-DCB) by human hepatic microsomes

Since chlorine placement and the degree of chlorination of the biphenyl nucleus play an important role in the metabolism and ultimate elimination of polychlorinated biphenyls (PCBs), we have studied the metabolism of 4,4'-dichlorobiphenyl (4-DCB) by human hepatic microsomes. This low molecular weight PCB congener is substituted at the preferred site of metabolism (para-position). 4-DCB was metabolized by human microsomes with a Km of 0.43 microM and a Vmax of 1.2 pmoles/mg microsomal protein/min. Six metabolites were identified: 4,4'-dichloro-3,3'-biphenyldiol, 4'-chloro-3-biphenylol, 4'-chloro-4-biphenylol, 4,4'-dichloro-2-biphenylol, 4,4'-dichloro-3-biphenylol (most abundant), and 3,4'-dichloro-4-biphenylol. [14C]-4-DCB equivalents were found to covalently bind to microsomal protein. Addition of a 1 mM concentration of reduced glutathione decreased the degree of covalent binding. These data suggest that human microsomes metabolize this PCB through an arene oxide and that an "NIH shift" occurs. When UDPGA was added to the incubation, human microsomal glucuronosyltransferase catalyzed the formation of the glucuronide of the major metabolite, 4,4'-dichloro-3-biphenylol. These and previous in vitro results show that the biotransformation of PCBs by humans is governed by the same principles established for the in vivo biotransformation of PCBs by the rat, mouse and monkey. That is, PCBs without two adjacent unsubstituted carbon atoms are poorly metabolized and that an unsubstituted para-position facilitates metabolism.     

Rapid isolation of some antiepileptic hydantoins and their analogues with Sep-Pak C18 cartridges and capillary gas chromatography with splitless injection

Summary A simple and rapid method for isolation of seven antiepileptics (2 hydantoin, 2 oxazolidin, and 3 suximide derivatives) from urine and plasma is presented. Urine and plasma (1 ml) samples containing seven antiepileptics were mixed with distilled water (4 ml), and the sample solution was poured into a pretreated Sep-Pak C₁₈ cartridge; this was washed with water and chloroform/methanol was passed through it to elute the antiepileptics. The eluate was mixed with isoamyl acetate and evaporated under a stream of N₂. The drugs were detected by gas chromatography with fused silica capillary columns, splitless injection and flame ionization detection. Separation of the seven antiepileptics from each other and from impurities was satisfactory with the use of an SPB-1 capillary column. The detection limit for the seven antiepileptics with the present method was 0.1–1.0 g/ml urine or plasma. The recovery of the drugs from urine and plasma was more than 70% and 50%, respectively. Offprint requests to: O. Suzuki     

枸杞明目前囊安全性研究

目的：研究枸杞明目胶囊的安全性。方法：小鼠急毒性试验及大鼠长期毒性试验。结果：小鼠急性毒性LD50大于90．0ml/(kg.bw)。大鼠30天喂养试验,未见动物出现行为,体重,血象,肝,肾功能等的毒性变化,组织切片也未见各组之间,两种性别之间脏器结构有明显差异。结论：枸杞明目胶囊长期服用安全无毒。     

湖南麦饭石卫生学评价

目的　为开发利用湖南 Ｆ６、 Ｆ７ 麦饭石矿物营养的有益资源。方法　毒理学试验,观察实验动物存活、生长状况;生物活性实验,证实麦饭石中微量元素对动植物的营养作用。结果　急性、８０ 天生长试验实际无毒,并能提高小鼠的游泳耐力,延长金鱼存活时间,花卉枯萎时间后移,伤口愈合时间缩短以及吸附水中氰化物、铅、汞、砷、镉和甲醇等有毒物质。结论　麦饭石作为矿物营养资源具有广阔的的应用前景。