摘要:

The development of drugs to combat diseases, chemicals to im prove food production, or compounds to enhance the quality of life necessitates, by law, the use of laboratory animals to test their safety. In order to sim ulate the human condition it is necessary to choose a species in which pharmacokinetic and toxicokinetic mechanisms are established and resemble those of humans. The advantages of the use of the rat in drug and chemical toxicity testing include (a) metabolic pathway similarities to humans; (b) numerous similar anatomical and physiological characteristics; (c) a large database, which is extremely important for comparative purposes; and (d) the ease of breeding and maintenance of animals at relatively low cost. However, the choice of rat can be complicated, especially when over 200 different strains of rat are known to exist. The aim of this review is to summarize genetically determined differences in the responsiveness of rat strains to drugs and naturally occurring chemicals and to show that susceptibility is dependent on the target organ sensitivities, which may also be strain dependent. It is suggested that detailed studies of strain differences may help to clarify toxic mechanisms. Such studies are usually best conducted using inbred strains in which the genetic characteristics have been fixed, rather than in outbred stocks in which individual samples of animals may differ, the phenotype is variable, and the stocks are subject to substantial genetic drift. The fact that strains may differ also needs to be taken into account in assessing the potential hazard of the chemical, particularly when a study involves only a single strain and therefore provides no assessment of likely strain variation.

ISSN:0098-4108    

DOI:10.1080/009841096161960

出版商:Informa UK Ltd    

年代:1996

数据来源: Taylor

摘要:

Hydroquinone (HQ) is a nonvolatile chemical used in the photographic, rubber, chemical, and cosmetic industries. HQ is also known to occur in nature as the-D-glucopyranoside conjugate (arbutin), and free HQ is a known component of cigarette smoke. Low concentrations of HQ have been detected in the urine and plasma of humans with no occupational or other known exposure to HQ. The studies reported here investigate dietary and other potential sources of HQ and their contribution to HQ concentrations in the plasma and urine of human volunteers. Analysis of possible food sources of HQ by GC indicated significant amounts of arbutin in wheat products (1-10 ppm), pears (4-15 ppm), and coffee and tea (0.1 ppm). Free HQ was found in coffee (0.2 ppm), red wine (0.5 ppm), wheat cereals (0.2-0.4 ppm), and broccoli (0.1 ppm). After consuming a meal including arbutinand HQ-containing foods, volunteers showed significant increases in plasma and urinary levels of HQ and its conjugated metabolites (total HQ). Mean plasma concentrations of total HQ peaked at 5 times background levels at 2 h after the completion of the meal, and mean urinary excretion rates of total HQ peaked at 12 times background at 2-3 h after the meal. Immediately after smoking four cigarettes in approximately 30 min, mean plasma concentrations of total HQ were maximally 1.5 times background levels; mean urinary excretion rates of total HQ peaked at 2.5 times background at 1-3 h after smoking. These data indicate that considerable human exposure to HQ can result from plant-derived dietary sources and, to a lesser extent, from cigarette smoke.

ISSN:0098-4108    

DOI:10.1080/009841096161915

出版商:Informa UK Ltd    

年代:1996

数据来源: Taylor

摘要:

The extensive growth of Caulerpa taxifolia in the Mediterranean sea produces important quantities of bioactive secondary metabolites unable to enter the food chain. The cytotoxic effects of caulerpenyne, the major secondary metabolite from C. taxifolia, was studied in different in vitro models: skin cells, primary cultures of melanocytes and keratinocytes, immortalized keratinocytes (HaCaT and HESV), and bone marrow cells (hematopoietic progenitors CFU-GM). Typical dose-response curves from neutral red uptake and MTT assays were recorded in all models with IC50 ranging from 6 to 24 mu M . Hematopoietic progenitors were more sensitive to caulerpenyne than melanocyte and keratinocyte cell lines, which could be due to their higher proliferative rate. The distribution of aggregates in colonies, macroclusters, and microclusters of hematopoietic progenitors was also altered in the presence of caulerpenyne. From our evaluation of the caulerpenyne concentrations required to result in cellular toxicity, the risks of cutaneous and/or food intoxication to humans may be considered minimal.

ISSN:0098-4108    

DOI:10.1080/009841096161924

出版商:Informa UK Ltd    

年代:1996

数据来源: Taylor

摘要:

The generation of reactive oxygen species by Co(II) from H2O2 in the presence of chelators and related DNA damage was investigated by electron spin resonance (ESR), electrophoretic assays, and high-performance liquid chromatography (HPLC). Incubation of Co(II) with-alanyl-3-methyl-L-histidine (anserine) and H2O2 generated OH radicals. Omission of any one component sharply reduced the amount of OH radicals generated, indicating that anserine modulated the oxidation potential of Co(II) to enhance its capability to generate OH radicals from H2O2. Formate only moderately decreased the OH radical generation, while ethanol had no observable effect, indicating that the generation of OH radical is site specific. The metal ion chelator 1, 10-phenanthroline reduced the OH radical generation, and deferoxamine suppressed it with the formation of deferoxamine nitroxide radical. Electrophoretic assays using both Hind III linear DNA and PM2 supercoiled DNA showed that OH radicals generated from a mixture of Co(II), H2O2, and anserine caused DNA strand breaks. A mixture of Co(II), H2O2, and 1, 10-phenanthroline also caused DNA strand breaks, which were inhibited by sodium azide, indicating that 102 was involved in DNA damage. HPLC measurements showed that OH radicals and 1O2 generated by Co(II) reactions caused 2'-deoxyguanosine hydroxylation to form 8-hydroxy-2'-deoxyguanosine. ESR spin trapping measurements provided evidence for 1O2 generation by Co(II) from H2O2 in the presence of 1, 10-phenanthroline. The results indicate that the oxidation potential of Co(II) can be modulated by chelators to facilitate its generation of reactive oxygen species from H2O2. These species may be involved in Co(II)-induced cellular damage.

ISSN:0098-4108    

DOI:10.1080/009841096161933

出版商:Informa UK Ltd    

年代:1996

数据来源: Taylor

摘要:

Both a subchronic inhalation study and a developmental toxicity screen were performed with vapors of light catalytically cracked naphtha (LCCN). In the subchronic study, four groups of mice and rats (10 animals per sex per species) were exposed for approximately 13 wk (6 h/d, 5 d/wk) to concentrations of LCCN vapors of 0, 530, 2060, or 7690 mg/m3. An untreated control group was also included. Animals were observed daily and body weights were taken weekly. No significant treatment-related changes were found in clinical signs, body weight, serum chemistry, hematology, histopathology of 24 tissues, or weights of 12 organs. A marginal decrease was noted in the number of sperm per gram of epididymis. In the developmental toxicity screen, presumed-pregnant Sprague-Dawley rats were exposed to 0, 2150, or 7660 mg/m3 of LCCN vapors, 6 h/d on d 0-19 of gestation. Females were sacrificed on d 20; dams and fetuses were examined grossly and fetuses were later evaluated for skeletal and visceral effects. The number of resorptions was increased by ~140% in the group receiving 7660 mg/m3; no other definite treatment-related changes were observed. Overall, the effects of exposure to partially vaporized LCCN were minimal.

ISSN:0098-4108    

DOI:10.1080/009841096161942

出版商:Informa UK Ltd    

年代:1996

数据来源: Taylor

摘要:

Exposure to silica, a cytotoxic and fibrogenic mineral dust, has been demonstrated to cause pulmonary inflammation and damage to the lung tissue. In contrast to the longterm consequences, little information exists on the sequence of inflammatory/damaging events occurring acutely after exposure to silica. The purpose of this study was to determine the minimum time after the administration of silica that the inflammatory/damage response is detectable and the temporal relationship of these processes. Male Fischer 344 rats were dosed intratracheally with silica (2.5 or 10 m g/100 g body weight) or saline vehicle. At 2 and 4 h after instillation, both cellular (total cell count and neutrophil count) and biochemical (total protein, albumin, and-glucuronidase and lactate dehydrogenase activities) parameters of inflammation and damage were evaluated in the bronchoalveolar lavage fluid. At 2 h, total protein levels were elevated at both silica doses, but all other parameters were unchanged; however, 4 h after silica exposure all parameters were elevated over those of the saline control. In a further attempt to characterize the inflammatory/ damage processes, luminol-dependent chemiluminescence (LDCL) was performed on aliquots of chopped lung. At 2 h after silica instillation, phorbol myristate acetate-stimulated lung tissue from silica-treated rats had no increase in light production when compared to controls, whereas after 4 h there were significant increases in LDCL activity in both dose groups when compared to controls. The addition of superoxide dismutase (SOD) decreased LDCL activity of the 2.5 m g/100 g group by 59% (2 h) and 66% (4 h), and of the 10 m g/100 g group by 49% (2 h) and 73% (4 h). Alternatively, the addition of N--nitro-Larginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, decreased the 2.5 mg/ 100 g group by 52% (2 h) and 60% (4 h). The 10 m g/100 g group was decreased by 67% (2 h), but only exhibited a 12% reduction at 4 h. SOD and L-NAME also inhibited the background LDCL in saline-treated rats. These reductions in LDCL activity indicate that reactive oxygen and nitrogen species play a role in the acute phase pulmonary response from silica. The results of this study indicate that the initial stages of damage begin to appear by 2 h, but damage and inflammation are definitive by 4 h after administration of silica in rats.

ISSN:0098-4108    

DOI:10.1080/009841096161951

出版商:Informa UK Ltd    

年代:1996

数据来源: Taylor