摘要:

Optimal experimental designs for carcinogenicity bioassays conducted for the assessment of risks associated with exposure to environmental chemicals are derived. For our purposes, an optimal experimental design is a design that minimizes the mean‐squared error of the maximum likelihood estimate of the virtually safe dose from the Armitage‐Doll multistage model and maintains a high power for the detection of increased carcinogenic response. Three‐ and four‐dose designs (including control as one of the doses) are discussed for a variety of dose response patterns. Monte Carlo simulation techniques are used to estimate the power and mean‐squared error for small samples sizes. Two forms of the multistage model are used to estimate the virtually safe dose: the linear model and the linear‐quadratic model. The optimal designs for fitting the linear model used a control group and a group administered the maximum tolerated dose, with about 50% of the animals at each dose. The three‐ and four‐dose optimal designs when fitting the linear‐quadratic model were found to be equivalent. However, after considering several biological issues, including overt toxicity, the optimal four‐dose designs were found superior to the optimal three‐dose designs. An optimal four‐dose design would use between 150 and 300 animals, with 50 to 60 animals in the control group, and 40 to 60 animals in the group administered the maximum tolerated dose. One‐third of the remaining animals would be administered a dose between 10 and 30% of the maximum tolerated dose, and two‐thirds of the remaining animals would be administered 50% of the maximum tolerated dose.

ISSN:0098-4108    

DOI:10.1080/15287398309530403

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

ISSN:0098-4108    

DOI:10.1080/15287398309530402

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

A method is presented for identification of viable and nonviable cells in scanning electron microscopy by use of maps of colored light micrographs of conventionally stained monolayers of alveolar macrophages. The content of phagocyted metal particles in relation to the cell viability can be estimated by using a scanning electron microscope combined with an energy‐dispersive X‐ray analyzer. This method makes it possible to assess the toxic effects of different air pollutants in combinations occurring in the general environment and different working conditions.

ISSN:0098-4108    

DOI:10.1080/15287398309530404

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

Lung epithelial cell (cell line designated LEC) and Chinese hamster ovary (CHO) cells were grown on hydrated collagen gels and exposed directly to toxic vapor‐phase pollutants. The cells were exposed to graded concentrations of phenol, formaldehyde, a volatile fraction of process stream material from an experimental coal gasifier, and the nonparticulate, vapor phase of diesel engine exhaust. During exposures, the cells were maintained at an air/collagen interface by removing the medium overlying the hydrated collagen gel. Morphological changes indicative of cell retraction were found in LEC cell cultures exposed to phenol, formaldehyde, or diesel exhaust Damage following exposure to the toxicants was quantitated in LEC and CHO cells by Trypan blue dye exclusion, a measure of plasma membrane integrity. Clone‐forming ability was also used to measure cell survival in CHO cells. When measured by Trypan blue dye exclusion, phenol (EC50 = 2.1 mg/l) caused membrane damage to LEC cells but not CHO cells, while formaldehyde (EC50–31 and 42 μg/l for LEC and CHO, respectively) and diesel exhaust (EC50 =11 and 29% of tailpipe exhaust in LEC and CHO cells, respectively) caused damage to both cell types. No cytotoxicity was observed in LEC or CHO cells exposed to the fraction from the coal gasifier. Essentially no mutagenic activity was associated with the exposure of CHO cells to formaldehyde or the vapor phase of diesel exhaust. Mutagenic activity was found in CHO cells exposed to ethylene oxide, the positive control. The results of this study indicate that mammalian cells grown on collagen gels can readily be exposed to vapors of chemicals and chemical mixtures. The cell exposure system may be generally useful in the analysis of toxic damage to mammalian cells resulting from gaseous or vapor‐phase pollutants.

ISSN:0098-4108    

DOI:10.1080/15287398309530405

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

A brand of cigarette with nominal tar and nicotine yields of 4.0 mg and 0.4 mg, respectively, was examined under various machine‐smoked conditions that reflect the wide range of human smoking behavior. Three levels of each of five smoking parameters‐butt length, puff duration, puff interval, puff volume, and ventilation occlusion‐were examined, and the effects on puff number and total particulate matter (TPM) as well as gas phase, particulate phase, and total HCN yields were estimated. Yields of hydrogen cyanide (a ciliatoxic agent) and TPM varied significantly under different smoking conditions. Ventilation occlusion had the most pronounced effect, accounting for 34% of the response variation of TPM yields and 42% of the response variation for total hydrogen cyanide yields.

ISSN:0098-4108    

DOI:10.1080/15287398309530406

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

Mice exposed 5 h/d, 5 d/wk up to 103 d, to 0.2 mg O3/m3or to a mixture of O3, 13.2 mg SO2/m3, and 1.04 mg (NH4)2SO4aerosol/m3showed significantly greater susceptibility to group C streptococcal aerosol infection relative to filtered air controls. Pulmonary bactericidal activity by alveolar macrophages was significantly enhanced in the lungs of mice exposed to the mixture relative to those inhaling filtered air or O3alone. The total number and distribution of the free cells lavaged from the lungs, as well as cellular ATP levels, did not change due to the pollutant exposures. In vitro cytostasis in tumor target cells cocuitured with peritoneal macrophages from the exposed mice was significantly enhanced in the O3‐exposed and in the mixture‐exposed treatment groups relative to controls and also in the mixture‐exposed relative to the O3‐exposed group when a target‐to‐effector‐ceil ratio of 1:10 was used; no such effects were observed when this ratio was 1:20. Splenic T‐lymphocyte function, as measured by blastogenesis to mitogens and alloantigens, was affected by exposure to O3and/or the mixture, although the patterns of effects were qualitatively different. Splenic B‐cell function and macrophage antigen processing, as measured by the generation of antibody plaque‐forming cells, was unaffected by exposure.

ISSN:0098-4108    

DOI:10.1080/15287398309530407

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

Previous work in our laboratory suggested that toxicity resulting from acute postnatal administration of triethyitin (TET) was Influenced by the treatment condition of litter‐mates. To test this possibility, two dosing models were compared. For the split‐litter model (N = 20 litters/dose), 1 male and 1 female pup per litter received a single dose of 0 (saline), 3, 6, or 9 mg TET/kg on postnatal d 5; the remaining 6 littermates were not injected. In the whole‐litter model, all 8 littermates received 0, 3, 6, or 9 mg TET/kg (N — 5 litters/dose). Differences between dosing models were found for preweaning body weight and adult figure‐eight maze activity. Body weights were reduced in all TET‐dosed pups; for 3‐mg/kg animals, the reduction in preweaning growth was more persistent for pups in the split‐Utter group. Motor activity in a figure‐eight maze was increased in both 6‐ and 9‐mg/kg animals; for the high dose, the increase in activity was greater for animais in the split‐litter group. There were no differences between dosing models in mortality, brain weight, or postweaning body weight. Approximately 50% of the 9‐mg/kg animals died; there was no treatment related mortality at lower doses. Adult body weight also remained decreased only in the 9‐mg/kg animals. Brain weight was reduced for all TET dose groups. These results indicate that developmental toxicity produced by TET is not primarily determined by the dosing regimen.

ISSN:0098-4108    

DOI:10.1080/15287398309530408

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

Dimethyltin dichloríde (DMDC) is commonly used as a stabilizer in PVC pipe used for transport of potable water. Learning deficiencies have been observed postnatally in pups from DMDC‐treated dams. Studies were conducted with female Sprague‐Dawley rats to determine whether DMDC was absorbed by the dam and transferred across the placenta to fetal blood and brain tissue. This was accomplished in three phases: (1) a comparison of absorption of organic and inorganic tin from drinking water, (2) a comparison of prenatal and postnatal levels of tin in the pups in cross‐fostering studies, and (3) a [14C]dimethyltin dichloríde tracer study to determine whether organic tin passed to the pup intact Major findings include: (1) DMDC is absorbed in the gastrointestinal tract of the dam much more rapidly than Sn2+; (2) the more rapid absorption of DMDC results in higher concentration of tin in fetal blood and brain; and (3) in fetuses that receive tin as DMDC, both tin and the methyl carbon are absorbed by the dam and transferred to the blood and brain of the fetuses.

ISSN:0098-4108    

DOI:10.1080/15287398309530409

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

The relative merits of a comprehensive series of contemporary methods for detection of acute nephrotoxicity were evaluated. Male Sprague‐Dawley rats were given 0, 0.25, 0.5, 1.0, or 3.0 mg mercuric chloride (HgCl2)/kg body weight by ip injection. Indices of nephrotoxicity were examined 8, 24, 48, 72, and 96 h later. Alterations in urine osmolality, volume, and protein levels were seen within 24 h in response to 1 mg/kg or more of HgCl2. Administration of 0.5–3.0 mg/kg produced dose‐dependent increases in urinary excretion of maltase activity and glucose by 24 h, the period of peak effect. There was no increase in maltase or alkaline phosphatase (AP) activity in the serum of these animals. Enzymuria was not apparent in rats that had marked elevations in serum AP, argininosuccinate lyase, and ornithine carbamyl transferase activities as a result of physical (i.e., dichlorodifluoromethane‐frozen) or chemical (carbon tetrachloride‐induced) damage of the liver. Morphological alterations, in the proximal tubular epithelium of perfusion‐fixed kidneys from HgCl2‐dosed rats, paralleled the changes in enzyme excretion with respect to time of onset and dose‐effect. There was a dose‐dependent inhibition of tetraethylammonium (TEA) and p‐aminohippurate (PAH) uptake by renal cortical slices at 24 h. Interestingly, increases in uptake of TEA and PAH were seen 8 h after a 1‐mg/kg dose. Clearance of inulin and PAH in vivo were altered at 8 h by 0.5 and 1 mg/kg. Marked depression of these functional indices was seen at 24 h, by which time blood urea nitrogen (BUN) levels were increased. The 0.5‐ and 1.0‐mg/kg doses also produced time‐ and dose‐dependent increases in intracellular Na+content which were maximal at 24 h. These results illustrate the importance of using a combination of biochemical and functional tests to elucidate the sequence of events in the kidney following toxic insult. Nevertheless, some of the simpler, traditional techniques (e.g., histopathology, urinalyses, BUN) were sensitive and organ‐specific, and should continue to be very useful in nephrotoxicity testing/screening.

ISSN:0098-4108    

DOI:10.1080/15287398309530410

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

Vanadate (Na3VO4) in micromolar concentrations enhanced the in vitro formation of adrenochrome from epinephrine, and of aminochrome from dopamine. Lipid peroxides in various tissues of the mouse and rat, particularly brain, were increased. Products of both catecholamine oxidation and lipid peroxidation may be the basis of the cardiotoxic and neurotoxic effects of vanadium.

ISSN:0098-4108    

DOI:10.1080/15287398309530411

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor