Substantial world-wide resources are being committed to develop improved toxicological testing methods that will contribute to better protection of human health and the environment. The development of new methods is intrinsically driven by new knowledge emanating from fundamental research in toxicology, carcinogenesis, molecular biology, biochemistry, computer sciences, and a host of other disciplines. Critical evaluations and strong scientific consensus are essential to facilitate adoption of alternative methods for use in the safety assessment of drugs, chemicals, and other environmental factors. Recommendations to hasten the development of new alternative methods included increasing emphasis on the development of mechanism-based methods, increasing fundamental toxicological research, increasing training on the use of alternative methods, integrating accepted alternative methods into toxicity assessment, internationally harmonizating chemical toxicity classification schemes, and increasing international cooperation to develop, validate, and gain acceptance of alternative methods.

Animal Testing Alternatives↗

PubMed1997

Arsenic can mediate skin neoplasia by chronic stimulation of keratinocyte-derived growth factors.

Although numerous epidemiological studies have shown that inorganic arsenicals are human skin carcinogens, there is currently no accepted mechanism for its action or an established animal model for its study. We observed increased mRNA transcripts and secretion of keratinocyte growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF) and transforming growth factor-alpha (TGF-alpha) and the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in primary human epidermal keratinocytes cultured in the presence of low micromolar concentrations of sodium arsenite. Total cell numbers, as well as c-myc expression and incorporation of [3H]thymidine, both indicators of cell proliferation, were also elevated in keratinocyte cultures treated with sodium arsenite. As an in vivo model, the influence of arsenic on mouse skin tumor development was studied in transgenic TG.AC mice which carry the v-Ha-ras oncogene, and can serve as a genetically initiated model for skin carcinogenesis. Following low-dose application of 12-O-tetradecanoyl phorbol-13-acetate (TPA), a marked increase in the number of skin papillomas occurred in transgenic mice receiving arsenic in the drinking water as compared to control drinking water. Papillomas did not develop in arsenic-treated transgenic mice that had not received TPA or arsenic-treated wild-type FVB/N mice, suggesting that arsenic is neither a tumor initiator or promoter but rather an enhancer. Injection of anti-GM-CSF antibodies following application of TPA in transgenic mice reduced the number of papillomas. Consistent with that observed in human keratinocyte cultures, increases in GM-CSF and TGF-alpha mRNA transcripts were found within the epidermis of arsenic-treated mice when compared to controls within 6 weeks of treatment. These results suggest that arsenic enhances papilloma development via the chronic stimulation of keratinocyte-derived growth factors and represents the first example of a chemical carcinogen that acts in this manner. These studies suggest that in vitro studies with human keratinocyte cultures examined in conjunction with TG.AC transgenic mice can provide a useful model for examining the tumor enhancing properties of environmental chemicals.

Animals↗

PubMed1996

Mechanism of skin tumorigenesis by contact sensitizers: the effect of the corticosteroid fluocinolone acetonide on inflammation and tumor induction by 2,4 dinitro-1-fluorobenzene in the skin of the TG.AC (v-Ha-ras) mouse.

The effect of the corticosteroid fluocinolone acetonide (FA) on skin tumor induction and inflammation by the contact sensitizer dinitrofluorobenzene (DNFB) was examined. This study broadly relates to the question of whether contact sensitizers, as electrophilic chemicals that produce protein adduction, may constitute an environmental cancer hazard. The specific aim of this study was to evaluate the extent to which the immunogenic inflammatory response to DNFB, in contrast to DNFB cytotoxicity, might be responsible for tumor induction. Experiments were conducted on a transgenic (TG.AC) mouse, incorporating a mutated ras oncogene (v-Ha-ras) that responds rapidly and profusely with skin papillomas to tumor promoters as if it were genetically initiated. Various doses and patterns of DNFB and FA were applied to the skin in a 2-week period; DNFB was given four times and FA was given either with the DNFB or daily. The tumor response to DNFB was completed by 8 weeks from the first dose and was consistent with a dose-squared relationship. FA was not tumorigenic alone; when given with DNFB, it caused only a small reduction in inflammation and tumor yield. When given daily, FA increased ulcerative skin damage, inflammation, and the yield tumors. The results suggest that tumorigenesis by DNFB, in the high-dose short-term regimen used here, is mainly due to its cytotoxicity and not contact sensitization.

Animals↗

PubMed1994

Focal transgene expression associated with papilloma development in v-Ha-ras-transgenic TG.AC mice.

The homozygous transgenic mouse line TG.AC contains a v-Ha-ras transgene and rapidly develops epidermal papillomas in response to either wounding or treatment with tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate (TPA). The transgenic v-Ha-ras protein product was detected in all papillomas removed from TPA-treated TG.AC mice but not in vehicle- or TPA-treated TG.AC skin without tumors. In situ hybridization demonstrated that focal expression of the transgene was limited to regions of papilloma development and further localized the expression of the transgene message to the epidermal component of the papillomas, with the strongest signal in the basal epidermoid cells. Cellular proliferation, as indicated by immunohistochemical staining for proliferating-cell nuclear antigen (PCNA), was similarly localized primarily to basal epidermoid cells and, to a lesser extent, stratum spinosum cells in all papillomas analyzed. Cells that stained positively for PCNA were much more common in the papillomas than in the surrounding, normal-appearing skin. The focal nature of papilloma development was also evidenced by protein kinase C activity and hyperplasia after TPA treatment. As early as 18 d after the start of TPA treatment, focal hyperplasias associated with the follicular epidermis were observed in TG.AC but not nontransgenic FVB/N skin; these hyperplasias were assumed to be the precursors of the epidermal papillomas. To explain the development of transgene-expressing tumors from apparently transgene-negative, normal-appearing skin, we hypothesize that the papillomas arise from the clonal expansion of focal areas of epidermal cells that overexpress the transgene. We also propose that the TG.AC line is an excellent model for studying very early events in papillomagenesis.

Animals↗

PubMed1994

Transgenic mouse models in chemical carcinogenesis studies.

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Animals↗

PubMed1992

The scientific basis of cement versus cementless fixation.

The arguments for and against three implant materials (polymethylmethacrylate, cobalt-chrome alloy, and titanium aluminium vanadium alloy) when used as interfaces between a loaded implant and bone are reviewed from mechanical and biologic standpoints. It is concluded that there is neither an overwhelming advantage nor a disadvantage for any one of them.

Alloys↗

PubMed1992

Transgenic mice in carcinogenicity testing.

The biological effects of the expression of single genes can be evaluated in transgenic animals. Transgenic techniques have been used to investigate a wide variety of biomedical topics, including the consequences of oncogene expression, but their use in carcinogenicity testing is just beginning. Probable future developments involving transgenic animals are new short-term assays for carcinogenicity in vivo and methods for detecting and characterizing the critical genotoxic events in carcinogenesis.

Animals↗

PubMed1989

Comparison of the Magill and Lack anaesthetic breathing systems in anaesthetized patients.

The Magill and Lack anaesthetic breathing systems were compared by measuring inspired and expired carbon dioxide concentrations and expired minute volumes in lightly anaesthetized, unstimulated subjects. There were no significant differences between the two breathing systems at fresh gas flow rates of approximately 50 and 70 ml kg-1 min-1. Inspired carbon dioxide concentrations increased in one of six subjects at the higher fresh gas flow rate using the Magill system and in two using the Lack system. Inspired carbon dioxide concentration did not increase in only one of six subjects at the lower fresh gas flow rate with both systems. Expired carbon dioxide concentrations and expired minute volume increased in the majority of subjects at both fresh gas flow rates using each system. We conclude that a fresh gas flow rate greater than 70 ml kg-1 min-1 (which approximated to alveolar minute volume in our subjects) should be supplied to the Magill and Lack breathing systems.

Adult↗

PubMed1987

Management of endoscopically removed malignant colon polyps.

The medical records of 87 patients with 89 malignant colorectal polyps removed endoscopically between 1971 and 1983 were reviewed retrospectively. Fifty-five polyps contained carcinoma-in-situ. Four polyps had "pseudo-invasion" by displaced mucosal glands. Thirty polyps contained invasive carcinoma. No patients with carcinoma-in-situ or "pseudo-invasion" had either local residual disease or metastatic disease at the time of colectomy or which was detected during subsequent follow-up. Four patients (14%) with invasive cancer would have been inadequately treated by polypectomy alone, since one had residual disease at the polypectomy site, one had nodal metastases, one had liver metastases at the time of colectomy, and one subsequently developed liver metastases. Three histologic criteria correctly predicted all four cases where residual or recurrent disease was present: involvement of the polypectomy resection margin, lymphatic invasion within the polyp, and poorly differentiated histology. Polyp size, histology (villous adenoma, adenomatous polyp, or villo-adenomatous polyp), or anatomic location did not identify those patients who warranted further therapy. We conclude that polypectomy alone is adequate treatment for polyps containing carcinoma-in-situ. Polypectomy alone is also adequate treatment for most polyps containing invasive carcinoma. However, patients with lymphatic involvement within the polyp, poorly differentiated cancer, or resection margin involvement should probably undergo colectomy.

Adult↗

PubMed1987

Oxygen analysers. An evaluation of five fuel cell models.

Five currently available fuel cell oxygen analysers were studied with a view to their use in anaesthesia. The accuracy, response time and safety features of these analysers are discussed. Fuel cell analysers appear to be suitable oxygen monitors for routine anaesthetic use.

Anesthesia, Inhalation↗

PubMed1985

Congenital alveolar capillary dysplasia: a developmental vascular anomaly causing persistent pulmonary hypertension of the newborn.

The clinical course and histologic findings are presented of an infant with an unusual form of pulmonary dysplasia. Characteristic sonographic findings and progressive hypoxemia led to the diagnosis of persistence of the fetal circulation. The patient expired despite ventilatory and pharmacologic intervention. Postmortem findings of severe pulmonary capillary hypoplasia, despite normal anatomical and biochemical parenchymal maturation, were observed. It is suggested that factors controlling pulmonary capillary maturation may be significantly different from those involved in airway and pulmonary parenchymal development.

Capillaries↗

PubMed1984

Fixed performance oxygen masks: an evaluation.

Fixed performance oxygen masks operate by supplying mixtures of oxygen and air at rates exceeding the inspiratory flow rate of the patient. In this study the oxygen concentration delivered by three fixed performance oxygen masks was determined non-invasively at various inspiratory flow rates. At low inspiratory flow rates all the masks studied acted as fixed performance devices. When the peak inspiratory rate increased the performance of all the masks showed some variability. The change from fixed to variable performance depended on the relation between inspiratory flow rate and the total gas flow delivered by the mask and was independent of the volume of the mask. Hence the use of low volume masks and high oxygen flow rates should produce more consistent results than high volume masks and lower flow rates.

Carbon Dioxide↗