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The invention of electric light has facilitated a society in which people work, sleep, eat, and play at all hours of the 24-hour day. Although electric light clearly has benefited humankind, exposures to electric light, especially light at night (LAN), may disrupt sleep and biological processes controlled by endogenous circadian clocks, potentially resulting in adverse health outcomes. Many of the studies evaluating adverse health effects have been conducted among night- and rotating-shift workers, because this scenario gives rise to significant exposure to LAN. Because of the complexity of this topic, the National Toxicology Program convened an expert panel at a public workshop entitled "Shift Work at Night, Artificial Light at Night, and Circadian Disruption" to obtain input on conducting literature-based health hazard assessments and to identify data gaps and research needs. The Panel suggested describing light both as a direct effector of endogenous circadian clocks and rhythms and as an enabler of additional activities or behaviors that may lead to circadian disruption, such as night-shift work and atypical and inconsistent sleep-wake patterns that can lead to social jet lag. Future studies should more comprehensively characterize and measure the relevant light-related exposures and link these exposures to both time-independent biomarkers of circadian disruption and biomarkers of adverse health outcomes. This information should lead to improvements in human epidemiological and animal or in vitro models, more rigorous health hazard assessments, and intervention strategies to minimize the occurrence of adverse health outcomes due to these exposures.

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As recently characterized, following s.c. implantation into syngeneic C57BL/6 mice, E0771 tumor invades locally into dermal layers and peritoneum, metastasizes to the lung, and induces a nonspecific immunosuppression in the host. Using this breast medullar adenocarcinoma model, a therapy consisting of a single moderate dose of doxorubicin followed by twice daily moderate doses of interleukin-2 for 30 days was examined for efficacy and mechanism of action when given to animals with established disease. This combination treatment, but not combinants alone, resulted in tumor-free long-term survival of 40% of the mice without significant toxicity and 83% of survivors had immune memory specific for E0771 cells. Treatment also decreased immune suppression induced by E0771 tumor. Full response to treatment required functional CD8(+) T cells, whereas depletion of natural killer cells caused only a reduction in response rate. A serum "biomarker" profile that correlated with, and seemed predictive of, response to treatment was identified by nuclear magnetic resonance-based metabonomic analysis. The efficacy of this nontoxic treatment and the potential to be able to predict which individual is responding to treatment are characteristics that make this chemoimmunotherapy attractive for clinical testing.

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BACKGROUND: Breast cancer treatments are most effective when initiated early, with very poor efficacy against metastatic disease. In seeking a readily metastasizing mouse breast cancer model to facilitate the search for effective therapies, E0771 medullary adenocarcinomas implanted subcutaneously in syngeneic C57BL/6 mice were studied. MATERIALS AND METHODS: Standard pathological, histological and immunological methodologies were used. RESULTS: The aggressive estrogen receptor-positive tumor invaded locally into the peritoneal cavity in 56% of mice, as well as metastasizing to the lungs in 52% of mice. The metastasis was a spontaneous event and immunosuppression was seen (e.g. generation of lyphokine activated killer cells and allogeneic cytotoxic T lymphocytes cytolytic activities ex vivo were suppressed). Other pathological events noted as the tumor progressed were: bloody ascites (56%) and shock (72%), both attributed to local (peritoneal) tumor invasion. CONCLUSION: The E0771 metastatic breast cancer model, which mimics the human disease, should be useful in testing new treatments against this disease and/or in examining the metastatic process.

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The administration of 5-fluorouracil (FU) and leucovorin (LV) to rats induced a previously unreported sialoadenitis-like toxicity. Four different treatment regimens were used: daily-times-5 iv or ip injections of LV (200 mg/kg) followed 30 minutes later by FU (27.5 mg/kg or 35 mg/kg). These treatments resulted in 3 severity levels of systemic toxicity indicated by changes in body weight. In addition to the well known FU+LV-induced diarrhea, myelosuppression, and stomatitis, facial edema, and enlargement of the submandibular salivary gland were consistently seen. Facial edema occurred almost exclusively in rats that subsequently underwent excessive weight loss and were euthanized. The submandibular, but not parotid or sublingual, salivary gland was enlarged and the severity of this effect changed in a bell-shaped relationship with respect to increasing FU+LV induced loss of body weight. Histologic examination of affected glands established the occurrence of bacterial infection, sialoadenitis and destruction of gland tissue. This paper provides the first known documentation of FU+LV treatment-induced selective pathology of the submandibular salivary gland. The selectivity of this toxicity, apparently not normally seen in humans, to the submandibular salivary gland of the rat is of interest and its mechanism warrants further investigation.

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