A subchronic exposure to trichloroethylene causes lipid peroxidation and hepatocellular proliferation in male B6C3F1 mouse liver.

The common groundwater contaminant trichloroethylene (TCE), when given by oral gavage, can produce free radical species during metabolism. Furthermore, TCE end-stage metabolites, trichloroacetic acid and dichloroacetic acid, cause lipid peroxidation in mouse liver. The time courses of lipid peroxidation, free radical generation, and 8-hydroxydeoxyguanosine (8OHdG) formation were used to assess the level of oxidative stress in the liver of B6C3F1 mice dosed orally once daily, 5 days a week for 8 weeks at 0, 400, 800, and 1200 mg/kg TCE in corn oil. Peroxisomal proliferation, cell proliferation, and apoptosis were evaluated at selected times during the study. Lipid peroxidation, as measured by thiobarbituric acid-reactive substances (TBARS), was significantly elevated at the two highest dose levels of TCE on days 6 through 14 of the study. 8OHdG levels were statistically significant in the 1200 mg/kg/day group on days 2, 3, 10, 28, 49, and 56 only. The highest measured free radical load, 307% of oil control, occurred at day 6. A significant increase in cell and peroxisomal proliferation was observed during the same time period in the 1200 mg/kg/day group. Necrosis or an increase in apoptosis was not observed at any dose. The temporal relationship between oxidative stress and cellular response of proliferation, both of which occur and resolve within the same relative time period, suggests that TCE-induced mitogenesis may result from alteration in the liver microenvironment which offers a selective advantage for certain hepatocyte subpopulations.

Inflammatory damage to skin by prolonged contact with 1,2-dichlorobenzene and chloropentafluorobenzene.

Skin samples from Fischer-344 rats and Hartley guinea pigs exposed dermally to 1,2-dichlorobenzene (DCB) and chloropentafluorobenzene (CPFB) for up to 4 h were examined for chemical-induced damage. Samples were stained with hematoxylin and eosin and scored for polymorphonuclear cell (PMN) margination, dermal inflammation, and epidermal necrosis by light microscopy. Ultrastructural evaluation of samples fixed with 2% glutaraldehyde and postfixed with 1% osmium tetroxide was used to visualize margination of PMNs. Guinea pigs exhibited postexposure inflammatory changes following an exposure of about an hour-and-a-half shorter duration than rats. DCB-induced inflammation and PMN margination occurred following an exposure about a half hour shorter in both species compared to CPFB. In contrast, epidermal necrosis was more severe with CPFB than with DCB. These changes may account for decreases in chemical penetration rates which have been observed in previous studies with DCB and CPFB in rats and guinea pigs.

Significance of the dermal route of exposure to risk assessment.

The skin is a route of exposure that needs to be considered when conducting a risk assessment. It is necessary to identify the potential for dermal penetration by a chemical as well as to determine the overall importance of the dermal route of exposure as compared with inhalation or oral routes of exposure. The physical state of the chemical, vapor or liquid, the concentration, neat or dilute, and the vehicle, lipid or aqueous, is also important. Dermal risk is related to the product of the amounts of penetration and toxicity. Toxicity involves local effects on the skin itself and the potential for systemic effects. Dermal penetration is described in large part by the permeability constant. When permeability constants are not known, partition coefficients can be used to estimate a chemical's potential to permeate the skin. With these concepts in mind, a tiered approach is proposed for dermal risk assessment. A key first step is the determination of a skin-to-air or skin-to-medium partition coefficient to estimate a potential for dermal absorption. Building a physiologically-based pharmacokinetic (PBPK) model is another step in the tiered approach and is useful prior to classical in vivo toxicity tests. A PBPK model can be used to determine a permeability constant for a chemical as well as to show the distribution of the chemical systemically. A detailed understanding of species differences in the structure and function of the skin and how they relate to differences in penetration rates is necessary in order to extrapolate animal data from PBPK models to the human. A study is in progress to examine anatomical differences for four species.

Animal issues and society.

Animal use topics are sensitive issues today. Animal uses issues are often presented as black and white or 'we' are right and 'they' are wrong. This is clearly demonstrated in the available literature from most organizations. Topics presented will include: delineation of issues and concerned groups; examples of animal issues in education and agriculture; the terrorist issue; examples of animal issues/sportsman issues; examples of political and legislative impact; and examples of biomedical and toxicology animal use issues.

Effects of a 13-week chloropentafluorobenzene inhalation exposure of Fischer 344 rats and B6C3F1 mice.

Chloropentafluorobenzene (CPFB) has been identified as a candidate simulant for nonpersistent chemical warfare agents. Acute toxicity studies have shown that CPFB has limited adverse effects on laboratory animals. A 21-day inhalation study of rats and mice to 2.5, 0.8, and 0.25 mg CPFB/liter resulted in reduced weight gain in male and female rats exposed at the high concentration only and identified the liver as a potential target organ. This multiconcentration inhalation study was designed to detect a no-observable-effect level associated with repeated exposure to CPFB. Male and female rats and mice were exposed to 250, 50, or 10 mg CPFB/m3 (0.25, 0.05, or 0.01 mg CPFB/liter) for 13 weeks. No treatment-related effects on body weight, clinical chemistries, mortality, absolute or relative organ weight or histopathology were noted.

Pancreatic polypeptide and insulin-secreting tumor in a dog with duodenal ulcers and hypertrophic gastritis.

A 7-year-old spayed female Cocker Spaniel was hospitalized with a history of chronic vomiting, anorexia, and weight loss. Laboratory abnormalities included leukocytosis, metabolic alkalosis, hypoglycemia, hypoproteinemia, and hyperinsulinemia. Gastroscopy and ultrasonography revealed multiple gastric masses and a possible pancreatic mass, respectively. Examination of tissues obtained at necropsy showed a pancreatic adenocarcinoma with hepatic metastasis, gastric hypertrophy, and multiple duodenal ulcers. Immunocytochemical staining of the neoplasia was positive for pancreatic polypeptide (PP) and insulin and negative for gastrin, calcitonin, adrenocorticotropic hormone (ACTH), serotonin, L-enkephalin, chromagranin, glucagon, and somatostatin. Subsequent serum gastrin and PP assays showed a fasting hypergastrinemia with a normal response of gastrin to provocative testing and extremely increased PP values. The high PP values may have resulted in the vomiting and gastrointestinal ulceration. A PP-secreting tumor has not previously been reported in the dog.