Ethane sulfonate metabolite of alachlor: assessment of oncogenic potential based on metabolic and mechanistic considerations.

Chronic administration of alachlor has been shown to produce neoplastic responses in the nasal turbinate mucosa, glandular stomach mucosa, and thyroid follicular epithelium of rats. Subsequent studies have shown that specific metabolic activation of alachlor is required for nasal tumor formation, and that non-genotoxic, threshold-sensitive processes produce all three tumors. The herbicide alachlor is degraded in the soil by microbial action to the tertiary ethane sulfonate metabolite (ESA). The acute and subchronic toxicity of ESA is very low, and the metabolite did not produce developmental toxicity or genotoxicity. The studies described here were conducted to determine whether ESA shares a common mechanism of oncogenicity with alachlor in rats. Specifically, we studied ESA's pharmacokinetics and ability to produce changes that are causally associated with the oncogenicity of alachlor. These studies demonstrated that ESA was poorly absorbed and underwent minor metabolism, which contrasted with the significant absorption and substantial metabolism observed with alachlor. ESA was also excreted more quickly than alachlor and showed no evidence of accumulation in the nasal turbinates, a site of oncogenicity for alachlor in the rat. In addition, ESA did not elicit the characteristic preneoplastic changes observed in the development of alachlor-induced nasal, stomach, and thyroid tumors. The results of these studies support the conclusion that ESA does not share a common oncogenic mechanism with alachlor and would not be expected to produce the same oncogenic responses observed following chronic alachlor exposure in rats.

Effects of tromethamine and sodium bicarbonate buffers during cardiac resuscitation.

The effects on cardiac resuscitability of iso-osmolal solutions of tris-hydroxymethyl-aminomethane (tromethamine), sodium bicarbonate (NaHCO3) and sodium chloride placebo were compared in 30 domestic pigs using a well-established model of electrically induced cardiac arrest and resuscitation. We hypothesized that a carbon dioxide (CO2) consuming buffer like tromethamine would reduce and sodium bicarbonate would increase the respiratory acidosis of mixed venous blood, which had recently been demonstrated in our laboratory, Tromethamine did decrease and sodium bicarbonate did increase both arterial and mixed venous CO2 during cardiopulmonary resuscitation (CPR). Both concentrations of end-tidal CO2 and coronary venous PCO2 were significantly lower after tromethamine than after bicarbonate. However, tromethamine produced an unexpected vasodilator effect with reduction of mean aortic and coronary perfusion pressures to levels that are known to reduce resuscitability and survival independently of its buffer action. Neither resuscitability nor survival was altered by bicarbonate therapy in comparison with sodium chloride placebo.

T-cell mitogenesis and natural killer cell activity in colonic tumor-bearing and nontumor-bearing rats fed diets high in lipid with and without cholesterol.

It has been shown that rats fed diets high in lipid and cholesterol develop more 1,2-dimethylhydrazine (DMH)-induced bowel tumors than those fed diets low in lipid or without cholesterol. To further explore the effects of these dietary regimens on immune function, rats were fed diets containing 20% safflower or coconut oil, with or without cholesterol (1%) and cholic acid (0.3%), for 35 weeks during which time they were given DMH. Only rats bearing one or more colon tumors and that showed no evidence of weight loss were utilized. Two parameters of cell-mediated immune function were assessed in tumor- and nontumor-bearing control rats: a) response to the T-cell mitogen, phytohemaglutinin (PHA), and b) natural killer cell activity (NKCA). Nearly total suppression of PHA response was observed in the polyunsaturated fat diet group compared with the saturated fat diet groups. Addition of cholesterol to either the polyunsaturated or saturated fat diets diminished PHA response and, to a lesser degree, of T-lymphocytes from rats fed these diets. NKCA, however, was unaffected by either the quality of dietary fat or cholesterol. There were no detectable effects of DMH per se 15 weeks after the last injection (or in the presence or absence of tumors) on T-lymphocyte response to PHA or on NKCA. The relationships among lipid nutrition, carcinogen-induced tumorigenesis, and immunologic events is obviously complex. These studies imply that nutritional interventions may have a selective rather than a generalized effect on various immunocompetent cell populations. Furthermore, the effects of lipid nutriture, rather than long-term effects of carcinogen administration, or the presence of bowel tumors appear to play the major role on perceived alterations in in vitro immune function. Thus the effects of these lipid nutritional interventions on DMH-induced tumorigenesis seem independent of their effects on immune phenomena with the immune probes utilized.

Natural killer cell activity and MMPI scores of a cohort of college students.

Natural killer (NK) cells are important in immune function and appear, in part, to be regulated by the CNS. The authors compared NK cell activity and MMPI scores of 111 healthy college students and found weak but statistically significant correlations between NK values and psychopathology for 10 of 12 scales. Students with the highest NK values had a "healthier" MMPI profile than those with the lowest. Students with high MMPI scores (T greater than 70) had NK values below the sample median. These findings support theories of interaction between mental state and immune status, but the mechanisms and direction of interaction remain largely unexplored.