A specific stimulator of granulocyte colony-stimulating factor accelerates recovery from cyclophosphamide-induced neutropenia in the mouse.

We have identified a small molecular weight compound, SCH 14988, which specifically stimulates in vitro granulocyte-colony stimulating factor (G-CSF) production from activated human peripheral blood mononuclear cells and monocytes but not other cytokines or CSFs with hematoregulatory activity. In vivo administration of SCH 14988 to mice rendered neutropenic by cyclophosphamide treatment resulted in the accelerated recovery of the peripheral neutrophil compartment. This activity correlated with increased in vivo G-CSF levels and stimulation of marrow granulopoiesis, and was comparable to that of exogenously administered recombinant human G-CSF. No alterations to other leukocyte populations in peripheral blood, spleen, or the peritoneal cavity were observed. These findings suggest that SCH 14988 may be clinically useful to enhance neutrophil granulopoiesis, as well as to study the mechanisms involved in G-CSF gene regulation.

Various approaches to damage assessment.

There are two main approaches used to assess the damage to human health from exposure to low-level ionizing radiation. The first is a realistic best-estimate approach. The second is performed in support of the development of radiation standards to protect workers and the public, and tends to overestimate risk. This paper reviews these approaches to damage assessments as they have been applied to the development of radiation protection standards and current estimates of risk. Technical issues affected by these two different approaches include use of the linear hypothesis, use of relative and absolute risk projection models, dose-rate effectiveness factor, appropriateness of data sets, and the transfer of risks between populations. The prudent approach may be justified for radiation protection purposes, but scientific estimates of risk should reflect the state-of-the-science and include estimates of uncertainty.

Stimulation of cytolytic activity by interleukin-10.

Interleukin-10 (IL-10), originally identified as an inhibitor of cytokine and monokine synthesis [e.g., IL-2, interferon-gamma (IFN-gamma), and tumor necrosis factor (TNF-alpha)], modulates a wide range of immunologic activities. In the present study we have examined the induction of non-major histocompatibility complex-restricted cytolytic activity in human peripheral blood mononuclear cells (PBMCs). PBMCs incubated with human IL-10 for 3 days were used as effector cells in cytotoxicity (i.e., 51Cr release) assays against a panel of human tumor cells. In a concentration-dependent manner. IL-10 stimulated or potentiated lytic activity against several human tumor cell lines. Induction of cytolytic activities by IL-10 was neutralized by anti-IL-10 monoclonal antibodies but not by antibodies against IFN-gamma or TNF-alpha. Co-incubation of PB-MCs with IL-10 and IL-2 or IL-10 and IFN-alpha augmented cytolytic activity, in particular at lower effector-to-target ratios. IL-2-induced release of TNF-alpha was dramatically reduced by IL-10; however, the expression of lymphokine-activated killer (LAK) activity was not affected. PBMCs preactivated with IL-10 before addition of IL-2 displayed higher levels of LAK activity. Inhibition of IL-2-driven LAK activity by IL-4 is alleviated by IL-10. Finally, IL-10 is not affected by inhibitors of IL-2, such as IL-4 and transforming growth factor-beta. Potential application of IL-10 to anti-tumor therapies is discussed.

Synthetic-fuel plants: potential tumor risks to public health.

This article quantifies potential public health risks from tumor-producing pollutants emitted from two synthetic-fuel plants (direct liquefaction--Exxon Donor Solvent: and indirect liquefaction--Lurgi Fischer-Tropsch) located at a representative site in the eastern United States. In these analyses gaseous and aqueous waste streams were characterized; exposures via inhalation, terrestrial and aquatic food chains, and drinking water supplies were modeled. Analysis suggested that emissions of "polycyclic aromatic hydrocarbons," "aromatic amines," "neutral N, O, S heterocyclics," "nitriles," and "other trace elements" pose the largest quantifiable risks to public health. Data and analysis for these pollutant categories should be refined to more accurately match compound-specific estimated exposure levels with tumorigenic potency estimates. Before these results are used for regulatory purposes, more detailed analysis for selected pollutant classes are needed, and more sophisticated aquatic exposure models must be developed. Also, differences in geographic scales among the environmental transport models used need to be rectified.

Coal conversion technologies: some health and environmental effects.

Several technologies to convert coal to liquid and gaseous fuels are being developed in the United States, some with support from the Department of Energy. Substitution of these technologies for those currently being used will produce different health and environmental hazards. In this article, selected health and environmental effects of four coal conversion and four existing technologies are compared. For each technology, the emission estimates for complete fuel cycles, including all steps in fuel use from extraction to the end use of space and water heating by electricity or direct combustion, were prepared by means of the Brookhaven Energy System Network Simulator model. Quantitative occupational health and safety estimates are presented for the extraction, transportation, distribution, processing, and conversion activities associated with each technology; also included are some public health damage estimates arising from fuel transportation and air pollution impacts. Qualitative estimates of health damage due to polycyclic organic matter and reduced sulfur are discussed. In general, energy inefficiencies, environmental residuals, and hence implied environmental effects and health damage increase in the order: (i) direct combustion of natural gas and oil, (ii) direct combustion of synthetic gas and oil, (iii) central-station electric power produced from synthetic gas, (iv) central-station electric power produced from coal, and (v) central-station electric power produced by the combustion of synthetic liquid fuels. The compliance and conflict of these technologies with the amendments of the Clean Air Act and other legislation are discussed.

Biochemical significance of the hard and soft acids and bases principle.

The hard and soft acids and bases (HSAB) principle, which states that hard acids bind preferentially to hard bases and soft acids to soft bases, may serve to assess specific chemico-biological interactions. As living systems are composed mainly of "hard" elements, molecular events taking place within the cell are dominated by "hard-hard interactions". On this premise, it becomes likely that extraneous "soft" agents are particularly injurious to life. In the HSAB context a selected number of variegated phenomena are briefly discussed qualitatively; these include biocidal actions, heavy metal poisoning, chemical carcinogenesis, some enzymic reactions, and nucleic acid complexations. Although the HSAB principle cannot be used as a tool for mechanistic explanations of biochemical processes, it may provide clues to likely target molecules and the loci of action.

Enzymatic repair of UV-irradiated DNA in vitro.

Excision repair of UV-damaged Bacillus subtilis transforming DNA has been carried out by a sequential enzyme system in vitro. Incision adjacent to the pyrimidine dimer in the DNA strand by correndonuclease II-initiated excision of the damage by the 5' in equilibrium 3'-directed exonuclease of the Micrococcus luteus DNA polymerase. Reinsertion of nucleotides into the gap in the strand by the DNA polymerase at 10 degrees C terminated in a single-strand break which was sealed by a polynucleotide ligase, thereby repairing the DNA strand. This restored biological activity to damaged DNA up to doses resulting in 60% inactivation of transforming activity. At higher doses, less repair was achieved, due to the development of double-strand breaks during the in vitro incision and excision steps.

Poly(inosinic acid)-poly(cytidylic acid) inhibition of DNA synthesis in synchronized HeLa cells.

Inhibition by double-stranded polyribonucleotides of DNA synthesis in synchronized HeLa cultures is dose- and time-dependent. Inhibition by poly(I.C) primarily affected late G(1) and early S phases of the cell cycle. Single-stranded polynucleotides, native calf-thymus DNA, and yeast RNA had no effect. Radioautography showed that after 2-hr exposure the synthetic polyribonucleotides were predominantly inside the nucleus. The results extend the spectrum of action of double-stranded RNA.

Observations of cattle, goats and pigs after administration of synthetic interferon inducers and subsequent exposure to foot and mouth disease virus.

Polyriboinosinic-polyribocytidylic acid (poly [rI.rC]) was administered intravenously to 11 cattle and 13 goats in doses of 0.25 to 4.0, and 1.0 to 5.0 mg/kg, respectively. Subsequent exposure of these and untreated control animals to foot and mouth disease virus (FMDV) failed to demonstrate any differences in either the course or severity of the disease. Serum interferon was detected in cattle one hour after the intravenous administration of poly (rI.rC). Six pigs given 4, 20, or 100 mg/kg of itaconic-acrylic acid copolymer (IAA, HMW) intraperitoneally reacted clinically the same as six untreated control pigs after contact exposure to FMDV. Three pigs given 50, 100, or 200 mg/kg of divinyl ether-maleic anhydride copolymer (DVE/MA, pyran) intraperitoneally similarly failed to show any difference in clinical reaction from three untreated control pigs after intranasal instillation of FMDV. Three pigs given 100, 200 or 400 mg/kg of DVE/MA intraperitoneally developed rapid diffuse peritonitis causing the death of one in 48 hours.

Antiviral activity and side effects of polyriboinosinic-cytidylic acid complexes as affected by molecular size.

The decrease of the molecular size of poly(I.C) to less than 10(6) decreases its ability to induce interferon, protect mice against virus, or enhance the immune response. Immune adjuvant activity appeared more sensitive to molecular weight than the other protective activities. The composition of the complex-the molecular size of the individual homopolymers when one was large and the other small-did not affect antiviral activity; the activity of a complex made from large poly(I) and small poly(C) was similar to one made from small poly(I) and large poly(C). Molecular size of the complex did not profoundly alter the side effects of poly(I.C). At 2 mg/kg, none of the complexes markedly altered phagocytic function. Only the largest complex sensitized the mouse to endotoxin. However, all of the complexes studied profoundly inhibited drug metabolism by the liver microsomal enzymes between 24 and 72 hr after their inoculation. Decreasing the molecular weight did not alter this inhibition.