This volume is the completion of work initially planned several years ago as a compilation of selected aspects of the biological effects of fluorides. The first portion appeared in Volume XXII (1966) of this Handbuch, under the title "Pharmacology of Fluorides, Part 1. " Inasmuch as the present volume is an integral part of the original project, justification for offering it to the scientific community remains the same as that originally set forth. This may be recapitulated as follows. The tremendous increase in the annual production of fluorides over the amounts produced thirty years ago, together with the increased diversity of their uses has correspondingly increased the hazard associated with these materials. That is to say, the possibilities of encountering their characteristic toxic effects under the conditions of their use has increased because the variety, amounts and ways of usage have increased. Their inherent toxicity, of course has not changed, but the increased hazard has led to a vast increase in the amount and scope of research reported. It is the purpose of these volumes to review selected aspects of this literature. Rochester, N. Y. , February 1970 FRANK A. SMITH Acknowledgements Even the casual reader of this volume will soon realize that contributing authors, as well as those contributing to its predecessor, Volume XX/I, have made good use of tables of data, figures and pertinent quotations from previously published work.

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1: Methods of Analysis for Fluorine.- I. Introduction.- II. Methods of Sample Preparation.- A. Organic Compounds.- 1. The Oxygen-Flask Method.- Procedure for Oxygen-Flask Combustion.- 2. Fusion with Alkali Metals.- Procedure for Alkali Metal Fusion.- 3. Reduction with Alkali Metal in Organic Solvents.- 4. Wickbold Oxyhydrogen Flame Method.- B. Inorganic Samples.- C. Agricultural and Food Samples.- D. Miscellaneous Samples.- III. Methods of Separation.- A. Separation of Fluorosilicic Acid by Distillation.- B. Separation by Pyrohydrolysis.- C. Separation by Diffusion.- D. Separation by Ion-exchange.- E. Chromatographic Separation on Paper and Thin Layers.- F. Other Methods of Separation.- IV. The Detection of Fluoride.- Procedure for the 8-Hydroxyquinoline Test.- V. The Determination of Fluoride.- A. Gravimetric Methods.- 1. Precipitation as Lead Chlorofluoride.- a) Recommended Lead Chlorofluoride Procedure.- ?) Reagents.- ?) Procedure.- 2. Precipitation as Calcium Fluoride.- B. Titrimetric Methods.- 1. Titration with Thorium Solution.- a) Interferences.- b) Direct Titration Procedure.- c) Back-Titration Procedure.- 2. Titration with Aluminum Solution.- 3. Acid-Base Titration of Hydrofluoric Acid.- 4. Titration with Rare Earth Solutions.- 5. Other Titrimetric Methods.- a) Titration with Calcium Solutions.- b) Titrations based on Lead Halofluoride Formation.- c) Titration with Iron(III) Solutions.- d) Titrations based on Fluorosilicic Acid.- C. Colorimetric Methods.- 1. The Alizarin Fluorine Blue Methods.- a) Recommended Lanthanum-Alizarin Fluorine Blue Procedure.- ?) Reagents.- ?) Calibration Graph.- 2. The Bleaching of Zirconium-Dye Complexes.- a) Recommended Zirconium-Eriochrome Cyanine R Procedure.- ?) Reagents.- ?) Calibration Graph.- 3. The Bleaching of Thorium-Dye Complexes.- 4. The Bleaching of Aluminum-Dye Complexes.- 5. Other Colorimetric Methods.- a) Titanium(IV) Complexes.- b) Iron(III) Complexes.- c) Chloranilie Acid Methods.- d) Molybdenum Blue Methods.- D. Polarographic Methods.- E. Direct Electrometric Methods.- F. Radiometric Methods.- G. Catalytic Methods.- H. Determination of Elemental Fluorine.- VI. The Determination of Common Elements in Organic Fluorine Compounds.- A. Carbon, Hydrogen and Nitrogen.- B. Other Halogens, Sulfur and Phosphorus.- References.- 2: Effect of Inorganic Fluoride on Enzymes.- I. General Introduction.- II. Enzymes, Inhibited by Fluoride, Requiring Metal Ions, and Whose Inhibition is Enhanced by Phosphate.- A. Enolase.- B. Phosphoglucomutase.- C. Lecithinase (from Clostridium welchii).- D. Succinic Dehydrogenase.- III. Enzymes, Inhibited by Fluoride, Requiring Divalent Metal Ions.- A. Phosphatases.- 1. Acid Phosphatases.- 2. Alkaline Phosphatases.- B. Pyrophosphatases.- 1. Acid Pyrophosphatases.- 2. Alkaline Pyrophosphatases.- C. Kinases.- D. General.- 1. Cholinesterase.- 2. Glutamine Synthetase.- 3. Alcohol Dehydrogenase (Liver).- 4. ?-Amylase (Ca++-activated).- 5. Comments on Non-Inhibition by Fluoride of some Enzymes Activated by Divalent Metals.- IV. Enzymes Inhibited by Fluoride; No Requirement for Metal Ions Demonstrated.- A. Liver Esterase.- B. 5'-Adenylic Acid Deaminase.- C. Phosphoglycerate Mutase.- D. Hydrazidase.- V. Enzymes, Inhibited by Fluoride, Containing Trivalent Metal Ions.- A. Catalase.- B. Peroxidase.- VI. Concluding Comments.- References.- 3: Changes in Cell Function Due to Inorganic Fluoride.- I. Introduction.- II. Effect of Fluoride on Metabolic Pathways.- A. Outline of Intermediary Metabolism.- B. Glycolysis.- C. Pyruvate Metabolism and Oxidation in the Tricarboxylic Acid Cycle.- D. Oxidative Phosphorylation.- E. Respiration.- F. Protein Synthesis.- G. The Response of Tissues to Hormones.- H. Fat Metabolism in Adipose Tissue.- I. Lipases.- III. Effects of Fluoride on Physical Activity of Cells.- A. Movement.- 1. Motility.- 2. Phagocytosis.- 3. Contractility.- B. Transport Across Cell Membranes.- 1. Intestinal Epithelium.- 2. Non-Polar Cells.- IV. Effects of Fluoride on the Growth and Development of Cells in Tissue Culture.- V. Concluding Remarks.- References.- 4: Pharmacology of Sodium Fluoride.- I. Introduction.- II. Effect of Sodium Fluoride on Blood Pressure and the Heart.- A. Hypotensive Activity of Fluoride.- B. Pressor Effect of Fluoride.- C. Stimulatory Effect of Sodium Fluoride on Isolated Heart Preparations.- III. Effect of Sodium Fluoride on the Gut.- A. Effect of Fluoride on the Gut, in Vivo.- B. Effect of Fluoride on Dog Gut, in Vitro.- IV. Effect of Sodium Fluoride on Respiration.- V. Summary and Conclusions.- References.- 5: Fluoroamino Acids and Microorganisms.- I. Introduction.- II. Fluoroamino Acids and Cellular Microorganisms.- A. General Toxicity and Effects on Growing Cells.- B. Incorporation of Fluoroamino Acids into Proteins.- C. Effects of Fluoroamino Acids on Specific Cell Functions.- 1. Cell Division.- 2. Motility.- 3. Capsule Formation.- 4. Regulation of Enzyme Synthesis and Activity.- 5. Transport Systems.- 6. Bacterial Sporogenesis.- 7. Respiration and Photosynthesis.- 8. Ribosome Synthesis.- 9. Antibiotic Production.- 10. Maintenance of Diploid State in Fungi.- 11. Virus and Bacteriocin Production.- D. Catabolism of Fluoroamino Acids by Bacteria.- E. Bacterial Adaptation to Fluoroamino Acids.- 1. Physiologic Adaptation.- 2. Amino Acid-Secreting Mutants.- 3. Mutants with Altered Transport Systems.- 4. Mutants with Altered Amino Acyl-tRNA Synthetases.- 5. Mutants with Altered Ribosomes.- References.- 6: Fluorine-Containing Steroids.- I. Introduction.- II. Fluoro Steroids with Respect to Glucogenic, Anti-Inflammatory and Mineralocorticoid Effect.- A. The 9?-Fluoro-Substitution in.- 1. Cortisol.- 2. ?1-Cortisol (Prednisolone).- 3. ?6-Cortisol.- 4. Other Pregnane Derivatives.- B. Fluorination at other Positions and in Combination with 9?-Fluoro.- 1. In Cortisone, Cortisol, Prednisone or Prednisolone.- a) 2?-Fluoro.- b) 4-Fluoro.- c) 6? -Fluoro and 6?,9? -Difluoro.- d) 15?-Fluoro and 9?,15?-Difluoro.- e) 16? -Fluoro, 9?,16?-Difluoro, 6?,16? -Difluoro and 6?,9?,16? -Trifluoro.- f) 16?-fluoro and 9?,16?-Difluoro.- 2. In other Pregnane Derivatives.- a) 1l?-Fluoro.- b) 12? -Fluoro.- c) 17? -Fluoro.- d) 21-Fluoro.- e) Fluorine in 16?,17? -Ketal.- C. Other Groups in.- 1. 9? -Fluorocortisol and 9?-Fluoroprednisolone.- a) 1-Hydroxy.- b) 2? -Methyl.- c) 4-Methyl and 4-Ethyl.- d) 6? - and 6?-Chloro.- e) 6? -Fluoromethyl.- f) 6? -Methoxy.- g) 6? -Methyl.- h) 7? -Acetylthio.- i) 16?-Acetoxy.- j) 16?-Chloro.- k) 16? …