No abstract

"Criteria and Procedures for Evaluating Assays for Carcinogenic Residues," popularly known as the "Sensitivity of the Method (SOM)" proposal for the regulation of animal drugs and feed additives, employs an initial analysis to determine whether a compound must meet the requirements as a suspect carcinogen or the requirements for general food safety (GFS). Metabolism and kinetics of drug depletion play an important role in the six-step procedure that is used for either set of regulatory criteria. The only significant difference that exists between the two sets of criteria is the degree of testing required. However, the difference will usually not be manifest until positive findings of carcinogenicity in the chronic studies in laboratory animals trigger a further evaluation of the metabolism of the drug or feed additive. For both SOM and GFS, metabolic information will be used to determine the appropriateness of the test species as well as to help select a compound for residue analysis. Residue depletion kinetics in the food animals also play an integral role in the selection of species-strains for toxicity testing selection as well as in the selection of the compound for residue analysis in food. Furthermore, depletion kinetics are used to set a safe withdrawal period. The development of guidelines is discussed.

No abstract

The relationships between membranes and intramembrane compartments of isolated heart mitochondria are inadequately defined to express the induced morphological changes associated with the structural organization. The inner membrane and matrix are the major structural entities which undergo transformation upon alteration of metabolism or incubation conditions. To better express these morphological changes within a mitochondrion, two inner membranes plus enclosed matrix are defined as an inmerix (plural inmerices). Three general morphological forms of mitochondria can be distinguished by the size and shape of inmerices. These are distended, condensed, and coalesced inmerixal configurations. Hypotonic conditions and Pi in isotonic sucrose generate distended configurations. This Pi distention is apparently dependent on utilization of energy. It does not occur under anaerobic conditions. Oxidizable substrates generate condensed configurations. ADP and dADP generate coalesced configurations and stop formation of condensed and distended inmerixal configurations in the absence of inhibitors. ADP coalescence is apparently not dependent on an energy input. It occurs under aerobic and anaerobic conditions, and in isotonic and hypotonic media. Atractyloside completely inhibits the effects of ADP on inmerixal membranes whereas oligomycin does not. Distention by Pi is unaffected by the two inhibitors. Distended inmerices, without added Pi (12 mM and 62 mM sucrose), are coalesced by ADP. These studies indicate that coalescence of inmerixal membranes probably reflects the consequences of specific stoichiometric binding or translocation of adenine nucleotides.