An expert meeting was organized by the World Health Organization (WHO) and held in Stockholm on 15-18 June 1997. The objective of this meeting was to derive consensus toxic equivalency factors (TEFs) for polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) and dioxinlike polychlorinated biphenyls (PCBs) for both human, fish, and wildlife risk assessment. Based on existing literature data, TEFs were (re)evaluated and either revised (mammals) or established (fish and birds). A few mammalian WHO-TEFs were revised, including 1,2,3,7,8-pentachlorinated DD, octachlorinated DD, octachlorinated DF, and PCB 77. These mammalian TEFs are also considered applicable for humans and wild mammalian species. Furthermore, it was concluded that there was insufficient in vivo evidence to continue the use of TEFs for some di-ortho PCBs, as suggested earlier by Ahlborg et al. [Chemosphere 28:1049-1067 (1994)]. In addition, TEFs for fish and birds were determined. The WHO working group attempted to harmonize TEFs across different taxa to the extent possible. However, total synchronization of TEFs was not feasible, as there were orders of a magnitude difference in TEFs between taxa for some compounds. In this respect, the absent or very low response of fish to mono-ortho PCBs is most noticeable compared to mammals and birds. Uncertainties that could compromise the TEF concept were also reviewed, including nonadditive interactions, differences in shape of the dose-response curve, and species responsiveness. In spite of these uncertainties, it was concluded that the TEF concept is still the most plausible and feasible approach for risk assessment of halogenated aromatic hydrocarbons with dioxinlike properties.

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Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife

Eighteen animal, models of depression are reviewed in relation to three sets of validating criteria. Of the 18 models, five could only be assessed for predictive, validity, seven could be assessed for predictive and face validity, and six could potentially have predictive, face and construct validity. Some traditional models (reserpine reversal, amphetamine potentiation) are rejected as invalid; the models with the highest overall validity are the intracranial self-stimulation, chronic stress and learned helplessness models in rats, and the primate separation model.

The validity of animal models of depression.

Introduction LITTLE IS known about the possible etiological biochemical factors relating to depressive reactions. Clinical evidence suggests that many depressions respond to the following somatic treatment: electric convulsive therapy (ECT), the imipramine type of drugs, and the monoamine oxidase inhibitor group of drugs. 2,3 Do these two classes of drugs have common factors in their mechanism of action and can this be related to the fact that one antihypertensive agent, namely, reserpine, produces severe depression in a small but consistent number of hypertensive patients? 4-8 Rosenblatt et al, 9 in 1959, were among the first to specifically suggest that changes in brain norepinephrine (NEP) may be involved in depression. Based in part on the knowledge of the effect of reserpine and monoamine oxidase inhibitors on depressed mood and norepinephrine (NEP), they hypothesized that the depressive state might be associated with a relative decrease of norepinephrine

https://jamanetwork.com/journals/psych/articlepdf/488901/archpsyc_13_6_001.pdf

Norepinephrine in Depressive Reactions: A Review

A cholinergic-adrenergic hypothesis of mania and depression

The transformations of nitrogenous compounds by soil bacteria have beenstudied for over a century. In terms of the global fluxes between aerial and terrestrial-aquatic systems, the simplified nitrogen cycle can be envisioned as a triangle where the only biologically reversible reaction occurs between ammonium and nitrate. The reverse reactions of dinitrogen fixation or denitrification by biological means do not occur in nature. Hence, the reductive process of denitrification, defined as the reduction of nitrate or nitrite to gaseous nitrogen (usually N2), is intimately associated with the oxidative process of nitrification.

Biochemical Ecology of Nitrification and Denitrification

N-Oxides are oxidation products of tertiary amines. They were detected as a new class of chemical compounds before 1900 and were later found to occur as constituents of living matter. In recent years an increasing number of studies by biomedical scientists has been devoted to N-oxides for several reasons. The natural occurrence of N-oxides in plant and animal tissues has posed interesting problems as to the biochemistry and function of these compounds in biological systems. In several cases N-oxides are more active than their corresponding tertiary amines. Hence several N-oxides are important as pharmacological or toxicological agents, e.g. , in the groups of alkaloids, chemotherapeutics, antibiotics, psychotropic drugs, methemoglobin forming compounds, and carcinogenic agents. Certain oncogenic N-oxides act as antimetabolites and have been postulated as inducers of spontaneous cancer. Finally, a large number of tertiary amine drugs produce N-oxides as metabolites or intermediates in drug metabolism.

N-Oxides have been detected in animals, plants, and microorganisms. TrimethylamineN-oxide, which occurs primarily in marine species but also in mammals, including man, has received most attention; however, its biosynthesis and its physiological functions have not yet been fully elucidated. In addition to the pharmacologically active N-oxides of natural origin, many others have been prepared synthetically.

Many findings suggest that N-oxides play an important role in the metabolism of drugs. In addition to N-oxidation of tertiary amines, N-dealkylation of N-oxides has been detected. This suggested a pathway of oxidative N-dealkylation of tertiary amines in which N-oxides would be intermediate metabolites. On the other hand strong evidence for a direct tertiary amine N-dealkylation has also been presented; in this case N-oxides would be by-products. However, N-oxides could also be intermediate metabolites because of the frequently occurring N-oxide reduction which transforms them into the corresponding tertiary amines. With some substrates several or all of these four reactions have been observed to occur simultaneously. Despite many investigations carried out in an attempt to elucidate the mechanisms and enzymatic characteristics of these reactions, our knowledge is stifi incomplete.

The pharmacology and biochemistry of n-oxides

Desmethylimipramine (DMI), a major metabolite of imipramine, elicits no obvious pharmacological effects of its own but, in doses comparable to those used to treat primary depression in man, prevents the syndrome of effects produced by reserpine-like drugs in rats. In larger doses, DMI "reverses" the effects of reserpine-like drugs to a unique hyperactive state (spontaneous excitation) in which rats fail to respond to external stimuli.

DMI counteracts the reserpine syndrome by blocking the cholinergic effects through a central action and by sensitizing the action of the brain catecholamines at central adrenergic receptors. The anticholinergic action antagonizes the muscle rigidity and the increased parasympathetic output and occurs whether DMI is given before or after reserpine. The sensitization of central adrenergic sites is observed only when the rats are pretreated with DMI; this effect of DMI does not occur in animals which have been depleted of catecholamines by α-methyl- m -tyrosine. Furthermore, more, DMI counteracts reserpine sedation only if catecholamines are released rapidly by the reserpine-like compound. The importance of this rapid release is shown in studies with benzquinamide which, in DMI-treated animals, produces hyperactivity in doses that do not produce obvious sedation in normal animals and which release only 40% of brain NE.

The action of desmethylimipramine in counteracting sedation and cholinergic effects of reserpine-like drugs

The binding of model drugs to human blood and individual blood components has been determined by equilibrium dialysis and expressed in terms of classes of binding sites, association constants and binding capacities. Chlorpromazine and imipramine are bound to three major components: membranes of red cells, albumin, and lipoproteins. The affinity and capacity of lipoprotein binding is at least as high as that of albumin and is equally distributed on HDL, LDL, VLDL, and on the chylomicrons. White blood cells and platelets are of minor importance in terms of binding capacity. No binding was detected with gamma-globulins or alpha- or beta-globulins other than lipoproteins. In contrast, salicylic acid was not bound to red cells or lipoproteins.

Marcel H. Bickel

Papers

The pharmacology and biochemistry of n-oxides

The action of desmethylimipramine in counteracting sedation and cholinergic effects of reserpine-like drugs

Binding of chlorpromazine and imipramine to red cells, albumin, lipoproteins and other blood components.

Binding of basic and acidic drugs to rat tissue subcellular fractions.

The metabolism of imipramine and its metabolites by rat liver microsomes