This study was done to generate kinetic data on individual congeners of chlorinated biphenyls in the low dose range, which could be of value in the risk assessment procedure. Male Sprague-Dawley rats were given a single oral dose of a mixture of polychlorinated biphenyls (CBs) containing either CBs 105, 118, 138, 153, 156, 157, 170, and 180 (A-mix) or CBs 28, 52, 77, 87, and 101 (B-mix). Liver, serum, and adipose tissue were collected after 6 h up to 135 days, from rats given the A-mix, and after 6 h up to 4 days from rats given the B-mix. CB concentrations were measured in liver, serum, and adipose tissue. In addition, this study provides kinetic data of one of the major CB metabolites, 4-hydroxy-2,3,3',4',5-pentachlorobiphenyl (4-OH-CB107). The low doses used resulted in serum CB concentrations similar to human background serum concentrations. In the A-mix experiment all CBs show high initial liver and serum concentrations followed by redistribution into adipose tissue. Differences between congeners were correlated to molecular weight. High molecular weight correlated to lower uptake and slower redistribution. During dynamic steady-state the tissue concentrations decreased with a calculated first order rate between 54-129 days for halving the concentrations (half-life). Most of the decrease in concentration was explained by the growth-related increase of tissue masses in general and adipose tissue in particular. In the B-mix experiment, the concentrations of CBs in adipose tissue decreased with between 25 and 59% from day 1 to day 4. These results show that the B-mix congeners, given at low dose, have longer half-lives than previously reported in high dose studies. Partition coefficients between body compartments are reported and for the first time a high and congener specific liver-to-serum ratio of CB 77 is observed.

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Chemical formation of dichlorvos (2, 2-dichlorovinyl dimethyl phosphate) was found to occur in mouse brain after i.p. injection of metrifonate (2, 2, 2-trichloro-1-hydroxyethyl dimethyl phosphonate). A mass fragmentographic technique was used. Different isotopic variants were used both as internal standards and to compensate for dichlorvos formed during the workup procedure. The dichlorvos formed in vivo was found to have its maximal concentration a few minutes after the maximum of the metrifonate itself. The effect of metrifonate and dichlorvos on acetylcholine levels, acetylcholinesterase activity and synthesis rate of acetylcholine in mouse brain was also studied. In all three cases the effect of metrifonate was found to be prolonged and delayed as compared to the effect of dichlorvos. It is concluded that metrifonate acts as a slow release formulation in the body giving rise to dichlorvos nonenzymatically. This circumstance at least partly explains its efficacy in the treatment of schistosomiasis.

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The polychlorinated dibenzo-p-dioxins/dibenzofurans 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) were studied for liver tumour promoting activity in a medium-term altered foci assay in nitrosamine-initiated female Sprague-Dawley rats. The congeners under study were administered by weekly subcutaneous injections at three dose levels for 20 weeks. Evaluation of gamma-glutamyltranspeptidase (GGT+), altered hepatic foci development, showed that all congeners studied acted as potent promoters of hepatocarcinogenesis. TCDD and PeCDD were virtually equipotent as enhancers of foci development while PeCDF displayed approximately ten per cent of the activity of the dioxins. Analysis of the dioxin- and furan-congeners by gas chromatography/mass spectroscopy (GC/MS) technique showed that the retention of PeCDD and PeCDF in liver tissue was approximately 7 and 20 times, respectively, as high as the retention of TCDD. Based on the concentration of the respective congener in liver tissue, PeCDD and PeCDF were 0.14 and 0.007 times as active as TCDD as promoters of foci development. The dose related enhancement of GGT+ foci development induced by the PCDD/PCDF congeners was accompanied by an increased incidence of histological changes in the liver.

The organophosphorus compound 0,0-dimethyl-(1-hydroxy-2,2,2-trichloroethyl)-phosphonate was introduced as an insecticide, trichlorfon, in 1952 (Lorenz et al., 1955) and as a drug, metrifonate, in the treatment of schistosomiasis in 1960 (Lebrun and Cerf, 1960). This organophosphorus compound is unique in that it has been claimed not to be a direct acting cholinesterase inhibitor but being transformed nonenzymatically into an active component dichlorvos, 2, 2-dichlorovinyl dimethyl phosphate (DDVP). The evidence for this transformation has mostly been indirect. Recently it has been proved chemically and quantitatively that this transformation occurs in the animal body (Nordgren et al., 1978). Metrifonate is the sole organophosphorus compound currently studied clinically in schistosomiasis. A substantial therapeutic effect is obtained only in Schistosoma haematobium infections. In this review on available data of metrifonate it is suggested that further more detailed studies of both S. haematobium and S. mansoni are necessary. This should include studies of the enzymic properties of the worms and the reaction of their esterases towards both metrifonate and DDVP as well as the pharmacokinetics of these compounds in man. In addition there are still unsolved discrepancies reported regarding organ toxicity of the compound which may, however, be due to different grades of parity of the test material.

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The cognitive decline in Alzheimer's disease has been shown to correlate with deficits in central cholinergic neurotransmission. Among various treatment attempts using cholinergic drugs a trial of the cholinesterase inhibitor tetrahydroaminoacridine (THA) (Summers et al., 1986) attracted considerable interest due to the positive effects reported on dementia symptoms. We have studied the effects of THA and placebo in a double-blind crossover trial over 9 weeks in 15 patients with dementia of Alzheimer type. Doses of the drug (75-150mdday) were titrated for each patient before entering the study. Clinical and biochemical effects were monitored using a battery of psychological tests, clinical rating scales and laboratory tests, including measurements of monoamine metabolites in the cerebrospinal fluid (CSF). The clinical results were mostly negative. Almost half of the patients had elevated liver enzymes (ALT and AST) in the THA period and these subjects showed more improvements of clinical ratings and psychological tests than did the patients without elevated liver enzymes. Levels of acetylcholine and the monoamine metabolites HVA and 5-HIAA in CSF were elevated on THA. The results indicate that THA has a therapeutic potential, although its pharmacokinetic profile and its liability to induce liver damage may limit the clinical use of the drug in the future.