1
872 static hypotension is uncertain: the formation of ab- normally high concentrations of dopa and dopamine metabolites may disturb normal sympathetic activity, either by interfering with noradrenaline storage, by block- ing uptake mechanisms, or by providing false neuro- transmitters. It is of interest that 6-hydroxydopamine has been shown to produce prolonged depletion of noradrena- line in the rat brain.18 The production of choreoatheroid movements by L-dopa arouses the suspicion that large amounts of this compound or of a metabolite might be concerned in other conditions in which involuntary move- ments arise. Cotzias et al.15 therefore gave L-dopa and a-methyldopa to a patient with Huntington’s chorea and found that, although L-dopa in doses up to 8-0 g. daily did not affect the neurological signs, x-methyldopa (3-75 g. daily) produced a striking but intermittent diminution of choreiform movements. More information is required from controlled trials about the effects of changing brain monoamine levels on the clinical manifestations of diseases such as parkin- sonism and Huntington’s chorea (in which the low plasma- aminoacid levels recorded by Perry et al. 19 may be a reflection of an underlying biochemical error). Animal research may provide much information of value, but, since the basic defect is likely to be enzymatic, either genetically determined or the result of viral or metabolic factors, the mechanism may have to be finally worked out in patients and in normal volunteers. Future trials should include investigations into the metabolic pathway of L-dopa and into changes in catecholamine metabolism; and intensive studies of autonomic activity may demon- strate more precisely the nature of the therapeutic action. Another line of inquiry into the effects of L-dopa is set out in a letter on p. 885 by Dr. Bunney and his colleagues, who report reversal of depression in a 56-year-old woman given large doses of L-dopa-this could be a vital link in the biochemical hypotheses of mood disorders. At the moment medical treatment of parkinsonism largely means anticholinergic drugs. While the action of dopamine in the basal ganglia is predominantly inhibitory, that of acetylcholine is excitatory,20 21 the two transmitters having opposing effects. It is not surprising, therefore, that both anticholinergic drugs and L-dopa should be useful in a condition associated with dopamine deficiency. Amphetamine possibly affects dopamine receptors,22 which may explain its value in some cases of parkinsonism. FROM PAINT TO PIKE? POLYCHLORINATED biphenyls are used in industry as lubricants, heat-transfer agents, and insulators; and they are also added to paints, synthetic resins, varnishes, and waxes to improve their properties. They were first identified in animal tissues in 1966.23 Human hair and the tissues of an eagle and 200 pike from different areas of Sweden contained substances which appeared to be identical to commercial samples of polychlorinated biphenyls. The laboratory of the Government Chemist in the United Kingdom reported 24 that quantities of sub- 18. Uretsky, N. J., Iversen, L. L. Nature, Lond. 1969, 221, 557. 19. Perry, T. L., Hansen, S., Diamond, S., Stedman, D. Lancet, April 19, 1969, p. 806. 20. Bloom, F. E., Costa, E., Salmoiraghi, G. C. J. Pharmac. exp. Ther. 1965, 150, 244. 21. McLennan, H., York, D. H. J. Physiol., Lond. 1967, 189, 393. 22. See Lancet, April 12, 1969, p. 765. 23. New Scientist, 1966, 32, 612. 24. Holmes, D. C., Simmons, J. H., Tatton, J. O’G. Nature, Lond. 1967, 216, 227. stances resembling polychlorinated biphenyls were present in the livers, fat, and eggs of birds, especially predators such as sparrowhawks and kestrels and marine feeders like the guillemots and kittiwakes. Appreciable quan- tities were present in freshwater fish but only small amounts in samples of human and animal fat. Seven compounds which appeared to be polychlorinated biphenyls were also found in the blubber of seals and porpoises around Scotland and Canada 25 and interfered with the detection of pesticide residues. Koeman et al. 26 have now identified polychlorinated biphenyls in fish, mussels, and birds from the river Rhine and the Netherlands coast. Earlier work had identified polychlorinated biphenyls by their behaviour on gas-liquid chromatograms. In these new experiments the gas chromatograph was linked with a mass spectro- meter in order to determine the molecular mass number and number of chlorine atoms in the molecule for each peak appearing on the chromatogram. Koeman et al. examined apolar lipid extracts of roach and groundling from the Rhine, mussels from the West coast of the Nether- lands, and sand eels, sandwich tern, and eider from the Wadden Sea area. The fungicide, hexachlorobenzene, p, p’D.D.E. (related to dicophane or D.D.T.), and the insecti- cide telodrin were found in all the extracts. With these exceptions and one peak whose chemical composition was unknown, all the compounds in the chromatograms were identified as chlorinated biphenyls. One polychlorinated biphenyl appeared in the gas chromatogram in the same position as p, p’D.D.E. and will therefore interfere in estimations of this insecticide in tissues. The fish tissues contained many more compounds with small numbers of chlorine atoms than the tissue and egg extracts from the birds (some of these compounds with few chlorine atoms were not present in the three commercial polychlorinated-biphenyl mixtures examined). Japanese quail were fed a diet containing 0’2% of one of the commercial polychlorinated biphenyl mixtures. All the birds died between 6 and 55 days after starting this diet. Chromatograms of liver and brain extracts from the quails showed that there were far fewer poly- chlorinated biphenyls, particularly those with small numbers of chlorine atoms, in the quail tissues than in the mixture fed to them. Polychlorinated biphenyls can therefore be metabolised to some extent, though the metabolism probably differs in different species. Semi- quantitative estimations of the compounds in the extracts showed that the quail tissues contained twenty times as much polychlorinated biphenyls as the liver and brain of the eider living in natural conditions. The most obvious toxic effect, the development of hydro- pericardium in the quail, was never seen in the wild birds. Polychlorinated biphenyls are recognised as toxic hazards in industrial conditions. Enough evidence exists to associate acute yellow atrophy of the liver and acnei- form dermatitis with chlorinated diphenyls, though their effects are often hard to separate from those of the chlorinated naphthalenes present in the same material. It is alarming that once again chemicals which are never intended for consumption find their way into the environ- ment and may eventually be consumed by man. Con- tamination of wild life by polychlorinated biphenyls must be closely watched: it may be necessary to review the uses of these compounds and introduce more stringent control over their applications. 25. Holden, A. V., Marsden, K. ibid. p. 1274. 26. Koeman, J. H., Ten Noever de Brauw, M. C., de Vos, R. H. ibid. 1969, 221, 1126.

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872

static hypotension is uncertain: the formation of ab-

normally high concentrations of dopa and dopaminemetabolites may disturb normal sympathetic activity,either by interfering with noradrenaline storage, by block-ing uptake mechanisms, or by providing false neuro-transmitters. It is of interest that 6-hydroxydopamine hasbeen shown to produce prolonged depletion of noradrena-line in the rat brain.18 The production of choreoatheroidmovements by L-dopa arouses the suspicion that largeamounts of this compound or of a metabolite might beconcerned in other conditions in which involuntary move-ments arise. Cotzias et al.15 therefore gave L-dopa anda-methyldopa to a patient with Huntington’s chorea andfound that, although L-dopa in doses up to 8-0 g. daily didnot affect the neurological signs, x-methyldopa (3-75 g.

daily) produced a striking but intermittent diminution ofchoreiform movements.More information is required from controlled trials

about the effects of changing brain monoamine levels onthe clinical manifestations of diseases such as parkin-sonism and Huntington’s chorea (in which the low plasma-aminoacid levels recorded by Perry et al. 19 may be areflection of an underlying biochemical error). Animalresearch may provide much information of value, but,since the basic defect is likely to be enzymatic, eithergenetically determined or the result of viral or metabolicfactors, the mechanism may have to be finally worked outin patients and in normal volunteers. Future trials shouldinclude investigations into the metabolic pathway of

L-dopa and into changes in catecholamine metabolism;and intensive studies of autonomic activity may demon-strate more precisely the nature of the therapeutic action.Another line of inquiry into the effects of L-dopa is set outin a letter on p. 885 by Dr. Bunney and his colleagues, whoreport reversal of depression in a 56-year-old womangiven large doses of L-dopa-this could be a vital link inthe biochemical hypotheses of mood disorders.At the moment medical treatment of parkinsonism

largely means anticholinergic drugs. While the action ofdopamine in the basal ganglia is predominantly inhibitory,that of acetylcholine is excitatory,20 21 the two transmittershaving opposing effects. It is not surprising, therefore,that both anticholinergic drugs and L-dopa should beuseful in a condition associated with dopamine deficiency.Amphetamine possibly affects dopamine receptors,22which may explain its value in some cases of parkinsonism.

FROM PAINT TO PIKE?

POLYCHLORINATED biphenyls are used in industry aslubricants, heat-transfer agents, and insulators; and theyare also added to paints, synthetic resins, varnishes, andwaxes to improve their properties. They were firstidentified in animal tissues in 1966.23 Human hair andthe tissues of an eagle and 200 pike from different areasof Sweden contained substances which appeared to beidentical to commercial samples of polychlorinatedbiphenyls. The laboratory of the Government Chemistin the United Kingdom reported 24 that quantities of sub-

18. Uretsky, N. J., Iversen, L. L. Nature, Lond. 1969, 221, 557.19. Perry, T. L., Hansen, S., Diamond, S., Stedman, D. Lancet, April 19,

1969, p. 806.20. Bloom, F. E., Costa, E., Salmoiraghi, G. C. J. Pharmac. exp. Ther.

1965, 150, 244.21. McLennan, H., York, D. H. J. Physiol., Lond. 1967, 189, 393.22. See Lancet, April 12, 1969, p. 765.23. New Scientist, 1966, 32, 612.24. Holmes, D. C., Simmons, J. H., Tatton, J. O’G. Nature, Lond. 1967,

216, 227.

stances resembling polychlorinated biphenyls were presentin the livers, fat, and eggs of birds, especially predatorssuch as sparrowhawks and kestrels and marine feederslike the guillemots and kittiwakes. Appreciable quan-tities were present in freshwater fish but only smallamounts in samples of human and animal fat. Sevencompounds which appeared to be polychlorinatedbiphenyls were also found in the blubber of seals andporpoises around Scotland and Canada 25 and interferedwith the detection of pesticide residues.Koeman et al. 26 have now identified polychlorinated

biphenyls in fish, mussels, and birds from the riverRhine and the Netherlands coast. Earlier work hadidentified polychlorinated biphenyls by their behaviouron gas-liquid chromatograms. In these new experimentsthe gas chromatograph was linked with a mass spectro-meter in order to determine the molecular mass numberand number of chlorine atoms in the molecule for each

peak appearing on the chromatogram. Koeman et al.examined apolar lipid extracts of roach and groundlingfrom the Rhine, mussels from the West coast of the Nether-lands, and sand eels, sandwich tern, and eider from theWadden Sea area. The fungicide, hexachlorobenzene, p,p’D.D.E. (related to dicophane or D.D.T.), and the insecti-cide telodrin were found in all the extracts. With theseexceptions and one peak whose chemical composition wasunknown, all the compounds in the chromatograms wereidentified as chlorinated biphenyls. One polychlorinatedbiphenyl appeared in the gas chromatogram in the sameposition as p, p’D.D.E. and will therefore interfere inestimations of this insecticide in tissues.The fish tissues contained many more compounds

with small numbers of chlorine atoms than the tissueand egg extracts from the birds (some of these compoundswith few chlorine atoms were not present in the threecommercial polychlorinated-biphenyl mixtures examined).Japanese quail were fed a diet containing 0’2% of oneof the commercial polychlorinated biphenyl mixtures.All the birds died between 6 and 55 days after startingthis diet. Chromatograms of liver and brain extracts

from the quails showed that there were far fewer poly-chlorinated biphenyls, particularly those with smallnumbers of chlorine atoms, in the quail tissues than inthe mixture fed to them. Polychlorinated biphenylscan therefore be metabolised to some extent, though themetabolism probably differs in different species. Semi-

quantitative estimations of the compounds in theextracts showed that the quail tissues contained twentytimes as much polychlorinated biphenyls as the liver andbrain of the eider living in natural conditions. Themost obvious toxic effect, the development of hydro-pericardium in the quail, was never seen in the wild birds.

Polychlorinated biphenyls are recognised as toxichazards in industrial conditions. Enough evidence existsto associate acute yellow atrophy of the liver and acnei-form dermatitis with chlorinated diphenyls, though theireffects are often hard to separate from those of thechlorinated naphthalenes present in the same material. Itis alarming that once again chemicals which are neverintended for consumption find their way into the environ-ment and may eventually be consumed by man. Con-tamination of wild life by polychlorinated biphenyls mustbe closely watched: it may be necessary to review the usesof these compounds and introduce more stringent controlover their applications.25. Holden, A. V., Marsden, K. ibid. p. 1274.26. Koeman, J. H., Ten Noever de Brauw, M. C., de Vos, R. H. ibid. 1969,

221, 1126.