Document jmOd2xVy8NJQ5em1JNynknqwZ

not be metabolized by the host be fore it could act. Another approach to viral chemo therapy is development of drugs that induce production of interferon, a spe cial protein that stimulates production of antibodies, is effective against prac tically all viruses, and is thus the body's natural antiviral weapon. A drug that would induce interferon production in a controlled manner might be a panacea for viral disease. Some drugs with interferon-induction activity have been developed, though none is yet in clinical use. And those developed so far can only be used as preventives since they apparently must be administered before virus in fection occurs in order to have any significant effect. Virazole, Dr. Sidwell says, does not act by inducing interferon production. It apparently interferes with the vi rus's ability to reproduce itself. Tra cer studies in rabbit kidney ceil cul tures using radioactive thymidine in dicate that Virazole inhibited the rate of DNA synthesis by as much as 90%, according to Dr. D. G. Streeter. More than 500 potential antiviral compounds have been designed and synthesized at ICN's nucleic acid re search institute in the past two years. More than 100 of these have shown sig nificant antiviral activity. Virazole shows the greatest potential as a broad-spectrum agent. According to Dr. Roland K. Robins, ICN's vice pres ident for research and development and director of the institute, precllnical studies of Virazole are in progress with a view to clinical evaluation. Research heightens concern over PCB's PESTICIOC--The controversy over the effects of polychlori nated biphenyls in the environment and in biological systems is relatively recent, but already PCB's are vying for a share of the dubious limelight ac corded DDT. Recent research on PCB's was highlighted at the opening session of the Division of Pesticide Chemistry: A trace contaminant has been iden tified in one lot of Aroclor 1254, a com mercial PCB made by Monsanto Co., the sole U.S. producer of PCB's. Al though it has not yet been conclusively identified, the contaminant may be a tetrachlorodibenzofuran, a toxic ma terial already found in some Europeanmade PCB's. PCB's mimic the action of DDT in their effects on some biological sys tems. Unlike DDT, however, PCB's do not appear to cause the production of thin eggshells in Japanese quail. The residue behavior of Aroclor 1254 in cow's milk Is similar to that of DDE, a persistent metabolite of DDT. Distribution. It Is only in the past few years that PCB's have been found extensively distributed in the environ ment, particularly in wildfowl, al though PCB's have been used since at least 1930 as plasticizers in paints, resins, and plastics, as well as in in sulators. heat exchangers, and other applications. In 1970 Monsanto discontinued all sales of PCB's for such open systems as plasticizers and sealants. Late in 1971 the firm began to phase out sales of PCB's for heat transfer systems. When the phase-out is completed this year, the only sales of PCB's by Mon santo in the U.S. will be for closedsystem electrical uses. Nevertheless, even as the uses of PCB's are being limited in the U.S. by Monsanto, scientific data on the action of PCB's are beginning to accumulate at a rapid rate. One discovery about PCB's, likely to create considerable concern at Monsanto, comes from the Environmental Protection Agency's Chamblee, Ga., Toxicology Laboratory. August Curley and coworkers V. W. Burse and Ralph Jennings have found a nonpolychlorinated biphenyl in the urine of rats fed 100 and 500 p.p.m. Aroclor 1254 for 58 and 252 days, re spectively. They find the same non polychlorinated biphenyl in the Aro clor 1254 that was administered to the rats, thus eliminating the possibility that the substance in the rat urine was derived solely by metabolism. The substance identified by the Geor gia chemists has a mass spectra num ber (m/e) of 304. A contaminant with m/e 304 has already been identified as tetrachloroparadibenzofuran in two European PCB's--Phcnoclor DPG, a French product, and Clophen A 60, a West German product--by Dr. J. G. Vos and coworkers at the Institute of Veterinary Pathology, Utrecht, the Netherlands. Tetrachlorodibenzo- furans are highly toxic substances and are suspected teratogens. At the time he tested European products, Dr. Vos did not find the substance in the Mon santo product (Aroclor 1260) he tested. In fact, even to date tetrachlorodiben- znfurans have not been identified con clusively in Monsanto's PCB's. Mr. Curley and his colleagues iden tified a trace concentration of the con taminant m/e 304 of less than 1 micro gram per gram in the Aroclor 1254 he tested using the combined gas chroma tography-mass spectrometry method of Dr. Vos (Food Costttct. Toxicol., I, 625 (1970)]. Mr. Curley emphasizes that mass spectral data alone have not proved conclusively the identity of the component having m/e 304. But. he says, "It is certain that the component is not the result of fragmentation of a higher molecular weight component of the Aroclor preparation. ' The com ponent m/e 304 could be tetrachloromethyl biphenyl, which would give the same mass spectra peak as tetrachlorodibenzofuran. Methvl biphenyls are present in trace concentrations in the feedstocks used to make PCB's. However, Mr. Curley points out that toxicological and chemical evidence by his group and other workers suggests that his substance could be tetrachiorodibenzofuran. His own toxico logical studies on rats fed various doses of Aroclor ranging from 0 to 500 p.p.m. for eight months reveal (hat at the higher dietary levels rats have en larged livers and other abnormalities in the liver cells. Whether trace quan tities of the 304 component in the diet might have contributed to the toxic effects is not yet known, he points out. Eggshell. Mr. Curley's study is part of a larger une to determine the effects of PCB on heme synthesis and inter mediate metabulism. Another area in which PCB's are being extensively in vestigated is their role in the form*' tion of thin eggshells produced bv some birds of prey. Incorporation of calcium in eggshells is the end result of a complex pathway of calcium metabolism. Inhibition of a crucial step in the pathway by PCB's or DDT. or any other material for that matter, could result in the.production of thin eggshells, many scientists suggest. In eggshell formation, dietary cal cium is absorbed from the intestine into the blood. This transfer is medi ated by vitamin D, which must first be metabolized to an active form. From the blood the calcium is deposited in medullary bone for storage until it is mobilized for eggshell formation. Mo bilization occurs by a synergistic ac tion between androgens and estrogens. Calcium is reabsorbed into the blood from the medullary bone, transported across the eggshell gland, and de posited in the shell as calcium car bonate. Biochemists at the University of California. Riverside, have studied the effects of PCB's and DDT at several points of this pathway. For instance, the effects of PCB and DDT on the metabolism and functioning of vitamin D have been studied bv Dr. Henrv G. Nowicki. (now at the 5th Army Medi cal Laboratory, St. Louis, Mo.) and Dr. Anthony W. Norman. Thev find that rachitic (vitamin D deficient) HONS 069642 APRIL IT, 1972 CN If te--caAi--------- c*/sostfa.+^-QtAo siH-ofc^te--------------OTHER THIOL ACIDS AVAILABLE THIOLBENZOIC DITHIOLTEREPHTWAUC CHcmcTicA me Cable: CVAN8CNCM 7WX. 7UMBMRB chickens pretreated with PCB's show I dum tnuiapoit when givn vitamin D. In addition, pretreatlnf the rachitic rhtrkf with PCB blocked the ability of vitamin D, when it was administered, to mobilise bone calcium Thaee are essentially the same findings that the two biochemists had found last year for DDT. Their results. Dr. Nowicki explains, provide a partial explanation for the insolent of PCB in thinegg- sheil formation and subsequent repro ductive failure of boom avian spedes, Since both PCB and DDT treatment blocked the responae to vitamin D the biochemists examined rt--t chlorinated rh.mir.1. *> determine if they act by eitnring the metabolism of vitamin D. Vitamin D must go through at let two umversions to an active form prior to stimulating intestinal calcium transport The biochemists find that neither DOT nor PCB appears to inter fere with the metabolic conversion of vitamin D. Thus, this result dons not explain how PCB and DDT inhibit the biological response to vitamin D. PCB's and DDT did appear, however, to exhibit similar responert in the biolonknl itiirlUnI Dr. Nowicki, Dr. Norman, Richard Wong, and Betty Murray decided to see if both PCB's and DDT would cauaa the thin eggshell syndrome in Japanese quail, a game bird that adapts well to laboratory conditions. Chronic ex posure ofJapanese quail to DDT for 14 weeks resulted in eggs* that had a index 1SH lower than the eggs of quail that were not fad DDT. PCB treatment, however, showed no deleterious dfects on the of the quail compared to the controls, oiMwarinlhirknassorhirivwearrinnal H-bondlng studied by neutron diffraction PHVWCMU-X-ray diffraction is the key tool for determination of the three dimensional structure of bio logical molecules, but it is a virtually control the ultimate stereochemistry of such macromulsculss. X-ray dif fraction can rarely determine the posi tion of hydrogen atoms to an accuracy better than 0.2 A* says Dr. Walter C. Hamilton of Brookhaveo National Lalv oratory, whereas a change in length caused by hydrogen **"*"**" may be on the order of 041 to 045 A. But neutron diffraction, he points out, can determine the position of hydro* gm atoms to au accuracy tench better than 041 A* and is tfaaa a valuable technique for the links that control, among other tMogs the wheUx in protein structures and base-pairing in nucleic adds. Neutron diffraction is a jteig tech nique, however, and much of the work with it has been on compounds such ss --two Dr. Hamilton and Ms Brookhaveo associates Dr. Thomas F. Hostile. Dr. Mogsos S. Inhmami, Dr. M. Frey, Dr. L. Gottc, Dr. F.-G. JBosaon, Dr. A. Kvick, and Dr. Jacques J. Verbist have so far com* pleted single crystal neutron diffrac tion studies on some 14 amino adds and the dipeptide glycylgtycine HQ. Mae These msanrstesnts. Dr. formation about the nature of hydra MR. Diuihsmii si similarities bo tween PCB's and DDT which do not hold in all cases are further sub stantiated by Dr. George F. Fries at USDA's_ research canter at Beltsville, Md. FCBnootenrinated silage has caused PCS rssidu-- in milk above the levels recommended by the Food ami Drag Administration, Dr. Frias an* plains, and a few farmers have bad to remove their milk from the market. Dr. Fries and coworken studied nine cows fed 200 mg. per day of Arodor 1294 Bor M days. They find an aver* age concentration of PCB in milk after 40 daps of 404 *4J micrograms per gram of fat Whan feeding stopped, PCB concentration in milk fat dncltneri SDH. but after 15 days the rate of de> dine was quite small. In these re spects the residue behavior of Arodor 1254 is *--m-- to that of DDE, the nost persistent degradation product of DDT, Dr. Prim says. There is an excellent inverse cor relation between N -- H and H * * O distances m N -- H O hydrogen bonds. N O distances are leas im portant Many hydrogeu bonds are considerably bant Barriers hindering rotation of anv monlum groups, as well as other thermal pnramaters, an sensitive func tions of hydrogen bond g**" One hydrogen of the vNHi* of ly sine HCL for example, forms a very strong bond with a neighboring car- baxyl group. The bonier to rotation of this nwMHhiwi group is 74 keel./- mole; the barrier for the wnino group, which does not form such s strong bond, is 24 kcaL/mois. A Van dar Weals radius of 1.0 A. seems more appropriate for hydrogen- bonded crystals than is the commonly adopted 1.2 A. True bifurcated hydrogen bonds rarely exist in these MGNS 069643