Document BRDggdpL6gXvg226rBYKBjpjo

vo'tiplex. Kuther to the south. rububumMrontium whole-rock ages between Aim -* so x 10" and 5lM> s: 35 x 10s tars have been reported (27) from the Prfmpeun tanges of northwestern Argen tina. They could also be related to the Late Precambrian orogeny, if we considei that the numerous Hercynian gran itoid intrusions in this area have pro duced thermal effects that may have opened the rubidium-strontium system ot the Late Precambrian rock's with quite high rubidium-strontium ratios (25). 31 I he presence of the granulitecharnockite complex 2 x I0'1 years old along the Peru-Chile Trench must be tak en into account in genetic models of An dean voleanism. James et til. (29) and Hamet cr al. (20) have suggested crustal contamination as a possible explanation for the variation of ":Sr/""Sr isotope ra tals ((I 7055 to 0.70X0) in recent cale-alkaline lavas (Arequipa and Barrosso units) erupted through the thick Peruvian continental crust: these data contrast with lower isotopic ratios (0.7030 to (1.7042) generally found in similar rocks associated with subduction zones, where ihe crust is intermediate or oceanic. New strontium isotopic measurements have Ken carried out on rocks of the same units (2/ |. ( valuation in terms of "mix ing models ' Ol, 22) o` all these stron* un data support the tssumplton that the observed high stron'ium isotopic ra il i' are due to a crusta: contamination. Vote tallied in proof, While this report was in press, a paper by Cobbing et al. about similar Rb/Sr studies was published 12 0. B. Dalmaskac Lahortuoirc tie Geologic Strut turale. Office tie la Recherche Seieniifique et Icthmque Outre-Mer, (Jniversite ties St tent e\ ei Techniques tlu Lunguedot. J-ftifiU Montpellier Cetlex. France J. R. I.anc h ot Serene C'ommun ile Gcochronoiogic 11 Je (ictn liiniic lsuti `fili/tte. Unner.silc tiev Science* et 1 et lintques tin Languedoc A. Leyreloup Luhorutoire tie Petroiogie, Universile tit s St ietlces et Techniques <iu Languedoc Reference* end Nolen 1. C Martinez. P Turnasi, B. Dutmxyrac, G. Laub-ichcr. R, Maroccu. Pan 24th Ini. Gent t'unyr t Munlrtal), sect. 1 (19721. p. 136 E Beftidn. Verv Or,-/ Ifin lljma. Peru! Hot. 22 119691 > H D.ilma>rac.f . * A, ad Sri. Srr D 270. IOSH i 197(11 4 b Audebaud. J P Bald K Capiicvila, B Llalmavrac. K MariKCo, I Menard. J. Paredes, ibid 173, 4V)||V7||. J K 1 .incelot, B. Dulmay'aw, A Leyreloup, paper presented at (be 4th European t .IIikjuium of (teocbronvilogy l. irimrs'hronoloyi. and IsiUoix- Geology. Amsierdam. 19*6 ' IX'TOHt R (V77 5 J Siewart. J, F Everdcn, N, J Snelling. Geol Sue Am Bull IS, 1107 (19741, 6. B Oalmayrac and A t cyreloup, paper present ed al ihe 3rd Annual Meeling of Earth Sciences, Montpellier, 1975. 7 The term ' khondahic kinzigite sequence" is used for a suite of high-pressure granulate alu minous paragnetsses Iquartz. mesopenhitic po tassium feldspar, antiperthitic oligoclase. kyanne or pnsmalic sillim.inae. almandin-pyrope garnet, graphite, prismatic rutile, apatite,''zir con. monazite. oresl v .rytng from a quartzo-orthoclasic ikhondalttei pole to a plagtoclasic (ktnzigtte) pole (81 8 A Leyreloup. thesis University of Names (19731 9 The term "enderbnic gneiss" is used for hypersthene-beartng diontic gneisses. to. D H Green and A L Ringwood, Geochim Cosmuchim Acta 31, 7<i7 (1967), tl. A Leyreloup er al . Pfrrp/ogie 1, 43 (19751. 12, J R Lancelot, thesis. University of Pans VII (19751. 13, T E Krogh, Grtiebuu Cosmuehtm. Ana 7). 485 ((973) (4 J R Lancelot. A, Vnrac, C, J. Allfgre. C, R. Atad. Set. Ser D 277, 2317 (1973): Earth Plan et Sei Leu. 29. 357 (1976), 15. Using old decay constants: Xa,, * 0.1537 x 10'* year'1 anil X,,, * 0.9722 * 10"* year-1; T, * (946 z 36 * UP years and T, 725 s 29 x 10* years IA. H. Jaffey, K. F. Flynn, L. E Gtendcnin. W C. Bentley, A. M. Esslmg, Phys. Rev 4. 18*9(1971)1 16. G. W. Wethenll. Tram Am. Geophys. Union 37.320 (1956): S.S Goldich and M G. Mudrey, Grot. Soe. Am. Abstr. Programs (Part 7) (1969). p, 80. 17. G. R. Tilton. J. Geophys. Res. IS. 2933 (I960). (8 J. Ulrych, Mature ILundonl 200. 561 ((963); G. J. Wasserburg, J. Geophys. Res. it. 4823 (1963), 19 C. J. AIKgre. F. Albarede. M GrUnenfleder. V Koppcl. Cornell, Mineral. Petrol. 43, 163 (19741 20 C J Allegre, R Caby M Taisumoio, Abstr Am Geophys Union ifeet 5, 136(1972) 21 G Ferrara and M GraveMe. Earth Planft Set Lett 1.3I9(!%6);C J Allegre and R Caby.C. R Aiud. Su Ser O VS. 209< <19721. D Rousseau, C J Allegre, R Caby.J R Lance* tot. paper presented at the 3rd Annual Meeting of Earth Sciences. Montpellier, 1975 22. J Delhal, D. Leileni. 0 Cordani, Ann Soc Geol Bela 92, 271 <1969) 21 U Cordani, J Delhal, D, Ledent, Rev Bras Geouehi. S l (1973) 24 F Megan) and J, Paredes P,. Boh Tec. Asm Geol Peru 2. 7? t)%8) 25 F Megard. thesis. University des Sciences et Techniques du Languedoc. Montpellier (1973) 26. J F Everdcn. S J Knz, C, M Cherrom, lloja Inf. Ser Geol tBolivia) / (1966) 27 M Halpern, An Acud. Brasil Ctenc. (Suppl.) 44. 149(1972) 28, W R Van Schmus and M. E Bickford, paper presented at the 4th European Colloquium of Geochronology. Cotmochronology. and Isotope Geology. Amsterdam, 1976; J Ducrot and J R Lancelot, ibid . I Wendt, ibid. 29 D E James, C Brooks. A Cuyubamba. t arrtef(ie Inst Washington Yeurb 73, 983 (1974). Geol Soc. Am Bull 17.592(1976). 30 J Hamet et al, Geoiogv, m press, 31 L Brtqueu and J R Lancelot. Soc Geol. Fr. (special issue), in press; Bull Soc Geol Fr . m press. 32. J R Lancelot and C. J. Alltgrc, Earth Planet. Sc/ Lett. 22, 233 <|974); S S Sun. M Tatsumoto, J G Schilling. Science 190. 143 (1975) 33 E. J. Cobbing er al., Geol Soc. Am Bull tt, 241 (1977). 34. We thank Dr. A Kroner, Prof, M Matuuer. Dr. D. F. Strong, and the reviewers for valuable discussion and Tor reading the manuscript The geochronology studies were supported by the Office de la Recherche Scienufiquc et Technique Outre-Mer. 27 September 1976; revised 22 June 1977 P' Cancer Mortality in U.S. Counties with Petroleum Industries Abstract. A survey of cancer mortality from 1950 tty I960 was conducted in U.S. counties where the petroleum industry is mast heavily concentrated. Mate residents of these counties experienced significantly higher rales for cancers of the lung, ihe nasal cavity and sinuses, and the skin (including malignant melanoma) compared to mule residents of counties with similar demographic characteristics. Further study is needed to determine whether these patterns result from exposure to chemical carcin ogens. including poly cyclic hydrocarbons, involved in the manufacturing of petro leum. Polycyclic aromatic hydrocarbons (PAH) are found in crude petroleum, in the high boiling residues of catalytically cracked oils, in other pyrolysis products, in soots, and in air surrounding refining operations (/). Although exposure to PAH in several occupational groups has induced cutaneous and pulmonary can cers in man (/, 2), there has been no clear indication that petroleum refinery workers are exposed to excess risk (2). However, indirect evidence of a hazard was suggested recently by a national sur vey of lung cancer mortality indicating that such mortality was higher among males in U.S. counties with petroleum manufacturing industries, and by a Los Angeles study correlating lung cancer rates in census tracts to airborne levels of PAH emitted, in pan. from petroleum refineries W). To evaluate this issue fur ther, we compared the mortality rates from various cancers during 1950 to I960 in U.S. counties involved in petroleum manufacture with the rates in a group of counties with similar demographic char acteristics but no involvement in the in dustry. A total of 604 U.S. counties had plants engaged in petroleum manufacture (standard industrial classification code 29) according to the 1963 Census of Manufadures. although there were less than 20 employees in over one-third of these counties (J). Selected for study were 39 petroleum-industry counties (PIC) where at least 100 persons were employed and where the estimated number of workers divided by the county population ex ceeded 0.01. The fraction employed reached 0.07 in one PIC but was usually under 0.02. It was ().0|7 for the 39 PIC combined, involving about 50.000 petro leum workers. The number employed by sex was not available per county, but na tional statistics show a predominance of 51 Tjhle^l. Demographic indices for the petrolerm-mdustry counties tPIC) and control counties m I960. Indicator PIC Control counties turn. Low mortality was observed for brain cancer. Table 3 lists the mortality ratios for these cancers among white males in three groups stratified by population. Table t Ratios of age-adjusted mortality rates from 195(1 to 1969 among u hite males m petro leum industry counties to rates m control counties separated according to population size for selected cancer sites. Percentage urban Population density* Median school years completed by adult population Median family income Percentage nonwhite Percentage foreign parentage 74.2 53.5 10.6 6083 112 10.5 Population per square mile 71.1 58 1 10.7 5635 94 hi male workers over female (ratio 7:1). with 95 percent of all of the employed The rates for cancers of the nasal cavity, lung, and skin weie high for all three groups, while the excesses for other can cers were limited to highly populated counties (9). Among white females in the PIC. the mortality rates were significant ly high for lung cancer but not for can cers of the nasal cavity and skin nor for all cancers combined (10). The cancer patterns in the PIC may be due partly to the concomitant presence of chemical industries, which have been previously correlated on a county level Cancer site Stomach Rectum Nasal cavity and sinuses Lung Testis Brain Melanoma and other skm All cancers combined Population (1000 si <25 0 99 0.85 1 29 25 to 99 100 + 1.02 1 01 1 78* 1 15* t 13" l .45* 1 l+ 0 89 1 01 I 21 l 15* t) 94 0 9R 1 03 1.17* 1 18+ 0.93 1.12 + 1 03 I 05* 1 08* being white (6). with various cancers, including cancers p < ,oi + ot < p < os Nearly all the PIC were involved in pe of the nasal cavity, lung, and skin (II). troleum refining, at least since 1940. Al For the II PIC with heavy involvement though located in 16 states, over one-half in the chemical industry, the nasal can and if the remainder of the population were concentrated in Texas. Louisiana. cer mortality rate was exceptionally were at normal risk, then the relative risk Arkansas. Oklahoma, and Kansas. The high, while the rate for the remaining 28 to workers would be substantial, particu PIC ranged in population from about PIC exceeded the control rates to a far larly among subgroups exposed to haz 5000 to 500,000 (median 37,000) as of lesser extent (12). For lung and skin can ardous processes. However, these corre I960, the midyear of the study period, cers. rates were also highest in those PIC lations should be interpreted cautiously with a total of about 3 million. with chemical plants, but the relative ex Information was not available on the oc For comparison, we selected 117 cess associated with the presence of both cupations or other exposures of county counties comparable by geographic re industries was not as great as for nasal residents who died of cancer, or on their gion (same or neighboring state), popu cancer (13). Bladder and liver cancers, specific location or duration of residence lation size, and various demographic in prominently correlated with chemical in within the county. Nonfatal cancers dicators (Table I). Nonpetroleum manu dustry counties (II). were not excessive were not ascertained, and the informa facturing industries were nearly equally in the PIC. tion obtained from death certificates may apportioned between the PIC and con If. in fact, the higher cancer rates in not accurately refleci incidence. Al trol counties, except that chemical man the PIC resulted mainly from the small though the PIC and control counties ufacturing plants tended to occur in the percentage of males employed in the in were generally comparable with respect PIC. In 11 of the 39 PIC the chemical and dustry being exposed to petrochemicals. to region, urbanization, and socioeco petroleum work forces were about equal. nomic status, there may be differences in Only 6 of the 117 control counties had similar involvement (a fraction em ployed of at least 0.01) in the chemical industry. Age-adjusted mortality rates during 1950 to 1969. for 23 cancer sites, were Table 2. Ratios of age-adjusted mortality rates, 1950 to 1969. among white males in pe troleum industry counties to those in control counties by cancer site. Cancer site Ratio other variables that influence the results. Nevertheless, the geographic patterns are in line with published observations on cancer in related occupational groups. Squamous skin cancers have been reported as a complication of expo calculated among white residents in the individual PIC and control counties (7). in all PIC combined and all control coun ties combined, and in groups of PIC and control counties stratified by urban ization category. Standard errors were computed (S) for comparisons (Student's r-iest) of the differences in mortality rates between the PIC and control groups. Ratios of the age-adjusted cancer mor tality rates among white males in the PIC to the rates in control counties are shown in Table 2. Mortality in the PIC was sig nificantly high for all cancers combined. The largest ratios were for cancer of the nasal cavity and sinuses and for lung cancer. In addition, mortality was signif icantly high for cancers of the skin (both malignant melanoma and nonmelanotic skin cancer), testis, stomach, and rec- Buccal cavity and pharynx Esophagus Stomach Colon Rectum Liver Pancreas Nasal cavity and sinuses Larynx Lung Prostate Testis Kidney Bladder Melanoma and other skin Brain Thyroid and endocrine Bone and connective tissue Hodgkin's disease Other iymphomas Multiple myeloma Leukemia All sites combined p < Ot. +.01 < P + 03. 1.04 1.06 1.09* 1.02 1.07t 1.06 1.05 1.48* 1.09 1.15* 0.98 1.10+ 1.05 1.02 1.10+ 0.94+ 1.04 0.9R 0.96 t.01 1.05 1.03 1.06* sure to PAH among wax pressmen, workers in the shale oil industry, and mule spinners and machinists exposed to cutting oils (/). A possible excess of melanoma was recently noted among workers who handled polychlorinated biphenyls in a northeastern petrochemi cal plant (M). Nasal cancers have not been related to petroleum exposures, ex cept for tumors of the ethmoid sinus in a small group of workers manufacturing isopropyl alcohol (IS). Potentially leukemogenic is exposure to benzene in the petroleum industry (/6). but no signifi cant excess of leukemia was found in the PIC. The correlations with lung cancer m the study are a cause for concern be cause lung cancer occurs excessively among other PAH-exposed groups, in cluding roofers, coke-oven workers, and gas-generator employees (/. 2): and the 52 science, vnt, im OLI 7172 -iigh rate' lung cancer among female residents ?n the PIC raise the possibility of a pollution hazard spreading beyond the workplace. "*he findings of this survey suggest the . lor industry-wide epidemiologic studies to clarify the risk of cancer among various groups of 'petroleum workers and to evaluate the possible ef fects of petrochemical emissions re leased into neighboring communities. Wit 11 \m J. Bt OT i.ouisi A Brinion Jost t*H F Frai'mlni, Jr. B J, Smtst Environmental Epidemiology Bium h. Motional Cam er Institute. Bethesdu. Maryland 20014 References and Notes I Committee on Biologic Effect* of Atmosphere Pollutants, Purtuuiute Pol\tuhc Orvunu Mut' ter (National Academy uf Science*. Washing* ton. 0 C 1972), M D Kipling and H A. Wal dron Pre\ Mrd 5. 262(1976). 2, R Doll M P Vesscy.R W R, Beasley. A. R. Buckley. E C. Pear. R E, W Fisher. E J Gammon. W Gunn. G U Hughes. K. Lee. B. Norman-Smith. Br J hid Med, 29,394 11972); J, W Lloyd J On up, Med, 13. 53 (1971). M Kauai H Amumolo. K, Horada. Arch, Envi ron Health 14 8*9(1967), E (.' Hammond. I J koft P L Lavtlhcr. H Seidman, Ann .V I \ind.Sii 271. 116 (1976); J F Fraumeni. Jr ,j Vd// Canter Inst 55. 1039 U97M. I V C Baird. ; Otiup Med 9 415 (1967): L. Wadi,' \rih Environ Health 6, 730 (196,3), Tahei'`havi./Cooper Associates, A Mortality Studv it] Pi troleum Rchnerv Workers, Project OH-I. prepared for ihe American Petroleum Institute. NVa Kington D C , September 1974 4 W ' Blot and J F, Fraumeni, Jr,. Am. J. Epi demiol 103. *39(1976), B E Henderson. R J Gordon. H Menck. J Soohoo. S, P, Martin. M. C hke.iftid 101.477 0975). U S Department of Commerce Census of V/dn* ufuctures l I96J) (Government Printing Office, Washington D C,. I%6>. vols I and 2 6 US Bureau of the Census. U S Census of Pop ulation 11960), voly I and 2. tharaitenstu s of the Population (Government Printing Office. Washington, D C , 1963) ^ T J Mason and F W McKay US Cancer Mortality by Counts 1950*49 (Government Printing Office. Washington, D L . 1973) 8 C L (_hiung. Vital Stutistus 'selected Reports (Government Printing Office Washington, D C . 1973). vol 47 No 9 9 For lung cancer, the rates (deaths per year per 100.000 population) increased from 30 0 to JV7 to 45 5 among the three urbanisation groups of the PIC a* opposed to 27 2 to 31 1 to 39 0 for the control counties The rales for nasal cancer var ied little svith urbanization, remaining at about 0 6 m the PIC and 0,4 m the control counties Skin cancer rate* declined vuth urbanization (4 2 3 3, and 3 3 in the PIC compared to 3 4. 3 2. and 3 0 in the control counties) 10 The PIC/control counties mortality ratios for white females were (total and three urbanization categories ofTable 3, respectively): lungcancer. 1 06, I 21. 1.07. 1,05; nasal cancer, 0,77. 0 70, 0 58, 0 76. skin cancer. I 01. I UO, 1,05, 0 99. all cancers combined. 101,0 98, I 02. I 02. 11 R Hoover and J, F. Fraumeni, Jr.. Environ. Res. 9, 1% (1975). 12 The mortality rate for nasal cancer for the U PIC combined was 0.8 (about double the control and national rates) and exceeded 0 7 in eight of (he 11 counties. The rate for the 28 P!C without heavy chemical industrial involvement wasO 5 13. The mortality rates for each of nasal, lung, and skm cancers were reported to be higher by 10 percent in chemical-industry counties (//). The mortality rates for lung and skin cancers in the PIC where chemical industries were heavily concentrated were roughly 10 percent higher than in the PIC without a heavy concentration of chemical industries, which were m turn higher (12 percent for lung cancer and 7 percent for skin cancer) than the control rates. However, rates for nasal cancer in the PIC with chemical industries were over 50 percent higher than rates in the remaining PIC. 14 A K Bahn. ( Rosenwaike, N. Herrmann, P Grover, J. Siellman. K. O'Leary. .V, Engl. J Med. 295. 450 s 976) 15 C S Weil. H F. Smyth. T W. Nate, AMA Arch. Ind. Hyg. Occup. Med 5. 535 (1952). 16. J J Thorpe. J. Occup. Med, 16. 375 (1974). 13 January 1977; revised 17 May 1977 Bifunctional Intercalators: Relationship of Antitumor Activity of Diacridines to the Cell Membrane Abstract, The in vivo antitumor effectiveness [as measured by the percentage in crease m life-spun t ILSrT)l of28 dim ratine his-intercalulors of nucleic acids shows a highly significant correlation n itli their effect on phenomena associated with plasma membrane as well as a high degree of structural specificity. In contrast, the ILS% does not correlate with the uptake of these diucridines by cells, nor with the inhibi tion oj RNA synthesis or of DNA synthesis or with the inhibition ofgrowth of cells in t allure. The possibility that the antitumor effectiveness of actinomycin D. another DNA interialator. is associated with sites of action other than the lubition of RNA synthesis is discussed. In an attempt to develop new antitu mor compounds, we have enhanced the well-known ability of the acridine ring to intercalate with DNA by synthesizing diaendines (/-J). These compounds con sist of two acridine rings connected through their 9-amino position by hydro carbon chains of various lengths. In ad dition. various substitutions have been made on the acridine rings; only sym metrical compounds have been synthe sized. the two acridine rings of each diacridine are identical (see Table I). It was anticipated that such compounds would intercalate more strongly with DNA. In order for the DNA to be free of the diacridine, both rings would have to deintercalate simultaneously; a delay of one ring would permit the other ring to reintercalate. Work done m our laborato ry (/. 2). as well as in others, with a limit ed number of diacridincs (-/) has shown them to bind more strongly than monoacridines to DNA and RNA. In the biological studies described be low. the diacridines in which the con necting paraffinic chain has six or more methylene groups In ^ 6 in Table I) have proved more effective than when n ^ 4. This result seems to find an expla nation both in model building (/) and in studies on PM 2 DNA with Wakelin er al. (.5). These studies II, 5) indicate that when u -- 6 the diaennes can effectively act as bifunctional intercalators with PM 2 DNA while they act only as monofunctional intercalators when n 4; when n - 5, intermediate results are ob tained. The diacridines are potent inhibitors of the growth of P-388, L-1210. and HeLa cells in culture (b). More detailed studies with these cells indicated that RNA syn thesis was the pumary site of action; DNA and protein synthesis were af fected to a lesser extent (6. 7). Additional studies showed that the synthesis of 455 ribosomal RNA was specifically inhib ited as well as the further processing of this RNA to 285 and 185 RNA 18. 9) and the methylation of transfer RNA (tRNA) (P). A study of the synthesis of well-de fined messenger RNA's (mRNA) in vitro (T7 DNA-dependent RNA polymerase transcribing the late cistrons of T7 DNA' in vitro) showed that the diacridines in hibited the initiation of RNA synthesis in contrast to actinomycin D, which inhib ited elongation 110). In addition, we have found the diacridines to be extensively taken up by cells in culture (5) and by tumor cells in vivo (R.M.F., unpublished observations). The diacridines also have considerable in vivo antitumor effect when assayed in BDF/I mice bearing P388 leukemia tumors in ascites form II). It was therefore of interest to establish whether the in vivo antitumor effect of these diacridines, as measured by the percentage increase in life-span (ILS%>), would correlate with the well-defined in hibition of RNA or of DNA synthesis or with their cellular uptake. Using all the diacridines for which we have in vivo an titumor data (ILS% values), we related the ILS% with the ability of the diacri dines to inhibit RNA synthesis (Fig. la) and DNA synthesis (Fig. lb), as well as their uptake by P-388 cells in culture (Fig. Ic). These results indicate that there is no significant correlation be tween any of these three parameters and the antitumor activity of the diacridines as represented by 1LS%. A correspond ing study relating ILS9f to the inhibition of growth of P-388 cells itr culture also showed no significant correlation (J). However, we also evaluated the cell membrane as a possible site of action of 7 OCTOBER 1977 53 OLI 7173