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mak n Jr. auamtm, EXPERIMENTAL CONTRIBUTIONS IN IDENTIFYING BRAIN POTENTIAL CARCINOGENS IN THE PETROCHEMICAL INDUSTRY Cesare Maltoni, Adriano Ciliberti. and Donata Carreiti Institute ofOncology Bologna, Italy Introduction Data on the correlation between hair, tumors and ..xcgenous (environmental and occupational) agents are scanty, but extremely sinking. Historically, Dr. Thomas F. Mancjso '.as the first to id.'ntiiy an eptdemblcgica! relationship between industnal employment in a specific industry Irubber) and the subsequent development of malignant tumors of the brain: In a series of studies, including demographic, retrospective, and cohort longitudinal investigations, a higher risk of death due to tumors of the central nervous system among rubber workers-was established.1-* Following the experimental results showing that vinyl chloride was producing brain tumors (neuroblastomas).' epidemiological studies demonstrated an increase in brain neoplasias among workers of the vinyl chloride--polyvinyl cnloride industry,4 which was confirmed by many further investigations. Recently a two-fold increase in brain tumors in several petrochemical plants and refineries in Texas, was found by some U.S. epidemiological groups. This find ing is still under debate (this volume). So far, only in the case of VC-PVC workers has the direct casual agent been identified. In both the case of the rubber industry and that of Texas petrochemical plants and refineries, workers have been potentially exposed to a multitude of compounds (several known as human carcinogensi: none of them, however, can at present be definitely linked to the excess of brain tumors. Theoretically, the experimental approach to the study of brain environmental and occupational carcinogenesis may help to do the following: . to predict the carcinogenic action of environmental agents (identification!; 1 to assess the degree of carcinogenic potential of environmental agents (quantificationl. in relation to concentration, length of exposure, and so on: 3. to provide the basis for [he evaluation of the relative carcinogenic risk of various agents: 4. to evaluate the possibility of sincarcinogenetic effects of exposures to different car- anogenic agents: 5. to help to interpret epidemiological findings showing an increased brain tumor rate among people exposed to a multitude of compounds: namely, to identify the risky single agent(s): 6. and finally, to provide basic information on the mechanisms of brain carcinogenesis by environmental agents. The possibility of producing brain tumors in laboratory animals is well known. Many chemical agents, of different types, following direct implantation and general administration, may produce different types of tumors in a variety of experimental rodents (Table 1). Rats, at present, appear to be the most suitable species. Three industrial compounds, in recent years, have been experimentally shown to produce brain, and brain-correlated, tumors in rats of different hiscotypes: these are bis (chloromethyl) ether, vinyl chloride, and acrylonitrile (Table 2). 216 0077-1923/1103*1-0216 SI '3.0 f 19*1 NYAS OLI 6953 tONS IN IDENTIFYING 1NOGENS IN THE INDUSTRY j. and Donata Carretti >logy ') N tors and exogenous (environmental !y striking. he first to identify an epidemiotogim a specific industry (rubber) and . of the brain: In a series of studies, ort longitudinal investigations, a ral nervous system among rubber that 1 chloride was producing stuu demonstrated an increase nyl chloride--polyvinyl chloride ivestigations. s in several petrochemical plants tpidemiological groups. This find- has the direct casual agent been and that of Texas petrochemical tally exposed to a multitude of l; none of them, however, can at mors. he study of brain environmental : following: 1 agents (identification): auronmental agents (quantification), ii so on; dative carcinogenic risk of various feels of exposures to different cat ling an increased brain tumor rate mds; namely, to identify the nsky thanisms of brain carcinogenesis by natatory animals is well known, itrect implantation and general <rs in a variety of experimental tost suitable species, ve been experimentally shown ts or "Vent htstotypes; these 'tut Table 21 H NVAS Maltoni et of.: Experimental Contributions 217 Table 1 Experimental Chemicals Used to Produce Experimental. Brain Tumors Experimental Systems Chemical Substances Route Animal Species Tumors Aromatic hydrocarbons 20-Methylcholamhrene J-Methylcholanthrene 3,4-Benzopyrene Direct implantation Rats Mice Syrian hamsters Gliomas Sarcomas 1,2-Benzopyrene 3,4.8,9-Dibenzopyrene l,2.J.6-Dibenzanlhracene 1 ib-Dibenzanthracene 9.10-Dimethyl-12-benzanthracene 6.9.10-Trimelhyl-l,2-benzanthracene Derivatives of aromatic hydrocarbons ZV-2-Fluoren y lacetam ide General Rats administration Gliomas N.N'-2.7-Fluorcnyibisacelamide IV-Nitroso compounds Methyl-tf-nitrosourea (MNU) General Rats administration Rabbits Gliomas Sarcomas tVjV-Dtmethyi-iV-nitrosourea (DMNU) /V,JV'JV'-Trintethvl-.V-nitrosourea (TMNU) Ethyl-nitrosourea (ENU) Triazenes I -Phenyl-3J-dimethylmazene General Rats administration Gliomas Hydrazines 1,2-Diethylhydrazme General Rats administration Gliomas Sarcomas Neuro- csthesio- epitheliomas I Ji ! Tabu 2 | Industrial Chemicals Known to Produce Brain Tumors in Experimental Animals t Compounds Route Animal Species Turnon References it Bis (chloromethyl) ether Inhalation Rats Neuroesthesio- 7 epitheliomas Vinyl chloride Inhalation Rats Neuroblastomas (similar to 5,S,9 i human medulloblastomas) : Acrylonitrile Inhalation Rati Ingestion Gliomas mainly oligodendrogliomas 10.11 1 OLI 6954 Tale 3 The Incidence of Brain Tumors Among Untreated Sprague-Dawley and Wistar Rais at the Institute of Oncology and Tumor Center of Bologna (Italy) Animals Ral Strain Sex Ependymomas Average Latency Time No. No. % 1 Weeks) No. SpragueDawley M 1,384 J 0.2 1- 1.412 4 0.3 M&F 2.796 7 02 95.0 105.5 101.0 13 8 21 Tumors* Gliomas Meningiomas Average Average Latency 1 alency lime % (Weeks) No. % (Weeks) No. 09 118 5 10 07 96.6 26 0.6 81.3 9 0.6 117.1 21 0.7 104.3 19 0.7 106.3 47 Total Average Latency lime % (Weeks) 1.9 107.4 IS 101.3 1.7 104.6 Wistar M 170 0 -- - 6 3.5 102.5 1 0.6 119.0 7 4.! 104.9 SS69 n o No neuroblastomas were found. * m SS3 3 9 v> r** -- o -- g 2 r- * v OPP O 9 4""i r**i at 3 " Vt g -- o c ooo r- -- 5 u. ii 2 aw ww*Vi iifilwin i Maitoni et at.: Experimental Contributions 219 Table 4 The Incidence of Brain Tumors Among Sprague-Dawley Rats, Treated with 1 ml of Olive Oil per kg Booy Wt by Gavage. Once Daily. 4-5 Days Weekly, for 52-57 Weeks Ependymomas Tumors* Gliomas Meningiomas Tout SpragueDaw ley Rati Sex No. Average Latency No. % (Weeks) Average Latency No. % (Weeks! Average Latency No. % (Week!) Average Latency No % I Weeks) M 325 F 325 MA F 650 1 0.3 2 0.6 3 0.5 104.0 91.5 95.7 3 0.9 2 0.6 5 0.8 102.0 114.2 106.9 3 0.9 102.3 4 1.2 100.2 7 1.1 101.1 7 2.1 102.4 8 13 101.5 15 13 101.9 * No neuroblastomas were found. To achieve the above-listed finalities, the experimental investigations, aimed at studying environmental and occupational carcinogenesis, should meet the following prerequisites: 1. i suitable animal model should be used: 1 the spontaneous background lumonsram of the animals employed must be known: 3. the expertmema I protocols and procedures must be kept highly standardized for the different experiments, performed in the same laboratory. In our opinion, in order to obtain natural, worthwhile, and comparable data, one must: A. keep the animal alive until spontaneous death: B. perform, at autopsy, careful gross examination: C. trim the organs and make histological sections in a standard way: D. make histological sections, highly representiative of different pans of the brain, available: and E follow the same histological classification of tumors. This report presents our data on the incidence of brain tumors in rats, following the treatment with a variety of industrial compounds, given by inhalation and or by ingestion, at different doses and. in some instances, for different durations and with different schedules. These data have been collected in the framework of a long-term project on industrial carcinogenesis which was started in 1970 at the Institute of Oncology and Tumor Center of Bologna, and is still going on. OLI 6956 MUrn iff Table 5 The Incidence of Brain Tumors Among Sprague-Dawley Rats Exposed by Inhalation to Vinyl Chloride in Air at Various Concentrations. From 30,000 to I ppm, 4 Hours Daily, 3 Days Weekly, for $2 Weeks* * Vinyl Chloride (ppm) Animals Sex No. Tumors Neuroblastomas F.pcndymomas Gliomas Meningiomas Average Average Average Average Latency Latency Latency Latency Time Time Time Time No. % (Weeks) No. % (Weeks) No. % (Week*) No. % (Weeks) No. Total Average Latency Time % (Weeks) tm! 3 o f H cr\ u> U1 30,000 KUXXI 6,(XX) 2,500 500 250 M F Ml M 1 Ml M 1 MF M F MF M F MF M 1 Ml 30 1 .10 0 60 1 30 2 10 5 60 7 30 2 30 1 60 3 30 2 30 2 60 4 30 0 30 0 60 0 30 0 10 0 Mi 0 3.3 -- 1.7 6.7 16.7 11.7 6.7 3.3 5.0 6.7 6.7 6.7 -- -- - 800 0 .0 800 0 650 0 672 0 66.6 0 750 0 63.0 0 710 0 89.5 0 97.0 2 93.2 2 --0 0 0 -- 0 -0 -0 -- -- ... -- -- -- -- -- -- 6.7 3.3 -- -- - -- -- -- 0-- -- 0-- -- 1 3.3 80.0 -- 0-- -- 0-- -- 0-- 0- 0- 1 1.7 80.0 -- 0-- -- 0 - - 2 6.7 65 0 -- 0-- -- 0-- -- 5 16.7 67.2 -- 0-- -- 0-- -- 7 11.7 66.0 -- 0-- -- 0 -- -- 2 6.7 750 -- 1 3.3 115.0 0 -- -- 2 6.7 890 -- 1 1.7 115.0 0 -- 4 6.7 82.0 --0 -- 0 -- -- 2 6.7 89 5 99.5 0 -- -- 0 -- 4 13.3 98.2 99.5 0 -- -- 0-- -- 6 100 953 -- 1 3.3 105.0 0 -- -- I 3 3 1050 -- 0-- -- 1 3.3 84.0 1 3.3 840 ... 1 1.7 105.0 1. 1.7 - 84.0 2 3.3 94 5 --0 - 0-- -- 0-- -- 0-- 0-- 0 -- 0 0-- -- 0 M* If If V-- 3 I0.IMI M 30 67 650 0 30 3 16.7 672 0-- 1 1.7 HO.O 0~ -- o -- -- 2 6.7 65 0 t 6.000 2.500 5U) :vi MF M F Ml M 1 Ml M 1 Ml M 1 Ml 60 7 11.7 666 30 2 30 1 60 3 6.7 75.0 3.3 63.0 JO 71.0 30 2 6.7 89.5 30 2 6.7 97,0 60 4 6.7 932 30 0 ,_ 30 0 60 0 Mi 0 --. Ml a Ml 0 0-- 0 0-- 0-- 0-- 2 6.7 2 13 0-- 0 0 0 <1 II -- -- 0 -. 0- - - 0I 3.1 115.0 o -- I 1.7 115.0 0 -- 0- - 0- 99.5 0 - - 0 _ 99.5 - - 0- I 33 105.0 o -- 0 I 3.3 1 17 105.0 | / 7 0 -0 n -- i 16.7 67 2 -- 7 11.7 660 -- 2 6.7 750 -- 2 6.7 890 4 6,7 82 0 - 2 67 89 5 -- 4 13.3 98 2 -- 6 100 953 --1 84.0 1 84.0 2 -- 0 0 33 105.0 3.3 84 0 33 94 5 1 < ii ii .111 M 1 Ml HI ii Ml 0 120 0 150 M 60 0 F 60 0 MF 120 0 100 M 60 0 F 60 0 MF 120 0 50 M 180 0 F 180 0 MF 360 0 23 M 60 0 F 60 0 MF 120 0 10 M Ml 0 1- Ml 0 MF 120 0 5M Ml 0 1 Ml 0 MF 120 0 1M 60 0 F 60 0 MF 120 0 Conlrolst M F Ml- 225 0 240 0 465 0 Tuuil 2.025 -- " ___ -- -- -- -- __ -- -- -- -- -- -- -- -- -- -- ___ -- -- II -- 0-- -- 0-- 0 -- 0-- -- 0-- -- -- __ -- -- -- -- --. 0 0 0 1 0 1 0 0 0 -- -- -- 0.5 0.3 -- -- -- 0-M- -- -- 0-- -- 0" -- 0-- -- 0-- 0 .... -- 0-- 0 -- -- 0- -- 01 0.4 -- 1 0.2 * Age nf I lie iiiiiiii.iIs .ii siai'l.' 13-17 week \ t Nil Ifc.iliiR'iu -- -- -- -- -- -- -- 123.0 -- 123,0 -- -- -- -- -- -- -- -- -- -- -- 122.0 122.0 II 0 0-- ... -- -- 0-- -- 1 1.7 *120.0 1 as 120.0 1 1.7 0-- 1 0.8 82.0 -- 82.0 2 1.1 2 l.l 4 1.1 108.0 90.5 99.2 0-- 0-- 0-- -- -- -- 0-- 0-- 0- -- --- 1 1.7 0-- 1 OK 132.0 -- 132.0 1 1.7 0-- 1 08 930 - 93.0 2 0.9 0 2 04 138,0 138.0 0 0-- 0 0-- 1 1.7 1 0.8 I 1.7 0-- 1 0.8 1 0.5 0-- 1 0.3 0-- 0-- 0 0 -1 1.7 l 08 0 -0 0-- 0-- 0-- 0-- 1 04 3 1.2 4 o,# -- -- -- 94.0 94.0 102.0 -- 102.0 124.0 -- 124.0 -- -- -- 91.0 91.0 -- ~ -- -- -- 106.0 113.0 II 1,2 ii 0-- 0~ 0 *-- 2 3.3 2 1.7 2 3.3 0-- 2 1.7 4 2,2 2 l.l 6 1.7 0-- 0-- 0-- 0-- 1 1.7 1 0.8 1 17 0-- 1 0.8 1 1.7 0-- 1 0.8 3 1.3 4 1.7 7 1.5 -- -- _ 107.0 107.0 92.0 -- 920 115.7 90.5 107.3 -- -- .... 910 91.0 132.0 -- 1320 93.0 -- 930 1273 1155 1204 OLI 6958 nafcgi.'txa 4**' ' AtfV -v4NMMARi*m4 ,'A .*V Tai_e 6 The Incidence of Brain Tumors Among SpragueDawley Rats Exposed v Inhalation to Vinyl Chloride in Air at Various Concentrations, 4 Hours Daily, 5 Days Weekly, for 17 Weeks* Tumors 0 Vinyl Chloride Ippnif Aninrals Sci No. Neurobljsiomas Average latency lime Nu 1 Weeks) Ependymomas No. ... Average Latency Time (Weeks) Gliomas Average Latency Time No. (Weeks) Meningiomas Average Liiicncy lime No. % (Weeks) Nu. Tot*) Average Latency Time % (Weeks) 10.000 M 50 F 30 MF 60 3 100 6 200 9 150 6,000 M 50 3 100 F 50 9 30.0 Ml 60 12 200 2.500 M 50 1 50 MF 60 4 133 1 33 5 43 500 M 30 0 F 50 0 MF 60 0 250 M 50 0 -- F 50 0 -- MF 60 0 -- 50 M 50 0 -- 50 0 -- MF 60 0 -- ConiroUt M HW 0 _ r H2 0 -- MF 190 0 -- Tout $50 62 J 750 700 713 7K3 766 45 7 760 6.7.4 -- -- -- -- _ -- -- -- -- -- 0_ 00" 0-- 00 0-- 0 -0- 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- 1 09 0-- l 05 --- -- .. -- -- -- -- -- -- -- -- -- -- -- 1260 -- 1260 0 0-- 0- 0-- 0-- 0-- 0_ 0-- 0- 0-- 0-- 0-- 0 0-- 0-- 0-- 0-- 0-- 1 09 3 37 4 21 _ -- - -- ... -- _ -- -- -- -- -- tooo 817 862 0 1 33 1 1.7 _ 60.0 60.0 0 00 - 0-- 0-- 0 -- -- ... 0-- 0-- 0-- 0 0-- 0-- 0_ 1 3.3 1 1.7 . -- -- _ -- -- _ 130.0 1300 2 1.1 1 1.2 3 1.6 v 46 5 710 61 3 3 100 7 233 10 167 621 73 1 69.9 3 100 9 30.0 12 2U0 713 74 3 76 6 4 1.31 i 1.3 5 63 45 7 760 63.6 0 0- 0-- - 0-- 0-- 0-- _ 0-- 1 3.3 130.0 1 1,7 130.0 4 37 4 4.9 g 42 99.7 790 894 * Age of ihe animals Hi start. 12 weeks, t No ue.iimciil OLI 6959 on ou 9 VI *3 8 MO M JO 0 F JO 0 _ _ -- MF 60 0 -- -- 0- 0-- 0-- 0-- " -- -- 2M M JO 0 _ F 30 0 -- MF 60 0 -- _ -- -- 0-- 0 0-- -- -- M M 30 0 _ F 30 0 -- MF 60 0 -- . _ -- 0 0-- 0" -- -- Controlit M F 106 82 0 0 -- --- MF 190 0 -- _ _ _ 1 0.9 0 1 0.5 126.0 -- 1260 Tout *50 * * 4|f "i V- i Ihtf 4f|(ftt4U *4 41 4UII 0-- 0 0 0-- 0 __ 0 0-- 0 *_ 0 0-- 1 0.9 3 3.7 4 2.1 ___ -- ___ -- _ ___ -- 100.0 81.7 86.2 0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 1 3.3 1 1.7 2 1.8 1 1.2 3 1.6 -- -- -- -- - -- -- 130.0 1300 16.5 710 81.3 I 31 3 13 0 0 _ 0-- 0 0 _ -- 0-- 0 1 33 1 1.7 4 3.7 4 4.9 8 4.2 760 03 8 __ _ -- _ _ -- _ 1300 130.0 99,7 790 894 fw tm m> i i# n* Tit* Hni4i.ii Ha* I inmn 8* Ikhaiais** if* Vinw Ciiititiut in Am ai iOjmuo and ,(* rrM hm Vahhm lixmaintt SkiiMMJiMtlOO Mmms TmTai-J* Tumors Neuroblastomas Ependymomas GliomM Meningioma* Total VC Cone <PP"l3 Ekpoiurct Animal. Sex No. 10,000 4x5x5 6,000 4x5x5 10.000 1 x 4 x 25 6.000 1 x 4 x 25 10.000 4 x 1 x 25 6000 4 x 1 x 25 Control*} 1ot.il M F MF M F MF M F MF M K MF M F MF M F MF M F Ml 60 60 120 60 60 120 60 60 120 60 60 120 60 60 120 60 60 120 109 120 229 949 Average Latency No. % Time No. % (Week.) 0-- 0-- 0-- _ -- 0-- 0-- 0" 0-- 1 1.7 1060 1 OS 106.0 0-- 0-- 0-- 0 0-- 0 -- -* -- 0-- 1 1.7 1 0.S 0-- 0-- 0 -- -- -- 0-- 0 "" 0-- 0-- 1 1.7 1 OS -- S4.0 S4.0 0-- 0-- 0-- 0-- 0" 0-- -- -- -- 0-- 1 1.7 1 0.8 0-- 0" 0 -- -- 0-- 0-- 0 Average Latency Time (Weeks) ... -- -- -- -- -- 116.0 116.0 -- -- -- -- -- -- 83.0 83.0 -- -- No. % 3 5.0 0-- J 2.3 2 3.3 0-- 2 1.7 2 3.3 0-- 2 1.7 1 1.7 0-- 1 0.8 1 17 1 1.7 2 1,7 0-- 0 0-- 2 IS i 08 3 13 Average Latency Time (Weeks) No. % 102.3 0 _ -- 0-- 102 3 0 -- 755 0 -- -- 0-- 75 5 0 -- 92.5 1 1.7 -- 2 3.3 92 5 3 IS 58.0 1 --1 58 0 2 1.7 1.7 1.7 80,0 0 90.0 1 17 85.0 1 OS -- -- -- 114 5 94,0 107.7 0-- 2 3.3 2 1.7 0_ 0-- 06 Average Latency Time (Weefce) No. % _ 3 5.0 _0 -- 3 2.5 ___ 2 3.3 -- 1 1.7 -- 3 2.5 56.0 3 5.0 97.5 3 50 S3.9 6 5.0 7J.0 2 33 1110 1 1.7 93.0 3 2.5 ... 1 1.7 580 1 50 5S.0 4 3.3 ___ 0 78,0 3 5.0 78.0 3 25 ___ 2 1 8 -- i 0.8 3 1.3 Average Latency Time (Weeks) 102.3 -- 102.3 75.5 106.0 85.7 540 1037 78 8 665 II 1.0 81 3 80.0 770 78.0 797 79.7 114 5 94.0 1077 1 Aye (d AiiiiiidU i iijri 13 week* I t|NAW( (tllK ||l| Jj)| |*l) J N> ti(4iHKnl 0969 n o tlOl ili Mik Table 8 * The Incidence of Bbain Tumors Among Male Wistar Rate Exposed by Inhalation to Vinyl Chloride in Air at Various Concentrations 4 Hours Daily, 5 Days Weekly, for 52 Weeks* Tumorst Neuroblastomas Gliomas Meningiomas Total Average Average Average Average Vinyl Latency Latency Latency Latency Chloride lime lime lime Time Group (ppm) Animals No. % (Weeks) No. /ll (Weeks) No. .11 (Weeks) No. % (Weeks) & 1 I0.D00 .TO T 100 82 0 0 -- 1 T.T 650 4 1 .T.T 77.7 2 A,(88) 30 1 T.T k4(> 3 10.0 88.3 0 - 4 13.3 87 2 3 2.5(8) TO 1 J.I ti*;o 0 -- 0-- - 1 T.T 69 0 4 5<N> TO 0 -- ... 0 -- -- 0 -- --0-- ... 5 250 TO 0 - 0 0 *" 0 6 50 TO 0 -- -- 0 -- 1 T.T 93 0 1 3.3 93.0 7 1 120 0 -- -- 5 4.2 107.6 1 0.8 1100 6 5.0 108 0 8 Controls} 170 0-- -- 6 3.5 1025 1 0.6 119.0 7 4.1 104.9 Total 470 * Age of animals al star! 11-I T weeks. 7 No ependymomas were found. } No treatment OLI 6961 Total '.AAI 6.000 2.500 500 250 50 1 Controls* .10 30 30 30 30 30 120 170 470 3 100 1 3.3 1 3,3 0 ___ 0 __ _ 0 ___ 0-- 0-- 82.0 84.0 690 _ * Age of animal* a( suit 11-13 week*. 3 No ependymomas were found. J No treatment. 10.0 8ft 107.6 102.5 I Wk) 3.3 65.0 4 13.3 77 7 4 13.3 87.2 -- I 3.3 69.0 '1--1 -- 0 -- -- --0 3.3 93.0 1 3 3 93.0 0.8 110.0 6 5.0 108.0 0.6 119.0 7 4.1 104.9 The Incidence or Brain Tumors Amino SrnAOiic-DAWitv Rat* Exkkiu it Inhalation to Vinyliiuna Chlohide in Am at 150, 100 50, 25, and 10 ms, 4 Hours Dailv, 4-5 Days Weekly, fur 52 Weeks* Ependymomas Gliomas Tumors! Meningiomas * Total Average Average Average Average Vinylidene Animals Latency Latency Latency Latency Chloride Time Time Tune Time Group ippnt) Sex No. No. % (Weeks) No. % (Weeks) No. % (Weeks) No. % (Weeks) _1 150 M 60 0 __ __ 0_ 0 __ . 0 -- f 60 0 -- -- 0-- -- 0-- -- 0-- -- M* F 120 0 -- 0-- -- 0-- -- 0-- 2 (0Q M 30 0 __ 0 .-- _0 -- 0_ _ F 30 0 -- -- 0-- -- 1 3.3 108.0 1 3.3 108.0 M4f 60 0 -- ~ 0-- -- 1 1.7 I0H.0 1 1.7 108.0 B 3 50 M 30 0 1 3.3 )) 10 1 33 1270 2 6.7 . 1190 1 30 1 3.3 95.0 1 3.3 840 1 33 1240 3 10.0 101.0 M & F 60 1 1.7 95.0 2 3.3 97.0 2 3.3 125.0 5 8.3 1022 4 25 M 30 0 -- -- 0 w. _0 ... 0 __ ... 1- 30 0 -- 0 - --0 0 M & F 60 0 -- 0-- -- 0-- -- 0-- -- 5 10 M 30 0 __ -- 1 3.3 1)10 0 -- -- 1 3.3 II 1.0 F 30 0 --- -- 0-- -- 0-- -- 0-- M & F 60 0 -- -- 1 1.7 II 1.0 0 -- 1 1.7 II 1.0 6 Controls! M 1(10 0 -- -- F 100 0 -- -- M A F 2(81 0 -- -- 2 2.0 )32 5 I 0-- -- 1 2 10 132 5 2 1.0 52.0 3 1.0 105.0 1 1.0 785 4 3.0 105.7 1.0 1050 2.0 1055 Total 560 * Age of the umiruU a\ *1.111 lf> *cckk t N* ViCfc foutul | No OLX 6962 HM i*M Table 10 The Incidence of Brain Tumors Amono Spracue-Dawley Rats Exposed by Inhalation id Ethylene Dichloride in Air at 250, 150, 50, 10, and 5 ppm, 7 Hours Daily, 5 Days Weekly, for 78 Weeks* Group Ethylene Dichloridc (ppm) Animals Set No. ' Tumorst Ependymomas Gliomas Meningiomas Total Average Average Average Average Latency Latency Latency Latency Time Time Time Time Na % (Weeks) No. % (Weeks) No. % (Weeks) No. % (Weeks) 1 250-150 M 90 0 ___ -- F 90 0 -- - M AF 180 0-- -- S2 50 M 90 0 -- F 90 0-- -- M A F 180 0-- -- 3 10 M 90 0 -- F m 0-- -- M A F 180 0-- - 4 5 M 90 0 ___ -- F 90 0 -- M & F 180 0-- -- 5 Controls) M 180 0 -- F 180 3 1.6 100.0 M A F 360 3 0.8 100.0 Total 1,080 0-- 0-- 0-- | 1.1 0 1 0.5 0-- 2 2.2 2 1.1 0-- 0-- 0-- 0-- 0-- 0-- ___ -- -- 155 0 -- 155.0 -_ 94.0 94.0 -- -- -- 0 ___ 0-- 0-- -- -- -- 0 ___ 1 1.1 1 0.5 -- 97.0 97.0 0 -- ` --a 0-- -- 0 -- -- 0 0 0 -- -- -- -- 1 0.5 86.0 1 0.5 112.0 2 0.5 fe 99.0 0-- 0-- 0-- ___ -- -- 1 1.1 1550 1 1.1 970 2 1.1 ' 126.0 0-- 2 22 2 1.1 -- 94.0 94.0 0-- 0-- 0-- 1 0.5 4 2.2 5 1.4 -- -- 86 0 103.0 996 -- t No ncurohljsloniiii were found 4 No Irculmcni. i , f T if * s t IO Ij 6 9 6 3 r MAF 90 IH0 1 10 M 90 F 90 M 4 F 180 4 5 M 90 F 90 M 4 F 180 5 Controls) M 180 F 180 M & F 360 Total ------ - 1,080 * Agr M Urf ihinuU 41 mm 12 cckt * *** Nwi Uiit wtt ft 1 g 4Wvi 0 0-- 0 -a_ 0-- 0-- 0 ___ 0-- 0-- 0 ___ 3 1.6 3 0.8 -- -- -- ___ -- _ 1000 1000 0 1 0.5 I*'0 0 2 2.2 2 l.l 94.0 940 0 0 __ 0-- r__ 0* 0 ___ 0-- -- o1U 1 as -- 97*0 97.0 0-- 0-- 0-- -- -- 0-- 0-- 0-- -- -- l as 86.0 1 as 112.0 2 as 99.0 i l.l 155.0 i l.l 97.0 2 l.l 126.0 0 __ 2 2.2 2 l.l _. 94.0 94.0 0 -_ 0_ 0-- _ ._ -- 1 05 86.0 4 2.2 103.0 5 1.4 99.6 Tim II Tin IwiofNit w gum Tumors Amono Snuuis-Oawuv Rats Exposed r Inhalation to Acrylonitrile in Air at 40, 20, 10, anu 5 ppm, 4 Hours Daily, 5 Days Weekly, por 52 Weeks* Tumor*t Gliomas Meningiomas Tout Group Acrylo- niinle Cone (ppm) Animals ____________ Ses No. Average Latency Time No. % (Weeks) No. Average Latency Time % (Weeks) No. Average Latency Time % (Weeks) i 40 M 30 F 30 M4 F 60 2 20 M 30 F 30 M 4 1 60 3 10 M 30 1- 30 M 4 F 60 4 5 M 30 F 30 M 4 F 60 5 CnntritU} M 10 1 Kl M 4 1 Ml Tula! TtX) 2 6.7 75.5 1 3.3 108.0 3 5.0 86.3 1 3.3 96.0 1 3.3 121.0 2 3.3 108.5 0-- 0-- 0-- -- -- -- 0-- 0-- 0 _ -- -- i) --* 0-- 0-- -- -- -- 0-- 0 0-- -- -- _ 2 6.7 75.5 t 3.3 108.0 3 5.0 86.3 1 3.3 99.0 2 6.7 975 0-- 1 3.3 1210 1 1.7 99.0 3 5.0 1053 0_ _ 0 _ 1 3.3 115.0 1 3.3 II S.0 1 1.7 1150 1 1.7 115.0 0_ 1 3.3 1 1.7 _ 0-- 98.0 1 3.3 98.0 1 1.7 98.0 98.0 1 3.3 134.0 1 3.3 1340 0 0-- - 1 1.7 134.0 1 1.7 134.0 * Age of the animals at start; 12 weeks, t No neuroblastomas or ependymomas were found, t No treatment. O IiI 6964 ^ n&mtmrn ma<*a Tarie 12 Tut Ihcwwi or Brain Tumou Among Seraoue-Dawley Rah Eiiobb ry Inhalation to Styrene in Air at 300, 200, 100, jo, AND 2} rru, 4 Hours Daily, S Dayi Weekly. w* J2 Weeks* Glionut Turnout Meningiomas Total Tf Group Styrene Cone (ppm) Average Lslency Time Ses No. No. % (Weeki) No. Average Lslency Time % (Weeks! No. Average Latency Time % (Weeks) 1 300 M 30 0 _ -- 0 ---- 0 ---- F 30 0 -- 0 ---- 0 ---- MtF 60 0 -- 0-- 0 A-- -- 2 200 M 30 0 -- -- 0 -- 0 --- F 30 0 -- -- 0 ---- 0 *-- Koo MAF 0-- -- 0-- 0-- 3 100 M F 30 0 30 0 _ _ _ A-- 1 3.3 120.0 1 3.3 120.0 3 10.0 112.7 3 too 112.7 M A F 60 0 -- -- 4 t.7 114.3 4 t.7 114.5 4 30 M 30 0 -- 0 ---- 0 ---- F 30 0 -- -- 0-- 0 ---- M AF to 0 -- 0 -- 0-- 3 . 25 M 30 0 _ 1 3.3 132.0 1 F 30 1 3.3 106.0 0 -- -- 1 M A F to I 1.7 106.0 1 1.7 1310 2 3.3 132.0 3.3 106.0 3.3 119.0 6 Conlrolit M F 60 0 to 0 -- -- M A F 120 0 -- -- -- 0 --0 ---- 0 ---- 0 --0 0 ---- Tolol 420 * Ags >4 iN Animal' il VIAll 11 aVi t Nu MwuihlAAlonui 111 rpcnd|in<HilAi lfe found | Nu Iftiiwini OLI 6965 4 5 6 Tout 50 25 Control,} MAF M F MAF M F MAF ,A# 60 50 30 60 30 30 60 M F MAF 60 60 120 420 V 0 0 0 0 0 1 1 0 0 0 _ ___ 33 1.7 _ Iwo 106.0 3 4 0 0 0 I 0 I 0 0 0 too 112.7 4.7 114.5 i 3 4 3.3 1200 10.0 HIT 4.7 114.5 ---- --u. -- -- 0_ 0 --_ 0 __ 33 13X0 1.7 13X0 1 1 2 3.3 132.0 3.3 106.0 3.3 119.0 ---- -- 0 -- __ 0 .-- _ 0 __ * Afi of Ihc animal,al uart: I) wccki t No iwuroblattoma, or ependymoma, were round I No treatment t r c Table 13 The Incidence of Brain Tumor* Amono Sprague-Dawley Rats Exposed by Inhalation TO Propylene in Air at 5,000, 1,000, and 200 ppm, 7 Hours Daily, 5 Days Weekly, for 104 Weeks* Tumorst -- *--- Gliomas Meningiomas Total Group Propylene Cone (ppm) Animat, Set No. Average Latency Time No. % (Weeks) Average Latency Time No. % (Weeks) Average Latency Time No. % (Weeks) 1 5,000 M 120 F 120 MAF 240 2 1.000 M too 1' MR) MAF 200 3 200 M 100 F MX) MAF 2<R> 4 Control,} M 120 F 120 MAF 240 0-- 0-- 0-- 0 00" 0 0-- 0-- 2 1.7 1 0.8 3 1.2 -- -- - -- -- -- --- -- 108.5 88.0 101.7 0-- 0-- 0- 0 1 10 1 0.5 0-- 0-- 0-- 0-- 0-- 0-- -- -- - _ II 1.0 II 1.0 -- "" -- -- - 0_ 0-- -- 0- 0_ 1 1.0 1110 1 0.5 II 1.0 0 0 ... 0- -- 2 1.7 108.5 1 0.8 88.0 3 12 101.7 Total HH0 o * Age of (he animals al start 17 weeks, H t No neuroblastoma* or ependymomas were found. | No treatment. o\ io <T\ o\ I ; l ,iiNrtiwftiiTfrti^rw-n^ i `*n*"* MM Table 14 . # The Incidence of Brain Tumors Among SpraOUE-Dawley Rate Exposed ry Inhalation to Trichlorofluoromethane in Air at 5,000 and 1,000 ppm, 4 Hours Daily, 5 Days Weekly, for 104 Weeks* Tumorst Group Tnchlofofluro* methane Cone (ppm) Animals ----------------------- Sea No. Ependymomas Gliomas Meningiomas Total Average Average Average Average Latency Latency Latency Latency Time Time Time Time No. % (Weeks) No. % | Weeks) No. % (Weeks) No. % (Weeks) 81 5.IKI0 M r 90 0 _ 90 0 -- 0-- 0-- -- 0 2 2.2 90.0 0 -2 2.2 900 M&1 1X0 0-- -- 0-- - 2 l.l 90.0 2 l.l 90.0 2 1.01X1 M 90 0 -- 2 2.2 129.5 1 l.l 720 3 3.3 110.3 F 90 1 LI 103.0 1 1.1 75.0 1 LI XX 0 3 3.3 XX 7 M&F 1X0 1 0.5 103.0 3 1.7 II 1.3 2 l.l X00 6 3.3 99.5 3 Controls! M F M&F 150 150 300 1 0.7 94.0 1 0.7 840 0 -- 0-- ~ 2 1.3 82.5 0 -- 1 0.3 940 3 1.0 83.0 0 -- -- -- 2 1.3 2 13 4 1.3 89.0 82.5 85.7 Total 660 * Age of the animals at start V 1 .1 weeks, t No neuroblastomas were (ouiul t No treatment The same control group is common for the experiments ECU and FCII. O LI 696 2 3 Total r M&F 1,000 M F M Sl F Controls} M F M&F 90 1X0 90 90 180 150 150 300 660 0-- 0-- 0-- 1u 1 0,5 1 0.7 0-- 1 0.3 -- -- 103.0 103.0 94.0 -- 940 -0-- 0- 2 2.2 1 l.l 3 1.7 1 0.7 2 1.3 3 10 -- -- 129.5 75.0 1)1.3 840 *2.5 83.0 0-- 2 2.2 2 1.1 1 l.l 1 l.l 2 l.l 0_ 0. 0_ Age uf ihc animats at start 9 11 N.i neuti>Mjsi..niat weie found N> |h MIM gioup II common for the cipeitmcnls FC12 ami Fell -- 90.0 90.0 720 88.0 80.0 -- -- -- 0_ 2 22 2 II 3 3.3 3 3.3 6 3.3 2 1.3 2 13 4 1.3 90.0 90.0 110.3 88.7 99.5 890 82.5 857 Table IS* The Incidence of Brain Tumors Amono Spradue-Dawley Rats Exposed by Inhalation to Dichuiroohluorcrhethane in Air at 5,000 and 1,000 ppm, 4 Hours Daily, 3 Days Weekly, for 104 Weeks* Group Dichlorortuoro- methane (ppm) Animals Sex No. 1 2 3 Total 5,000 I.IXXI Controls} M 1 M&F M IM&F M F M&F 90 90 180 90 90 180 150 150 300 660 Ependymomas Average Latency Time No. % (Weeks) 0 ___ 0-- 0- 0 0-- 0-- 1 0.7 0-- 1 0.3 _ -- -- -- -- 940 -- 94.0 Tumorsf Gliomas Average Latency Time No. % (Weeks) 1 1.7 1090 l 1.7 970 2 1.7 1 13(1 3 33 1(81.4 1 l.l 90.0 4 22 97.8 1 0.7 2 13 3 1.0 840 82 5 83.0 * Age of the animals ul slarf;9 -13 weeks, t No neuroblastomas or meningiomas were found. ; No treatment. The same control group is common for the experiments FCI2 and FC'I. . Total No. % Average Latency Time (Weeks) 1 1.7 I 1.7 2 1.7 3 33 1 l.l 4 2.2 2 1.3 2 1.3 4 1.3 1090 97(1 1030 1(81.4 900 97.8 89.0 82.5 857 6969 110 sms, MM Table 16 4 The Incidence oe Bbain TiuoAS Among Sprague Dawley Rats Exposed bv Inhalation to Chlokopiploobomethane in Aw at S.000 and 1,000 ppm. 4 Hooks Daily, 5 Days Weekly, km 104 Weeks* Tumoist Epeniiymomo Gliomas Meningioma* Total Group Chloro difluoromethane (ppm* Animals Sen No Avenge 1 atency Time No. % (Weeks) Average Latency Time No % (Weeks) Average Latency Time No % (Weeks) Avenge Latency Time No. `J-li (Weeks) 1 i.uo M 60 0 ,, 2 13 78.5 0-- 2 33 78.5 fci 60 1 1.7 460 0 2 1.3 W5 3 5.0 101 7 M A 1 1:0 1 OK 460 2 1.7 78.5 2 1.7 VV> S 4.2 42 4 2 1.000 M 60 0 0* 1 1.7 124.0 1 1.7 1240 1 60 0 - 0 ... -- 0 --* 0 -- M & 1 120 0- - 0- 1 01 1240 1 OK 1240 J Controls) M 60 0 -- 1 60 0_ -- M A F 120 0- - 0-- 0-- 0-- -- -- 01 17 t 0.8 136.0 1360 0 1 17 1360 1 OK 1360 Total 360 * Age of an.mals at start H week*, t No ncuioHakloinus were found \ No treatment. ----------------- V f r if ilr t i l l I Ir l. n 2 3 Total 1,000 ConlruliJ M F MA F 60 to 120 M F M(F to to 120 260 * Age of animal* at sun: 8 weeks, t No neuroblastomas were found. J No Ireatment. 000-- 0-- 0-- 0~ _ _ _ -- _ -- 1, / /* > ---- " ---- -- " 2 1.7 1 1.7 0 ~~ 1 0.8 01 1.7 1 08 99.J 1240 -- 124.0 -- 1360 IJ6.0 j 42 *2.4 i 1.7 124.0 0 ___ 1 0.8 124.0 0 __ 1 17 1 0.8 1360 1360 Ini iium i m Kaain Iimmi Awimi Hfv I iham i ls<uhuh n \tMi t hi. <** Ou at 50.01. 14.65, .1)1, 10, 0 3, anp 0.03 mc/ku Buoy Wr. Omc Daily. 4 3 Days Wijilly. h 52 M Wilts* Turnout Croup Vinyl Chloride Ingested img/kg body wi) Ependymomas Glioma* Meningiomas Animals No. at Sex Start No. Average Latency Time (Weeks) No. ,, Average Latency Time (Weeks) No. Average Latency Time (Weeks) No Total Average Latency Tune % (Weeks) 1 2 J 4 5 6 7 Total 50.00 M F MF 1665 M F MF 3 33 M F Ml 10 M F Mb 03 M 1 MF 0.0) M F MF Controls^ M F MF 40 40 80 40 40 80 40 40 80 75 75 150 75 75 150 75 75 150 115 115 230 920 00-- 0' 0-- 0-- 0- 1 2.5 0-- 1 II , 1.3 0-- 1 07 0_ 0-- 0- 0 2 27 2 13 i 09 | 09 2 09 -- - -- 92,0 92.0 1150 -- 1150 -- -- 90 5 90.5 1040 87.0 95.5 0_ 0-- 0 -- 0-- 0-- 0- 0-- 0-- 0- 1 13 0-- 1 07 4 5.3 2 2.7 6 4.0 0-- 0-- 0- i 09 2 1.7 3 13 _ - -- - ~ 121.0 -- 121.0 96.7 96.5 96.7 -- -108.0 1142 112.0 0 I 25 1 1.2 1 25 0-- 1 12 0-- 0-- 0" 0-- I 1.3 1 07 0-- 0-- 0- 0-- 0-- 0-- 1 09 1 0,9 2 09 0 590 1 59,0 1 1200 -- 1200 1 0 1 -- 11 -0 1 -2 710 1 710 3 _4 --2 t --o --2 2 76.0 3 92.0 4 840 -- 25 1.2 25 -- 1.2 25 12 2.7 1.3 20 53 2.7 4.0 -- 27 1.3 2.7 3.4 30 - 59.0 590 120.0 -- 120.0 93,0 92 0 imo 710 102 3 967 965 967 -- *05 90.5 960 101.8 993 Ag. i4 tniouli ii ti<i(i 10 llcckt t Ni uciniiNaUiMit.it vtcic I*>un4 J (Kite ml OLI 6970 yfufiaYwttiui i*"* `T i *' ' ' * *v.is Mi* Tabu 18 The Incidence of Bbain Tumou Among Spraque-Dawuv Rato, Exposed by Ingestion to Vinylipcne Chlobide in Ouve Oil at 20, 10,5. 0.5 mg/kg Bogy Wt, Once Daily, 4-5 Days Weekly, lot 52-59 Weeks* Tumorsf " # Vmyhdcnc Chloride Ingested ImgAg body wl| Animals No. *i Su sun Ependymomas Gliomas Meningiomas Total Average Avenge Average Average Latency Latency Latency Latency Time Time Time Time No. % (Weeks) No. % (Weeks) No. % (Weeks) No. % (Weekl) 1 20 M F M&F 2 10 M F M) 2s M 1 MAF 4 OS M F M 2k F 5 Controls} M F MJF Total 50 so 100 so so 100 so so 100 so so 100 >75 175 350 750 0_ 0- 0-- 0 0-- 0-- 1 2.0 0 1 1.0 0 0-- 0-- 0-- 1 06 1 0.3 " 160 -- #6.0 -- -- 87.0 87.0 0_ 0 ... 0-- -- 0 0-- 0-- 0_ 0-- 0- -- -- _ - 1 2.0 0 1 10 80.0 - 800 2 II 109.5 2 l.l 114 2 4 1 1 111.8 0_ 0-- 0-- -- 0-- 0-- 0-- -- 1 2.0 1110 0 -- 1 10 1110 1 2.0 II 1.0 0 " I 1.0 II 1.0 1 2.0 1 20 2 20 121.0 IIH0 INS 2 40 103 5 1 20 into 3 30 ions 0 0 0- 1 20 0 1 10 no #0 2 l.l 1130 4 2.3 1112 4 23 iao.s 7 40 102 5 6 17 1047 ii 31 lOS.g * Age of .iniffltib .il tiarl: 9 10 vii'ek^ No ncuiohUMontJi were found J OllVC Oil O L I 6973. ' * S Tail *M F M* F 0.5 M F MAF Control*} M F Mtr 30 50 100 50 50 100 175 175 350 750 * A(C ofanimal* *1 sun: 9-10 week* No ncurohlmoaMi were found } Olive oil 1 20 0 1 1.0 0 0 0-- 0 1 0.6 1 0.3 1_60 860 -- 87.0 87.0 ---- -- -- 2.0 #00 -- 1.0 <0.0 II 109.5 l.l 114.2 II 111.8 1 2.0 1210 1 2.0 111.0 2 2.0 119.5 0_ - 0-- 0-- 2 1 1 113.0 4 23 100.5 6 1.7 104.7 < l-U 1(1.0 2 4.0 103.5 1 2.0 1)8.0 3 3.0 I0< 3 1 2.0 01 to g.O -- <0 4 23 7 4.0 II 3.1 1112 102.5 I0S.S Tail* 19 Tut Incidence or Brain Tumor* Amono Sfraoue-Dawlev Rata ExKmep y Inciextion to Acryumiwuli in Olive Oil at 5 mo/ko Bout Wt, 3 Time* Weekly tor 52 Week* Group* Acfylonilrile Dote (mg/kg body wt) Animal* -------- ----------- No. at Sea Start l 5 M 40 F 40 M AF <0 2 Control*) M 75 F 75 M AF 150 Total 230 rbiem = = .= ---------- =.-~ ---- Age ol the animal* at Hart: 10 week*, t No ncoroMatlomat were found. } Olive oil. Ependymoma* Glioma* Turnout Meningioma* Toial Average Average Average Average Latency Latency Latency Latency Time Time Time Time No. % tWeck*) No. % (Week*) No. % (Week*) No. X (Week*) 0 ___ 0-- 0-- _0 0___ ___ ___ ___ -- 1 2.5 430 0 - 1 1.3 430 0 0-- - -- 1 H 430 -- I 1.3 43.0 0-- -- 1 1.3 logo 1 1.3 76.0 2 27 920 1 1.3 <7.0 2 2.7 1142 1 1.3 920 4 5.3 1017 1 0.7 <7.0 3 . 2.0 112.0 2 1.3 <4.0 6 40 ) o> VO -o (O i 1 'i r- 2 i . N*> T*u 20 The Incidence of Brain Tumors Among Sprague-Dawley Rate, Exposed ry Ingestion to Styrene in Olive Oil at 2SO and SO mg/kg Body Wt. Once Daily, 4-S Days Weekly for 52 Weeks* Tumorsf Group Styrene Dose Ingested Ung/lg body wt) Ependymomas Gliomas Meningiomas Total Animals Average Latency Average Latency Average Latency Average Latency No. at Time Time Time Time Sex Sturt No. % (Weeks) No. % (Weeks) No. % (Weeks) No. % (Weeks) 1 250 M 40 0 0 1 2.5 90/: 1 2.5 900 ts Qs F 40 0 -- - 0-- -- 1 2.5 10.10 1 2.5 1010 M * F HO 0 -- 0-- 2 2.5 9li5 2 25 965 2 SO M 40 0 -- 1 2.5 106.0 0 -- - 1 2.5 1060 F 40 1 2.S 82.0 0 -- -- 3 7.5 l32/ 4 10.0 1195 M 2k F HO 1 1.2 82.0 1 1.2 106.0 3 3.7 1321 5 6.2 116 8 3 Controls^ M 40 0 -- -- 0-- -- 0-- - F 40 1 2.5 96.0 0 -- 0-- M & F 80 1 1.2 96.0 0 -' 0 -- -- 0-- 1 25 1 1.2 960 96.0 Total 240 * Age of Ihe animals al start: 13 weeks, f No neuroblaslomas were round ; Olive oil. OII 6973 91^ Q vi oe O O ^o ;og* 2i 2i * I1 os <ost. <WNi <--N ;s (Ss iii <' <PN fI <-: r*ri [IIiIi * f*t O n n OOO 1 1 iM I S I2 M i -- O -- OOO PP J oo SS i * ?g 3 * Sto St 552 (2 Controls} -3 o fi _3 3u *W (3 o6 E c jg -s *1- i I! g,o <20 -A-: MM Maltoni ec a/.: Experimental Contributions 237 Table 21 The Incidence of Brain Tumors Among Sprague-Dawley Rats, Exposed by Ingestion to Styrene Oxide in Olive Oil at 250 and 50 mg kg Body Wt, Once Daily, 4-5 Days Weekly, for 52 Weeks* * Group Styrene Oxide Dose (mg/kg body wti Animals No. at Sex Start Meningiomast Average Latency Time No. % (Weeks) i 250 M 4ri 0 --- * F 40 2 5.0 129.5 MAF SC 2 23 129.5 2 50 M 40 1 15 107.0 F 40 l 15 126.0 ! MAF SO 2 15 116.0 3 Controls} M F MAF 40 1 . IS 40 0 -- SO I 1.3 S1.0 -- 81.0 Total 240 * Age of the animals at start: 13 weeks, t No neuroblastomas, ependymomas, or gliomas were found. } Olive oil. Plan of the Studies: Materials and Methods The incidence of brain tumors has been systematically studied in our Labora tory for the following: 1. untreated rats I Sprague-Dawley and Wislari; 2. rats (Sprague-Dawleyl treated with virgin olive oil which is the vehicle used for (he ingestion fgavage) experiments: 3. rats (Sprague-Dawley and. in ihe case of vinyl chloride, also WislarL treated by inhalation at ditfetent doses (and, in the case of vinyl chloride, also for different limes and with different schedulesl with: i A. vinyl chloride. B. vinylidene chloride: C. ethylene dichlonde, D. acrylonitrile. E. styrene. F. propylene, G. trichlorofluoromethane(FC UL H. dichlorodifluoromethanelFC 12L I. chtorodiRuoromeihanelFC 22): 4. rats (Sprague-DawleyI. treated by ingestion at different doses with: A. vinyl chloride. 8. vinylidene chloride. C. acrylonitrile. 1 t 1 OLI 6974 J. iT \ 238 Annals New York Academy of Sciences 0. styrene, E. styrene-oxide. F. vinjlidene fluonde, G. trichloroethylene, H benzene, 1. 'asbestos (Crocydolitet, J. polyvinyl chloride (PVC). All the supplies of the compounds used were examined in order to determine whether they meet the required standards. The concentrations, when the compound was administered by inhalation, were controlled by continuous gas chromatographic monitoring.. Treatment was always performed by the same people. This is particularly im portant for gavage, since the animals become accustomed to the same operator. The animal breeds have been routinely employed in our Laboratory for many years. It should be pointed out that, whatever their use. all the animals of our colony undergo periodic examination and complete autopsy, giving us extensive infor mation concerning their pathology. The age of the animals in the experiments considered in this report, at the start of treatment, varied from II to 16 weeks. The animals were kept alive until spontaneous death. Every two weeks, they were submitted to an examination for the detection of any gross changes. Full autopsy was performed on each animal. Ai! the different parts of the body were explored, and specimens for histology were taken from all major organs and any other organ with pathological lesions. As far as the brain was concerned, careful gross examination was made, and all lesions, either superficial or discovered bv dissecting the organ (after fixation) were measured and described. The brain was always trimmed in a standard way. and sections were routinely stained with hematoxylin-eosin and, when necessary, with special techniques. The criteria for histopathological characterization and classification of brain tumors were kept standard for all the experiments. The observed tumors were grouped in four major categories: neuroblastomas (similar to the human medulloblastomas), ependymomas, gliomas, and meningi omas. Gliomas and meningiomas in the original records were also subclassified ac cording to histotype. The distribution of the different histotypies in those two cate gories of tumors, however, did not seem to be relevant. Most of the gliomas are oligode nd rogliomas. Results* The incidence and the latency time of brain tumors among 2,796 SpragueDawley and 170 Wistar untreated rats in our colony, and among 630 SpragueDawley rats following long-term treatment with olive oil, by gavage, are given in Tables 3 & 4. respectively. The incidence of these tumors appears to be higher in Wistar rats (whose number, however, is lower). The treatment with olive oil does not appear to affect the onset of brain tumors. Tables 5-t6 give the results of the experiments studying the effects of the exposure by inhalation to the following: vinyl chloride (Tables 5-8), vtnvlidene * The incidence of the tumors is referred to the total number of animats at stan: the time of latency as age of the tumor-beanng animals. OLI 6975 * t0UI number of animal! at start; the time -- 3. 8.3 o-- 28 3. 5 8-k ^c H S' 5: ,yi aa0O A <f *: CAl n"* 3? ^O Iy SS-OQ* si a 2^ PI' 13 I2 o^ p J. 5x 5 co "* cr "si- *! f J2".#3') o! S'as p3 3O 2 55" Ol/l' fs--fIl S t'aan<o? m-ov"oIjn(TV^n3i 3-SS i4 O o U. sr|t .9aftsesc*fe-8S S'S'* 3 5-3-1 - 3 " s "- s. -I Jva 2.38 W3? 2 JT iC/iL r* K' ^ ssai 3l ?s 3-g.S :fs: i'll *8a 3 SR #9 ^ 31 aa.;s ?o'* i . go 3 og'i5s |a5- ^K Ef => 2," (3U 3-B Cnl ,,c Zo-2 3n-S3 gr-> *s 5_ oo,,naO. 38 a!5*c2n oaP-SS.i**?0 gS8-.32? QI?.Z ? gli^teas^l 3- </ ^s3a as3 oc^-Ir BA ET 2.o 32 *6 fpS-B fi-s 3a" .' 3e oir a` 25 A 52 S|!E -g s g{a/> =gmasoJsS '3SS0< O0< 3Adnq-0\ *"0* 1 A 4 P 3" w 382 <? ? ?ea.l * r 4 I S s-t i g 3 s ^ ft 5 9 o w 2o 1p *a< 3? u** s2' |as ^ as-a^a-f ? J ICT. o p o 3 " < 5- 00 fi r- " 32T* | g- S _ "g53a 2 cr S o P ff o Ort 3 w3 OTO^ a n 5 c r-H E A * 3 o p " a O* _3. sr sPr 5r2C. t3 --< ? ,2 .2 3 s p 3 ! o' o ao ** ro. "Ai 3 (X y o if OA3 8 fcj O t* H o\ \o -O C\ Table 22 The Incidence or Brain Tumors Among Smlagub-Dawley Rats, Exposed by Ingestion to Vinyudenb Fluoride in Olive Oil at 8.25 and 4.12 mg/kg Body Wt, Once Daily, 4-5 Days Weekly, for 52 Weeks * Group Vmylidcne Fluoride Dose (mg/kg body wt) Animal! No. at Sex Start 1 2 3 Total 8.23 4.12 Control! M F M&F M F MiF M F MAF 35 35 70 30 30 60 30 30 60 190 Ependymomas Average Latency Time No. % (Weeks) 1 2.8 1130 0-- -- 1 1.4 1130 0 ___ 0-- 0-- -- -- -- 0-- 0-- 0-- -- -- -- Turnout Gliomas Meningiomas Average Latency Time No. /. (Weeks) Average Latency Time No % (Weeks) 0-- 0-- 0-- 0 1 3.3 1 1.7 1 3.3 0-- 1 1.7 _ -- -- -- 116.0 116.0 87.0 -- 87.0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0-- -- -- ~ -- -- -- -- -- -- Total Average Latency Time No. % (Weeks) 1 2.8 0-- 1 1.4 0 1 3.3 1 1.7 1 3.3 0-- * 1.7 113.0 " 1130 -- 116.0 116.0 87.0 87.0 * Age or the animats al start: 13 weeks, t No neuroblastomas were found. ; \ < ; * > -lM J'j t W W r jW Pi 1 * 'm i ij m m w m Table 23 The Incidence of Bbain Tumors Among Sprague-Dawixy Rais Exposed by Ingestion to Tkichlokoethylene in Olive Oil at 250 and 50 mo/ko Body Wt, Once Daily, 4-6 Days Weekly, tor 52 Weeks* Group , 2 3 Total Trichloro ethylene Dose (mg/kg body wt) 250 50 Controls^ Animals No. at Scs Start M F MAF M F MAF M F MAF 30 30 60 30 30 60 30 30 60 180 Gliomas Average Latency Time No. % (Weeks) 0 ---- 0 ---- 0-- 1 3.3 100.0 0 ---- 1 1.7 1000 1 3.3 87.0 0 ---- l 1.7 87.0 Tumorst Meningiomas Average Latency Time No, % (Weeks) 0-- 0 ---- 0 ---- 0 ---- 1 3.3 108.0 1 1.7 108.0 0 ---- 0 ---- 0 ---- Total Average Latency Time No. % (Wccksl 0 ---- 0 ---- 0 1 3.3 100.0 1 3.3 1080 2 3.3 104.0 1 3.3 0 . --1 1.7 87.0 -- 87.0 * Age of the animals at slurI: 13 weeks, t No neuroblastomas and ependymomas were found. { Olive oil. 'j^ i " i h OLI 6977 * i Total <H Citniiiiui M* I M I M A I' M ! MAP Ml HI III Ml .Ml 30 AO 180 II 1 11 IIMIII II 1 1.7 urn ii 1 3,3 87.0 0 ---- 1 1.7 87.0 * Age of the animals n start: 13 weeks, t No neuroblastomas and ependymomas were found t Olive oil. i < i Iihiii I U Him ii 0 0---- 0---- (i H 1 11 imiti 1 4 1 III* II i It IlMH 1 3.3 *7.0 0 1 1.7 87.0 Table 24 The Incidence of Brain Tumors Among Sfrague-Dawley Rats Exposed by Ingestion to Benzene in Olive Oil AT 250 AND 30 MG/KG BODY WT ONCE DAILY, 4-5 PAYS WEEKLY, FOR i2 WEEKS*___________ ^ Tumorst* Group Benzene Dose (mg/kg body wt) Animals No. at Sex Slarl Gliomas Average Latency Time No. % (Weeks) Meningiomas Average Latency Time No. % (Weeks) Total No.' % Average Latency Time (Weeks) 1 2 3 Total 230 M F MAP 30 M F MAP Controls} M |* MAP 35 35 70 30 30 60 30 30 60 190 i 2.8 0-- 1 1.4 0-- 0-- 0-- 1 3.3 0-- 1 1.7 157.0 157.0 -- 87.0 -- 87.0 0-- -- 1 2.8 123.0 1 1.4 123.0 1 3.3 0-- 1 1.7 1 50 115.0 0 -0-- 0-- -- - 1 2.8 1 2.8 2 2.8 157.0 123.0 1400 1 3.3 115.0 0-- 1 1.7 1150 1 3.3 0" 1 1.7 87.0 87,0 * Age of the animals at star1: 13 weeks, t No neuroblastomas or ependymomas were found. { Olive oil. OLI 6978 -<' .V>.- */**,, Table 25 # The Incidence of Brain Tumors Among SpraGue-Dawley Rats Exposed by Ingestion to 2 mg of Asbestos (Crocydoute) in Olive Oil, Once Every Two Weeks, for 52 Weeks* Ependymomas Group Animals Average Latency No. al Time Sex Start No. % (Weeks) HI 2 mg M Ashcsios F (Crocy- M & F iloltlu) (2) Controls M (olrvc F oil) M&F 40 40 BO 75 75 150 0_ 0-- 0 0-- 1 1.3 1 0.7 _ -- -- S7.0 87.0 Total 230 Turnout Gliomas Meningiomas Average Latency Time No. % (Weeks) 0_ 0 -- 0-- -- -- Average Latency Time No. */. (Weeks) 0_ 0-- 0 -- 1 1.3 108,0 2 2.7 114.2 3 2.0 112.0 1 1.3 760 1 1.3 92.0 2 1.3 84.0 Total Average Latency Time No. (Weeks) 0_ 0-- 0-- _ -- --` 2 2.7 92.0 4 5.3 101.7 6 4.0 98.5 * Age of ihc animals ai sun: 10 weeks, t No neuroblastomas were found. O LI 6979 II) 2 mg M Arbeslos F (Crocy. MAF dolitc) 40 40 80 (2) Controls M (olive F oil) M A F 75 75 ISO Total 230 0 0-- 0-- 0 ___ 1 13 1 0.7 __ ___ -- ___ 87.0 870 * Age of the animili at siart: 10 weeks, t No neuroblastomas were found. 0-- -- 0 --. -- 0 1 1.3 108.0 2 2.7 114.2 3 2.0 112.0 0-- 0-- 0-- -- -- -- 1 13 76.0 1 13 92.0 2 1,3 84.0 0 ___ 0-- 0-- -- -- 2 2.7 92.0 4 5.3 101.7 6 4.0 98.5 Table 26 The Incidence or Brain Tumors Among Sprague-Dawley Rats, Exposed by Ingestion to Polyvinyl Chloride (2 mg in Olive Oil), Once Every Two Weeks for 52 Weeks * Group PVC Dose Animals No. at Sex Start Ependymomas Average Latency Time No. % (Weeks) Tumorat Gliomas Meningiomas Average Latency Time No. % (Weeks) Average Latency Time No % (Weeks) Total Average Latency Time No. % (Weeks) 1 2 3 Total 2 mg (suspension) 2 mg (emulsion) Controls} M F M 2k F M F M&F M F MAF 20 20 40 20 20 40 75 75 150 230 0 0-- 0-- 0-- 0 0-- 0 l 1.3 1 0.7 -- -- -- -- -- -- 87.0 87.0 0-- 0-- 0-- 0-- 0-- 0 -- -- -- -- -- 1 1.3 1080 2 2.7 114.2 3 2.0 112.0 0-- 0 0 0 0 -0-- 1 1.3 1 1.3 2 1.3 ... -- -- -- -- *-- 76.0 92.0 84.0 0-- 0 0-- 0-- 0-- 0-- 2 2.7 4 5.3 6 4.0 -- -- -- -- 920 101.7 98.5 0 * Age of the animals at slarl: 10 weeks, t No neuroblastomas were found. H { Olive oil- 01 to 00 o i c, rigVfc A ........... - - ^ niriJiuLnfim a <i 244 Annals New York Academy of Sciences Tasle 27 The Incidence of Neuroblastoma is Spragle-Dawley Rats is ReLaiios to CONCENTRATION OF VlNYL CHLORIDE ADMINtSTERED BT ISKALATIOS.FOR 52 WEEKS Experiments Vinyl Chloride (ppm) BT 6 BT1 BT 2 BT 1, BT 9 BT IS Controls BT 1, BT 2, BT 9, BT IS 30.000 10,000 6,000 2JOO 500 250 200 ISO 100 50 23 10 3 l 0 % Animals with Neuroblastoma M FT 3J --- 1.7 6.7 16.7 11.7 6.9 3.3 XI 6.7 6.7 6.7 -- ---- ---- -- ---- -- ---- -- ---- ---- -- ---- -- ---- -- ---- -- ---- chloride (Table 91, ethylene dichloride (Table 10), acrylonitrile (Table 11). styrene (Table 12), propylene (Table 13V, tnchlorofluoro methane (Table 14), diehiorodifluoromethane (Table 15), and chlorodifluoromethane) Table 16). Under our experimental conditions, only two of the above-listed compounds, given by inhalation, appear to produce brain tumors, namely vinyl chloride and acrylonitrile. Vinyl chloride appears to produce neuroblastomas both in Sprague-Dawley and Wistar rats, at a concentration of 30,000. 10.000, 6,000, and 2,500 ppm, when given for 52 weeks, 17 weeks, or less. Acrylonitrile produces an increase in the incidence of gliomas (oli godendrogliomas) at 40 and 20 ppm. Tables 17-26 present the results of the experiments studying the effects of the exposure by ingestion to the following: vinyl chloride (Table 17), vinylidene chloride (Table 18), acrylonitrile (Table 19). styrene (Table 20), styrene oxide (Table 21). vinylidene fluoride (Table 22), trichloroethylene iTable 23), benzene (Table 24). asbestos (Crocydolite)(Table 25). and polyvinyl chloride (Table 26), Under our experimental conditions none of the above-mentioned compounds, given by ingestion, seemed to produce brain tumors. idcmy of Sciences 27 raGUE-Dawley Rats in Relation to mstered *y Inhalation, for 52 Weeks % Animals with Neuroblastoma M FT 3.3 -- 1.7 6.7 167 11.7 69 3J 5.1 67 67 67 -- ---- -- ---- _-- -- -- ---- -- ---- ---- _-- -- -- ---- -- ---- -- ---- ---- I i | T % j ! 1 i -E 10), acrylonitrile (Table 11), styrene luoromethane (Table 14), dichlorodimethane (Table 16). y two of the above-listed compounds, m tumors, namely vinyl chloride and roblastomas both in Sprague-Dawley X 10.000, 6,000, and 2,500 ppm, when 16# incidence of gliomas (oli- txperiments studying the effects of the hloride (Table 17), vinyIidene chloride (Table 20), styrene oxide (Table 21L (Table 23), benzene (Table 24), yl chloride (Table 26). f ( bove-mentioned compounds, wnors. | , ; Maltoni et ai: Experimental Contributions 245 Conclusions and Discussion In the reported experiments, two compounds, vinyl chloride and acrylonitrile, appeared to cause brain tumors, neuroblastomas and gliomas (oligodendrogliomas), respectively, when given by inhalation. Such an effect is not seen with vinyl chloride at 500 ppm and below (Table 27) and with acrylonitrile at 10 ppm and below. In Table^28 and 29 the overall incidence of brain tumors (different types and totals) in Sprague-Dawley rats following exposure, respectively, by inhalation and ingestion to different industrial compounds, without taking into account con centrations and duration and schedule of treatment, is presented. From Table 28 it appears that when the level of dose and the type of tumor are not considered, the incidence of brain tumors may be "lowered" to borderline levels. Such an "artifact" finding, in our opinion, is extremely important, and it stresses the point that, in epidemiological investigations tn humans, reference must always be made to defined types of tumors and to groups of individuals with the same level of exposure (homogeneous groups). Our research in the field of carcinogenesis is now being extended to other ' industrial compounds. Furthermore, in consideration of the higher responsiveness of embryos and newborn animals, we are now testing a series of compounds (including some of the ones considered in this report), by treating the breeders from the 12th day of pregnancy, and continuing the exposure of offsprings up to adult age. References 1. Mancuso, T. F., E. M. Mac Farlane & J. D. Porterfield. 1955. The distribution of cancer mortality in Ohio. Am. J. PubL Health 45 (It 2. Mancuso. T. F. 1963. Tumors of the central nervous system. Industrial considerations. Act* Unio. Int. Contra. Cancrum 19:488-489. 3. Mancuso, T. F,, A. Ctocco & A. A. El-Attar. 1968. An epidemiological approach to the rubber industry. A study based on departmental experience; 1. Occup. Med. 10:213-231 A Mancuso. T. F. 1975. Epidemiological investigations of occupational cancers in the rubber industry, in The New Multinational Health Hazards. C. Levinson, Ed, pp. 80-136.1CF. 5. Maltoni, C,, G. Lefemine, P. Chieco & D. CarrEm. 1974. La cancerogenesi ambiemale e professionale: nuove prospective alia luce della cancerogenesi da cloruro di vinile. Gli Ospedali della Vita i :4-66. 6. Wagoner, J. K. 1974. Statement before the Subcommittee on the Environment of the US. Senate Commerce Committee. 7. Kuschner, M,, S. Laskin. R. T. Drew, V. Cappiello & N. Nelson. 1975. The inhalation carcinogenicity of alpha halo-ether 3. Life-time and limited period inhalation study with bis (chloromethyl) ether at 0.1 ppm. Arch. Environ. Health 30:73-77. 8. Maltonl C. & G. Lefemine. 1975. Carcinogenicity bioassays of vinyl chloride: Current results. Ann. N.Y. Acad. So. 246:195-218. 9. Maltonl C. 1977. Vinyl chloride carcinogenicity: An experimental model for car cinogenesis studies. In Origins of Human Cancer, pp. 119-146. Cold Spring Harbor Laboratory, N.Y. 10. Maltonl C, A. Ciliberti & V. Di Maio. 1977. Carcinogenicity bioassays on rats of acrylonitrile administered by inhalation and by ingestion. La Medibna dd Lavoro 60:401-411. 1L U.S. Department of Labor. 1978. Occupational exposure to acrylonitrile (vinyl cyanklL Proposed standard and notice of hearing Fed Regisl. 432586-2621. OLI 6982 ;<* Tabu IS Oveaall iNciDeNCi or Baain Tumoa* in Siaou-Oawlsy Rats. Foilowino thb Exraune bv Inhalation to Outwent Industalal CONFOUNDS Agent Vinyl chloride Vinylidcnc chloride Dichloroethane Acrylo* nitrile miuiuis No. at Sex Start M 7K0 F 780 MF 1,560 M 180 I- ISO MF 360 M 360 F 360 MF 720 M 120 F 120 MF 240 Tumor* Neuroblastoma* Ependymoma* Glioma* Meningioma* Total Average Average Average Average Average Latency latency latency Latency Latency Time Time Time Time Time No. % (Weeks) No. % (Weeks) No. % (Weeks) No. % (Week*) No. % (weeks) 7 0.9 S 1.0 15 1.0 0 0 0 ___ 0-- 0-- 0-- 0 ___ 0-- 0-- 77.0 74.1 75.5 ___ -- ___ -- -- -- ___ -- -- 1 0.1 2 0.2 3 0.2 0 -----1 0.5 1 0.3 0-- 0-- 0-- 0-- 0-- 0 --- 1230 995 107.3 95.0 95.0 -- -- " -- -- -- 6 OS 4 0.5 10 0.6 2 l.l 1 0.5 3 0.8 1 03 2 0.5 3 0.4 3 2.5 2 1.7 5 2.1 104 7 104.7 104.4 II 1.0 840 102.0 155.0 94.0 114.3 82.3 114.5 95.2 2 02 3 04 5 0.3 1 05 2 II 3 0.8 0-- 1 0.3 1 0.1 1 0.8 2 1.7 3 '? 113.0 89.7 99.0 127.0 116.0 119.7 -- 97.0 97.0 99.0 106.0 104 0 16 2.0 17 2.2 33 2.1 3 1.7 4 2.2 7 1.9 1 03 3 0.8 4 0.5 4 3.3 4 3.3 8 1.3 94.7 86.9 90.7 116 3 102.7 108.6 1550 95.0 110.0 86.5 II0S 98 5 i I L 6 9 8 3 OLI 6984 Vinyl ' bride Vinylidenc chloride Dichloroclh*ne Acrylo nitrile 0 0 0 0 0 0 1 0.S 2 It 3 0.8 0-- 1 03 1 01 1 08 2 1.7 3 1.2 127.0 116.0 119.7 -- 97.0 97.0 99.0 106.0 104.0 3 1.7 4 2.2 7 1.9 1 0.3 3 0.8 4 0,5 4 3.3 4 3.3 3.3 116.3 102.7 108.6 155.0 95.0 110.0 86.5 110.5 98 5 Styrene M 150 F ISO MF 300 0-- 0-- 0-- -- -- -- Propylene M F MF 320 320 640 0-- 0-- 0-- -- -- Trichlorofluoromcihene M F MF 180 >80 360 0-- 0-- 0-- -- -- -- Dtthlorodifluoromclhane M F MF 180 180 360 0-- 0-- 0-- -- -- -- Chloroa diOuoro$ muthiine M F MF 120 120 240 0-- 0-- 0-- -- -- ConiroU M 1.3X4 0-- -- F 1,412 . 0 -- * MF 2,796 0-- -- 0-- 0-- 0-- 0-- 0-- 0-- 0-- l 0.5 1 0,3 0-- 0 0-- 0-- 1 0.8 1 0.4 3 02 4 0.3 7 0.2 *-- ._ -- _ __ -- ..... 103.0 103.0 _ _ -- ,, 96.0 96.0 95.0 105.5 101.0 0_ 1 07 1 03 0. 0 0-- 2 1.1 1 05 3 0.8 4 2.2 2 l.l 6 1.7 2 1.7 0-- 2 08 13 0.9 8 0.6 21 07 ,, 106.0 1060 _ -- -- 129.5 750 111.3 102.5 93.5 99.5 78.5 78.5 118.5 813 104.3 2 13 3 20 5 1.7 0_ 1 0.3 l Ol 1 0.5 3 1.7 4 1.1 0_ 0-- 0-- l 0.8 2 1.7 3 1.2 10 07 9 0.6 19 07 1260 112.7 118.0 -- 1110 111.0 72.0 89.3 850 -- -- -- 124.0 99.5 107.7 96.6 117.1 106.3 2 1.3 4 17 6 10 0-- I* 0.3 1 0.1 3 1.7 5 2.8 8 12 4 12 2 l.l 6 1.7 3 2.5 3 2.5 6 2.5 26 1.9 21 1.5 47 1.7 1260 1110 116.0 -- 111.0 111.0 1103 89.2 97.1 1025 93.5 99.5 93.7 98.1 960 107.4 101 3 104.6 1 iv * f ) \ ) ffcinatourciiiifi l jirflli'iif nr i I t S i*S\'b U . yf' i * , r -, vm4*m*mm*mmm***im*mm*m 1* i . ^ ' 9. 'J 4, iiliwiRiRR Rriin o H V0 00 U1 * Tabu 29 Overall Inodencb or Bilain Tumors in Sfraoue-Dawlsv Rats Following Exposure av Inorstion to Dutkrent Industrial Comnunw Agent Turnon* Ependymomas Gliomas Meningiomas Total Animali Average Latency Average Latency Average latency Average Latency No. at Time Time Time Time Sex Stan No. % (Weeks) No. % (Weeks) No. % (Weeks) No. % (Weeks) Vinyl chloride Vinylidene chloride Acrylonitrile Styrene M F MiF M F Mi F M F M&F M F MAF MS MS 690 200 200 400 40 40 80 80 80 too 2 0.6 2 0.6 4 0.6 1 0.S 0-- 1 0.2 0-- 0-- 0-- 0 1 12 1 06 103 5 90S 97.0 86.0 -- 86.0 -- -- -- 82.0 82.0 S 1.4 101.6 2 0.6 96.5 7 1.0 loot 1 0.5 0-- 1 0.2 80.0 -- 80.0 0-- l 2.5 1 13 -- 430 430 1 1.2 106.0 0 -- -1 0.6 1060 1 0.3 2 0.6 3 04 120.0 65.0 83.3 8 2.1 6 1.7 14 2.0 104.4 84.0 95.6 2 1.0 116.0 4 2.0 1 OS 118.0 1 0.S 3 07 116.7 . J 1.2 0-- -- 0 --* 0 --. -- 0-- 1 2.5 1 13 99.5 118.0 103.2 -- 43.0 43.0 1 1.2 90.0 4 3.0 124.7 S 3.1 117.8 2 2.5 3 6.2 7 44 98.0 116.2 111.0 . OLI 6986 MV* Vinyl chloride M F MAF Vinylidene chloride M F MA F Acrylonitrile M F MAF Styrene M F MAF .1MII 345 34$ 690 200 200 400 40 40 80 80 80 160 no. % (Wecki) No. % (Week!) No. $6 (Wecki) No. % (Weeks) 2 0.6 2 0.6 4 0.6 1 0.S 0-- 1 0.2 0 ___ 0-- 0 -- 0 ___ 1 1.2 1 0.6 103.$ 90.5 97.0 86.0 ___ 86.0 _ ____ -- -- 82.0 82.0 $ 1.4 1 2 0.6 7 1.0 100.1 1 0.S 0-- 1 0.2 800 -- 80.0 0-- 1 2,5 1 1.3 ___ 43.0 43.0 1 1.2 106.0 0-- -- 1 0.6 106.0 1 03 2 06 3 04 120.0 65.0 83.3 2 1.0 116.0 1 OS 118.0 3 07 116.7 0 __ -- 0 ___ 0-- -- 1 1.2 90.0 4 5.0 124.7 $ 3.1 117.8 8 2-3 6 1.7 14 10 104.4 84.0 95.6 4 2.0 1 0.5 5 1.2 99.5 118,0 103.2 0 1 2.5 1 1.3 43.0 43.0 2 2.5 5 62 7 44 98.0 116 2 1110 Stymie oxide M F MAF 80 80 160 ___ ___ __ ---- 0 ___ 0_ 0-- ___ -- 1 1.2 107.0 3 3.7 128.3 4 IS 123.0 1 1.2 3 3.7 4 2.5 107.0 128.3 123.0 Vinylidene fluoride Trichloro ethylene M F MAF M F MAF 65 65 130 60 60 120 1.5 0.8 o_ o 0-- 113.0 ___ 113.0 . _ -- 0_ 1 1.5 116.0 1 0.8 1160 , 1.7 100.0 0 ___ ___ 1 00 1000 0 ___ 0-- 0-- 0 ___ 1 1.7 l 0.8 -- ~ -- -- 1080 108.0 1 1.5 1 1.5 2 1.5 l 1.7 1 1.7 2 1.7 SI 30 1160 114.5 100.0 108.0 104.0 Benzene M F MAF 65 65 130 0 0 ___ 0-- ___ ___ 1 1.5 1570 0 ___ ___ 1 08 157.0 1 1.5 115.0 1 1.5 123.0 2 1.5 119.0 2 3.1 1 1.5 3 2.3 136.0 123.0 131.7 Asbestos M 40 0 -- 0-- --0 I (Crocydolite) F 40 0 -- MAF 80 ---- 0-- 0-- -- 0-- -- -- 0 0 -- Polyvinyl chloride M F MAF 40 40 80 .. _ ---- 0_ 0-- 0-- -- -- 0-- 0-- 0-- -- -- -- 0-- 0-- 0-- -- -- -- COnlrolxt M F MAF 325 325 650 0.3 104.0 0.6 91.5 0.5 95.7 3 0.9 2 0.6 5' 08 1020 114.2 106.9 3 0.9 4 1.2 7 l.l 102.1 100.2 101.1 7 2.1 8 13 15 13 102.4 101.5 101.9 * No neuroblastoma* were found, t Olive oil )