Document 6BqjVLQ1Q0bdBvmyEvoBDB1Z6

R&S 105872 BIO-MEDICAL RESEARCH DOCUMENT DESCRIPTION FORM 63 68 6 76 Duplicate in all cards: --} /9J>& year as-1961- File number [Right justify [Numeric only) Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space 1 ____ i 20 21 /? > v/v- , /' A 40 41 77 78 r"^ Sub-Index Code 60 61 62 11 12 13 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms, separated from each other with comma-space. Avoid other punctuation; do not abbreviate. ,,,, 1.. _ _ .. 0 1 /CvLahlt 'jJ 'S ' " ----------------- ' o of1 c _1 /:?/* .. 21 22 " 23 24 Source (Journal, Vol., Number, Pages, Date ) 12 <x rVJ 1 ,1 did v /977 ~D ---------- r--------- y ---------------------------------- 61 62 31 32 Brief Summary 12 10 SUMMARY: 61 62 61 62 63 64 ui wfj^ai tuuir^at 0000023 WU4y 4.<ct i * ; * 1 Dow researcji shows way oat he waits to see better evidence that it is a carcinogen. This lack of correlation with anim.d t? of chemical carcinogen problems results he suspects, despite the common suggestion that humans don't neces that chemical companies' worldwide are urgently researching short-term toxico ugy tests (such as rhat developed by Br-^e Ames of California Univer sity) indicates rhe significance of the "chemical carcinogen problem" and partly reflects the requirements cf legis lation coming into force in the US and be:ng formulated in Europe. Although still at an early stage of development the .ests are already being incorporated info new legislation (such as the UK Health and Safety Com mission's notif.^ation scheme) as a means of quickly screening compounds and as an indicator of v-hether animal tests should be carried out. ' The techniques will oe the major topic of ducuision at an industrial toxicology con erence being held at Surre. University next week, but they are u-deed only short-ferm and not entirely rebate indicators as to whetb : a chemical is lively to be a carcinogen, however de-arable a sub- .'.ute they may be tor' long-term .eeuii , naiv One of tho-ie who hold reservations about the tre; ce of ;.~ = ve techniques and .i.e . s. re con^ rned with the broaosf problem of how to deal wild carcinogen., or,., mev h..ve been identi fied ,. Dow\ head ot toxicological research Perrv Gearing He will be speaking at ih; Surrey unference on the n.ed for an understanding of the mechanisms of action of carcinogens before any extr ipulution on the result' of hi y dose animal tests to humans is carriea out ii.a : ' s case examining vinyl chloride). Inis reflects work ui <- at Dow Chen.al's Mi'iiigan I ah. to. rones which is helping to osetcome o e ot tne big gest 1 eoretieal obstacle' ;o a rational approach to chrmic.ii carcinogens--the fact that it has never open possible to show that there exi,; .ny safe ex posure levels, although -u-h "threshold'' levels of exposure h.-'e been long accei ed for substances which are Simpi/ toxic By understanding the- detoxification or excretion processes .-men can allow man and anim.ls to c-'pe with small doses of carcinogens, but which are overw --clmcd bv large doses. Dow Chemical has honn trut the normal latistical extrapolation of nich-uO'c re- ulls, io produce an irub- ;,>on of cancer incidence resulting trom reiUlitg exposure, le.ius to it overestima- tions Gehnng doesn t suceest ih.tt this means an early imroOuction of a "threshold'' c.-ncpet tor i., c`:ircinogens. but tnere Is already evioence. he savs. that high doses or some compounds overwhelm natural detoxification pro cesses. inis being so with vinyl chloride, styrene, carbon disulphide. T-naphthyla-mine and 1,4-dioxane. This is one reason why in vitro or short-term tests are so divorced from the real situation, notes Gehring. Be cause the cell cultures used to delect whether a compound causes mutation represent an artificial environment, the situation excludes the natural excretion and repair processes. The detoxification processes occur in different ways, sometimes involving ex cretion of rhe chemical itself or some times action on the active metabolite (the adduct, between the carcinogen and a macromolecule, which is usually the true carcinogenic agent). In the case of vinyl chloride, he says, the detoxification process involve.' a substance produced in the liver (gluta thione) which is only in limited supply, and it is therefore not surprising that the process proceeds faster at lower doves. It would r','_|uire unrealistic numbers of test animals to show a noeffect level experimentally in feeding trials, but Gehring's work characteriz ing the dove-re.vporvse data of VCMinduced angiosarcoma in rats has encouraged him to venture estimates of levels of expo.vure which he regards as likely to result in no greater occurrence ot human angiosarcoma than wculJ be expected to occur spontaneously. Geh ring juggests around 25ppm as being such a level. Neglecting the possibility that a threshold level might exist and the fact that rats have been shown to be >50 times more susceptible to VCM-induced lumours than humav.. Gehring's calcu lations based on rat data show that chronic exposure to VCM at the I ppm level would be expected to result in one case of angiosarcoma in 100m.'`subjects --lower than the spontaneous oc currence. Acrylonitrile, which has more re cently coine Linder scrutiny as a car cinogen. is already characterized by Gehring as combining directly with the basic life molecule DNA, rather than via a metabolite, like VCMAccording to (he evidence trom Dow's long-term rat-fccding trials which first raised ihe suspicion about acrylnnurde. the compound is also more potent because it causes tumours in the brain, where detoxification pro cesses do rust operate. But the tact that an excess of brain tumours w-.iv not revealed by Da Porn's recent epidemio logical study- at its pliant at (. amden. bouth Carolina, leads Gehring io be suspicious of that study's validity, and sarily exhibit the same effects as test animals. Asbestos. VCM and S-napnthyiamine, have all shown good correla tion in this respect, he notes. Nevertheless, Gehring believes that a threshold effect wj.ll be detected with acrylonitrile, with detoxification pro cesses operating in the blood and lungs. Duplicated Legislation These rapid developments in the state of the toxicological art come at a time when the chemical industry is being criticized for not detecting such chemi cal hazards earlier, although the means have not been available to allow such an understanding. In contrast, the US legislature's answer to the problem, the Toxic Suo stances Control Act, according to Gehring has only duplicated existing legislation which has never beer implemented. Although incidents such as the kepone pollution at Hopewell, Virginia, were cited as indications of the need tor ,0such new law, it simply reflected the result of ineffective implementation existing laws, according to Gehring, Gehring maintain' that bi) per cent of me new law's ai - cculd be achieve... with existing legislation, the only neg lected area having previously been law controlling disposals of solids on lorn! The strength of Drw\ belief in th,, led not just to etforts to modify its contents, Gehring admits, but to tv and prevent its ever reaching the statu.a book. What makes Dow's toxicology l work so important is not legi .lauon but the rate at whicn industrial chemicals are being labelled carcinogenic, otw ;iv a resuit of tne massive-dose teenniques which Gehring calls "solid state toxicology". Thus the US National Cancer Insti tute's bioassay programme, originally conceived a decade ago to examr.e highly bioactive compounds, particu larly pesticides, is now committed to re porting animal test data on more if.an TOO suspect chemicals at the rate c: three a week. The "Chemical carcinogen of the year" phenomenon of the recent past, notes Gehring. threatens to be come the "Chemical carcinogen of the week" in the near future. What can the industry do to pot new evidence m perspective ansi ensure a tair "trial by media" in such casev The recent reieave by the NCf of test d.it.i linkin'-' perchlurethvlene with Iiv-r cancer m mice provides an illustration of Dow's etforts. The fact that Dow continued on poye 'J r *. '* i fc /:; r'` -j : /. ... ft vik A ;r, r V f- r i j i. i