Document 6bg8ZXzbew3joqV9yEr1wzaBE

> AP00005688 Joseph e. wr.Li.cn JKUOMK It, HECKMAN CHAHI.ES M. MEDIAN VII.I.IAM H. nOIiGUESAKt, JTL nonr.irr h. tjernaN WAYNE V. IU.ACK DAVID L. 1IILL MAKT1N V BETCOVICX rKTEH t. NF.MKOV JOSEPH B. JIAULET CAROLE C. HARRIS rETEIt THOMAS SMITH MICHAEL T. MOIUIOJflS law orrrc&s Kellkr and Heckman 1150 ITt* STREET, XM, SUITE 1000 WASHINGTON. D. C. 20030 March 31, 1975 TELETHONS SOS S0~ft700 CABLE ABSCESS RELMAJi'* . ... Mr- John Stender. . 4 .Occupational Safety s'Health Administration Department of Labor Washington, D. C. 20210 ........ . Re* Standard for Exposure to Vinyl Chloride; Request for Interpretation and Other Relief Dear Mr. Stender: The purpose of this letter is to follow-up on a meeting held Thursday, March 20, of Mssrs.* Flowers and McClure and Mrs. Ryer of the Staff of the Occupational Safety and Health Administration and Mssrs. Thomas Smith, B. T. Goodrich Chemical Company? Grant Arnold, Ethyl Corporation; Philip Cupertino, Stauffer Chemical Company, and the undersigned on be half of the Committee on Distribution of the Society of the Plastics Industry, Inc. The subject of this meeting was the implementation of the OSHA Standard for Exposure to Vinyl Chloride 1/ with respect to la-r beling and other transportation related functions. As we are certain you are aware, the Society of the Plastics Indnstry (SP1) is the national trade association of the industry and represents approximately 99 percent of the production of vinyl chloride (VCM) and polyvinyl chloride (FVC) in this country. The Committee ` on Distribution is a service committee within SPI and is charged with the responsibility to study and work toward *1/ 29 C.F.R. Sl310-93g. AP00005689 Mr* John stender March 31, 1975 Page Two improvement of the function of physical distribution of materials and products* T\. Standard for Exposure to Vinyl Chloride is accordii ./ of extreme impor tance to the Committee on Distribution due to its impact upon materials handling, transportation equip ment, packaging and labeling* LABELING The Committee on Distribution-has adopted a program for the labeling of transportation equipment and packaged materials relative to the requirements for container labeling of subsection (1) of the Standard* We respectfully request your concurrence with our inter pretation that this program fulfills those requirements, and we further request that OSHA field personnel be advised'that the labeling program described herein sa tisfies compliance responsibilities of those employers whose employees may be handling VCM and PVC materials* The industry believes that a uniform approach to marking and labeling is desirable in order, first, that transportation companies and carrier employees will become accustomed to recognizing the prescribed warnings irrespective of the company making shipment. In this regard, carriers are accustomed to standardization in hazardous materials regulations; and a uniform industry approach would thereby facilitate not only industj^ but . also common carrier compliance obligations. Secondly, a uniform approach would be effective in warning em ployees of the fabricator segment of the industry who will become accustomed to seeing the warnings in similar fashion and location irrespective of the producer or plant wherein the shipment originates. Finally, uniformity will enable OSHA inspectors to impartially judge compliance and effect uniform enforcement, thereby assuring that all producers are treated in a similar manner, and further assuring that the same standard of compliance will be applied to a shipment at origin by one inspector as at destination by another* The provisions of subparagraph (1) of the Stan dard simply require that containers of vinyl chloride and polyvinyl chloride shall be "legibly labeled'1 with the mem AP00005690 Mr. John Stenucr March 31, 1975 Page Three warning statements designated therein. In formulating the program described below, the Committee on Distri bution has considered the intent of the Standard that employees handling vinyl chloride and polyvinyl chloride materials shall be reasonably apprised of the warnings prescribed by the Standard in view of the handling and exposure at all levels, e.g., producer, fabricator, carrier and warehouseman; and the Committee's deliber ations further took into account the specific charac- - teristics pertaining to each' "container" for marking purposes * Vinyl Chloride Vinyl chloride may be packaged for transportation In bulk in tank cars, in bulk in tank trucks, or in cylin ders. 2/ The practices and requirements of transportation for each mode mandate specific consideration. ' With respect to tank car movements, the industry has elected to employ option (ii) of subsection (1) (5) of the Standard to mark "Cancer-Suspect Agent" in conjunction with the DOT placard requirement. Associated with this letter and identified as Exhibit "A" is a DOT placard utilized for VCM movements as amended to reflect the OSHA-prescribed warning. Modification of the placard to accommodate the OSHA warning has been assented to by the Federal Railroad Administration of the Department of Transportation. 3/ This approach presents all transportation safety informa tion in one location, and railroad employees are accus- * tomed to looking to the placard for such information. Moreover, this approach appears to fulfill the intent of the Standard as described in the preamble, as follows: Since labeling or placarding that is in compliance with the U.S. Department of l 2/ For waterborne movement, the carcinogenic hazard of VCM will be regulated by the Department of Transpor tation. See, CGD 74-167, 39 Fed. Reg. 26752. 3/ Letter dated November 21, 1974, from Mr. W. F. Hall for Mac E. Rogers, Associate Administrator, Office of Safety, Federal Railroad Administration of the Department of Transportation, addressed to Mr. S. Kuzma, Allied Chemical Corporation. i |; | i !.- JUllW AP0000569I Mf. John Stender March 31, 1975 page Four Transportation regulations (49 CFR Part 173, Subpart H) already warns of the fire hazard, .only a statement concerning the carcinogenic hazard need be added to the Department of Transportation labels. 4/ The movement of vinyl chloride by tank truck Is currently very limited in scope, involving one VCM producer and a single motor carrier. .It is the position of the Committee on Distribution, and of the parties `particularly involved in this movement, that option (i) of subparagraph (1) (5) is preferable. It is intended that the full warning statement 5/ will be applied by a label, stencil or tag, as illustrated by Exhibit "B" to this letter, in the vicinity of all hatches and all outlets. The producer and customer personnel handling the material at both origin and destination will, of course, be familiar with and trained in the handling re quirements of vinyl chloride. Additionally, a single driver is'responsible for the truck during the entire transportation movement. Accordingly, it is believed that this system of notification will serve to adequate ly warn all employees who may be anticipated to be within working distance of the vehicle during transportation of the health hazard involved. 6/ /4 39 Fed. Reg. 35890., 35895 (Emphasis added). -5/ . It is understood that the shipper involved intends to petition for a variance to use the phraseology "Flam mable Compressed Gas" in lieu of "Extremely Flammable Gas Under Pressure" in order to correlate to DOT hazardous materials terminology. ./ Exhibit "B-l" hereto is a DOT placard used for truck movement of vinyl chloride. The nature of this placard, and its failure to identify the material in the vehicle, do not accommodate modification to include the OSHA4prescribed warning as readily as does the rail placard. This distinction, and.also differences in the manner of handling tank cars and tank trucks, has .caused the Com mittee on Distribution to select the labeling of hatches and outlets so to give particular warning to those ac tually handling the product. AP00005692 Mr, John Stender March 31, 197S Page Five With respect to cylinders, which move comparatively infrequently in transportation, it is intended to utilize the "Cancer-Suspect Agent" legend, in lettering bne-half the size of the "Flammable Gas" lettering of the DOT required label, near the DOT label on the cylinder. A sample DOT label is associated here- . with as Exhibit "C". Polyvinyl Chloride - Polyvinyl chloride may be'in either powder, pellet or liquid form. PVC is moved in bulk in hopper cars, tank cars, hopper trucks and tank trucks?, and PVC is packaged in bags, bulk boxes and drums, with respect to bulk equipment, whether rail or motor carrier, the Committee on Distribution program calls for warning with the legend prescribed in subsection (1)(4) of the Stan dard by label, stencil or tag in the vicinity of all hatches and all outlets, in the form of Exhibit "D" to this letter. Such a label will serve to give notice of the potential health hazard prior to handling the PVC material. Exhibit "E" to this letter is a label to be utilized on packaged material. This label will be applied to bags on the sides or ends, to boxes-on each side which bears the product identification, and to drums on the front, i.e., near the product identification. This ap plication of the warning is intended to be visible when the packages, particularly bags, are palletized, and so may be seen by warehouse personnel and also by employees* or fabricators who may be called upon to remove the bags from the pallets for usage. Waste Material Contaminated with Vinyl Chloride . It is intended to label waste materials con taminated 'with vinyl chloride, which move very occasionally in bulk in trucks, with the labeling prescribed by sub section (1)(3) of the Standard in similar fashion to the label identified as Exhibit "D" to this letter. AP00005693 Mr. John Stender March 31, 1975 Page Six. It is respectfully submitted that the fore going labeling program complies with the requirements .and intent of the Standard insofar as the responsi Ability of all employers, e.g., producer, fabricator, f warehouseman and transportation company, is concerned with respect to the movement of vinyl chloride and polyJ vinyl chloride materials; and we request your cont currence in this interpretation. ' )~'i TRANSITION " .............................. ... " : As the direct result of the present state of the economy, many, if not all, PVC producers find s themselves with substantial inventories of packaged ma *.- terials. As of December 31, 1974 these inventories amounted to approximately 300 million pounds. 7/ Such (cl inventories are held at public as well as company ware- house facilities. The provision of the Standard requiring that containers of polyvinyl chloride must be labeled effective April 1 apparently applies to existing inven- f<: tories as well as to newly packaged materials; however, whereas newly packaged PVC materials will be labeled in accordarice with the program described above, the labeling of each individual package in inventory may be highly if: impractical. * By and large, PVC materials are packaged in *' bags containing 40 or 50 pounds of material; and it is common industry practice that such packages are palletized, } . 50 bags to a pallet. Within each pallet, the bags are glued or banded together to maintain stability and fal cilitate handling of the palletized unit. In consideration I of the unitized nature of packaged PVC materials or pallets, I* it is our interpretation that each palletized unit may be t- considered to be a container, and accordingly that the 1 requirement of subsection (1) of the Standard may be sa tisfied by the labeling of each palletized unit itself. v Source: SPI Committee on Resin Statistics, as compiled by Ernst & Ernst. AP00005694 Mr. John Stender March 31, 1975 Page Seven To otherwise interpret the Standard may require that each pallet load be broken down, thereby resulting in a weakening of the individual packages as the outer ply of paper, glued to the next package, tears as the bags are separated from one another so that labels may be individually applied. While the PVC producers do not have a single approach to the labeling of packages during this transi tion period, it is.generally intended that labels will be'placed on each palletized load in*such'fashion as to be conspicuous to warehouse and transportation em ployees who will be handling the material. Additionally, the labels will be so located that the warning will be apparent to employees of fabricators as the bags are removed from the palletized load for use, until the last package has been severed from the pallet. It is respectfully submitted that the foregoing approach to labeling during the transition period, and until present inventories are depleted, will serve to fulfill the requirement of subsection (1) of the stan dard at all levels of handling; and we further request your concurrence in this interpretation. EXPORT Members of SPX*s Committee on Distribution have been advised that materials bearing the "Cancer-Suspect Agent" label will not be accepted for handling by certain stevedoring companies. Moreover, some foreign customers have indicated that they will not accept products bearing this- label since they can purchase PVC materials from producers in other countries which are not labeled in this fashion* r SMt*s statistics show that the export of PVC, ~ amounting to approximately 300 million pounds in 1974, accounts for 21% of all plastic materials exported. 8/ */ Sources SPX Committee on Resin Statistics, as compiled by Ernst & Ernst. la jjwi.mil AP00005695 Hr* John Stender March 31, 1975 Page Eight SPI is aware that the B. F. Goodrich Chemical Company has filed a request for an interpretation concerning this matter. Considering that (1) the warning is primarily intended for the benefit of employees ac tually working with the PVC material in the fabrication process, and that foreign employees are not within the purview of the OSH Act, (2) that producer and trans portation employees will be trained in-the handling of PVC materials, and (3) that longshoremen and other dock personnel have only .occasional and limited exposure, in an open air environment to packages of PVC material, the SPI Committee on Distribution supports the B. F. Goodrich Chemical Company request that the Standard be interpreted as not requiring the labeling of PVC materials in export movement. SAMPLES' It is common practice within the industry for OTC producers to ship samples of materials to customers, such samples ranging in amount from 5 pounds to one bag . consisting of 40 or 50 pounds of product. Such samples may be sent by United Parcel Service, parcel post or air freight and are appropriately packaged in outer containers sufficient to withstand the rigors of hand ling, As presently constituted, the provisions of the Standard, most particularly the monitoring, training, labeling and record retention requirements, would apply .. to the handling of these shipments in equal force as , '*they do' to the transportation of a 40,000 pound consign1: patent* Obviously, the burdens of compliance with the * -/Standard would make the handling of such sample shipments economically infeasible for the postal system, UPS or * the airlines. In view of the negligible exposure and .health hazard presented by the handling of such sample , -shipments, it Is respectfully requested that the Secretary X ..-either interpret the Standard sc to exclude such trans- ) ..^ortation from the scope of subsection (a)(3), or alter> /natively that the Secretary amend the standard to exempt /'from its scope the transportation of PVC in quantities exceeding 50 pounds. should such an amendment be .. required, it is submitted that it would constitute a M/uinor amendment within the context of Section 1911,5 of \X 7jF^7KgTCTuJJMrtHMl  * { Mr. John Stender March 31, 1975 Page Nine the Regulations. Your attention to the foregoing request is very much appreciated. Should there be any questions concerning the foregoing matters or should any further information be desired, please feel free to commu nicate with the undersigned. Very truly yours. Assistant General Counsel To: the!society op the plastics INDUSTRY, INC. Enclosures ec: Mr. Barry White Mr* Grover Wrenn Mr. Charles Ray McClure 1 > i' 1 v. I AP00005697 The Vcfite6fW^fe!v^B<:peri mental Bioassa E itvi rcSHffi&ftfei1(^SJ hft$geneses An ExM)$fe 'W^ilOrl'oride BY CESARE-\ttt1r5Wl The viny! chloride* carcinogenicity teH/njfgKeftemidl:Syrnp' released into th&6'lfi$<ftfift1 It is increasingly demonstratelf-an accepted!thit the* hlj^V *4 rising incidence of tumors, especially in pdctic'ulai1 site's (Jtfhfe, urinary tract, hemopoietic tissues},, is due to. the extensile end growing diffusion of oncogenic agents in the environment..... Furthermore it is assumed that 80. to 90 percent of .tumors depend on causes which are, or may be* Identified as being*, part of (he human environment. Recognition of.such causes gn< protection from their effects could significantly reduce tumor morbidity and mortality. - --------------- . .... This increasing diffusion of environmental oncogenic agents Is a phenomenon particularly correlated to the growth of industrialization, and especially to those Industries producing and manufacturing new synthetic compounds. In modern times, from >00 000 to 200 000 new chemical compounds are produced annually, and we know very little about their effects on man. There is a strict correlation between occupational apd general environmental carcinogeneses..Potential, carcinogenic agents spread in fact throughout the general environment from the factories where they are produced, thus rapidly cradling an ecological problem. Hence, results of studies in.the field qf occupational oncogenesis, directed, towards identifying. on? oogenic industrial agents and assessing protective ffleasufes.for workers, can be extrapolated easily to general environmental oncogenesis, -. .. ______,,... ... .... Environmental and occupational carcinogeneses ark, there fore. socially Important-As regards occupational carcinoge nesis. U is one of the mast interesting, tragic and difficult fields'll) onc.otegy: it is Interesting from a scientific standpoint because it represents, dramatically, an experiment on human beings which has* taught us much abont the natural history of turnon; (regie because work, which is, per se. a natural necessity of lifer, should not cause caneer, and difficult because the care of workers' health often conflicts with the productive goals of Industry and with major economic and political in terests. NEED FOfl PREDICTIVE CARCINOGENICITY BIOASSAYS Most of the oncogenic occupational and environmental agents have been identified when the incidence of a particular type of tumor in an exposed population has been outstanding, or on the basis of retrospective epidemiological studies. Progress in these areas of oncology should facilitate system atic experimental carcinogenicity testing of agents which are, or vvill be, released in the general and occupational environ ment. Th,ese testing should be carried out before the exposure of hujnani to potentially oncogenic agents takes place (since the specific effects on tissues produced by carcinogens are irreversible) and before economical, political and social in terests are well established (as then they can not easily be changed)., Carcinogenicity experimental bloassaya are surprisingly few as compared,with the need. This is due to several factors: scepticism concerning the validity of testing, the vast amount 18 AMHO, VOC 4 NO. 1 of ageats to be tested tests, lack of experime Let us briefly and cr Seepdebm. Too freqi occupational agents h results could not be ex mental testing has oft< ing carcinogenic risks, tical of the validity c critically evaluate the i Vast amount of agents tish priorities for tho widely diffused. Complications in pert experimental testa on human exposure, the r to be examined should in degree of precisene expose the more dangei Lack of experimental u number of oncological carcinogenicity btoarnv those centers or agenci promoting publie reiatic coordinated. Moreover the large number and mental and intergovem: promoting such studies, proper protective mcas commission, together w ties, should.' I) plan the an international level a experimental units, arc decide on proper preven In sharp contrast to mental carcinogenicity 1 there arc numerous peffect on experimental agents which are alrcac These studies, of cours oncology, but they ha\ occupational and envlro Furthermore, mcdica. phasis. In our opinion, mainly to determine th dcmiologica! data. In ft own experience have she on a broad range of o widely the target orgar AMMO. !97$ AP00005698 imental Bioassays in Occupational and es m a scientific standpoint n experiment on human ut the natural history of 1 is, per n, a natural cer, and dr//lculf because nicts with the productive anomic and political in- iQENicrrr bioassays md environmental agents ce of a particular type of been outitindini, or on cal studies. should facilitate systemins of agents which are. nd occupational envlronI out before the exposure agents takes place (since teed by carcinogens are political and social In: they can not easily be says an surprisingly few i due to several factors: train*, the vast amount AMBIO.VOL4N0.1 of agents to be tested, complications in performing elaborate potentially multicentrie. Consequently very little can be done tests, lack of experimental units and conflict of responsibilities. after the tumors have arisen. | Let us briefly and critically review these points: The major value of experimental testing in the prevention of occupational and environmental oncogeneses is demonstrated Scepticism. Too frequently in the past, environmental and cleatly by the story of vinyl chioride carcinogenicity. I occupational agents have been tested improperly so that the I results could not be extrapolated to man. Consequently, expert- j mental testing has often been considered obsolete for predict ing carcinogenic risks. In our opinion, one should not be seep- VINYL CHLORIDE CARCINOGENESIS j tieal of the validity of carcinogenicity bioassays, but rather Vinyl Chloride (VC) has been produced in many countries for I critically evaluate the methods of testing. more than 30 years. It is the constituent of polyvinyl chloride (PVQ which today is the plastic industrial material most often Yast amount of agents. Since this Is a reality, one must estab- used and diffused throughout the world. Moreover, it is used I lish priorities for the products which are, or will be, most as a copolymer in Saran and other plastics, as a chemical inter widely diffused. mediate, as a solvent, and as a propellant. In the past, for only I Complications In performing elaborate tastings. The more a short period, it was also used as an anaesthetic. VC at present is produced at a rate of almost 12 million tons per year. experimental tests on animats reproduce the conditions of The fotlowfflf population group* may be exposed to VC: t) human exposure, the more relevant they are to man. Agents workers engaged in the production of PVC and VC. and in the to be examined should follow a pattern of teste which progress use of VC for other industrial purposes: 2) workers manu in degree of preciseness and scrutiny, so as to filter out and facturing PVQ 3) residents In areas neighboring factories pro j expose tho more dangerous compounds.I ducing PVC and VC; and to a much lesser extent 4) people consuming products containing VC, as some propellent sprays; I Lack of experimental units and conflict of responsMIitles, The 3) people having contact with resins made with VC and with number of oncological units throughout the world performing materials containing these mins: and 6) populations consuming i atrcinogenidty bioassays is indeed low (if one docs not include food contained in plastic made by VC those centers or agencies whose activity is devoted mainly to Valuable bioassays on the long term effects of VC were not promoting publie relations in this field) and are not sufficiently available until 1970. This situation reflects the scarce con coordinated. Moreover it is often difficult to assess (because of sideration which has been given until now to experimental the large number and lack of correlation between yovem- bioassays in predicting the oncogenic effects of environmental mental and intergovernmental agencies) who is responsible for and occupational agents on man. promoting such studies, verifying the results and undertaking At the end of 1970 we planned a project of correlated in proper protective measures. A permanent intergovernmental vestigations to clarify the type and degree of carcinogenic risk commission, together with representatives from interested par fro* VC ries, should: I) plan the programs and priorities, 2) promote at This project included a series of experiments, which were an international level an adequate and integrative network of started in sequence. They were designed to study the effects of experimental units, and 3} critically evaluate the results and VC, administered through different routes (inhalation, inges decide on proper preventive programs. tion, peritoneal and subcutaneous injection), at different con In sharp contrast to the insufficient attention given experi centrations (by inhalation: 30 000, 10 000, 000, 2500, 500, mental carcinogenicity bioassays for predicting potential risks, 250,200, tSO, 100, SO. 25. 10, 5, l ppm), for varying periods of there are numerous projects which study the carcinogenic time (by inhalation: from 52 weeks to l week), by continuous effect on experimental animals and the metabolic patterns of or intermittent treatment, on animals of different species (rats, agents which are already known to be carcinogenic for man. mice, hamsters), strains (Sprague-Dawiey and Wietar rats), sex These studies, of course, may be of some interest for basic and age (adults, newborn, embryos). oncology, but they have little bearing on the prevention of occupational and environmental tumors. Furthermore, medical controls have been given great em The planning of the program and the preparation of suitable experimental conditions, particularly the building of an appa ratus for Inhalatory exposure, took until May 1971. In July phasis. In our opinion, the value of medical examinations is 1971 we started experimenting. The exposure by Inhalation was mainly to determine the risk; that is, they may provide epl- generally performed 4 hours daily, five days per week. 1 demiological data. In fact, as collective information and our The chambers or exposure, basically built of stainless steel own experience have shown, the carcinogens exert their effects and glass, hav* been designed to deliver concentration* of on a broad range of organs in exposed humans and affect gaseous agents varying from 30 000 ppm to I ppm of vc The widely the target organs, and the tumors which arise are VC concentration in the chambers is controlled by gas chrom- XMBtO, 191$ V 19 AP00005699 OOZSOOOOdV Sift `OIBNV <* m |* iu lit (itfstiq uM|ii (4) wn a joj J| III* t|IUf|V* U1 (*) dl "XT' III* N luiuqviq|d|i0|1| Midd M OA Ml 9A Mdd m sa add mi oa Mdd not OA Mdd HN1 OA P) IMUIItMJ 118 luawpadvi i iqri ajlw AMMinqn* i (*) t Mil* *|FU#|I# |(i*AS (pj (daejB iMjipip tin vi J (WUMIP* A||JMB) twq je tun (s) 1W (t i M tiwuq mv*is A) '* ii JOJ Mil wt* *j(ui|iit u A) HMIUlf Mid Bl wdd add emn 3*55 $ WlUMMUl N HI I--M--8 T *1Q1 M**iim Mlnm i iBv* |IU|UIOMl-tl|U| t W l iaueunaiou* j*|na ini vi waamoiSw* i Q) j) *Mi03j*cvi6vfl isvrui M) JS *UO*JMOifiu* l (|) l iui* |ui|v |*iM*s (ill *4nu( iuuijjis *MI Ui (nuMiipi Ai|i*u*S) JQ je lltto imam (S) -tunj d| Mlt*|*n tj) ini *mh Hinimn () ptuee j* a>iv*3>* (pi #ufi| et ummin (a) 'jtqumu JM4* n* rtuiwpjn I ij> *n* (itiuiuy (q) ** tt joj >M lit* l|IW|U mu A] US rtn MMAIIJI it MdK wdd Mt SA 9A (t w wdd antr u Wdd MH 9A m I0HI 9K 9 (Mi UtMdg) vwwiwr WM{W) Mil ui tv*wy*da -i *ni 1 "ON t 10A 'OIIKY o: -9i)vu;sXs pwapisuoa aq pinoqs vipqiopua puv sptnA poogq uo 34 jo laajja aq) `ajpjajaqx vvuiaSuv jo jtuioajvsciBui juv)$1P jo itao| )noqj| jo m;*s t[tuiiiit paivaj) ui tanttt) put tttvfjo jaqio uj pui jbajj an ui paAiasqo ujjjo sj*' `jeidXie j[0|(aa qip* pajvtarav )ou jo pa;iiaoss 'vuvjdjadXq (vjiaipopua 'w|5nsa (assaa poo|Q 'p9)C|)U9JajJ|p tt| JO 3JOUI Mv tciu09jno(3uc optdaqvj)*a put (t jn3jj> apvdan 9MuaaX|od ua)jo ajv Aaq) ja;i aqj u| -{viujuv aiuvs a141 ut ajts auo uuqi wow iv punoj aq Auiu (tiawuvq `93;ui `*)vj ut) tvuioiSua puv tvuioaJKOjfluy VBJOjsijqoiqCau uioqii* jo q)} `uej paioai) jo Xaupiq aq) u) pjAjasqo uatjo n anssii ajfi|.vui9)tV|qojqdau jo is|dJ8<MH Xaupijf jvuo.tiquia u jo"*n spuiuiu aJmaid paiS -o(om -|*j3ji[q uatjo an <nvj Uf) riiaottiqojt|dajq ' 'tiuat ltd snoqdjouU|Od puv a^njdauv 'pi|os *J[npuiS tnouivttbt jgwd Xaq; uaijo inq `puti> (vqujXz ]tuuou am jo ajrusaijt aip `luaixa Ufvuao * ot `aanpoidai Xjiuanbaij Xaqt X[|t3it 0(0]i|H 1ua)V|tq aq Xvm (t)j ui) scuiouiajaa pu*|> [aquiXz (vuipjv aoiH aqi u; auataid aq Xim uouint jo sadX] juajajjia a|qi[iAV jaX ;ou j vvp `tjuauiuadica jajiv] aqt jo*} i[eiuju< (j Q| niuoajnoiSuv j3ai| pot spiujjuv 0( U| punoj uaaq .\vq teuiouiajuo puc(8 (vqiuXz `mauiuadva aq> jo lujuuiBaq aq) uiojj sqaaM [9 on(ij* `ij.fi luauiijadxa jo i(vui)uv aqi > ,<m awn aq) u; (9X8) sqaaA joj 3a jo wdd 000 OC > uoi)8|it(U| Xq paiodxa am Xa|MeQ-an2cjd$ 09 tuouiy '9~*J ta|q*x i o.woqs ait (9 `p "J '4 '( '( XB) ^iuouj -fjpdxa i*j3ASt jo oi Jaqiuatoas oj dn mnsu juajjna aqx ttlOIJSI |03{8t>|0 qjvd qi)M ucfjo jaqto Xvt put )aj puv da] aqi jo tauoq nj|jq `jappviq '3U|taa)u; aq) jo v>uauiSas )uajajj;p `ipBiuois ua)ds `tXauptq `jaAi[ -t8un| `anSuoi <tput|f Xjvaucs "ivj uviojq jv|nde9uaiu( 'tpuv|i fvquiXz uo pauuojjad ajv tuoucuiwcxo |ailoiOK!H '|viu;uv qava uo apeui si Xsdojn* aia|duioo y `UffKvqiuusa piOAV o) japjo ui pa)e|osi ajv punqiioiu uaqM i(*uifui aqj. fOJtuoa atp Supnp papjoaai aje vaSunja (vafSoioqivd svajS aiqviaaiap ||y paiajduioa i; luauajcaj) J0)j Xiqjuoui puv popad )uaui)taj) aq) fuunp i^aa.v, om) Xjva paqSiam puv Xi^ivaa pa||OJ)Uoa tiv tjvuiiuv aqx mcp tnoaunuods num uoptAjatqo lapun )daq ajv i|vui;uv aqt nv Duauiuadxa |ri|U) aq) uiojj pauiviqo aaaM cqnsaj jijc pawn* aja* vaqio puv 'tuiuuJaq aq> )v pauiuivjlojd aja\s uiiq) jo autos ?*w*)i ait* (91--1X8) *)uata(jadva uaij;j 'ouapoj 00ft )*aJ) Xvui /[tnoauvqmufs a mou puv XqdcjSojv V-, 'Z t*. .* ^^ te*/*** .. 'ff i>.\ -w A 1* v*- * * V 1 . ? `afj? r^>;. Y#*t W .i - .a* * * 1 ' V ' -* .-i..,''tW,,, -^i r~. , *a F S' *~ v>"\ r <* ? '& :S-\ rpi*'-;j Table I. KiperfiMnt 1T1: Xeaulte altar ill wnto (end of Hh aiperfmenO Anhetls with turner* Treatment (a) Animal* Cymbal gland (Sgteg--eaaia* rata) euetnenM (a) NepnnblaHema* (a) Oar* Average Taw reeled number <W na. V, lituscy m lima (umaha) Na. h to htancy*. Hma NS, Imaabal Anffaaareamaa Uvarp) U4 Average 1, laiancy M Hne Na. tub* eutane* Skla cu* cant* angle* nomae ma* He. NS. H$ptIflMI Inin Mur* Mft Other type and/or alls (g) Na. no. Ne. VC tOOMpon* WS-aoM earnVfi isoa ppm vc mo earn Ve' 2 ppm" Vft * eem H h if is 2d M b 9 ii 44 i* i 3 44 tt 4 ~r H 44 -- -- 44 -- sa 44 tJ 4t t4 ia H M U 44 ' is i*4 a IS *4 ii M 13 n re 1 i! | 4t 4V 7i \4 144 2 (i) 3 <|> 3 (k) 1 iW iim) i y\) * 3 3 1 -- 1 3i 1i ii i4 4-- 1-- 7 7(0) 3 lot S 4 fUl 4 (r| 3 1*1 -- i|ii Ne baatment fatal ta in a *4* 1" 3" - ~ "52" - - "".7" -- - 14 "T5- it --f--"TT" <4 Total (h) NO. 38 it 5" ii 4 ii 1 !U {) The anknell were treated by inhalation (or 4 hour* daily, I deya weekly, (or SI week*. (b) Animal* alive alter 21 weeks, ehan the drat tumor (a Zvmbel gland carcinoma) waa ebearved. The percentage* are ralarred to the corrected number. Ie) Mataataaoa to lung, dl Percentage of corrected number, e) Meiasiaiea ie ilvar. lung, spleen and brain, n Mitiuiw to lung. g) Several cun ot breatt fibroadenoma*, adrenal and pituitary tumor* (generally idanoataa) have not bean eorteldartd. since thak diatnbuHen In in* amarant group* ogee not vsrjr, Ih) Several anlmala with 2 or mere lumen. (if t angiosarcoma of (he lip*; 1 angleiaraemt ot the note; 1 Intra-tMe- fninal ingloMrooma (neat to Irvor). D) t angiosarcoma in aubeuUnaout tlbrealng angioma; 1 piilfylng paraurl- euiar anatoiarcoma: 1 lmr*>aMeminil ingiotirsoma (nett to liver). (k> I Intra-abdominol angloaareomaa (I not to tplaen and 1 neat M every): t eerilyinf enalotarcema at the neeb. SI pulmonary angioaarcoma; 1 angiosarcoma oi lha gtaru*. ) 1 mba*abdominal angioaarcoma (neat ie plain); l invethoneie otartyIng angiosarcoma. (nl 1 (ntra-abdomlnal dllliised anglaaaresma. (oj 2 Cymbal gland adenomia; 3 mammary carctnamaa; 1 naunlammoms: t ovarian eyatoadaneearcinama. (p> 4 Cymbal gland adanomaa; 1 salivary gland adeMearsinoma: 2 haoibs ana t peflienaal angioma*. fl Cymbal gland adenoma; 1 mammary eareinoma; 2 epandymemae. 1 masunary carcinoma; 1 lymphoma*; t pulmonary libreiareom*. 1 Cymbal gland adenoma; 1 mammary carcinoma: 1 lymphoma, a Cymbal gland adanomaa; 2 mammary carcinoma*; 1 auMutanoou* angteparcitoma; 3 uterine adoneeardngtnao (1 with wcemalou* comoo* ntnt). (u) 1 Invasive acanthoma of Cymbal gland: t tubcutaneoua fibrourcoma: 2 peritoneal fibra angioma*. 2 uterine adeneetretnomu (t with aareomaiou* component); 1 uterine ioiomyotareoma; t ovarian libraureoma; t pul monary rhabdomyoiarcoma: 1 lymphoma. 13 animals. For the latter table. Different types of aimai. unay be bilateral. Hlitolo* to a certain extent, the td, but often they present ie and polymorphous pat* a bilateral. Their histoloyoral kidney. Hyperplasia i observed in the kidney of iastetna. rate, mice, hamsters) may t same animal. In the liver Figure 1) and extrahepatic remitted. hyperplasia, associated or .arc often observed In the in treated animals, with or as or angiomas. Therefore, rf endothella should be AMBia VOL 4 NO. I Table a. tiguNwant PTIt HaiuHa altar Od weaba Tnatmant (4 Number et aeaallmmaaloli (l^maua Oaelay T*W iurw* vert 11........ 1 Cymbal gland earWnaaiia Naphrable ataaMa Number ef animal* with tumere lb) " 1 "Ib_i_c_l_e_u__r_tt_m___a_e_ "*' cota Liver Other *Haa iiwn> blOOWM, Other type AWertlte (e) Total (d) ve lease ppm V4 4M4 Nm VC liUocrA VJ lei earn VC SO BBei VC W ppm Ne treatment Total m M m K 190 990 0 10 I 4r -(> -i*4 "-liLi3i t (? - 1 3> a fT) i(i (('*) f 41 is r aoi IS f !Jl M3S ji 4 "i -ta il-- t a[ -- c ---11f 1*> - / 3) - (ffl - Hi i(i| - C>) HD Iffl ! fi i f 51) 2 f 13] 41 *) ta m 1 fO - (4 4l U 124 J (k) ( )i JTT ' "444 It 1*7) 3 ftp -W ~l ~ww' __12____US!____ (a) Tlohre^anwimMaklsit mere treated by Inhalation 4 Mure daily, S Mura weakly, (b) istwean bracket* ara reeordad the nimara found in experiment Brt after aa waeka. (g) Several teat* of braut tersedenomes, tdranal and pituitary turnon <g*nriiiy adanomaa) have not been oenaldared, since their distribution In the dinerarn groups does not vary. S Several animals with i or more tumor*. i aupeutaneoua angiosarcoma. R f orbital angiosarcoma. 1 earturicurar fibrotareoma: 1 nasal papilloma: 1 reflet adanome. 1 cymbal gland fibreangieme; 2 akin earemomea: t tubcutanaoua an* gatsoimooan;a.1 mammary carcinoma; t forattomaeh papilloma: t cranial 2 lymphomas. 1 Cymbal gland adanome: 1 retrobulbar fibroma. 1 Zymbat gland adanema; 2 lymphomas. Tabfd t. EspartnwF BT7: ftaautk after rt araeka Treatment fa) Number ef animal* IWlatar mb) T5W vere Zymbal gland aarelnemae Nephrsbls-' Number d anlmala niu* tumere ib) VC IbOM ppm VC km ppm ve ISM ppm VC so* pem VC 2H ppm ve ISppm Ho treatment Tetal________ 2200 40 aa ;j =!! =* =i t ASL llSL -8 (a) The enlmaJa mare traalsd by Maiatian far 4 hours dally, t days vraeety, for S2 maaln. (b) Setween brackata are reeordad the tumors leund In mate Sp'*ueOiwlay fita Of Itta axpartmani art, alter rt weeks. (e) 2 Cymbal gland adanemae. (d) 1 anglama of the eaeeum. AUBKXmS Other t|*e ener sue Total i(4 1___ 2. ISO. 21 ,.Si:L JH I - LJ.IIlim LIIU ..LI!* AP00005701 TlW* 4. Bipeitmnt *T*i Raatfte alter W weah* AngtaMutic prolif the lived and in ether Trvatmtrt (a) VO tMOf asm Ufi si asm Vi ioM aoST ve IM MM fsiaT* Braada* Irtadvfl OKiarfna bMwrlna Nuatea* al anl*4la (Sgaaeow-Oawlay rata) Talal Survlvar* Zymhal gland riatthaaiaa NaghreUminai se a it ! eo. _u 21 ti il t ut-- Numbar al animal* wllh turnon Aneief-a-re-e-ni-a------ Uar aHa* Omartm War alia _ _---------nss-- 1 let --i -- () Tha braspara war* iritiafl by irmaiilisn lor 4 hours doily. Iron th* mh (b) Subeutenaev* angiMiroomo on 24MU4ld mala. vp* ism toy ot ptagnaney. (e) Subeuianaev* angiosarcoma an 23.w*ak*eM ramale. Tblal -------- 3---------1 i fibroplasia. From the local changes in the appear* to be as fol atypiae of endotheiii fkimaj, angiosarcoma Fibro-angfoblastie quently observed la Skin carcinomas Ir from sebaceous gland extent the morpholog Hepatoma* observe ferentiatad. Metastast Brain nearoblastotr Tabla *. ExperUnaat |T4t Raaulte after M waefca medulloblastomas. Lung adenomas (L rtumbar is higher is a Animal* ilwMa Meal Xnlaul* with tumor* of these tumors eppea Traaunert (a) Tatal Cerradad utnaa* C*l Hinlww* Pulmananr himan l) a <s d- Ma. d 9 9 e99 49 9 h Avaraoa i*w*r (waaka) Uammanrcaralnamaa Na. ft rmaaka) Livar angianrttaw vascular luman of auwr type anwar site Iplttailal luman *f tha aHa Othartm Total andterilte (a) Na. Na. Na. Ns. Me. ! tion. Mammarv'carcmos They are usually wc monomorphous or po tinct feature of these present areas of squut ve 1H0S asm M so 40 23 2* SO _ VC two atm innrv -- vc sin wm li H 23 so as w* vc am earn "%r U li U h tl ii vo is* eon ie 30 mnnr s 1 vo seeam -ir to 27 30 S7 1 1 id Ma Iriaunial 'V> )6 i 1* if Ui 1* 3* 4 ratal Ho iu Sid nt 141 <11 M 4 ) SI 4 id is Jl 1 4 iff m a *7 aa u 2 1 -- 34 4 4 41 4 M 4 -- (t) Th# animal* arar* i/aated by Inhalation ter * Mur* daily. ( day* wwkiy. tor jo waaii*. (b) Animaia aiiva altar if maaka. whan ma flrat iumer(a mammary eaipinema) was oeiarvao. Tha Barctmigaa ara rtlatrad to iha eerraetao aurnbar. Adaxoma*. toma ol which undargelrtg malignant transtermatien. f In (tmalaa. Savarai caaaa with 4 or mar* tumor*. a livar ribrgargioma*; } tubeutanaou* angioma*; 1 haart nbraartglama; 1 6n(yinj Interseapular angioma. to) 4 livar anglaiaat; 2 livar lAtraangioma*: 1 aubeulanaau* aitgteaareeraa; 1 ran*) (ibroangiemc: t ihymlo angioma. (h) S livar angiomas: $ tubeutanaou* anglaaaraamaa: T lubeutanaeua i gloma; 2 intra-abdaminai angiaaireamaa; 2 ranai angleaareomaa; 1 pul monary angioma. (I) I 1 liv*r angleina: aMcutanaaua a1ngliivoamrat;lkrteanugaleemmaonaa: etutsunhaorretnannaaleaum*aa: nfgloIcnatrrmceambdaoa-: minal llbrsangiama: a Intra-aUdanlnil anglsvarcomas; t angioma ol tha eatcum: t ranai angloaorsoma: t pulmonary ribroangiomo; s tstiicutef Pbroingioma. is *7 t 21 30 fu it ri 44 w M-- 31 4 as 'if da w -- a >(b i I*) ii u ihi M * is nv M i m > 11 (X) <7 n IP) (m) J lot ija) 11 * lb) H i r*i i iu 1M 1 tv) id * 4 It43 a~ 1* d W (J) I Jivar angioma#; f Mi llbroanglomai; a Ultra.abdominal angloaareom*a: 1 Bulmonanr angioma. 1 teislal angioma. (k) i livar angiomaa; i Uvor llbroanglomaa; f aubeutanaOM ingiMltedflU: 2 tubautonobua angioma*; 1 aubcutanaoua fibroangioina; 1 intra-aMte> minti angioma: t mucthorocle tibroangiama; 1 anglama ol tha Intar* aaapular kit pad. (l) t iqiamou* oareinomaa; 11nvulva atarithem*. (mj a tquamaua carcinoma*; 1 acanutomg In) 1 Muimoua carcinoma: 2 seanwomaa. (o) 1 acanthom*. ip) 1 Zymbal giaftd tdanoma: 1 leractomach papilloma. (0) t lymphoma; i aubcuianaou* lalaayeaaraoma: 1 teraaiamach papilloma; i nardaritn gland iCanom*. <0 < teraaiemaen pisilioma; 1 parotid gland mind tumor. (1) t Zymbtl gland adanoma. S> 1 Z.mbai plans aoanoma; t lymphoma: I Laydlg aall tumar. (v| t parotid gland atoaemcsronema. (v) T lymphoma. i i i Several of the turn exceptional.To our blastemas and ncurot spontaneously occurri sarcomes have been ir mental rodents {rats. M&ltoni end Lefemine time is -which uephrat experimentally raprod SUMMARY OF FINOI In conclusion we foun 1. Under our expert in the three animals s 2. The range of ind species to species. Wh rats, Zyrabal gland < cooias and angiomas e mas. hepatomas and adenomas, mammary sarcomas and angiotnt thelial tumors; in ham evidence seems to tugg Table . Exparhnaot NTI; Raaulte after 4S arooba and forestomach pap liver angiosarcomas h Tnatmanl (a) VC 1MM arm vc ino asm VC ISM earn VC UO aem vc jm ppm vc u arm Na iraatmaat fatal Numbar al animal* (Osldaa hamstan) Total Survtvaia 33 33 Ji ii 33 14 id k 33 1 di ' ... 70 7*4 da Uvar areamas _ -- am t -- *wa -- 1 kin tHho**JthaNamaa IW s 4 i d d d 13 Matehamae _ i 1 -- 2 N hiwM ranmamash gagUtaasaa and cintlia mas ---- id *i i1 1 1-- a1 k*l Tho animate w* traatad by inhttatian ter a hour* dally, s day* waakly. ler M waua. (b) Sava/ai ciua with aeantboate and aama undargalnf malignant Iran*formation. (c) aavaral animate with 2 ar mera iwnora. (<n 1 hapatociremcma. (*j I aubcutanaeus angioma, Ottaatne m4/ar*ha m 1 !) -- __ i TM (e) 3 I 4 v i 2 M species. 3. In the BT1 and I ogtnic effect at SO ppm 4. From the BTI ex dose-response relations!comas and nephroblasU ranges: le from 500 pr from 250 ppm to 50 ppn 5. A comparison of moment in rats expose DT3 experiments) sho licultrly at far at an concerned, is affected l 6. The comparison different strains, le Spi at the present moment, considerably affects the 7. The onset of two i Zyrabal gland carcinoa Tibia r. Tumors praaantly corralatod u VC oipoutra (by Inhalation) an aapartmortal lodonta and man. during pregnancy for * cental effect of VC. Ipaelaa Rat Maui* Himiitt Man Angleaaraoma* al livar Tamara at brain * % * --Ll_ Turner* at tang IfRIpHMlII fvukvmlM ki TUMOR* Analatareama* and angle**** al athar itt*i N*phre* btattamaa 4* * 4* (+5 tabseeau* caielnama* a * sguamaus tumara at aaiatrml* 4 Mammary aarelnetiaa f*l + Hapgtoftft* Farattsmach gapuiemta and icifllHfiAM + Our data have been p companies which have able to all interested pa Before the end of 197 VC was inducing In rats nephroblastomas and h also made known to (h< tion (MCA). This infer 22 AMB10.V0L4N0. AMKIO, 1972 AP00005702 Older tree anWer ilia Tatel _ -- -- aw mate. MS female. ----------J--------- 1 -------- 5 tMuemiaeawrksninseif OanVduterrtyilptee Tatel (a) <e. Me. He. 3i!it<<mw"l>>> . --_mm ----- * > * r 1 (#1 311 J ansit to&U1J1f " 2 inira-MdaiiMl tngleiir. eme. evbcutsneove amlsuKeM: < noceefielome; 1 tattaibde" it: t tftfliemt el tM Inter ne. Ulema. ne: 1 MntMMii paplllema: mt tumtr, * Mil (UMtr. and/ar kite 1 re) 1 TaW m s a 1 l i 1 i a Hit* temai ^erMiemacn paplllemas and AUBM.VOtdNO.1 Angioblastic proliferation, angiomas and anffossreemu la the Uvcr and in other sites may or may not be associated with fibroplasia. From the histologicat observations, the sequence of local changes in the lenesls or malignant vascular tumors appears to be as follows: endothelial hyperplasia, angiomas, atypias of endothelial cells in hyperplasia (dysplasia) and an giomas, angiosarcomas. Fibro-angioWastic proliferation undergoing fibrosis is fre quently observed in the spleen of the treated rats and mice. Skin carcinomas in treated mu appear frequently to arise from sebaceous glands, of which they may reproduce to some extent the morphological characteristics. Hepatomas observed in treated rats are usually well dif ferentiated. Metastases have been observed in the lung, Brain neuroblastomas (In rats) are very similar to the human medulloblastomas. Lung adenomas (In mice) are usually multicentrie: their number is higher in animals treated with heavier doses. Many of these tumors appear to undergo early malignant transforma tion. Mammary carcinomas (in mice) may be solitary or multipit They are usually welt differentiated adenocarcinomas, with monomorphous or polymorphous arrangement. The most dis tinct feature of these tumors b the frequency with which they present areas of squamous metaplasia. Several of the tumors produced by VC are quite rare or exceptional. To our knowledge liver angiosarcomas, nephro blastomas and neuroblastomas have never been described as spontaneously occurring in rats. Liver and extrahepatlc angio sarcomas have been induced only in a few Instances in ex perimental rodents (rats, hamsters and mice) (for references sec MeltonJ and Lcfcmine (1)], As far as we know, this is the first time in which nephroblastomas and neuroblastomas have been experimentally reproduced. tions which in December 1973, for the first time, identified a liver angiosarcoma--in a worker of a US factory producing VC-PVC--as occupational. Since then epidemiologies! invest:- gations have led to the discovery of nearly JO liver angiosar comas {Figure 2) among workers of VC-PVC industries in the USA and several European countries. Most of these tumors arose before 1973 (the first known dates from 1WI), but in absence of experimental data, they were not linked to the occupational exposure, and u a matter of fact, they were often not properly diagnosed. VC hat caused in one or more of the three animal species used in our experiments, all types of tumors, which at present, on the basis of available epidemiological evidence, are cor related to occupational exposure, le liver angiosarcoma], brain and lung tumors, lymphomas and leukemias (Table 7). CONCLUSIONS It is our hope that the story of VC carcinogenicity may serve u a convincing example to urgently promote experimental bioassays for all new Industrial compounds, and for those compounds which are already produced and widespread, but whose effect we still ignore. mmiii h*<m I. C MaJuai, O Ltfaiae, ArtramwifW IwMrt 7, 327 (1T74). SUMMARY OF FINDINGS In conclusion we found that: 1. Under our experimental conditions, VC produced tumors in the three animals species studied: rats, mice and hamsters. 2. The range of induced tumors varies to some extent from species to species. When given by inhalation vc produced: la rats, Zymbal gland carcinomas, nephroblastomas, angiosar comas and angionus of the liver and other sites, skin carcino mas, hepatomas and brain neuroblastomas: in mice, lung adenomaa, mammary carcinomas of a peculiar type, angio sarcomas and angiomas of the liver and other sites, skin epi thelial tumors; In hamsters, liver angiosarcomas and. as early evidence sec ns to suggest, skin trichoepitheliomas, lymphomas 1 and forestomach papillomas and acanthomas. Incidentally, liver angiosarcomas have been observed in all three animal species. 3. In the BTl and BT4 experiments, VC shows a cancer- ogenic effect at 30 ppm. *. From the BTl experiment (the only one completed) a dose-response relationship dearly emerges, as far as angiosar- I comas and nephroblastomas are concerned, in the lower dose ranges: It from 300 ppm to SO ppm for angiossreomas, and from 230 ppm to 50 ppm for nephroblastomas, i 5. A comparison of the results available at the present moment in mu exposed tor 52 weeks and 17 weeks (BTl aod i BT3 experiments) shows that the neoplastic response, particaJariy as far as angiosarcomas and nephroblastomas an concerned, is effected by the length of exposure to VC. Ptoteaaar Deeter Ce*ir* Italtanf. UD. Protease* e< Oinml Pathatapy and at tapertmanul Oneatopy, has been Mreeier el Vw Belepne Canter lor Prevention and Oetacttoa cl Turners and & The comparison of the results obtained in rats of two Oneonologicei Research tinea **e CeAterte feundetfen. Ha ha* different strains. U Sprague-Dawley (BTl) and Wlstar (BT7), bten hector et laUtute Onco'ogU In Bologna since sm, at the present moment, seems to suggest that the strain factor He le present President et the Italian Seelety tor Frarantton sad considerably affects the neoplastic response. DJagMsl* al Turners, Vfee-Preeideat at tha Italian Baodaty lar 7. The onset of two subcutaneous angiosarcomas aod of one Therapy al Turnon, and maatear at tha Kaacutlve Saaid el Ilia Zymbal gland carcinoma in the offspring of breeders exposed tetamalienal Shier Croup lor Canear Pn**nHen and Sateetlan 1 during pregnancy for 7 days, appears to indicate a transplncental effect of VC (Da P 6a|. and Is pasf-preafderil al Via Curepesn Coordinating CawniRaa an Human Tumara Investigation (tsrt--HDh Amen# Ms um prelastianat sehvWas, ha Is Miter al a aaw aartea Our data have been periodically transmitted to the European anHtlad Advances la Turner Prevenean, Pataatlen and Oharae- companies which have supported our research, and are avail filterHon published by Beerpta Medina. and la eeadhor ef Acte able to all intarested parties. Oncoleotoa (Italian leunal el eaeategy). Tha ratulta el Me re- Before the end of 1972. e short time after it was known that VCwas inducing in rats not only Zymbal gland tumors, but also nephroblastomas and liver angiosarcomas, these results were also made known to the US Manufacturing Chemists Associa aaarah and eelentHle ectfvHiee have baan reported In tie publics* Hens. Hia addraaa: ltdiuto dl Oneeiagta "Felice Addarir, Oape- dali Si Bologna, Enla Oepedallara Oeglenata. Viele Ereelanl 4/2, Ml 3* Batepna, Italy: tion (MCA). This information promoted the clinical observa AMBIO, 1973 23 i AP00005703 Recent Perspectives in Occupational Cancer BY IRVING J SEUKOFF in recent years, many previously unsuspected carcinogenic agents have been identified and new perspectives established for the evaluation of the Increasing numbers of chemica/ substances introduced into the environment. 1 past 30--50 yetis, u not be able, with pr< humans of recently ! three decades (II), | from other discipliiu must elapse before ' designed to correct i effective. This hu I i smelter workers (12) | The importance o haps nowhere been I [ associated with occ ! Laboratory, we hav. i sulation workers, c ( Union of such wort January 1, 1967(5). had died, almost 4( were 275 deaths of anticipated. Analysis catcd that the exce workers who had sc their work (Tables I The risk of lung asbestos could easil 1 drawn, if studies ar serve a sufficient nu from onset of work tained in studies of i refineries (14) and w cancers are seen if fi-chlonnethyltther intense exposure or p Attention is sometimes called to the fact that the first oeo* With this background, a good deal has been learned about plasm* for which etiological factor* could be established, were occupational cancer In recent yean. This has included identi occupational cancers. The report 200 years ago by Pereivall fication of carcinogenic agents previously unsuspected of such Pott of cancer of the scrotum in individuals who had been effects and the establishment of t number of perspectives employed as chimney sweeps (1), or that of chemical car* which are now available for tbe evaluation of other materials cinogenesis in humans first described 80 yean ago as `aniline used in industry and/or agriculture or which may be intro cancer" (2), or that radiation-induced cancer had on occu duced in the future (9). The latter achievement is perhaps more pational starting point among miners- in Schneeburg and important, sinee the number and complexity of new or re Joachimstal almost 90 years ago (3). are died. Thesa claims cently introduced agents has attracted much attention, and are true, yet it is equally true that each was an isolated de- little Is known concerning their carcinogenic potential. scripthe observation, of muffled impact in its time. Accelerated development of a connecting mature body of LATENT PERIOD knowledge, the discipline of occupational cancer, has rather Th* above term is perhaps inexact rinse we do not actually been a matter of the past two decades. Although it was related know what is happening in tissues between (he time of first to what went before by the continuing productive studies of exposure and initial evidence of clinical disease. Changes may the effects of carcinogenic aromatic amine* (2), if one event can be said to be the origin of this new phase, it msy be the brilliant description in 1955 by Richard Doll of the association be under way, albeit not detectable with current techniques. Perhaps `period of elinieal latency" or `lapsed period" would be more exact (10). In any case, each of these terms describes between occupational exposure to asbestos and an important an important phenomenon--that e considerable time must risk of death of lung cancer (-4). Doll's demonstration of the usually elapse between onset of exposure to an occupational 1 applicability of chronic disease epidemiology provided an carcinogen and the first evidence of resulting cancer. General important example for future research. Many of the concept* ly, this period is 20--35 yean, although as little as 10--15 we now take for granted in the evaluation Df occupational carcinogenicity, as, the nd for long period* of observation (5), the utility of cohort studies (6). the possibility of co yean may suffice, or 35--50 or more years will pass. The time sequenee ean be affected by a number of variables touched on below, but it is remarkable how their Influences operate with existence of cancer and other biological toxicity (7). were in herent in his classic report. Similar approaches have guided the best of experimental studies and have increased their relevance in relatively narrow constraints. Understanding this, two conclusions become evident First, it would have been difficult or impossible to establish the to human disease (8). carcinogenicity of substances widely introduced only in the MULTIPLE FACTOF Investigations of oc generally seek to iso able. Nevertheless, t carcinogenic agents complex work envii substances of unstu personal and social possibility of mterac known in the expe shown for oecupatio found among aabesfc. risk was not signifies not also have a hist* had much more [ling Asbestos exposure t risk of cigarette sn asbestos worker whe of death of lung ca same age who neith The powerful multij agents can be appr asbestos insulation v> established, the into! was recorded; 9590 h a history of pipe tnc mg. and 1457 had experience, with p detailed in Table 3. one lung cancer was cember 31, 1972. Th only one lung carter 179 lung cancer deal smoking, although ot This, despite the facsame trade, with eqt to asbestos. The significance r action has many ram first, some suhstanc genic effect: in com Such influence may 1 there could also he a substances now deen new circumstances; c there may be many 14 AMBIO, VOL 4 NO. 1 AMIIO. 1*79 AP00005704 in ,1 has been learned about This has included identlpudy unsuspected of such number of perspectives luation of other materials or which may be introsievement is perhaps more smplexity of new or re-ted much attention, and biogenic potential since we do not actually between the time of first ical disease. Changes may with current techniques, or 'lapsed period" would b of these terms describes considerable time must tosure to an occupational resulting cancer. General* sough as little as 10--13 : years win pass. The time er of variables touched on T influences operate with- ms become evident First, sponsible to establish rite y introduced only in the * past 30--50 yean, until the last decade or so. Second, we will not be able, with present knowledge, to Identify cancer risk in humans of recently introduced agents for another two or even three decades (11), and epidemiology must look to assistance from other disciplines. Parenthetically, a similarly long period must elapse before it can he ascertained whether measures designed to correct an occupational cancer hazard are actually effective. This has been the case, for example, among nickel smelter workers (12). The importance of the principle of clinical latency has per haps nowhere been better demonstrated than with lung cancer associated with occupational exposure to asbestos. In our Laboratory, we have been following a cohort of asbestos in sulation workers, composed of all 17 800 members of the Union of such workers in the United Stales and Canada on January I, I96T (S). By December 31. 1972, 1336 of these men had died, almost 400 more than had been expected. There were 37$ deaths of lung cancer, whereas only 56 had been anticipated. Analysis of the work history of these men indi cated thit (he excess deaths were largely limited to those workers who had achieved more than 20 yean from onset of their work (Tables 1 and 2). The risk of lung cancer with occupational exposure to asbestos could easily be missed, and inaccurate conclusions drawn, if studies are made without the opportunity to ob serve a sufficient number of individuals 20--30 or more yean from onset of work exposure. Similar results Have been ob tained in studies of uranium miners (13) and workers ia nickel refineries (14) end with other agents: indeed, when many lung cancers are seen after significantly shorter periods, u with B-chlonnethylether (15). one might justifiably suspect rather Intense oxpoeur* or particularly virulent agents. MULTIPLE FACTOR ETIOLOGY Investigations of occupational exposures for carcinogenicity generally seek to isolate the suspect materials. This is reason able. Nevertheless, this approach is in a sense artificial, since carcinogenic agents are infrequently used singly, but rather in complex work environments, often with a variety of other substances of unstudied potential, and by individuals whose personal and social environments are equally varied. The pOSibility of interaction of two or more agents has long been known in the experimental setting: since 1968 it has been shown for occupational cancer in humane as well (16). It was found among asbestos workers, for example, that lung cancer risk vis not significantly increased among those men who did not also have a history of cigarette smoking Those who did, had much more lung cancer than cigarette smokers in generaL Asbestos exposure thus markedly increased the lung cancer risk of dgarette smoking; it has been calculated that an asbestos worker who smokes cigarette* ha* 92 times the risk of death of lung cancer compared with an individual of the same age who neither smokes nor works with asbestos (16). The powerful multiplying effect of the combination of two agents can be appreciated by examining the experience of asbestos insulation workers cited above. When the cohort was established, the smoidng habits of the majority of the workers ' was recorded: 9590 had a history of cigarette smoking. 609 had a history of pipe and/or cigar smoking but no cigarette smok ing and 1457 had never smoked at all Their mortality experience, with particular reference to lung cancer, is detailed in Table 3. Among those who never smoked, only one lung caneer was seen from January I, 1967 through De cember 31. 1972. The pipe and cigar smoking group also had only one lung caneer death. On the other hand, there were 179 lung cancer deaths among those with a history of cigarette smoking, although only 32 such deaths were expected to occur. This, despite the fact that all of these men had worked In the same trade, with equal opportunity for occupational exposure to asbestos. The significance of the principle of multiple factor inter action has many ramifications. Two are of immediate interest. Pint, some substances, by themselves, may have no carcino genic effect: In concert with other*, malignancy may occur. Such Influence may be additive or multiplicative (theoretically, there could also be a protective effect, as well). As a corollary, substances now deemed innocuous may change their habit in new circumstances: our vigilanee must be constant. Too, since there may be many more substances of limited carcinogenic potential than those individually capable of inducing malig nancy, and since at least some working environments now tend to become more complex, this may turn out to he of consider able practical importance in the future. Second, animal studies generally are directed to the investi gation of one agent: negative results may therefore be mixleading Insofar as actual work rbk is concerned. (To com pensate, one should hasten to add. dosages can be far greater than those which occur in industry, and carcinogenicity en hanced). SIGNAL CANCERS Most occupational cancers are identified as occurring as in creased numbers of common malignancies. Thus, increased rates (taking age. year and sex into account) of lung cancer occur, for example, with occupational exposure to tulc. chro mates. arsenic, nickel carbonyl, uranium mining, fluorspar mining, hematite, /S-chtornttthylethtr and asbestos: of Wad- TaMe 1. Expected artd observed 4aa(h* among 17 IJO aaOostM insula- flan worksm ( the United State* end Canada January 1. IM7--Ooearnber si, sera. Ourttloa tram oniel at sipetura tea* dua a* yam wore ftan u year* flppaetad' ebaanod txpooto*- Obiontd ratal diadu oil cauaaa Caneat t[ sitae Lung canoar Aabaatoii* All other eeoaoo Member al portano 20349 34.49 2ft *t in 12 Ml 7H.13 141.13 * tlt.M till 110S *11 SIT M SO* ' Expected rata* v* band upon igs-i3Kifle whit# mat* ditto rat* data et tnt US National orr* at v>t*r statixtea. Rata* let i2 war* extra polated rrom rata* from 19S7--1971. " us rue* art not available. but that* ata rrt eauaaa of Oaats In toe ganarti plantation. Table 2. Daath* from lung aanear among 17 MS s*b**tea inaulallon maker* la the US and Canada, January t, 19*7--Oeeaabaa 31, i*73i relaSon w elapsed period (rent enaat of work exposure. lung Pancor Yuan free) anaat deatoe* daalli* Ratio <11 IS--It is-ia IS--St ss-ss **-44 a* a* 44--44 <S--4* 11 + Total ON i.tr .ft 10.70 1 *0 t.tt 4 44 4. SI 497 ts.tr ft a a 27* si 44 4.9 Expaoiad dtam* art baaod upon aga-ipaeitte whit* mala daath rata data *1 u>* us National Office or Vital statistics. ftatat tor 1172 ear* aatrapottitd from data from iptT--1*71. Table X Expected and oBaarved doatho of lung cancer among 17 *04 US and Canada aabastes Insufaden worker*. January 1, t**7 Oagombar si, i*7it rotation of efgirotto smoking. Bosnia from Ian* aanear ttnoAft Cxpectod* dburtrid Hallo making DaMla not known Hltlarv ol eloarott* xmaklno Ho Malory of vlgatatto amoving Never smoked Hialory of pip* and or cigar only i* KM sot* 1497 pgt w.n 3.11 1 0.1 Expected daithc bated upon ago-tpaolMo us mortality miss ter whit* malta dit/tearding amoving. Lung eancar aatimataa butd upon us rata* for oaneor of lung, pleura, bronchua and Iraenea, categorise 192 and 113 of ill* inwmitronil ClMtiflcariea of Oittiaaa and Cauaat of Ooalha, 7th Rtviaien. AMSIO, VOL 4 NO, I l AMfltO. 1973 15 AP00005705 der cancer with -ntphthyiamfee and benzidine; or leukemia with benzene and radiation. To find the effect of such sub stances, appropriate population studies arc necessary to see if the expected background rates are increased. Sometimes, espe cially if less common tumors are being considered, as brain or adrenal or kidney or lymphoma, extensive observations are necessary, if not of moderate sized groups over long periods of lime (after the 2D year pointl), then of very large groups for shorter periods (to achieve an adequate number of "personyears" of observation). In a number of instances, unusual tumors have been ob served in considerable numbers for which the usual expeetedobserved ratios are almost superfluous. When cancer of the scrotum occurred among Pott's chimney sweeps the absence of hiostatistieal calculations did not prevent recognition of the unusual situation. Sinus tumor* among woodworkers may be looked at in somewhat the same light (17). Two neoplasms, infrequent fn general but common with industrial exposure, have demonstrated that such "signal" tumors can be important factors In identifying occupational carcinogenesis. One, hemangiosarcoma of the liver, has as sumed such a role recently and will be discussed below. The second, mesothelioma, has a longer history. First reported the pleural cavity of an asbestos worker in 1953 (18) and In the peritoneum of another the next year (19), its link to asbestoc was firmly established in I960 (70) when, in a scries of 47 cases in one laboratory in South Africa, over a five year period, 45 were shown to have had opportunity for asbestos exposure of one or another type, decades before. The impact of this finding can be gauged by appreciation that, in general, approximately one in a thousand deaths in the general popu lation had been known to be caused by these previously un common tumors. With occupational asbestos exposure, these tumors have proven common (21). In some cohorts of asbestos workers, approximately fivt or six percent of deaths have been due to pleural and peritoneal mesothelioma (5). In-others, the percentage is lower: it has been reported, for example, that this neoplasm is less frequent among Quebec chrysotile asbestos miners (22), When found in family contacts, it led to the understanding of the danger 'of bringing dust from the factory to the home <23), when found amid residents in the neighborhood* about asbestos plants, it bespoke un controlled asbestos air pollution in the past. In South Africa's large aeries of cases, with adequate history, only approximately fifteen percent have been judged not to have had some known asbestos contact (24). Thus, wherever mesothelioma is Found, asbestos is sought. In this way, otherwise unsuspected oc cupational exposures to asbestos have been identified--in ship yards, especially (25X ENVIRONMENTAL CANCERS FROM OCCUPATIONAL SOURCES An important dimension was added to occupational cancer with the discovery that neoplasms might occur with the dis semination of the agent beyond the factory gate, either by its release during the manufacturing process or from resulting waste, or by contamination of households with the offending material being brought home on workers' clothes. Although Instances of such disease had been known before (20), tbe full Import of the problem was not appreciated until Newbouse's report in 1965 (23) when she demonstrated that, of 76 con firmed cases of mesothelioma in the files of the London Hos pital. of the 4} not known to have had occupational exposure to asbestos, nine had simply lived in the households of asbestos workers ('conjugal disease"] and 11 had neither worked with the material nor lived with someone who had been so em ployed. but had resided, many years before, within one half mile of an asbestos plant in London. This finding w soon confirmed (26). and the principle of carcinogenic risk derived from occupational sources is an important factor in current evaluation of control of environmental cancer, whether it be from radiation-producing power sources, agricultural use of pesticides, air and water pollution from petrochemical industry operations, carcinogenic mineral dust, or other substances or processes (It). These considerations are separate from those involving cancer risk with end-product use. either during further industrial manipulation of materials or in utilisation of consumer products. PETROCHEMICAL INDUSTRY CANCER There was a curious discrepancy during the first half of this century between continued concern regarding the potential for occupational cancer in the burgeoning petrochemical Industry and reliable evidence (hat this was occurring with any fre quency. In considerable part, the contradiction remains. On the one hand, the industry deals with a very large number of chemicals which either have been shown to have carcinogenic potential in laboratory animals, or are related to these chemi cals, belonging to such suspect groups as the polycyclic aroma tic hydrocarbons or some of the helogenated hydrocarbons; in several instances, as benzpyrene or (J-naphthylamine, occupa tional cancers in humans have been clearly established. On the other hand, the number of chemical agents so incriminated has remained comparatively small and the number of workers involved, limited. With the recent identification of vinyl chloride induced cancer (27, 28), the situation has changed somewhat It it still not known whether a good many of the petrochemical industry's materials will turn out to be carcinogenic--In large part, en adequate "latent period" has yet to run Us course, to allow for proper evaluation. Still, to find that a key chemi cal in the giant plastic industry was dearly carcinogenic has been disconcerting. Further, it was sobering to realize that If vinyl chloride's carcinogenicity had been expressed in increased risk of cancer of lung or colon, elevated rates of neoplasms of these sites among the affected workers might not have been identified for some years, at (he earliest. The fact (hat it was an unusual tumor, hemangiosarcoma of the liver, otherwise rare in the general population (perhaps one In 10 000--40000 deaths), which occurred, attracted attention. Three cases in one plant, the B F Goodrich Company in Louisville, Kentucky, were sufflccnt to establish a strong sus picion of the risk (29) and the suspicion became a virtual certainty when the same neoplasm was found in other vinylchloride polymerization plants, making vinyl chloride the likely offender, rather than other coexisting chemicals, as special additives or process chemicals, peculiar to the Louisville plant's operation. At the same time, the fact that only a dozen end a half cases came to notice in the first five months after discovery of the condition did little to allay concern, since these cases, when analyzed, had begun work, on the average, approximately 20 years before death, at a time when the vinyl chloride-polyvinyl chloride industry was limited in size and still employed relatively few workers. Of the 19 eases recorded by mid-June, 1974. 15 had begun work 1944--1952, with an overall average of 20.4 years from onset for the group as a whole. Sinee the great majority of workers in vinyl chlo ride-polyvinyl chloride plants were first employed during the 1950s and 1960s, It was evident that the full impact of vinyl chloride tumors would not be known for another two decades. Limited data so far available suggests that, at least for poly vinylchloride polymerization workers, the incidence of oc cupational cancer will be significant. We have examined the mortality experience of a cohort of workers employed at a large polyvinylchloride polymerization facility in the United States. The plant opened in 1946 and from that year to 1963, 257 individuals were employed in (he production process for five years or more. While exposures began in 1946, relatively few individuals were employed prior to 1951, when a significant increase in the work force took place. Thus, the majority of the cohort has had a bare 20 years or las from onset of exposure. An initial report of the experience of these men has been nude (30). We have traced each of the 257 individuals to December 31, 1973. Twenty-rive were found to have died, of ait causes. Three of the deaths, each confirmed at autopsy, were due to hemangiosarcoma of the liver (Table 4). Ages at death were 4t, 54, 60. Elapsed time from onset of first expo sure lo death was 14,17,23 years. DOSE-DISEASE RESPONSE RELATIONSHIPS Discussion of this thorny question, with social, ethical and economic implications co-tningted with scientific perspectives, was stimulated and made much more acute in the evaluation of regulatory measures necessary for the control of vinyl chloride cancer. While h has been generally agreed that the risk of malignancy increases with intensity and duration of exposure, there has been much less concordance in the evalu- 16 AMBIO.VOL4NO.) Table 4. CauMt el e. . ier f er "rare yean. j Cwobra at all in-- hseplxiws t* lymphatic Brain IQIioblwlonwl Panct--a Oaten _________ Bn>wt [with eaeoaaoa aeat-egwesw 41--4H>> CaiUlcreacgW Snrnt, ation of whether t Ic would not ocenr. The this aspect of tha qut be that such data ar menu, to be cottvin numbers of animals large numbers of v | longed period* of tin i the monomer. Even | would elwayt be onl conceivably could sh1 would seem to indii | threshold limit for i regulations for the c chloride in the Unit* j from this point of v been proposed (32) : might be considered ; aDowi for Inevitable I occur in the. industr of practical problem of tbe work enviroom PRETESTING OF NE Recognition of the onset of exposure to r and their carcinogen! raised the corollary qt evaluation and shorte ty, Much attention is recently, however, e> Although structural occasion a high level necessarily follow stru known. Further, whil with biological activl' with toxic effects on tem. without coneomi Experiences with suggests, however, tha for at least some age were able to establish stance whieh was late 33). It is not known * proaehes will be equ whether ether laborstudies. will extend tl hoped for and much mation on the questio for selection of agents inehide such considers other biological acti\ exposed. For substanc could apply, with the studies should he $ugg worker* whose exposu AMNO. 1975 AP00005706 2ER in| the first half of thla girding the potential for g petrochemical industry occurrinf with any Treintradiction remains. On i a very large number of yvsn to have carcinogenic e related to these chemi as the polycyclic aromagenated hydrocarbons; in f-naphthyiamine. occupa(early established. On the gents so incriminated has the number of workers ' vinyl chloride indueed rhanged somewhat. It is ny of the petrochemical be carcinogenic--in large as yet to run its course, to find that a key chemiclearly carcinogenic has obering to realize that if sen expressed in increased ted rates of neoplasms of ers might not have been lest The fact that it was a of the liver, otherwise .ps one in 10000--40000 sntion. F Goodrich Company in to establish a strong sustpicfon became t virtual vaa found in other vinyt* king vinyl chloride the coexisting chemicals, as peculiar to the Louisville ;he fact that only a dozen he first five months after t to allay concern, since zn work, on the average, th, at a time when the ustry was limited in size orkers. Of the 19 cases begun work 1944--1932, from onset for the group of workers in vinyl chlo- Irst employed during the the full impact of vinyl for another two decades. it that, at least for poly3, the Incidence of oc. We have examined the ? workers employed at a >n facility in the United i from that year to 1963, ie production process for began In 1944, relatively o JMI, when a significant re. Thus, the mafority of *s or less from onset of e of these men has been )f the 257 individuals to * found to have died, of dt confirmed at autopsy, a liver (Table 4). Ages at from onset of first expo- ( ' > j | 'l < j < j j i ! i noNSHtro with social, ethical and iih scientific perspectives, e acute in the evaluation For the control of vinyl generally agreed that the intensity and duration of concordance in the evalu- AUHO.VOL4HO. I Tahta e. mmm l <uH among *e wether* ergoeod to tor f er more yesra. eMerWe Cancer* *> ell cite* njmjngjojjgamajnwi^_________ Heepiefe el lymptietie end hemateaeleUe Uhum Irate (aUdblaetome) Paacteoo Colon Bene __ Clrriioel* (with eeephtaeel vorlceal feet eerimllee ktaedlng (CHeleinhleal* OiHleiraertHat aieeeeee. atbor 1 ation of whether a lower threshold existed below which cancer would not occur. There have been few data bearing dfreetly on this aspect of the question and,in the nature of things,Untight bn that such data are unlikely to appear. "Negative" expert* meats, to be convincing, would have to Involve very large numbers of animals and, more important, observation of very large numbers oF vinyl chloride worker* exposed for pro* longed periods of time at measured low levels of exposure to the monomer. Even if these data should be obtained, they would always be only an approximation, since further study conceivably could show exception!. Theoretical considerations would seem to indicate that there is no identifiable lower threshold limit for carcinogenic agents (31). The proposed regulations for the control of occupational exposure to vinyl chloride in the United States seem to approach the problem from this point of view; a level of one part per million has been proposed (32) which, interpreted in practical terms, might be considered a "no threshold" level but one which allows for inevitable mistakes ind accidents which might occur in the Industrial environment, u well si recognition of practical problems concerned with Instrumental monitoring of the work environment. phetestinq of new materials Recognition of the long period of clinks] latency between onset of exposure to msterials in the occupational environment and their carcinogenic effect, if thia is to occur, has recently raised the corollary question whether we might anticipate sueh evaluation and shorten, or eliminate, this period of uncertain ty. Much attention is now being peid to this possibility. Until recently, however, expectation and desire exceeded promise. Although structural similarity to known carcinogens might occasion a high level of suspicion, cancer potential does not necessarily follow structural resemblance; many exceptions are knows. Further, while suspicion could be directed to agents with biological activity other than cancer, many are known with toxic effects on kidney, liver, lung, central nervous sys tem, without concomitant recognized cancer potential. Experiences with vinyl chloride and 0-chlormethytether suggest*, however, that laboratory screening might be feasible, for at least some agents. In each instance, laboratory studies were able to esubliah the carcinogenicity of a chemical sub stance which was later shown to be carcinogenic in man (28, 33), It b not known whether such experimental screening ap proaches will be equally productive with other agents, nor whether other laboratory technique*, including mutagenic studies, will extend their utility (34). Certainly, this is to be hoped for and much work is heeng initiated to provide infor mation on the question. Guidelines that would point priorities for selection of agents to be tested are also being discussed, and include such considerations as chemical structure, evidence of other biological activity, number of worker* likely to be exposed. For substance* already in use, similar considerations could apply, with the added dimension that epidemiological studies should be suggested when there are available groups of workers whose exposures began HL--1j or more years ago. r---tt it'*"ilia I. fPatuCmetrefi**Jbeftrm. CMwikef Ohvrw/taor (Haoac Oar* tod Cat- Bass London, 1773) 63-41. IK Areas W M F Argot. CUtmkal tntueiloH tfCrnttr (Aadamto Pm*. New York, 1974) Vai IIS *p 3 - 4. 3, A Pirehaa aad H SiH. dmarfewa Jewnafqf Conor W, 41) (ina). 4, X 0*4 *UUA of MattiM 12.11 (S5V 3, IJ SeUtoff, C C tUmnond tad H Saidmin. in ttdogtctl Sffttu tfAtbtuot, t e*m*U, J C GUom. V TlmbatU and J C W**er. *<* (tawmmkoaal Aatney Re- ware*on Cancer. Lyon. I773)py 309--iia. A TTMuewetMEJCcuhif, Archnna/EtviroAmffiu/Hultiiifl), 110(1943). T. IJ %^ketr, }CkarfaJ t CiU*WMad.Jeu/ntlq/ihtAmrlemi i/4^*IAt*ottr- dents*. 22(1*64). a 3 C W*xnar. 0 tarry.J W Skidmore lad VTfabnL HrhkJmirmaltfCtMctr19, 252 (1974). 9. B C Hammond aad I 3 SrttkcIT. ia Analytic t*t! tp*HmtnmI Eptdcmicbfy tf Cawfar. W Nakihv*,T Himyoraa.K Niiiioki irtd HSu|*aa, 14* (Uniwnily at Tokyo Pm*. Jam*. Writ? 41 -49. M. f JSalko/rand EC Hammond. Imlroitmtniil Kctttrck 4 (2) il--UJ (1*71). U. i 3 SeUkoK and E C Hammond, Pntttdtngt tf i* M Naricmaf Ctncm Confir ms. La* Aesrica. 07 (1973). II It DaU, L 0 Morjan aad FE SpeUar, triritk Jaurttl of Cmtrr XXIV (4), 423 (inoL 13. PElundia. Jf.J W Lloyd. K Id Smith. V E AmWmMDA Holaday. Mi* A*)* 14.571 (1944). IS t Fade***, A Hcpatvml and A Andeia*. JournalofCmttrtt.n (19TJV II W 0 Ftgeoro*. X RaWemU aad W Wrba. Km MfW 2M (31). 1094(197}). IS. I ! ScEkeff, t C Hatwnend and J Ckwg, fawnl tfrAr 4h4*< IMIaJ At- MdariM tot (3), 164 (MIL IT. g D Artaon. X H Ceodcll and g Raa^ JMrM /*wn*(WAmlamnlarJ/edUaaSt, tl. A Wrte. V^liWiA#}, U (1954V 19. FUiAfr, AK**rJtirOnf'a*t+oiotkmtJGtwtrMi?rlrmlS,mil9SA}. UK Wagner, c A SUgp aad P ManWu4, tiiUM )uiWdMtaiW .V*4<cMr IT, 140(1960). 31. JiEnsictau9tndW.FSmiih*r.<W21.30(1944), 12. JCMcDonald, A !4<Doml4,C W OiMa3 SiamintyekiaadCI Romhcr, Af (AAwofAndronmmref ShaAA 23. ITT (1971) U. M L Nawheiu* an* H Ttawpw* WttUA /Ounui Muiutd Wntotw 32. to) (I963L 34. T Wdae, gmr* Ajrtcm M*dk4/oum* ST (3). 1*3 (1973). 23. F O Haniaa. Arumh </ Om^wIciW 11. ]JS (19441. 34, t Liakin end H Fidawka. AatAhier tftmirmmnMl Httitk Id. 379(1947). 37. FL Viola. A Bi*oltind ACapuu. dinar ftearrt >!. 316(1971). ZZ. C MlHaa* and 0 Laftwina. Awtrwviwnul Xemotek 7, )I1 (1974). 29. JLCnadiaad MM Johnon. AatmaWofOecup*io'*tMt4kt*t 14, 130(1974). 301 W J NMotaon, H SeMman. E C Htetnoad Ud IJ SaSkad AmtliefHn Yt* Ai iWiiiij tfStttnm. in yra*. 31. IViantai tf rni'Mwiwud wrWfmi. X*n to in* Surim Oenerel. USFH*. Afeil SL197ft. Ad HeaCaaoUnaeon Uw gvsluailoe efLewLateItoTEto idranmanml Chwnkal Carctocftoe, 3k VSOtpmmmof UUt OttyptJitnt) s^itj t*4 Ut*h>i A+Witru&t, xp* Mm t y+ri diMAt: eer*yr*emtJ*V<ny ewd hnith weedardr (Federal Rtfiaar 3933(90--3}MI.Oeiotor A 1974). 33. B L Van Du urea, B M OeMacbnidL C Kio. L lanpmk. C Macando and A Sivall.ArrAAotr/AWwv'wrval Htthh 14,472 (1941). 34. U Rannu*. A Johanmcn. C KamtL C A WatHmam*r Ambit 3. 194 (1474! 33. Xeaaarehnifponad fcy j*I ES 40911 ofthe Naiteul liudtute tf Envlrenmcnol Hanlto Seiaaaa ard fey M Cavteanmteul Cancar Rciaueh Fiejaet f Um Amen* out Cancer Society R-33 *. Or Selffceff aerron t$ Prefeaner tt Community MedMne at th* Karat Blnai Sehoo) el Modtolne el the City tMveraliy el New York; and ee Dheetor el (to Cnvtrenmenul MeeW) Betanec* Coaler. A part Preildent ef the New York Academy of artenoee. Me Intereeto new empMrtce problem* el environmental cancer. pertJcdarty thee* aaceetaiM wKti materials In Induetry. Hew- aver. Me research has In the past alee Included ether d>i***e*; end (or many. Me aehlevemertt* In environmental dtseete reMarch ere malebed py Mt eoniilbuiierw in the Introduction al laoMaxld fw the chamoihernpy of (ubereuleale, tor which he we* honored by tho Lacker Award ( th* American Public HaalUt AmocUUo* in ms. Hie Mdreee: Mount Sinai School el Medi cine, FIMi Avt and 100 Street, Mew York, N Y tons, USA, AMMO. 1973 17 AP00005707 'A ~Pk9duL Ci&mjesali. From: Gerald J. Mantell 7 April 1975 ri/i tn~ Route cc: M. H. Danzig C. A. Helberger E. H. HoJJ4Sfer* W^Wfstawasz Note^&qe 2 re samples. Route CC:*W? u \ lngunnr' *{?> ffY'Wamwn ff ^ flrinlln QL_ It - see page 4 G. J. Mantel1 - last AP00005708 J interoffice ^^ *o^MEM0RANDUM C. E. Bowman To y M. F. Smith R. C. Danzlger KECJfciVJiii APR 2 MIS J, M. D. Subject tu> A&s yt#/ ZL$A? TAprll 1975 Labelling Requirements to Meet OSHA Standards \ (Location, Orftniutfon, or Department} Valley Forge_____________ (Location, Organization, or Department) cc; A. R. Adams J. T. Barr U. W. Brand S. F. Burke T. 1. Carey Jo.,.?l...Dav1dspa R. Fleming R. E. Jones J- D. Kramer v* -\ J. C. Novak --"*7^ Ho A* Qulgl J. T. SebastlaneTl^T V. H. smith 6.3. J1. 3peed . ^r H. L. Uatson rtitfr* --rSss-.^ APR 4 1976 Confirming my telephone conversation of 31 March 1975* the following Is a breakdown of labelling and -marking requirements v * necessary to comply with OSHA standards,. Rad Hopper Cars ' * * ' X Should be stencilled on or In 'the-'-vicrlnity of all hatches and all outlets in 3/8 Inch lettering.^;. rJ~ ,'?&$ /S&Zr'ig-*- V, Bulk PVC Trucks .. a "it --Should be tagged with tags already:provided on or In the vicinity ' "f -of all hatches and outlets, j.XX-.-- . -Bags -All bags -Should be labelled or stamped on one aide or on one end. JSaylords or Bulk Boxes . Should be labelled or stamped on-the side or-sides which bear the product identification. Pox Cars. Vans and Containers ^Outsides of these units should not be labelled, since lags or -boxes inside are labelled and it is -not necessary to label .a secondary -container. r/.sz? bi-:spa.-:m;; - *320} ;-wy -4T -. ?mn AP00005709