Document RazXdzKwZY7gbkvya470n4g3n

s 1/ PUBLIC HEALTH sr.nviCC national iNiiyiTurcu c:-" health January 14, 1975 NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES P.O. DOX 1*231 RESEARCH TRIANGLE PARK* N.C.. 27709 919/549-8411, Ext. 3201 Dr, Robert M. Kereness ci;J..ive Director Asbestos Information Association/Ncrth Am* ri Co 1660 !. Street, N.W. Washington, D. C. 20036 Dr. Mereness: Recent events indicate a need to assess the carcinogenicity of orally ingested asbestos or asbestiferm minerals. As Chairman of the DHEU Comnittee to Coordinate Toxicology and Related Programs, I asked Dr Raymond E. Shapiro, Food and Drug Administration, to head a Subcorcnittee on Asbestos Protocols. The purpose of this subcommittee was to review all existing data with respect to the biological effects of orally administered asbestos, with particular reference to carcinogenesis; and, if necessary, to develop appropriate protocols tor studies to elaborate ori any data deficiencies in this area. After reviewing the existing data the subcommittee developed a draft of a working document which is enclosed. This subcommittee working draft is not intended to be a final protocol. Rather, it provides a basis for comment and discussion which will lead to the development of a protocol for studies. The subcommittee believes, however, that the working draft is far enough along that it is now appropriate to seek the comments and views of scientists working in this area, affected industries, and public interest groups. I invite your written comments on this working draft by February 14, 1975. In addition, subcommittee members will be available on Tuesday, February 11, 1975, to discuss the working draft and answer any questions you may have. This discussion will begin at 10:00 a.m., Conference Room 8 of Building 31, (Sixth Floor - C Wing) on the RIM Campus. If you plan to attend the meeting, please notify my office as soon as possible so that we may be sure adequate meeting space is available. Sincerely yours Enclosure David P. Rail, M.D., Ph.D. Director 1 BB 0016049 | ' WORKING DRAFT PROTOCOL SUBCOMMITTEE ON ASBESTOS PROTOCOLS DHEV7 Conanittce to Coordinate Toxicology and Related Programs f The Subcommittee on Asbestos Protocols determined that adequate data is not available for a determination of the carcinogenicity of orally administered asbestos. It considered many experimental approaches as to the best means for securing adequate data and reached the opinion that, as a minimum, a major chronic carcinogenicity study is warranted. The current major study working draft reflects the Subcommittee's consideration and response to critiques received on its initial draft proposal. The current working draft consists of: (1) Outline (2) Written comments providing insight as to the background deliberations and rationale for the decisions (impasse) reached (3) Comments relevant to the deliberations of the Subcommittee? regarding a multispecies approach <*) The Proposed Memorandum of Need developed by Dr. W. Horowits, Food and Drug Administration, with respect to methods development for quantification of asbestos fibers was accepted by the Subcommittee. The work defined in this memorandum is now being conducted through an FDA contract CHAIRMAN, SUBCOMMITTEE ON ASBESTOS PROTOCOLS | BB 0016050 | OUTLINE OF THE WORKING DRAFT OF THE ASBESTOS SUBCOMMITTEE'S MAJOR STUDY Test Species - Rat Test Strain - Inbred F344 or other (see comments) Positive Control: a) chemical producing gastrointestinal in rat strain chosen b) one dose level c) two groups exposed via food or water Duration of Study: a) life time (36 mo.) b) SPF condition Fiber Type by Priority Rank: a) Chrysotile b) Crocidolite c) Tremolite d) Amosite > Fiber source - UICC preferred Diet: a) b) c) powdered defined, constant formulation control contaminants Dose and Route Food; high dose 1% (0.5gm/kg/day) low dose (see comments) Water: 10-20 ppm dependent upon suspension properties (see comments) Number of Animals: Control - 1000 Positive Control - 200 for food; 200 for water Chrysotile: Food - 2 doses, 550 each dose Water - 550 | BE 0016051 ( Number of Animals: (Cont'd.) Crocidolite: Food - 2 doses, 550 each dose Water - 550 Tremolite: Food - 2 doses, 550 each dose Amosite: Food - 2 doses, 550 each dose Water - 550 C | BB 0016052_J[ Another consideration was the postponement of the chronic study until a species more suitable for the model test system than the rat was found. These searches would be predicated upon demonstration of the penetration of asbestos fibers into and through the gut. Such penetration has been reported by South African workers for the baboon. While these studies are highly important and necessary in the long run, the Committee did not feel that the chronic carcinogenicity studies should be postponed while this data base was being developed. Even with the rat, such a chronic study would take 3 to 4 years to complete. choice op strain and positive control The problem in using an inbred vs. an outbred strain were discussed. Ideally, the F^ generation resulting from the cross of two inbred ` strains would be the best test animal model since it allows genetic uniformity coupled with hybrid vigor. However, this may not be feasible in a study of this size. In addition, we might also lack the necessary background data with respect to this cross. Therefore, the Subcommittee recommends the use of an inbred strain. The criteria for the choice of a specific strain for this proposed study is twofold: (1) a knomt high survival rate of control animals into the third year of life, and (2) a known low spontaneous tumor incidence. The key point is that whatever strain is chosen, it should not have an early proclivity to specific tumor type(s) which affect survival. Various strains were discussed and the Fisher 344 rat appears to be a suitable possible candidate. "}~BB~00l6053_| SUBCOMMITTEE COMMENTS Marking Draft on Oral Asbestos Major Study ' TEST SPECIES The Sr.huOipjiittee discussed the pros and cons of using rodents, for the testM-.g of oraljy ingested asbestos for carcinogenicity. On the one hand, vu had to consider the statements at the North Carolina Asbestos Conference that the rodent was a poor animal model for this purpose. In addition, several negative feeding studies have already been completed in this area. On the other hand, since these studies are, in the main, unpublished, one does not know if the negative results obtained were confirmation of the objections raised at North Carolina, or possible inadequacies in design and execution. In addition, alternative animal model systems that might be chosen, e.g., dog, minipig or non-human primate would require up to 7 years or longer before meaningful results V might be obtained. Even with the potent liver carcinogen, aflatoxin, fed to non-human primates at high doses, it took 5 to 7 years for a hepatoma to develop. Therefore, in light of the charge to this Subcommittee it was concluded that a properly designed and executed ingestion study with asbestos should be undertaken with the rat to determine whether this model system does or does not respond to ingested asbestos. The Subcommittee recognizes that while positive results will be immediately accepted, negative results may be interpreted as a choice of the wrong model system to test the question. In partial recognition of this situation, the Committee discussed a multispecies approach. However, t until definitely proven otherwise, the Subcommittee feels that a major effort should be made along classical toxicological lines, i.e., a well designed rodent study. ( BB 0016054 -3The C'oi :'ij t l.i-c. concluded th.it in terms of whether or: not ingested asbestos fibers my induce gastrointestinal ennters, the animal strain should have a demonstrable potential to develop such tumors when exposed to a chemical carcinogen. Therefore, the choice of the chemical for the positive control and the choice of strain are interrelated. The only positive control of any real meaning is one producing C.I. tumors. t The emphasis on gastrointestinal cancers with respect to asbestos is predicated on the reported increase in these cancers in occupationally (inhaler.ion) exposed workers. Since small amounts of asbestos may be ingested in food and fluids,, the possible significance of these background exposures is of interest. *t It is also recognized that while we may be interested mainly in the target organs, the gastrointestinal tract with respect to man, challenging any model animal system with the same agent does not mean the same response patterns will be seen in the animal model as is speculated for wan. Work at NCI has indicated that rats of the AxC strain develop gastro intestinal tumors when fed N,N'-2,7-fluorenylenebioacetamide (2,7--FAA). Choice of this strain, therefore, would meet the requirements stated above. In addition to 2,7-FAA some other chemical carcinogens that warrant consideration are cycasin, nitrosogunuiline and nitrosourea. | BB 0016055 ] The Committee felt that data should, be sought on other strains that develop gastrointestinal tutors after ingestion exposure to chemical carcinogens. These might lead to possible alternatives. The Subcommittee recommended tliet the question of strain and choice of positive control be discussed with Drs. Katherine Snell and Howard Stcv/ard of the i:CI. A meeting was arranged by the Chairman with these two individuals on Wednesday, July 17, 1974. These discussions will continue. On Monday, July 22, 1974, the Chairman contacted Dr. Sid Siegel of the KCI. Dr. Siegel has promised to search their files for a list of compounds eliciting a carcinogenic response in the G.I, tract, when administered orally, and where it was published. With this data base, from which we can also determine the species and strain used, the final choice of strain and positive control should be that much easier to.make. The use of 2C0 animals at one dose level is considered adequate for each route of administration. DURATION OF STUDY The study is to encompass the life of the test animals. Given that a long latent period could precede neoplasia, survival through the second and into the third year of life is desired. The need for utilizing SPF rats, housed under SPF conditions, is an explicit re commendation. 1 BB 0016056 The. bubcommittec recommended the use of a nutrient defined, constant formula diet. This diet would be monitored for contaminants. If / v'-'L'inie, maximum contaminant levels will be set. The question of nixing asbestos fiber and powdered chow together, then pelKti.KJ.ng, v.v.s discussed. The Subcommittee felt that the pressure and hem generated in pelletization might alter the asbestos fiber. The consensus of the group favored checking out the use of a powdered chov; dispensing unit as now being used at NCTR. This unit apparently appreciably reduces the dust and inhalation hazard. The possibility of mixing the asbestos fiber and chow with 3% corn oil was also discussed. The Comr.iittee discussed the purity of the diet and the drinking water to be nsec. If a purified senisyntnetic diet and pure water were used, a positive response in these studies might be interpreted as showing that asbestos, per se, is a carcinogen. On the other hand, if the diet and/or water contained trace amounts of chemical toxicants or carcinogens, a positive effect might have two possible interpretations: (1) asbestos is a carcinogen, per se, and/or (2) asbestos is a cocarcinogen. Since man lives in the "real world" the use of a defined (not purified semisynthetic) diet and tap water should be used. The use of a semisynthetic diet would be recommended for other studies when one might wish to carefully study possible interactions. When a semisynthetic diet is chosen, one would again have to search the literature for data on strains that will tolerate this particular diet. 1 BB 0016057 I DOSE AJE) ROUTE ' Tiic Coiicn.itucc reco-n.icndo that asbestos bo tested in food as well as water. Human asbestos exposure estimates were determined several ways: Estimates of Human Ingestion Exposure 1. Cunningham mass: 1x10*6 gm/liter. 70 leg man: drink two liters: O.OlxlO^gin/kg/day plus cook liters : 0.06>:1C"6 gn/kg/day and if assume inhaled and completely swallowed an amount equivalent to the above: total ingested: 0.11x10*6gm/kg/day. 2. Kay mass: lxIO-^gm/liter (Ontario) drink 2 liter: 0.03:-:10~9gn:/kg/day plus cook 2 liters: 0.06:;]0""g:.i/kg/doy plus cquiv. swallcncd air exposure: total ingested: 0.11x10*9 c^./kg/day. 3. Duluth: assume mass: 25pg/liter drink 2 liters: 0.7xlO~6g;n/kg/day plus cook 2 liters: 1. ^xlO'^g^/kg/day plus assume equivalent swallovjod air exposure: total ingested: 2,SxlO"6gm/kg/doy. 4. Range; 0.03x10*9 to 3xlO~6gTn/kg/day a range of 5 orders of magnitude depending on assumptions j BB 0016058^1 7- ','?} -;r Pr.^ y')\ x 4u x g-,t x 2p :: 2ji Or X ly X li-O C-ll X 0.3 X 0.3vj) Dally Permitted Occupational Exposure (gm)l IC>.25 X 10-3 2 X 10-3 (0.25 X 10-3 (7.5 X 10-6 1. Air St.; :..\r,vd:' 3 fibers/cc (>5y) Fiber U.- G. = 3 G hcr.-T. day Kc&p, air intake: 0.7m3/hr. 2. 70 kg iJit Assume Inhaled is all Swallowed (vg/kg/day2) 230 29 (4) (0.1) Diet Leveln ' The maximum dose in the diet was set at 1%. If we assume a 20 gm per day food intake by a 400 gm rat at 1% asbestos in the diet, we have an 4* * --5 11 exposure of 0.5 gm/kg/day. This level ranges from 1.6 X 10 to 1.6 X 10 time our projected level of possible human exposure. Since animal exposure is at least 160,000 times higher than projected human exposure, nothing is gained by raising this relationship another order of magnitude relative to the potential loss in adversely affecting animal health. The use of such high levels in carcinogenicity testing of chemicals has raised the question by some of measuring the potential of an effect of alternate or aberrant metabolic pathways. However, in terms of asbestos fibers, one is possibly dealing with a physical or physical/chemical cellular interaction, non-metabolically related in terms of chemical degradation. In this case, the use of high doses of asbestos does not carry the same implicative objections associated with chemicals. _ I BB 00 ^6059^ There were several recommendations that: the study Include the definition of n dose-response curve for each asbestos fiber type being tested in the food. Implicit in this recommendation is the assumption that a positive response is expected. This is precisely the question being asked; namely, is orally ingested asbestos carcinogenic. The Subcommittee feels that it is premature at this time to go to the expense of testing four dose levels of each asbestos fiber type in the food. With the number of animals involved per level of exposure, additional exposure levels within each fiber type would push the proposed study into even still larger cost figures. Therefore, in the working draft, the Subcommittee, in order to be able to cover all asbestos fiber types of interest, recommended two dose levels per asbestos fiber type in the food. We reaffirm this recommendation. The question of what two doses to recommend was next considered. As discussed previously, 1% in the diet was agreed upon as the upper dose. Initial discussions recommended 0.01 or 0.001% in the diet as the second dose. The Subcommittee recognizes that this dose is too low. Two alternatives then discussed were 0.5%, or 0.1%, in the diet. These discussions were predicated upon the assumption that the highest dose elicited a positive response. Those advocating 0.1% in the diet felt that if the response obtained at 1% was on a plateau of the dose-response curve, reducing the exposure by one-half may not be sufficient to produce a significant change in observed tumor incidence. If one was not on the plateau, one would still see a change in tumor incidence with reduction in dose by a factor of 10. 1 Bfi 0016060 | 9- V.'lioue ir cring G,,:;% avgucd that it the tumor incidnacc at .1% asbestos in 1 the- t var ov,.-,. high as 50", with a projected slope of one, a reduction of dose by a factor of 10 would civs a tumor incidence of only 5%. This v:ight not be significantly different from the background level to estrh'.i i-sh a second ''effect*' point. If the projected slope were greater th-si 1 or if the tumor incidence at 1% asbestos in the diet were i.'.udi less ix.r.n 50%, the possibility of obtaining a second "effect" point was still further reduced. Even with a projected shallow slope, this argument still holds true. The discussion then resolved into which is of greater importance: establishing the second point as a possible "no-effect" level or deter mining two effect points. Since this study is designed as a carcinogenicity study, those advocating doses of 1 and 0.5% in the diet felt It was necessary' to maximize the potential for obtaining two effect levels. i Thus, if a positive response is obtained with two effect*points, a batter approach to a mathematical calculation of a possible permitted level of exposure may be made with two dose related effect points than just one. Proponents for choosing the second dose at 0.1% recognized this point, but felt it was of greater importance to define a possible no-effect point. The Subcommittee was unable to reach unanimity on this point. Of those present at this time, Drs. Groth, Ligon, Munro, Shibko and Tardiff voted for the second dose at 0.1% in the diet, while Drs. Shapiro and Stanton voted for a second dose at 0.5% in the diet. | BB 0016061 ^ -10- Another discussion with respect to doses of 1.0 and 0.5% in the diet centered uper. passih:111 r.y of dose overlap, Dose is a function of food consumption and variation in food consumption per day leads to dose variation. Also, any variation in food consumption per unit weight of animal .leads to possible dose variations. If there is n 20% variation around the mean,, then the doses we are then comparing are 0.5 gm/kg/day t (range 0.4 to Q.G) vs. 0.25 gm/kg/day.(range 0.20 to 0.30). If one Look 1/2 the log difference between 1 and 0.1, the antilog of 0.5 x 10 would give a dose of 0.3% in the diet. This would then result in a sharper Food consumption records are, therefore, absolutely necessary and the total dose received should be calculated from the start to finish of the experiment. Water Levels If municipal water contains 25 ug/liter, an 80 fold increase in water content would give 2 ppm in the water. If one assumes that the rat food contains some fluid phase to reduce dust, let us then assume the 400 gm rat will drink 10 ml/day, or an exposure of 5 X 10 gm/kg/day. The three doses, two routes are now geometrically related. A key point is how much fiber and at what size distribution will stay in suspension. Preliminary EPA studies (Dr. Tardiff) have indicated that - up to 10 mg/liter (10 ppm) of chrysatilc, crocidolite, and another omphibolc may be suspended in water. This is primarily small material. Thus, the asbestos in water study appears to be feasible. However, it should be recognized that the particle size distribution to which the animal is orally exposed by placing asbestos in water is different from -U" that hen ashes u-.. is mixed into the diet. The actual particle size but:'on in water should be accurately determined. For the asbestos in water treatments, in order to minimize the effects of settling out of fibers, it was suggested that water bottles be prepared ovejy ;.f 1-nrr.oon and taken away in the morning. Dietary preparation and waste disposal must.be carefully standardized. Air monitoring for fiber content should also be done every six months: at night as well as during the day when cages are being changed. At each time of sacrifice, several fecal pellets should be saved from the cage holding that particular animal. These pellets should be analyzed to see whether the size distribution and chemistry of the asbestos fiber changed during passage through the G.I.' tract. The Committee considered and rejected the gavage route of administration for the following reasons: (1) possible bolus effect, (2) time and cost factors for the number of animals involved, (3) possible loss of animals during the period of treatment and (4) interactive irritation artifacts leading to cancer. NUMBER OF ANIMALS The number of animals chosen is based on a lifetime study, under SPF conditions where a significant number of animals will survive into the third year of life. If one expected a 50% survival into the third year, starting with 500 animals (250 M, 250 F), would only give 250 animals on | BB 0016063 J -12- which to base a conclusion. One assumes, in this case, the pcs of no effect being seen the first two years ;mj any -.a'ei 1 ity ( \ that may occur in the third year occurring at a low incidence, Therefere. the Committee recommended 500 animals for each treatment level. ) The Subcommittee also recognizes that it is never possible, in the iccl world, to have a sufficient, number of animals per treatment group to reduce the possibility of a false negative to a mathematical near zero level. Ue do feel that the number of animals chosen is adequate, particularly when one considers the large number of questions we arc attempting to answer at the same time. The numbers chosen are a compromise based upon feasibility of carrying *p out the total study as well as the assumption that possible target `Organs, particularly the gastrointestinal tract, will have a low noise level. The more accurate the determination of background noise, the better one may be able to measure possible treatment differences. Therefore, the Committee recommended that 1000 animals (500 II, 500 F) be established as a control group. s The Subcommittee recommends that an additional 50 animals be added to each treatment group in the major rat study. In this way, 10 animals may be sacrificed at 6, 12, 18, 24 and 30 months. With this serial sacrlf^ce> have a samll pathogenicity study as well-as time frame reference for tissue fiber content. McCrone Associates will analyze 7 tissues, from one animal, for asbestos content, at a cost of of $200. 1 BB 0016064 2 TYPE Tho. Cor.i: Ltee r: jkl:P . fiber type ns to priority in oral carcinogen testing. In order of decreasing priority they are: chrysotile, crocidolite, tremolite and ar.iosite. Hie priority ordering is based on the total number of the population that may be exposed. Chrysot.i.'le exposure may occyr in fluids due to the use of chrysotile containing filters for certain beverages, the possibility of abrasion from chrysotile containing asbestos-concrete water conducting pipe, and from the geological contribution to water that may be used for drinking. Colid phase ingestion of asbestos may occur from possible chrysotile contamination of talc used in foods and orally ingested drugs. Therefore, chrysotile should be tested in food as well as in water. It was recently reported that crocidolite was used in asbestos-concrete water conducting pipe. If abrasion of fibers from this pipe occurs, crocidolite would then appear in the water and could also be contained in foods prepared from this water. ; \ \\ \ ) Therefore, crocidolite should be tested in food as well as in water. It should be noted that placing the amphibole crocidolite in the second Pr^or^-ty ranking, we recognize that the level of exposure is possibly much lower than for amosite but the number of people potentially exposed in the former case is inordinately larger than the latter. Furthermore, if the asbestos question is only a subset of the more general fiber question, the choice of several fiber types within the subset may give | BB 0016065 J -14- a clue as to whether any possible response is physical or physical/ chemical in nature. Therefore* the Committee strongly recommends that all fiber types be considered simultaneously in the major chronic feeing study. Tremolite is the major possible asbestos contaminatnt of talc used in fpod and in orally Ingested drugs. ' ^ Therefore, tremolite need only be tested in food. ' \ Since talc contains anthophyllite and chrysotile, as well as tremolite, the Subcommittee recommended that consideration be given to feeding a mixture of the three in proportion to their occurrence as a contaminant in talc. 't Amosite exposure is a case of a localized situation rather than a national one; namely, the problem at the western end of Lake Superior. The question is one of amosite in the water which could also be contained in foods, prepared from this water. Therefore, amosite should be tested in food as well as in water. '\ J FIBER SOURCE ASP QUANTITY The Subcommittee agreed that the U.I.C.C. standard asbestos fibers should be used whenever possible. It was recommended that U.I.C.C. Chrysotile D be chosen, a mixture of chrysotile from 8 mines in Canada. In addition, U.I.C.C. crocidolite and amosite would also be used. Dr. Groth mentioned that the only comm.rcial deposit of tremolite was in Northern Italy. He had obtained a small sample of this material from j BB 0016066 2 -15- John S. Mnnvillc. The Chairman has already written Johns-Manville about ... obtaining a sufficient quantity of this tremolite material to conduct our proposed feeding study. The Chairman has been formally notified that U.I.C.C. material would be available for our purposes. The Subcommittee recommended that all asbestos fiber types used be carefully characterized as to fibers within each size category, and a distribution by weight. The protocol recommends, at the highest level, 1% in the diet. This is 0.2 gm/rat/day. For 1000 days this would be 200 gm/rat and for 500 rats the total amount of asbestos fiber needed would be 100 kg. A level of 0.01% in the diet would only take, a total of 1 kg for the same number of animals. The water intake study would be still lower. '' If one considers a factor of 50% to 100% as a loss factor in preparing diets, spillage, waste, etc-, the fiber needs are therefore from 150 to 200 kg per asbestos type. In the consideration of smaller scale studies with other species in the multispecies approach, additional amounts of fiber will be needed. In addition, if other laboratories, possibly in other countries, want to undertake studies on other facets of the asbestos question, again additional quantities of fiber will be needed to have a common baseline for comparison. Finally, if any one fiber type should give positive results in any of the proposed studies, a sufficient amount of material should be on hand to be able to conduct further investigations. I BB 0016067-! -16Consic'crir.g all these factors, the Committee felt that It w:i. reasonable to start out with 1 ton of each material. These samples should ho well characterized and contain a complete spectrum of fiber sizes. The logistics implied in the above arc enormous. One might approach industry to solve this problem, but this approach would be criticized in some quarters. On the other hand, the UXCC Committee which prepared the previous set of International Standards are an alternative source. They have had past experience in handling quantities of material of this size and in these characterizations. The solution to and successful operation of this aspect of the protocol is the key to everything else. Miscellaneous Factors A pathology protocol at sacrifice must be developed with particular. attention paid to the means of examining the G.I. tract. Asbestos in the food and waste contaminent in the cage must be so handled that .there is not a confounding inhalation exposure to the test animals. In addition, occupational health aspects of all people associated with all phases of the animal study must be carefully controlled relative to safety. Waste disposal must be such, with the quantities of asbestos involved, that there is no environmental aspect. The question was discussed of randomization of animals and *|~Bb" 00 the potential for cross contamination when all treatments are in the same room. It was felt that due to the known carcinogenicity of the positive control, these animals should definitely be kept in a separata room. Perhaps, the asbestos' levels and controls should be separated. -17- n t ib c t- Loo. recommends i:hat this question be aired with the s ti ' ;: re should he strict guidelines for animal observations during cour:-'.o of the experiment. ] BB 0016069 ] sun coin; ittec co.rients Kultispcciec Approach ( Only to involve chrysotile and crocidolite in diet at dose of 0.5 gm/kg/day. Harmonat A-t the San Antonio meeting, November 1973, of Dr. Saffiotti's contract carcinogenesis program, a report was given of spontaneous intestinal tumors in the Oak Ridge marmoset colony. Depending upon the passible availability of animals, chrysotile and crocidolite, 0.5 gm/kg/day, should be tested on up to 50 animals for each fiber type-food exposure. Considering the time needed for any possible positive results, this or any other possible non-human primate study should be initiated as early as may be practically managed. Hamster Colonic cancers have been produced by chemical agents in certain strains of hamsters. These strains, when identified should be challenged with chrysotile and crocidolite, at a dose of 0.5 gm/kg/day, 100 animals for each fiber type, 100 animals for the control, food exposure. Mastomys The mastomys, a South African rodent, shot's many spontaneous tumors. From our point of view, the tumors of interest arc carcinoids of the glandular stomach and adenomatous polyps in the area of the ilcocccal junction. Putting asbestos in the food, at a dose of 0.5 gm/kg/day, might exhibit a possible effect by either shortening i .duction time and/or increasing incidence. Cliyrsotilc and crocidolite will be tested, 100 animals for each fiber type, and 100 for controls. . __ ____ 1*iT 002&22 !! I Chit I.c nr The chicken, upon administration of asbestos intratracheally, has developed tumor.?.j indicating a susceptibility to asbestos. In addition, unlike the rode: ; j a pellet, former, the chicken has a continuous flow GI tract. * Cr.r^te end crocidolite will be tested, 100 animals for each fiber type and 100 for controls, at a dose rate, in the food, of 0.5 gm/kg/day. Trou_t Recentjy. the trout has been shown to be a very sensitive system indicating a carcinogenic response from a variety of chemicals. The Committee recommended that both chrysotile and crocidolite be tested, in the food, in this model system and possibly in water as v/ell. J BB 0016071 l sv?j"CT: rxorofhb of ?t:-d - L and Determination of Asbestos Tsolnt 1 rr:. TJeutiftcntion, a. Statement of !.Tarh Ti'.c purpose of this invastipat i on it. to develop a practical, reliable riot.i iciit for the. irc-Ia Lion, j.dr ,.t Lii cation t raid Jeter::, 'nation oi as has tos in foods, dru;", comaetics, consumer products end Liannes. Techniques roust bn developed to isolate the ashes'-os {where necessary) ar. us-rd in these, industrian Irani such diverse substrate.;; an r.inare.l col.icX. (a . g. , tele, filter:;, building :.:ni:crinJ s, food solid.'-; (c. g. , rice, coating nstcrials, f o a d -p ?. ekagi;>g natorjals) , senisolids ( c. g. , mayonnaise), and liquids (e.g., water, alcoholic bevara pee , filtered be verages, gnrer.tcra l. solutions). Solubilisation, filtration, centrifugation, and flotation have been used for this purpose. Alternatively, direct re a sure:., eat techniques ray be developed (a. g., X-ray diffraction.) and utilised where appropriate, or a cor.bir.aLi.on cf techniques, hovel techniques such, as electrophoresis, previously unexplored for this problem, ray be pursued. The method must contain prevision for estimating particle si so distribu tion. To be practical, the method trust require substantially less time for the analysis than the present 0 to 8 hours per sample required by electron microscopy' but without sacrificing reliability with respect to identifi cation. Computer interpretation of electron or optical images is a possible procedure. To be reliable, the method mist permit positive idcntlfication on identical samples by at least six laboratories on 10 samples with no false positive identification and not more than 1 false negative Identification per laboratory*. A lesser degree of reliability' may be accepted with some type of products. The development program should attempt to obtain reproduci bility in the sane laboratory on the same samolg within a factor of + 4 (c.g., results should fall within 0.25 to 4 X 10 fibers/unit volume). In the development of the method consideration also should be given to isolation, identification, and determination of asbestos after contact with foods and drugs for normal handling, storage, and distribution Limas encountered in commercial and consumer channels; and in contact with body fluids and tissues as would bo encountered in long-term animal feeding studies. The contractor must be aware that a laboratory' environment oflcn contains unsuspected sources of potential asbestos contamination. Adequate "c.lean-room" facilities is an essential requirement for the execution of this contract. ] BB 0016072 I lVga 2 ~ Proposed of Weed b. Fuadjug Bell .-ntod coat is of the order of $100,009 par year for two years. D.'ha pco: Ibil i.fy e: riots of cvuducflog this project ns n joint effort with the I'.vv: vov-'-.v.ite.l Prelection .'por.oy, Co err'mar Prodrets Safety Commission, and ether Uganda:-, Sirce ' vara is no way a contractor can assure success in r: :.'g the ;c ;e tror'.cnts, this project will of necessity have to be con- U on a "i-frf effort" bar;in as determined by the Project Advisory Gre r\. Uqdp/.ont and facilities arc not to be added to the cost of the contract. Contractor or life subcontractors nust have adequate equipment and facili ties prior to the submission of a proposal. c. "csrectivo Cp'1 tractors XX7 P.or.oarcb Institute 10 h'ent 35th Street Chicago, li, 60616 Battclle Institute Columbus, Ohio McCronc Associates Chicago, 1L California School of Public Health Berkeley, CA Materials lie near eh Laboratories Penn State`University State College, PA national Bureau of Standards Washington, -DC d. Procurement PI ami fun -^ * 1 Proposed Schedule f ;r Perforranca a-nl Critical Milestones w i Literature revie" of available methods and survey of asbestos use,s'in the food, drug, cosmetics and connuner products industries, including suppliers to those industries (purification techniques, weaving, packaging, etc.) and preparation of report. ii (a) Set up and familiarization with various techniques which may be applicable to the solution of the problem. (b) Testing various asbestos isolation techniques on a macro scale using optical microscopy. (c) Preparation of authentic samples for comparison and storage . experiments. iii Comparison of the various techniques on r.iodcl systems |_BB 0016073 [ 3 - Fvroposc.d f-nernnavin c f tl.-l <1 iv Asp 1 ion i. j :.; of the bolter 1`c-cb: i.-.ji: ,:s to p r: c ta s l savpl or, C- v Eof incs.uut of techniques Vused c-.> tbs result c of analysis oil practical . 00 Train' of OL ha i. J1 1,'UV vjIu^ t. o i.' es in th i*.* UL- w OwiJ, es (b) Cordue f j an method a (a). t erls.boj- o. 1' o y trial <jf the* d::V elope j (c) Final refill n y .*1 nL of the :moth.o:l based on appli C at ion r* by otb or labor 4+*. U*~ cri.cc. 00 A.ssist ance in ^ * vclopii.cm t of oor.pli.'s ;re pvoyr lAra (b) Trepan ..tion of r j inal rep art amis ted Fat ensl ons or Desirse JVd. OQ-t is a relatively ir.c rt . unreact. ; \ * ^ i icteric 1 occursIn 11 in a number ant forr.s. The tec Ml" leal pro'1iJ.1LA_. * i.o very difficul L. iii A may ore time th an es tir r. ed; or. tiiio or.har her;.-h the is rpe sc ale support by ETA nay cic.volcp solutions earlier then expected. If currcmr.lv. unhnoi.'Ji applieslions of asbestos arc encountered vbich ir, troduee net? ( probj ens, additions] time v.-ill have- to be allotted. XI cub or for. contam ination can be eliminated or controlled by inspect!'.ns, rcr,.i] scion, auditin';, or other ncvJaboro tory procedures, rcr'.: on the .-a types of controllable coiuucdiLlcs ray 'n: eliriiu Loci. 3. Teebnical Monitorinr The Troject Officer and/or the "Project Advisory Croup vitl meet with the contractor at bimonthly intnvvujs. At least t\:o of those rueetin^a will be site visits. Reports nust be oubr.itted at 3 east r.unrtarly or as specific phases arc completed. A final report in to be delivered 2u_months afterinitiation. 4. Evaluation Cyj tori a The submissions will be assessed as follows: a. Experience of principal invent.7priors b. . Availability of facilities and instruments c. Evidence of understaadinE the requirements d. fuhi/ rb i ? i i.y : o r.u; r.d\'v.g\11 i rr.! ('.'. raj up 50 25 10 10 J BB 0016074 | LIST OF lNV!T:;i;s nixtiwito discuss wotting r-kvrr asx'Sios f'o^ocot. February 11, .1975 Dr. William K. linker President. Bell Telephone Li'.boracar.les, Inc. Murray 11i 11.f;, Nut- Je rsey 07974 Dr. Arnold L. brown Kayo Clinic Rochester, Minnesota I Dr. Ed Burger, Jr. national Science Foundation Washington, D. C. Center for Science in the Public Interest 1779 Church S'treat, N. W. Washington, 0, C. Dr. Morris Cra.nrr.cr, Director National Center for Toxicological Research Pine Bluff, Arkansas 71601 Environmental Defense Fund 1525 ISth Street, N. W. Washington, D. C. 20036 Dr. Samuel S. Epstein Case Western Reserve University . Cleveland, Ohio Ms. Doris H. Fagan Executive Secretary Asbestos Textile Institute Willow Grove, Pennsylvania Dr. A1 Harvey R. T. Vanderbilt and Company East Norwalk, Connecticut 06550 Health P.csuarch Group 2000 P Street, N. W. Washington, D. C. 20036 Dr. Robert M. Hchir Consumer Product Safety Commission Ecthcsda, Maryland 20207 | BB 0016075 | (*' 1'rRe 4 - Proponed Rir.ornndu'ji ol I.Vod c. i'f'J.va eMd ;.iy to iniporvisc sabcen tractor (;;) t^tlc/oT a.^pOi.C parSOPmcl 5 e. r.-r.lc'or;a of Tnior-ration In. .> ! the is/a:a roe of fir;:1. regulations on the subject of asbestos .in .i f cc'^tiLs, oirj consumer products, intontntion can be rc- cn.iy \jj.wit the approval ol the Project Officer; C Revised 1/2/74; U, Rorwitz WIor\'i tKtnl'..' 1/4/74 | B6 0016076 | I (. .LIST 01' lEVI'iSES - continued be. Toe Jacl-.r.o i j E?: e'it v a D i v o o t o ** Cc .1 ;'l >' Prn.-ine.nr Washington, D. C. 20009 As inti on Dr. Paul Kotin Vine idcnt., Health, John.-:-Munvi Lie Denv . Co] ore .!o Safety and Environment P.`. 11 ' '1 i i n Kao ' 1 :i? SU.m I.L L. Stony let:iok S 10 ! y 2 too!;, V^C'w York l 117 Dr. flam:C:5 L, Livcrman Ate: 1 f. c Energy Comm.issi.Oil Wash Ing Lon, D . C. 20545 Dr. If V ing M. Lon dor. Dive C i O t , Hoi vard MIT Prog; Sc ica ccs r.n d Te chnclogy Comb r id a sac liusetts 1 Mr. Arthur Magee Stanford Eo search Institute Menlo Park, California 94025 Dr. Bernard P. McNamara Bio.ned ical Laboratory Edgavood Arsenal, A'C, Maryland 21010 Dr. P.obert H. Mereness Executive Director Asbestos Information Association/North America Washington, D. C. 20036 Dr. Norton Nelson Director, Institute of Environmental Medicine New York University New York, New York 10016 Dr. Russell W. Peterson, Chairman Council on Environmental Quality Washington, D. C. 20006 Dr. William E. Powers Kallinckrodt Institute of ltndiologv Washington University School of Medicine St. Louis, Missouri 63110 | BB 0016077 LIST OF ATTCNi'UN" - touL Li'.;n -I Dr. r rank J. Run.1.ichor. Jr. Dir'ater. Nst ilr*. . . U vim Cancer Institute Bet. Jc.ida, Mat:y 1 a: .d 20014 Dr. A1amender M. Schmidt. Con-: J.ssioner, For>d and Drug AriminisLmtion Rockville, Me ry-Utnd 20352 Dr. j i Sc likei if Do par-Lv ant of Cli-:nn.L>-y Mad '.cine Mrun i S'rai S che a ! of Medicine New York, New Yu i: k 1C029 Dr, David Sen ccr, Director Cent cr fur Dl S'C.S a Control At lanto, Geer glr. 30333 Dr. Mike Shim kin Univ ersity of Cal ifornia, San Diego LaJo He, Cali fore is 92037 Dr. Phillip Shubik Epnley Cancer kcsenrcli Institute Omaha, Nebraska 6S105 Dr. William E. Smith Health Research Institute Fairle.igh Dickinson University Madison, Men Jersey 07940 Ur. Kussell F.. Train, Administrator Environmental Protection Agency Washington, D. C. 20460 Dr. George Vogel Acting President National Association-of Filter Material Manufacturers Kingston, New York 12401 Dr. Bernie Weinstein College of Physicians and Surgeons Columbia University New York, New York 10032 Dr. Gerald N. Wognn Massachusetts Institute of Technology Cambridge, Massachusetts 02139 Dr. Ernest Wynder American Health Foundation New York, New York 10019 c I BB 0016073 1