Document evDMJjKkgOV0pKOaYbnO0ZX5g

a(Lc *n -Z*# uh>^&{<+ 6m-+A ^ ll! THE CHLORINE INSTITUTE, INC. 342 MADISON AVE., NEW YORK, N.Y. 10017 ^ >/--<r--i February 26, 1975 TO : HEALTH EFFECTS OF ASBESTOS T/F I FROM : Edmund J. Laubusch | SUBJECT: (l) CARCINOGENICITY OF ORALLY-ADMINISTERED. ASBESTOS (2) PULMONARY EFFECTS ON ASBESTOS WORKERS* ST006553I (I) Enclosed is copy of a letter of January ]lt, 1975, from the National Institutesof Health which mentions activities of DHEW Subcommittee on Asbestos Protocols and includes copy of a working draft of a proposed chronic carcinogenicity study using rats. Also included is an FDA Proposed Memorandum of Need relative to development of methods for the quantification of asbestos fibers; the work defined in this memorandum apparently is in progress through an FDA contract. The Chairman of the Health Effects of Asbestos T/F, Dr. Richard Henderson (01 in), requests comments regarding whether anything need be done by the Task Force at this time in view of the Governmental studies planned or underway. We would anticipate, of course, that the Task Force will consider Dr. Moolenaar's recommendation to the Institute relative to monitoring for asbestos in chlor-alkali process streams and products. (2) Also enclosed for your information is an excerpt from CDC Morbl dity 6 Mortality weekly report (2^:5, 2/1/75) on a study of pulmonary effects on asbestos-exposed workers. gw Enclosures cc: EHC Steering Group Medica1-Toxicologica1 F. W. Koerker R. J. Moolenaar C. H. Schmiege R. E. Shepard S/C C -- >.v_ "T . ' li 7/. -Ci- V/' L' 4. ST00G5532 1* DEPARTMENT OF HEALTH, EDL'EA'I !O.W AND WELFARE public iif:<\uti i ir.Rvicr. NATIONAL INL.VI X V f i'L GE Ll'iLTII January 14, 1975 national institute: ENVIRONMENTAL HEALTH SCIENCES P.O. BOX 122JJ RESEARCH TRIANGLE PARK. N.C. 7770 919/549-8411, Ext. 3201 D.\ Hobart II. Kereness Executive Director Asbestos Information Association/Nort.n America 1650 L Street, N.M. Washington, D. C. 20036 v Otar Dr. Mereness: Recent events indicate a need to assess the carcinogenicity of orally ingested asbestos or asbestiferm minerals. As Chairman of the DHEW Committee to Coordinate Toxicology and Related Programs, I asked Dr Raymond E. Shapiro, Food and Drug Administration, to head a Subcomittee 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; end, if necessary, to develop appropriate protocols tor studies xo elaDoraxe on 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 NIH 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 ST 0065533 WORKING DRAFT PROTOCOL SUBCOMMITTEE OM ASBESTOS PROTOCOLS DHEW Committee to Coordinate Toxicology and Related Programs 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 multispecias approach (4) The Proposed Memorandum of Need developed by Dr. W. Horowitz, Food and Drug Administration, with respect to methods development for quantification of asbestos fibers was - accepted by the Subcommittee. The vork defined in this memorandum is now being conducted through an FDA contract CHAIRMAN, SUBCOMMITTEE ON ASBESTOS PROTOCOLS OUTLINE OF THE WORKING DRAFT OF THE ASBESTOS SUBCOMMITTEE'S MAJOR STUDY ST-0065534 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 17. (0.5gm/kg/day) low dose (see comments) Water: 10-20 ppm dependent upon suspension properties (see comments) Humber of Animals: Control - 1000 Positive Control - 200 for food; 200 for water Chrysotile: Food - 2 doses, 550 each dose Water - 550 Nuiaber of Aninals: (Cont'd.) Crocidolite: Food - 2 doses, 550 each dose Water - 550 Tremolite: Food - 2 doses, 550 oach dose Amosite: Food - 2 doses, 550 each dose Water - 550 ST006S535 ST0065536 SUBCOMMITTEE COMMENTS Marking Draft, on Oral Asbestos Major Study test species T'uc Sl !>-C'.ai'ittee discussed the pros and cons of using rodents, for the tesLi'-y of orally ingested asbestos for carcinogenicity. On the one hand, va had to consider the statements at the North Carolina Asbestos Con fen c:\ce 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 cat 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 prim.3tc would require up to 7 years or longer before meaningful results 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, 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. ST0065537 -2- Auother consideration was the postponement of the chror.1 c study until a species more suitable for the model test system than the rat vas found. These searches would be predicated upon demonstration of the penetration of asbestos fibers into rind 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 OF ST'lAIh' AHD POSITIVE GOHTHOL The problem in using an inbred vs. an outbred strain were discussed. Ideally, t'nc F^ generation resulting from the cross of two ir.bred 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 n:ight 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 knorni 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 i/ere discussed and the Fisher 344 rat appears to be a suitable possible candidate. ST0D65538 -3Tltf*. f'o: 'ij'tl-i'0 concluded that in terms of vhathcr or' not ingested ar.be:;tor. fibers ray induce gastrointestinal emir err., the anim-l strain should have a demonstrahje potential to dove!op such tumors when exposed to a chemical carcinop.cn. Therefore, the choice of the chemical for the positive control and the choice of strain arc interrelated. 'j he on l,* primitive: control of any real meaning is one producing C.I. tumors. The emphasis on gastrointestinal cancers with respect to asbestos is predicate J on the reported increase in these cancers in occupationally (inha! a: j c .1) exposed corkers.. Since snail amounts cf asbestos coy be ingested in food and fluids., the possible significance of these background exposures is of interest. It is also recognized that chile vc may be interested mainly in the target organs, the gastrointestinal tract with respect to nan, challenging any node! animal system with the same agent does not mean the sane response patterns will be seen in the animal model as is speculated for man. Work at NCI has indicated that rats of the AxC strain develop gastro intestinal tumors when fed W,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, nitrosogunuidinc and nitrosourea. 6CSS9001S -4- The CommitLee felt that data should be sought on other strains that develop g.-.r.troinlovi inel Cursors after ingestion expose: e to <.hr:. ical carcinogens. These might lead to possible alternatives. The- Subcommittee recommended that the question of strain and choice of positive control be discussed with Drs. Katherine Se ll and Ho'vird Steward of the KCI. 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 NCI. Dr. Siegel her. preraised to search their files for a list of compounds eliciting a carcinogenic response in the G.I. tract, when edministored orally, and where it was published. With this data base, from which wa 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. 0*ISS90U1S il:ll The Subcommii I cc recommended the use of a nutrient defined, constant formula diet. This diet would be r.ionitored for contaminants. If f ,,'t li>'i.o , maxi ..'u:'. contain Lnxnt levels will be set. The question of nixing asbestos fiber and powdered chow together, then pelletizing, was discussed. The Subcommittee felt that the pressure and heal generated in pelletization night alter the asbestos fiber. The consensus of the group favored checking out the use of a powdered cliov; dispensing unit as now being used at NCTR. This unit apparently appreciably reduces the dust and inhalation hazard. The possibility of nixing the asbestos fiber and chow with 3% corn oil was also discussed. The Cor.'writtec discussed the purity of the diet and the drinking water to be used. If a purified senisyntnetic dies and pure water vere used, a positive response in these studies eight 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 semi synthetic) 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. -6- ST006554 I dosf, iV:n nouTC The Coio.itcce reco'-. :ends chat asbestos be tested ir. food as well as water. Human asbestos exposure estimates were determined several trays: Estimates of Human Ingestion Exposure " 1. Cunningham mass: lxl0~6g-.i/liter 70 kg rr.an: drink two liters: 0.03x10*^gm/kg/day plus cock liters: 0.OfxlCr r g~/kg/da- and if assume inhaled and completely swallowed an amount equivalent to the above: total ingested: 0.Ilxl0"6gn/kg/day. 2. Kay mass: 1x10-9gm/liter (Ontario) drink 2 liter: 0.03x10-9gn/kg/cay plus cook 2 liters: 0.06x]O'^gu/kg/dey plus equiv. swallcned air exposure: total ingested: 0.Ilxl0-9gm/kg/d3y. 3. Duluth: assume m.3ss: 25yg/liter drink 2 liters: 0. 7xlO"6;;i/lcg/day plus cook 2_ liters: 1. /ixlO-uo^/kg/day plus assume equivalent swallowed air exposure: total ingested: 2.8xl0-6gm/kg/day. 4. Range: 0.03x10-9 to 3xl0~6gm/kg/day a range of 5 orders of magnitude depending on assumptions -7~ '/i 1- jr b: I ' i >' 4ii X ' Gii x 2u :: r.';i C-: x 3ij x ip) 0-'. X 0.3 X 0.3y) Iip.Uy Permitted Cccupation.'il Exposure (gm)l 10.25 X 10-3 2 X 10-3 (0.25 X 10-3 (7.5 X 10-6 1. Air 5.1.; . .l.-.i.d: 3 fibers/cc (>5p) Fiber G. = 3 0 her-:-, doy Heap. ' ::: intake: 0.7n3/hr. 2, 70 kg me.! Assume Inhaled is all Swallowed (vc/kg/dny2) 230 29 (4) (0.1) ST00G5542 DJ C L Leve l:_ The maximum dose in the diet was set at 1%. If we assume a 20 gm per dry food intake by a 400 gn rat at 1Z asbestos in the diet, we have an 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/chcmical 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. ST 006 5 5(t3 _"cu> "* There were several. recommendations that the study include the definition of a dose--respond carve 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 la-ger cost figures. Therefore, in the working draft, the Subcommitt in order to be able to cover all asbestos fiber types cf interest, recommended two dose levels per asbestos fiber type in the food. We reaffirm Lhis recommendation. The question of what two doses to recommend was next considered. As discussed previously, IX 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. *i*lSS9U01S -9- hoc- or j.ng 0.5b argued that it the tumor incicVr.ee el. 1% asbestos in '.'be -'I, . r c* ?. ' high an 50b. with a pr ojrcted slope of one, a reduction of dose by a factor of 10 would give a tuner incidence of only 5%. 'fine right net be significantly different frern the background level to cate h'i inkr.cc^.-d "effect" point. If the projected slope were greater th-i 1 or :li the tumor incidence at lb asbestos in the diet vere j.iuch lee: than 50b, the possibility of obtaining a second "effect" point was still further reduced. Even with a projected shallow slope, this r.rgnr.eni; sl'i.'l holds true. The disc_r.. Lm 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 0.5b 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 0.1b 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, v.'hile Drs. Shapiro and Stanton voted for a second dose at 0.5% in the diet. S ^S S O O O IS -10- Another discussion with respect to doses of 1.0 and 0.5% in the diet '..entered upcr. pass lb i 11 ty of don overlap. j'-ce c io * lane .ion o' ; consumption and variation in food consumption per day leads to dose variation. Also, any variation in food consumption per unit weight of animal .leads t o possil.se dose variations. If there is a 20% varis; j <.,n aioL'ni the m in, then the doses wc are then comparing i re 0.5 gw/kg/day t (range 0.4 to 0.6) 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 weald 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 v?ater. If one assumes that the rat food contains some fluid phase to reduce dust, let us then assume the 400 grn 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/litcr (10 ppm) of chrysotilc, crocidolite, and another amphibole 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 -11" that when asbcstc... i': nixed into the di: t. The actual particle size din L'.'.'.b'i *. ? on in vs cv should he accurately determined. For the asbestos in water treatments, in order to minimize the effects of solUing out of fibers, it was suggested that water bottles be prepared evejy .'.ff'orr.oon ,-.nd taken away in the morning. l)ietr y preparation and waste disposal nust.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, sever::], 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 esbestos 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 ST006 55 ii 6 l ST00655U -12- vhich to base, a conclusion. One assumes, ir. this ca.su, the pcs:..-. ;ity of no effect being seen the first, two years and any ;.i . V:. ,e of?. that may occur in the third year occurring at a low incidence. There fere, the Committee recommended 500 animals for each treatnc:.;: level. The Subcommittee also recognizes that it is never possible, in the real 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. Vie do feel that the number of animals chosen is adequate, particular''y 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 out the total study as well as the assumption that possible target organs, particularly the gastrointestinal trace, 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 M, 500 T) be established as a control group. 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 sacrifice, we have a sarall 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. -13- ri: vYi'r-: T*ir. i '.tee r: fiber type ns to prioiity in oral carcinogen testing. In order of decreasing priority they are: chrysotile, crocidolite, tremolite and ar.osite. The priority ordering is based on the total number of the $ population that may be exposed. Cnrysol .i 1 e exposure may occur 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 pi.tr.e 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. CO --I CD CD CO on cn C- CD Therefore, crocidolite should be tested in food as well as in water. It should be noted that placing the amphibole crocidolite in the second priority 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 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 contaminat.nt of talc used in fpod and in orally ingested drugs. ^ ST00655U9 Therefore, tremolite need only be tested in food. Since talc contains anthophyllite and chrysotile, as well as tremolite, the Subcommittee reco.vmended that consideration be given to feeding a mixture of the three in proportion to their occurrence as a contaminant in talc. 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 x/ater which could also be contained in foods, prepared from this water. Therefore, amosite should be tested in food as well as in water. FIBER SOURCE AND 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 B 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 commercial deposit of tremolite was in Northern Italy. He had obtained a small sample of this material from ST0065550 -15Jo*-n S. MarvlUc. The Chairman ins already written Johns-Hanville about obtaining a sufficient quantity of this trenolite 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 Subcommi.i tee recommended that nil 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, 17, in the diet. This is 0.?. 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 multispecics 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. ST00G555I -1(3- ConsJdcrir.g all these factors, the Committee felt taut it vr:;. rcasunabj.u to start out with 1 ton of each material. These samples shoiud he wall 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 U1CC Committee which prepared the previous set of International Standards arc an alternative source. They have hnd 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 contaminant in the cage must he 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 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. 17Yr.j. fhthc ' liue ro>:x.-.i>"-r.Js that this question be aired with the '' ..isti r ' '. '.there should he strict guidelines for animal observations during the course of the experiment. ST006 5 55 2 ST0065553 p u n co: ': it t f. u c o: r.:r.; : s Kulti.spccios Approach Only to Involve clirysotilc and crocidolite in diet at dose of 0.5 gm/kg/eny. Marmoset At the San Antonio meeting, November 1973, of Dr. Saffiotti's contract care.' nugenosis program, a report v:as given of spontnnc.oTTs intestinal tumors in the Oak Ridge marmoset colony. Depending upon the possible 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 gr.i/kg/day, 100 animals for each fiber type, 100 animals for the control, food exposure. Mastomys The mastomys, a South African rodent, shows many spontaneous tumors. From our point of view, tha tumors of interest arc carcinoids of the glandular stomach and adenomatous polyps in the area of the ileocecal junction. Putting asbestos in the food, at a dose of 0.5 gm/kg/day,-might exhibit a possible effect by cither shortening induction time and/or increasing incidence. Chyrsotilc and crocidolite will be tested, 100 animals for each fiber type, and 100 for controls. i Chic 1. The chicken, upon administration of asbestos intratracheally, has developed tunes, indicating a susceptibility to asbestos. In addition, unlike the irodi! a pellet former, the chicken has a continuous flow Cl tract. t Chr, : and crocidolitc will be tested, 100 animals far each fiber type and 100 fer controls, at a dose rate, in the food, of 0.5 gm/kg/day. Troy_t_ Recently, 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 crocidolitc be tested, in the food, in this model system and possibly in water as v?ell. GO --I O o cn ec_.rnr cn -r* i stu'jrcT: rxoro.wh o:- v and Peccrr.i:i:!i.ic:\ of Asbestos T*;oJnt 1 o -. Iden r i T i cu lien ST0065555 a. Statement of '.'or!: The purpose of this invar,tipat ion i; Co develop a proc; leal, rul .iable not. 51 oil for Che. i sola I i on, iff if i entior,, and deter:.! nation of ;:u hastes in foot'r., drugs, cosmetics, consumer pxcluets and fins; nest La developed to isolate Live asbestos. (where- nee" :) as uu- XII these :i ndas tri ci; from cuuh diverse subs .rate;: ns i. inarat solids (e.g., talc, ii.ltor;;, building material s, food solids (e.g., rice, coating rr.atcri a Is, f ood-pnci:e giug materials), senisolids (e.p., mayonnaise), and liquids (e.g., valor, alcohol ic beverages, filtered b>. v c.ra gar. , g vcr.tcx . i. solutions) . Solubilization, iiltraLion, ceutrif up,at: or., and f J ctet.i cn have bean used for this purpose. Alternatively, evi: est res surer.;:::', t techniques i-:ay be developed (c.g., X-ray diffraction) and ulilinr d irhere appropriate, or a corbir.auio.i ci technic ,;cs. hovel Lsc'r siques .such as electrophoresis, previously vner.plorcd for th.is prcblc-, ray be pursued. The method must, contain, prevision for estimating particle size distribu tion. To be practical, the method must require substantially less time for the analysis than the present 6 io 8 hours pur sar.plc 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 must permit positive identification on. identical samples by at least si:-: lahoralories on 10 samples rich no false positive identification and not more than 1 false negative identification per laboratory. A lesser degree of reliability nx-.y be ncc.epLud w.tch some typo of products. The development program should alter..pt to obtain reproduci bility in the sane laboratory on the same sac,pig within a factor of + 4 (c.g., results should fall within 0.25 to 4 X 10 ' f.ibers/unit volume). In the development of the method consideration also should be given to isolation, identification, and determination of asbestos after contact with foods r.r.a drugs for no mol handling, storage, ami distribution tires encountered in ccrr.'.crcial and consumer channels; and in contact with body fluids and tissues as would ho encountered in long-term animal feeding studies. The contractor must be avaro that a laboratory environment often contain.-; unsuspected sources of potential asbestos contamination. Adequate "cleanroom" facilities is an essential requirement for the execution of this contract. lY~o 2 - I'ro/orcc- lY.r.or;'.! b W\ niry.i I'cll-nted cost i s of the order of (109,099 per year for two yon re. The . >b.r.J ity t*::i sf c of r; .oucl: i1''' Li:fnrc-"juct .'in p joint a -. ni'. t v.i 111 Luc J'.rvivon"natal Viv-tccfi'.'"i y, Ccuu -nw Products Sa'.cty CoMv.issioa, and <v. L.- c* [.Piruili1 ^ Since is no a contractor ten assure succors m ti tho ; n .;rcr.anls, this project will of necessity have to be con- do-.: or a rt effort:" basis r.c determined by rhe Project Advisor)' Gl'l. . i>v.: p. mt and facilities ere. not to be added to the cost of the contract. Cor.tree.tor or Ids subcontractors r.ust have adequate equipment end facili ties. prior to the submission of a proposal. c. Pvonrrctivo Centroatoys IIT Research Tustituic 10 rent 3f>Lu Street Chicago, 1 I. 60916 Battoilc institute Coin: hue, Ohio KcCrcnc Associates Chicago, 1L - California School of Public Health Berkeley, CA Materials Research Lcborr.torics Penn State 'University State College, PA National Bureau of Standards Washington, DC d. Procure~crt PI minin'' 1. Proposed Schedule fir Perforrmce n'd Critical Mi.lestpr.es i Lite ratuve revie.'.; of available rccthodr. .and survey of asbestos uscs'ir. the feed, drug, cos.'.atics and ccaruner products indr.:, tries, including suppliers to these industries (purification techniques, weaving, packaging, etc.) and preparation of report. ii (a) Set up and familiarization with various techniques which r.ay 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 ill Comparison of the various techniques on node! systems ST0065556 ! I i mmmm P.oge 3 -- Proposed IP J randv:::i c f Meed 1 iv A;-') liens L1 n f tu?: be! ter feci, j'' : ' i t- to p.v ct ira.l ra::-p] os V Hof in c. rent of LOCi Vriqu-.-s V :-e"v.' <: the rcrn.ltc of analysis of practical ;; y 1 e. s. vi 00 Train-'' 1 ` of ol.her Inborn!! o; J ill tl .e procedures 00 Condor . i . '-w rothod -(: :) . ir.tcrl-tbort:: 0 :y trial of Lhc developed (c) J.-innl yt i o.L of the i :CtVir-a based or. applications by oti: C1 labor *' t c r i c. z . vii (a) Assist :e in L.;.vcj:t;p:h'V.:; l. of ccr.piia ..re program (l>) Pre-par , ti.on of final repo1 J* 2. Conte . .-q .. ted !': : L'ji r- > r. i'-,- r C- -.O' ' As b e s L o : i .S c1 re]ativel y ir.: i:t. u nr a r.c.t.' V' ; ctcrie l occurrung in a number of dif fen eat fores. Ti'i e tee '-.iifcrl pro's ? c very difficult and r-ry require more time than cstir: red; cr. the other her.. Lba Jargo scale support by ;!PA ray develop sol i.tions cj r.* ' .:r cs.p'cted. If curreur.ly unknorn applications nf ashes:c* ere ere onntcrcd i Men ji,iroc!uct? net' prob'erS; additional tire have to hr. abbot ted. if asbestos conto.-.t- ination can be cliuinotrd or control ? i d rv inspcc ti.. ns, repo] ation, auditing, or ether r.o-.labors! ory rrocedv.verb on these types of controllable coumcditics rnav 1)'- eiiri::: Led. 3. Teel:)-; j cal Men j tor J ns The Project Officer cud/or the Project Advisory Creep '..-ill meet uith the contractor at bimonthly intervals. At icort tvo of i he-se meetings t;ili he site visits. Reports rust be submitted at le.nsi r.n.ar tar.ly or as specific phases arc completed. A final report is to be delivered 24 norths after initiation, ' A . r.valnation Cri tori a The submissions mill be assessed as follces: a. Experience of principal invest:gators 50 b. . Availability of facilities and instruments 25 c. Evidence of understanding the requirements 10 d. fuggy s' ability n !ur.o-..-[.; an! d..-re]r-p rue1 pro.-edin 10 ST00B5557 ( i t hlI f Y l'f.ii: 4 - Proponed ;.ornndir.'i of Rood c. Su.'.^cr.i .ivc nb.T] li v to o;i:>'/.rvir;c aubccntractor(..) and/or r.epport pr-.rscnnol 5 c. Polcar,; of 11ifo ~~ jtion_ I'n; ! ! tillc*. ir.:; nacre of fT r1 rcftulnt io.ic on the .subject: of n.ebastoa iu dii.p,;;, fc-ci'-JL-ies, rod connu :or products, inLoii.'.iCion can be re- .d only \>jlb the approval o the Project 0ffleer; ST 0065558 Revised 1/2/74; 1'. Hon.'it2 MJon.'i t v.: rilw 1/4/74 UST OF INl'i r.'iiib to discuss working *t ' February 11, 1975 Dr. William. Y.. linker presidert. f.el.l Telephone Lr.boratortes, Inc. Murray Hi Ur., Nov Jersey 07374 Dr. Arnold L. Drown Mayo Clinic Rochester, Minnesota t Dr. Ed Durg,?r, Jr. national Science Foundation Wushir.gtcn, D. C. Center for Science in the Public Interest 1779 Church Street, 1!. W. Washington, 0. C. Dr. Kerri a Cramer, Director National Cc.n.cr for Toxicological Re re nr eh Pine Pleff, ArR-'insas 71601 Environrental Defense Fund 1525 ISch Street, N. Vi. Washington, 1). C. 20036 Dr. Samuel S. Epstein Case Western Reserve University Cleveland, Ohio Ms. Doris M. Fagan Executive Secretary Asbestos Textile Institute Willow Grove, Pennsylvania Dr. A1 Harvey R. T. Vanderbilt and Company East Norwalk, Connecticut 06550 Health Research Group 2000 P Street, N. W. Washington, D. C. 20036 Dr. Robert M. llchir Consumer Product Safety Commission Ecthcsda, Maryland 20207 p 'C'lDCOk ST 0065559 LIST OF Ii-:VTi!'.i:S - continued ST 0065560 V . J;kj Jaci.r.o i | r>n' ive D i V C." to** . Crv i . ; . i > l'r ora*cor.' Ass- Wu.d.ii; , L Oil y U.. C. 20009 D;:. I'r.ml Ko^iii Vice I ''as id cu L , lien] th, Jen. I'aJ'.vi 11. Dei'iV . , Color. ,i -. Safety and Dr. !l .in ICrr i a: SU.. . a t f> ten/ freak Stc j P'-oek, N:;v York 11754 Dr. .la. ms L. I.Averman A( o: r Euer; \y Core; ir.rion Wa.-.hi" glon, D. C. 20545 Dr. I: V. Lor. dor. Diva.;, or, Hjvy ai d .'IT Program in If. Stic :i:cs rr.: 1 crk.nalor," Cembr- futchu setts 02129 Mr. Arthur Mag UC: Steal o rd Recta rck Institute Menlo Park, California 94025 Dr. Ku rnard P. Me lifter a E i o.r. c.-l i c a 1 L q h c rn t o r v Edgavood Arsenal, r., Maryland 21010 Dr. Robert H. Mereness Executive Director Asbestos In formation A.ssocintion/Ncrth America Washington, D. C. 20036 Dr. Norton Nelson Director, Institute of Environmental Medicine New York University New York, Nov; York 10016 Dr. Russell W. Peterson, Chairman Council on Environmental Quality Washington, D. C. 20006 Dr. William E. Powers Kallinckrodt Institute of Radiology Washington University School of Medicine St. Louis, Missouri 63110 ST006556 I LtJ'f of attendees - contim..-.! Dr. Friuli J. R.juscher. Jr. Director, National Cancer T.-.rtitute liet-ru.ida, Maryland 200] 4 Dr. Alara.nder M. Schmidt Conninsioncr, Food and Drug Atbr. inisUration Rockville, Maryland 20352 Dr. Kvlng Saliho if Depart."'.-.r c-T Co*--.-uni y Mf.d ' c lr.e r!.~i:ra 3.'-',.: Schrn! cf Med.i c i r.a Maw York, Few to.!; 10029 Dr. David Senccr, Director Center for Disease Control Atlanta, Ceorgi.r 30333 Dr. Mike Shir.kin UnivL-rr.it" of tk.li lo.nia, San Diego LaJollr., California 92037 Dr. Phillip Shubik Epoley Cancer Ease.Troll Institute Omaha, Nebraska 6S103 Dr. UiIlian E. Smith Heelth Research Institute Fairleigh Dickinson University Madison, New Jersey 075-0 Mr. Russell F.. Train, Administrator Environ.'.antel Protection Agency Washington, D. C. 20460 Dr. Ceorge Vogel Acting President National Association of Filter Material Manufacturers Kingston, New York 12401 Dr. Bernie Weinstein College of Fhysicians and Surgeons Columbia University New York, New York 10032 Dr. Gerald N. Wognn Massachusetts Institute of Technology Cat,-.bridge, Massachusetts 02139 Dr. Ernest Wynder American Health Foundation New York, New York 10019