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5 National Bureau of Standards Special Publication 506. Proceedings of the Workshop on Asbestos: Definitions and Measurement Methods held at NBS, Gaithersburg, MD, July 18-20, 1977. (Issued November 1978) GENERAL DISCUSSION OF RELATIONSHIP BETWEEN CHEMICAL AND PHYSICAL PROPERTIES AND HEALTH EFFECTS Editor's Note: This session was actually conducted on two days. The papers through Dr. M. Stanton's were given the first day and were followed by a general discussion. The remaining papers were presented the next day, followed by a second general discussion. These two general discussions have been combined below and are followed by a summary given by the Session Chairman, Dr. S. Schneiderman, at the start of the second day's papers. (CCG) A. SUNDARAM: I would like to address this question to Dr. Kotin. He mentioned that he believes that there exists a no-effect level for asbestos. Assuming that he is right, what are the future steps that industry is going to take? Are they going to conduct animal studies at various dose levels, come up with a no-effect level, extrapolate to the human situation, and have a TLV? Alternatively, are they going to do more epidemiological studies and come up with a no-effect level which can directly apply to humans? If we do these two types of studies, we are still faced with the problem of variability of suscepti- bility between different groups of humans as well as between animals and humans. P. KOTIN: The answer to the first part is obviously that industry has a respons{bility to support studies at all levels, from fundamental mechanisms to bioassay. My own bias is that there is a no-adverse effect level. The question of what will demonstrate the no- adverse effect level is one that is going to require a fundamental understanding of carcin- ogenesis. I think there are occupational asbestos exposures of sufficient duration where, to the best of our knowledge as of now (and you always have to put that in), there seems to be a level of exposure to asbestos not associated with asbestos-related disease. I will say, in advance, I am aware of and accept all the caveats that just as the rats have not lived three years, these people have not been exposed for forty years, and maybe at that end of the distribution curve some evidence of some response may come. There is no answer to your question, and I wish that there were, other than to say that industry has a responsi- bility and would be incredibly shortsighted and incredibly stupid if it were not on the leading edge of supporting all research in relation to fiber and its relation to any adverse human effect. M. SCHNEIDERMAN: Dr. Nicholson, would you care to comment on the no-adverse level problem since you presented information on individuals exposed one month? W. NICHOLSON: In fact, I was going to ask Dr. Kotin to elaborate on that. I recall seeing a quote from you that was made sometime in the late sixties before some congressional committee, when you were Director of the NIH. You felt at that time that there was no evidence that would indicate that a threshold exists. If you could elaborate on that, particularly on the hard data that exist for asbestos. As one knows, you need enormous populations in order to see what the dose-response is at lower levels of exposure. I am in complete agreement with you that there is a dose-response effect at the levels we are speaking of; as you go down in exposure and dose, you certainly go down in effect, but to my knowledge the difficulty of finding the existence of a threshold exceeds our capability either in animals or in man. KOTIN: The answer to your second part is the degrees of reliability that you are willing to accept in terms of the totality of any response. Let me elaborate a little more. First of all, indeed I did say that, not only before a congressional committee but before numerous congressional committees. I only have two comments: (a) I'm smarter now, and (b) I will send you reprints of three articles published in 1954 where I say, on the basis of what is now known, air pollution is infinitely more iAportant to the evolution of bronchogenic cancer than cigarette smoking. If I am dumb initially, at least give me credit 191 2063104986

for not being cast in concrete in opinion. No, the answer to your question is that there are no absolute data that a no-adverse effect level exists, because of the heterogeneity of man. So what I have chosen to do is look at the sequence of events that are necessary for the evolution of a cancer, and I have not used asbestos as a model but I have used other carcinogenic agents, such as aromatic amines and hydrocarbons. There is no such thing as a threshold for carcinogenesis, there are a series of thresholds. I am prepared to say that at the molecular level you may have a threshold, but in terms of clinical cancer and par- ticularly in the laboratory, one can quantify the exposure to carcinogenic agents and predictably get a carcinogenic response, including no tumor formation within the normal life span of the animal, with no evidence of any abnormality. This is a mumbojumbo answer because it is not a clear thing, otherwise we would just have to go to the blackboard and make this a seminar on just chemical carcinogenesis, which I would be delighted to do, and then get down to specifics rather than these generalizations. Cancer is not a simple process. It is a highly complex sequential process, with sequential steps dependent on the antecedent step, and the sequential steps capable of occurring or not occurring on the basis of what happened in the immediate antecedent step and this can be quantified beautifully. NICHOLSON: I don't think I want to pursue this, except to make one comment. Some of the extrapolation and theoretical predictions that one might make on the basis of chemical carcinogenesis, as opposed to asbestos carcinogenesis, may not be that direct. Let me ask a question of Dr. Stanton which has to do with relative risks of fibers of different lengths (as with the issue of threshold; it is a relative risk at different doses): finding in human tissue and in air samples the vast preponderance of fibers of the shorter sizes, less than 5 pm (we have had some air exposures where 99.5% are under 5 pm in length, others may be 98% or 95% depending upon the particular process), at what level can you say, or at what length can you say, that the shorter fibers are ten times or fifty times, or some rough estimate, less carcinogenic than the longer ones. Certainly your 8 pm value is not a sharp cut off. How might it go down with length, in other words just how does the response go down with dose? M. STANTON: Any correlation data are simply that. It doesn't say that only certain fiber sizes are carcinogenic, nor does it say that short fibers are not carcinogenic. Cor- relation suggests that, long, fine fibers are more carcinogenic than short fine fibers. There is no sharp demarkation line. I think, if anything, one should go back to the patho- logical data again, and I've been impressed by the fact that fibers up to 30 Nm in length can be picked up and effectively handled by a phagocyte. So it may be that we are far under what can be considered very hazardous. Maybe only fibers over 30 Nm in length are more hazardous. Now, what happens if you overload phagocytes? What happens if there are no phagocytes or they are inadequate to handle these fibers in individuals who have compromised the reticuloendothelial system? It may be the short fibers in such situations can be just as carcinogenic as long fibers. There is some suggestion that if the reticuloendothelial system is overwhelmed by foreign bodies, then perhaps short fibers can also be highly carcinogenic. What we are saying sisyly is that long, fine fibers seem to be the most carcinogenic; we are not saying that any fiber is non-carcinogenic. W. SMITH: Question for Dr. Stanton: The experiments that we have had a chance to hear about this afternoon certainly present an animal model for asking questions and gathering information that would be extremely hard to get at through more complicated procedures such as inhatation exposures; but, Dr. Stanton, what do you think about extrapolation of informa- tion gained from intrapleural studies over to situations more comparable to human exposures that could be approached by inhalation studies? We have done a number of experiments by intrapleural exposure of another species, the hamster, to different kinds of minerals. With long thin fibers we have been getting tumors, and with short fibers we have not. One of the materials that has given us a great many tumors has been a preparation of long, thin glass fibers that have dimensions approximately like those that induce tumors in some of the experiments that you just described. However, Dr. Gross, I believe, has exposed rats to some very similar types of fibers by inhalation exposures, and these fibers gave him no tumors at all on the inhalation tests. So here we have a problem of how to extrapolate data from the intrapleural situation, where the fibers are trapped, to the inhalation type of exposure, where they are subject to physiologic clearing mechanisms. 192

STANTON: Clearly, our experiments are designed to find out what happens once the fibers' get to the tissue that is going to respond. It doesn't take into consideration all the extraneous problems that might arise in the fiber getting to that tissue, which is what Bill Smith is saying. What about inhalation? There is no doubt about it; inhalation studies are the only ones that will really give us some reasonable means of extrapolating to human experience. Those experiments have not been adequately done, and there are not enough of them to really get a good handle on what's happening. Dr. Gross has done about the only experiments that have been done up to this point, with the exception of some that Chris Wagner did; he has shown that tumors develop in the lung from various types of asbestos inhalation. Glass has not been studied, or only studied as a large fiber or as non-fibrous material. Dr. Gross is in the audience and I am certain he would be pleased to tell us about his experiments with glass fibers. P. GROSS: We exposed rats and hamsters to fibrous glass dust for a period of two years. The fibrous particles had an average diameter of 0.5 Nm and a range of lengths 5 to 20 pm. Inasmuch as the average fiber length was 10 pm, one-half of the fibers were 10 to 20 pm long and the rest were shorter. Since the dust concentration was ti100 mg/M3, the exposure included ~50 mg/Ms of fibers 10 to 20 pm in length. Thin mineral fibers of this length have been found carcinogenic when implanted in the abdomen or thorax of rats. However, long-term exposure by inhalation of these long, thin glass fibers resulted neither in pulmonary fibrosis, lung cancer, nor mesothelioma in ahy of our animals. These were allowed to live out their lives. I. ASHER: We are concerned about parenteral drugs, and we are wondering if anyone has any information about subcutaneous or intravenous injection of solutions that contain asbestos or fiberglass fibers? EDITOR'S NOTE: No reply was received to the above question. (CCG) R. LEE: Questions for Dr. Palekar: First, what is the unknown amphibole,' PMP 1? Second, I'd like to point out that there were at least three or four people very familiar with scanning microscopy who picked up a possible trace quantity of potassium in what you called a non-calcium amphibole. It would be very surprising if that particular non-calcium amphibole x-ray spectrum looked just like that, and it was a grunerite! Next, I was wondering if PMP 1 is a mineral characteristic of the Peter Mitchell pit, and is that a fibrous or non-fibrous variety of material? Finally, what was the set of aspect ratios measured and particle sizes measured for the non-fibrous "grunerite?" Were they cleavage fragments or typical of amosite? L. PALEKAR: Yes, PMP 1 is the unknown sample. We did some analyses of the air samples in the taconite mine and it happens to be Peter Mitchell pit; that's correct. There were two samples, one had calcium and the other didn't. The first sample I believe had calcium and the second didn't. I wasn't aware of the fact that there was a potassium peak on it. According to our mineralogist colleagues from IITRI, the studies were done by using several other techniques, and they didn't find any potassium. LEE: In that particular spectrum you showed something which had at least, on a con- servative estimate, one percent and possibly two percent potassium. PALEKAR: I will have to take that into consideration. Your second question is whether we did any analysis on non-fibrous minerals. So far, we have not, but we intend to do it in the near future. LEE: Was the sample identified as PMP 1 characteristic of the grunerite minerals that are found in the Peter Mitchell pit? PALEKAR: Yes. K. HEINRICH: I would suggest that there is a subject that hasn't been discussed, although it is of great practical importance. We frequently characterize particles by their shape, and grinding is a very common industrial process. This process will change the shapes, and the question is this: I have heard isolated statements here which range from the suggestion that a massive material on grinding acquires characteristics equal to natural 193 2063104988

fibers, to the statement that you have to be careful in grinding asbestos because it loses its properties. Could we have a discussion of what the biological implications of grinding are and how one has to handle this situation? A. LANGER: Dr. Heinrich has touched upon an extremely important problem which concerns the biological activity of small particles. The origin of the theory concerning grinding and subsequent alteration of the activity of minerals dates back some 25 years to Great Britain, to its Pneumoconiosis Research Unit. At that date, this unit boasted of having the finest laboratory of its kind in the world. They are remembered for their fine work. At that time, the pathologists in the group observed that the smaller the size of quartz particles, the more biologically active the dust was. Indeed, a 5 Nm quartz particle was relatively "inert," if you can use that word, but a 3 pm particle of the same composi- tion was a thousand times more active. A 1 pm quartz particle was a thousand times more active than the 3 pm particle, and a 0.1 pm quartz particle was yet more active. At that time this unit was interested in the interaction mechanism of the silica particles in biological systems. One such proposed mechanism involved the generation of silicic acids in tissue. These acids were thought to be the agent in the production of the response called silicosis. Production of silicic acid is enhanced as quartz is made soluble. Grinding of quartz produces a more "soluble" material. To "prove" this theory, workers ground quartz in a mortar. The ground powder was split into two equal parts. One aliquot was then washed in hydrofluoric acid and a strong alkali, removing all of the surface layers, including the Beilby layer, which is the surface disrupted layer. This disrupted layer on the surface may be demonstrated by x-ray diffraction techniques. There was x-ray line-broadening produced in the ground material, without "treatment," and a very sharp x-ray pattern generated by the material that was acid and alkali "washed." These two preparations, both quartz, were then instilled into animals. According to theory, the solubility theory, the materials which had not been "washed" should have been more active. The reverse was found to be the case. It was found that the materials that had the amorphous layers on the surface had less biological activity as compared to those materials which had been "washed." They observed the "fresh" surface to be more biologically active. This has been re-established in many experimental models. If we carry this concept into the asbestos problem, one sees the extrapolation to the different sizes of the asbestos fibers and their different biological activities. The early investigators in this field were divided into two camps. One group demonstrated biological activity with short asbestos fiber; the other group demonstrated a lack of activity. The question may be asked as to how the same animal model, the same route of administration, and the same laboratory could produce conflicting sets of data? When one examines the process by which the experimental pathologists size reduced their materials, the explanation is there. These pathologists mechanically milled these materials to shorten the fiber length. They are not only dealing with short fiber, but also with milled fiber. We have looked at these reports in the literature, dating back to the 60's, many of which indicate that milling was used to reduce fiber length. Milling of chrysotile fiber produces a material with a disrupted surface. We have observed this with x-ray diffraction and electron microscopic studies. We have taken chrysotile asbestos so prepared and have examined it by x-ray diffraction step scan technique. We've followed the line-broadening and decreased crystallinity. We've looked at this material by infrared spectroscopy for specific structural changes corresponding to different molecular groups within the struc- ture. We have examined the material in hemolytic test systems for altered membrane activity. We have looked at these materials in regard to the ability to reduce free radicals. We've looked at these milled fibers by many, many techniques and have observed that those fibers that are produced as "short" fibers show a progressive decrease in surface activity. I think that it is the preparation technique which alters the surface of the material. The experimental pathologist may indeed be working with materials that are not "truly" asbestos. The circumvention of the problem may be brought about by, instead of using mechanically milled materials, using air-jet milling, or if not air-jet milling, water sedimentation techniques to separate small fibers. Wagner's group in Penarth uses sonification methods, air-jet milling, and water fractionation to separate and collect small fibers. They produce biologically active small fibers. G. WRIGHT: The inference has been made by Dr. Langer that the experiments using short fibers have no validity because the surface has been altered by grinding. I would like to report that Dr. Kuschner and I have used contrasting fibers prepared synthetically 194

and not involving any grinding. The short fibers produced no fibrosis, but from the same batch" permitted to grow long, we got well developed, extensive pulmonary fibrosis from intratracheal injection into guinea pigs. LANGER: Several years ago we ordered synthetic chrysotile from a company in Pennsyl- vania. The materials were obtained for animal work. We examined these materials very carefully; the material was half talc and half poorly crystallized chrysotile. I think when one talks about chrysotile grown in a thermal bomb in someone's laboratory, one has got to characterize it extremely well because the crystallization process is very difficult and very often one does not produce chrysotile. I see Julie Yang here in the audience who's done a great deal of work at Johns-Manville growing chrysotile. They had to use a number of compounds to grow really good chrysotile fibers. It is extremely difficult to do. J. LEINEWEBER: I would just like to comment that the synthetic chrysotiles that were made in our laboratory were the ones referred to by Or. Wright. I've also had the oppor- tunity to see the samples that were made by Tempress. Julie Yang can comment on the great divergence in quality between the two samples. Ours were good. I did want to say that the synthetic chrysotiles that were prepared in our laboratory were of good quality crystals and this is absolutely important. J. YANG: I worked for Johns-Manville making synthetic chrysotile. The synthetic chrysotile we made for Dr. Wright is the pure synthetic chrysotile; there was no mineralizer added. I think the electron micrograph shows the size distribution; it's all fibrous material. LANGER: Julie, didn't you use cobalt or nickel in the preparation of those materials? YANG: No, that's for a different purpose. When we put nickel or cobalt or iron into it, at that time, was for a different group of tests where we were trying to figure out whether or not any heavy metal substitution would cause carcinogenic effects. We also prepared the pure ones with no additives. LANGER: I think that another important issue should be raised. There were many discussions of a number of studies in which short fibers produced no biological signs of activity. There is for every study which shows no activity, another one which does indeed show that sma11 particles are active. As a matter of fact one of the first studies of short chrysotile fiber, which is cited extensively in the literature, is probably the most unread paper in the field today (Durkan, Vorwald, and Pratt on the biological activity of small fibers). These workers were interested in fiber length as related to biological activity. At that time they were impressed with the work to come out of Great Britain demonstrating that the small silica particles were far more active than the large silica particles. They of course used various size fractionated materials of chrysotile and in their paper stated that, although they saw no "increased effect" of short fiber they reported "more limited" activity of, the short fiber. Mineralogical analyses of the dusts used experimentally showed the "short dust material" consisted of only some 17 percent chrysotile, the rest being other materials. J. MOORE: I want to raise a question. Dr. Wright, is It possible for you to give me a reference for that work or to provide the audience with the data if it is not published? G. WRIGHT: With regard to the comment that Dr. Langer made about the work of Vorwald and others at the Saranac Lake Laboratory - I was working there at the time and, in the samples which produced fibrosis, at least five percent of the fibers were of the long, or greater than 10-micrometer, variety. In answer to the question for a reference to the work by Dr. Kuschner and myself, this has been published recently, in part, in Proceedings of an International Symposium on Inhaled Particles, IV, held at Edinburgh in September of T$7~ It s~f ed t~by Walton and-pubTished by er~gamonress. 195 ~

W. DIXON: I would like to ask about the toxic activity of several kinds of fibers: (1) partially coated asbestos fibers, for example asbestos fibers which have an organic coating, (2) talc fibers (I have seen true talc fibers, just as fibrous looking as any asbestos fibers), (3) fibers which are intermediate between talc and anthophyllite asbestos in composition, (4) substitute mineral fibers such as wollastonite which are used in place of asbestos. EDITORS NOTE: No response was made to the above question by anyone in attendance or in writing. (CCG) P. LEBER: I was interested in the macrophage work of Dr. Palekar. Do you have any information on the mechanisms of the site of toxicity? I'm thinking particularly whether you have any information supporting the cell membrane puncture ideas of Dr. Kotin, with the release of lysozymal enzymes or any organal changes that might occur after ingestion of these particles, or whether ingestion of particles is actually necessary for cytotoxicity? L. PALEKAR: Well, the data that I presented was very preliminary and I don't want to make any conclusions. We performed some standard tests for acid phosphatose and lactate dehydrogenase and we did find release of these two enzymes into the medium as well as within the cell itself. J. KRAMER: I have two questions. The first one is addressed to the taconite study. There were various comments earlier voicing concern about the characterization of the sample. I would like to add a few additional comments. First of all, I think that you will find that there is a large variation in the composition of both the tremolites-actinolites and the cummingtonites (Bonnichsen, 1969, Mineral. Soc. Amer. Spec. Paper 2; Kramer, 1976, Canad. Mineral, 14, 91-98), and I believe that you must be aware of these variants when you characterize your sample. You may wish to determine the cell constants, and there is literature relating cell volume to composition (Finger, L. , 1967, The ~cr,, crystal structures and cr stal chemistry of ferromagnesian amphiboles, PhD thesis, Umv Minnesota . here are other factors to consider. The cummingtontites contain variable amounts of manganese, for example. There are a large number of mineralogical factors that you may wish to consider prior to your animal studies. Also I would suggest that if you look at the tailings you will be able to ascertain these mineralogical variations. My second question regards the Connecticut survey. I think that there is one assump- tion that needs careful consideration, and that is the constant relationship between fiber number and mass. If this assumption is not valid, then your mass basis is not valid. Fibers appear to have size distributions over about two orders of magnitude. Therefore, the mass can be determined by a very small percentage of the fibers. In other words, if you consider one-100 pm fiber out of 100-1 pm fibers, you change your count by only one percent, but you change your mass by a factor of five or more times. Therefore, the size distribu- tion of the largest few percentile of fibers will be most significant in your mass/fiber ratio. Why are you using a mass basis and not a count basis? L. BRUCKMAN: There are many problems in developing that envelope besides what you just said, which are obviously important. What we were trying to do was to take today's information and develop some type of standard and again try and make it such that it would not be criticized as being too strict, and while we were studying and refining the rela- tionships between dose-reponse, we'd at least have a standard. Now we have places in Connecticut which are above that level, and pretty much everybody has said that there are some problems with it, but the level looks basically reasonable and I think that it should be promulgated as a first step. It's a lot better than a no-visible-emission standard. I forgot the second part of your question. KRAMER: No, it was basically related to why you used a mass standard rather than a count standard. BRUCKMAN: At the time that we were doing our analysis, the procedures available which were basically developed by Dr. Thompson at EPA, were based on mass measurements of chryso- tile. When we went out and did our ambient survey back then, and it took some time to get it done, that was the technique that was readily available. As we continued on, in order to get comparative numbers, in other words to say whether the levels were twice as high or ~ 196 w ~ ~ r

twice as low, we continued doing the same type of analysis through Battelle. I'm probably not the, one to comment on which way is the best way to do it, but when Battelle did the work for us, their mass analysis, based on activated chrysotile samples, was ±50 percent. It's a kind of reproducible, gross measurement of the amount of asbestos in the air, but it doesn't give you any information at all about fiber count. But mass was one way of relating back to our standard. The standard could also be expressed in terms of total asbestos fibers; I believe it's 30,000 total asbestos fibers for a cubic meter of air sampled. So if you do do a number determinations, you could still relate that back to the standard. Battelle does a mass analysis and that was the way we have been doing it all along. C. COOPER: I also want to comment on Dr. Bruckman's very practical approach to an environmental problem. I'm not going to comment on the audacious assumptions that went into it, because I think he'd be the first one to say that was the case. My comments are two- fold, that is, I saw two important things. One was that the bottom line (and it was the literal bottom line in his graphs) was a probability of certain events occurring. This cut right back to the dialogue between Dr. Nicholson and Dr. Kotin yesterday afternoon. It assumed a no-threshold response; a straight line relationship, but it acknowledged that at some point that the straight-line relationship reached a probability, or a level of risk, that was very, very low. There's a great deal of difference between a 1 in 10 risk of getting something, and a I in 100 million risk. I think Dr. Bruckman at least faced up to this important question, regardless of the validity of the assumptions that went into determining the actual values. The second comment I wanted to make was that using his 30 nanogram limit, the levels of 12 and 25 did not seem particularly alarming. Since he was basing his original case on 168 hours of exposure during a week, probably what one might call a time-weighted average would be well within the 30 nanograms that was proposed. I was struck by how low these observed concentrations were, using the assumptions in scale. R. BLEIFUSS: I want to return to the Peter Mitchell mine again and a sample p'repared by IITRI for the EPA. If you read the IITRI reports, it is apparent that the samp,le site selected represents unique geological situation within the Peter Mitchell mine, in the same sense that the Reserve operation is unique on the Mesabi Range. It does not really appear to be typical of the taconite in that area. The sample represents a local segregation of a rather.unusual mineral suite and it is doubtful that we should use such a sample on health studies. I really think we should go back and provide you with a better starting material for the kind of work you are proposing. 0. MENIS: I would like to address my question to Dr. Bruckman. I appreciate the advance of this mass measurement and simplification. I just have a question about the total volume of sample in which this was determined, and what kind of weight basis that was. What was the total sample of your low volume sampler that was used to establish the 40 nanograms or 10 nanogram levels that you distinguish between borderline cases and significantly high. BRUCKMAN: If I understand you right, it's just a different type of sampling equipment that we developed for this purpose. If you wanted to get a 30-day average sample with a high-volume sampler, which only runs for one day, you'd have to collect 30 samples. Thirty samples at $500 a throw is a lot of money. MENIS: My question was, what was the total weight of the collected dust during that period of time? BRUCKMAN: We didn't do that determination, because there are problems in getting total weight with cellulose nitrate membrane filters. They are very hygroscopic and that presents a lot of difficulty, but that would not affect the amount of asbestos there. So there were no total weight measurements made, only chrysotile asbestos determinations. We don't know what the total weights were. We did do total weight for one sample. It looked like we were getting reasonable numbers, therefore we didn't continue it. M. COSSETTE: I have a comment that I'd like to address to Dr. Bruckman. One author, Mr. Rutner, has published a paper on 19 cases of mesothelioma in Switzerland. And of these, only two were related to asbestos exposure. Also, in experimental animal studies, mesothe- lioma has been produced with many other materials. In the case of your survey of mesothe- lioma in Connecticut, did you make any attempt to relate mesothelioma to anything besides asbestos? 197 2063104992

0 BRUCKMAN: We only did a very preliminary study based an hospital records and death certificates. We'd like to get some money to do a detailed epidemiological study, a complete case history, occupational exposure, and whether these were relatives of people who worked in asbestos industries. We aren't able to do that. We haven't got any funds at all to do any of these studies, and it's impossible to carry them on without funding. We just haven't been able to get into it. Hopefully, the data that I reported on concerning mesothelioma incidence will be updated. My study was only up to 1972. It should be updated and maybe other types of potential causes, like fiberglass exposure or something like that, will come out of this. COSSETTE: Thank you. The data that you showed indicates that the number of inesothe- lioma cases has gone up dramatically in the last few years. Do you think this may be partially due to the fact that it's more easily found now, that we have better determina- tion techniques. BRUCRMAN: I think that's definitely a contributing factor. I would say yes. M. ROBERTS: A question for Dr. Palekar: Going back to the presentation of the slides, the slide with the 1 pm scale showed an electron micrograph of ambient air at the process plant and at the mine, as compared to the slide with the 10 Nm scale showing the preparation, that you have apparently prepared for your inhalation studies. On the slide from the ambient air at the plant and mine there was very few fibers more than 1 pm long, which was the scale shown on that slide, whereas the second preparation, on the 10 Nm slide, showed considerable material that was over 10 to 15 pm. You have replied to a previous question that the rock selected to be used in your preparation was representative, and I would like to ask how this was selected? Can you give a complete history as to the location and selection of this material? Further, if these studies are to reflect the pulmonary response of exposure to the dust from these ores, should not the rock be prepared from a blind selection of typical mine ore? The principal question here is how the sample was selected, and can you give some detailed history of where and how this was selected? PALEKAR: The purpose of this study was to evaluate the biological effects of the fibers which were emitted in the taconite mine. The air samples were procured from the mine area and the processing areas. Several samples were collected on filter papers and proper size distributions were made. I can understand the confusion here between the size distribution tables presented and the electron micrographs, and I would like to emphasize again that the electron micrographs are not truly representative of size. The tables presented are more accurate. Quite a few fibers were counted, and I think that the fiber size that I presented in those tables are more representative. Now, originally we selected air samples and characterized them, then we went back to the rocks. Several rocks were collected, about 50 or so, out of which we selected two rocks which represented the air samples and the processing area, as well as in the mining areas. We are studying the biological properties of these two samples. Currently we are not doing inhalation studies, we are doing intratracheal studies and intrapleural studies. In the future we plan to do inhalation studies. LANGER: I wonder if I could add something to this. I think that everyone is missing a very obvious point: It appears that the regulatory agencies operate in a "management by crisis" mode, and everytime some new material is dumped into a lake or a river or is thrown into the air, a few million dollars is then invested in investigating the biological activity of that particular substance. It is the consensus of workers in the field that something should be known concerning the properties of fibers in terms of the mechanisms of interaction. Whether or not one could get pure Peter Mitchell pit fiber, whatever that is, is an academic point. There are many lithologies in this mine, as described in Gunderson and Schwart and the Seven French monographs. Whether a "representative" fiber exists is probably unlikely. It was then decided that the Environmental Protection Agency should investigate a fibrous rock-forming silicate which was not asbestos per se. The materials which were fibrous and "pure," yet not exactly characteristic of the cummingtonitel grunnerite within the Peter Mitchell pit, occurred in localized veins. They were fibrous on a megascopic level and when comminuted they resembled asbestos fibers. But they were not asbestos per se. These were rock-forming fibrous amphiboles. I think that if these 198

materials induce changes in biological test systems, then we shall go further and investi- gate'-others. We must know something about the mechanisms of interaction. If they are not active, then everything else is academic. SCHNEIDER,MAN: RECAP OF SESSION. The session yesterday afternoon seemed to me vigorous and active and ended on quite a high note. This morning's session is a continuation of that, and in view of the speakers we have this will be at least as exciting and as inter- esting as yesterday's session. At this time I would like to give you a very short summary of what I thought happened yesterday. In the instructions that were given to the Chairmen, we were asked to summarize what things people agreed on, what things were learned or said or now accepted as fact, what things were questioned, and where further work should be done. I made some notes on this during the course of the day and I made some notes yesterday evening after having gone out to Wolftrap to hear the Preservation Hall "Jazz Band." The last number they always play is "As the Saints Go Marching In" and I think that if anyone tries to tell you what people fully agree on he has to be a saint, or as you know, fools walk is where angels fear to tread. I'm going to be foolish and try to tell you what people agreed upon. But as I looked at my list, I discovered that that list of agreements was really quite small, and my list of disagreements was quite long and, therefore, the list of further work to be done is even longer. Any of you that are involved in the funding agencies, I want you to hear that work to be done is quite long. It seemed to me, in the agreements, from the notes I have for myself, are that asbestos, whatever it might be, in many of its subclasses and subdivisions, whatever they are called, is a material which can have adverse health effects. We talked a lot about the carcinogenic effects and talked about how some of these might be different or have less intensity for certain forms of this mineral than for others. The discussions were tempered by the fact that some people said what looked like very sharp differences in the past don't look like such sharp differences any longer, and these materials have effects that now appear to be closer to eaGi other. All through that, there was an undercurrent that we really don't know this because;we have great problems of determining doses to which people were exposed. There was also the under- current, although a great deal of emphasis was on cancer, that there are other health effects, and we have to talk about those. There were questions during the day, as you may recall, as to whether the cancer effects were dependent upon some of these other effects having occurred. Whether these were independent, or whether these ran parallel with each other. Do you have to have hyperplasia, for example, as a necessary component? Was it a pre-cancerous condition? The major questions that people raised during the course of the afternoon were questions concerning two things: first, questions concerning particle size. What are the particle size variables with respect to health effects? What are the particle sizes necessary in order to produce health effects? Are there particle sizes that are safe? Are there particles that don't produce these kinds of effects? To address themselves to these questions, Dr. Bignon of Paris showed us information on distribution of particle size found in the lungs and tissues of individuals with various diseases associated with asbestos and showed for us - at least in the trapped particles, the remaining particles, the particles that are still there - a tremendous overlap of the particle size in persons with illness and persons without illness. This is not necessarily indicating that these particle sizes that he found (by the way you will recall he found rather smaller particle sizes than most people have indicated) were necessary to induce certain of these illnesses. He made it clear, this was not to say that these smaller particles were the ones that induce the illness. It may very well be these were the only ones that remained, these were the ones that were trapped, but that is what he found. Dr. Kotin, in a rather elegant lecture that he labeled as a kind of lecture in pathology that one would give to sophomore medical students (I rather think it was more elegant than one would give to sophomore medical students, having taught sophomore medical students myself), gave us a lovely theo- retical discussion of physiology of the lung and a lovely theoretical discussion on what might be going on in the pathogenesis of illness induced by, supported by, and/or stimulated by asbestos particles. Or. Kotin remarked that he would attempt to be controversial; he succeeded at least in asserting the existence of thresholds, with which, as you know, there is a great deal of difference of opinion. He in turn was challenged on this by Dr. Nicholson, who had earlier presented data showing relatively very low levels of exposure. He was also challenged by Dr. Sunderlin of Canada and also a gentleman from the State of Maryland. The discussion, seemed to me, at one point got really highly theoretical, and I think Dr. Kotin and other people indicated that there would certainly be a need for a full scale discussion of this issue. There was one, by the way, in 199 2063104994

Heidelburg last year; a whole meeting devoted to the problems of threshold. In relation to problems of particle size, Dr. Stanton and his colleague Dr. Layard described certain experiments they had done to see whether the carcinogenic effect that we found in these various materials was a carcinogenic effect peculiar to asbestos or whether it was an effect one would get from any particles of that size and of the same dimensions. The animal studies that Dr. Stanton described would seem to indicate that the very long, thin particles, longer than 8 N(I did not make a note of the diameter), but long thin particles, were the most carcinogenic. Stanton very carefully, it seemed to me, said these are (in answers to questions) the most carcinogenic, but he did not find a line below which you find materials which are not carcinogenic, that you could be certain that they are not carcinogenic. He said no he could not find such a line. It was just that these were more carcinogenic than others; the carcinogenicity fell off as the particles got shorter and stubbier, but he did not find any sharp line of of demarcation. Now, this is a problem for the regulatory agencies because they have set a measure relating to the size of the particle. There was then discussion concerning the sort of thing that Stanton had done, because he installs these particles where they can have their effect. People raised many questions about asbestos in the ambient air and problems that would be associated with such things as ubiquitous asbestos, most of which are smaller particles than the ones people are industrially exposed to. The questioning addressed - what about inhalation studies? The remark was made that with very few exceptions, the inhalation studies were not particularly well done. A nice reference was made to Dr. Gross saying that his studies were well done, and the remark further carried that the inhalation studies had not shown the same sorts of effects as the installation studies had shown. This bring to my mind the similar problem we have with tobacco carcinogeneSis, where again in the inhalation studies, unless done in some very peculiar way, by slitting the trachea in the neck of the dog and having the dog smoke through the slit, nobody has produced, so far as I know, lung cancers in any of the experimental animals. So the inhalation studies still have some serious difficulties with them. A question was raised by Dr. Ross, a geologist, about these ambient materials and the problems that strict standards would raise for small businesses. I think Dr. Ross' hope is that one could establish that there were particles sizes or materials or levels that were in some sense absolutely safe. These economic problems might not be loaded on the small businesses. It seemed to me what we had was a general agreement on the carcinogenesis of these materials, and their capability of causing other illnesses and a very large set of statements of all kinds of things we just don't know, and all kinds of things that we still need to have some work on. I have tried to list those for you. 200