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PLAINTIFF'S EXHIBIT
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814 844 138118 2
PARAMETERS OF IMPORTANCE IN ASSESSING BIOLOGICAL ACTIVITY OF FIBROUS MATERIALS
JACQUES DUNNIGAN UOEH - KITAKYUSHU - OCTOBER 19. 1989
More than 10 years have past since the benchmark publication by Stanton and Layard, which has become known as the Stanton Hypothesise. In their 1978 publication carcinogenicity of natural and man-made mineral fibers)), the authors Indicated that In relation with the carcinogenic potential of fibrous materials, ...Tha strongest correlation was found with fibers that measured *0.25 micron In diameter and 8 microns In length. And thus, fiber size was Identified as the first, most Important parameter of pathogenicity of fibrous materials. But this was construed to a point where almost all other possible parameters were excluded for consideration.
In the past decade however. It became increasingly difficult to relate exclusively all the known effects observed experimentally or following epidemiological Investigation to the sole parameter of size, and clearly, other-parameters had to be considered In addition to size to account for some peculiar differences observed In. the potential between mineral fibers.
One of the first Indications that the Stanton's Hypothesise could not explain everything appeared in 1983 In the British Journal of Cancer. In an investigation carried out on fibrous erlonite from Oregon, USA, British researchers of the MRC Pneumoconiosis Unit of the Uandough Hospital In Penarth found that when comparing Oregon erlonite with UICC crocidolite, the fibrous erlonite was shown to be far more potent than the amphibole asbestos, even when a much smaller number of fibers (*1000 times less) of erlonite fibers where used. The British authors commented: Either the fiber size hypothesis Is Incorrect, or there Is some other property of the zeolite fiber which
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This model shows that long, thin fibers are more carcinogenic than short, thick fibers.
With regard to short fibers (L <5 u). a consensus was reached In 1987 at the IARC/WHO Conference In Lyon. Sir Richard Doll summed up the evidence:
... there Is Increasing evidence that short fibers (properly described as elongated particles) are much less carcinogenic. If they are carcinogenic at all. It Is now IS years since Stanton and Wrench (1972) and Pott and Friedrichs (1972) Independently found that the physical dimensions of fibers were a major factor In determining their ability to cause cancer when Injected intrapleurally or Intraperltoneally; however, the difficulty In obtaining sufficient numbers of fibers of defined sizes made It difficult to be sure that the same was true when fibers were Inhaled. The data that Davis reported now make It highly probable that the physical dimensions of the fibers are equally Important in these circumstances and, taken In conjunction with the many studies of the effect of fibers on Intrapleural, intraperltoneal, or Intratracheal Injection, they Indicate that, to quota Davis, fibers <5 urn In length may be innocuous In lung tissues (Richard Doll),
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is responsible for Its activities, or which augments the activities of the few fibers in the active size range .
Since this first challenge of the Stanton's Hypothesis, much research has been published, pointing to other physico-chemical parameters of Importance In assessing the biological potency of fibrous materials.
1- SIZE
5uraly, size Is Important, and the contribution of Merv Stanton was capital In determining what size range was biologically pertinent. With regard to respiratory diseases, the first obvious requirement Is that fibrous materials must have size characteristics that enable penetration Into the deep recesses of the lung: the alveoli. In other words, the fibrous materials must be respirable. This requirement will automatically exclude any particle whose diameter Is approximately $3 y; for fibrous materials, this brings about the first concept of Importance with regard to respirablllty: the diameter. Put In other words, It is the THIN fiber which Is of concern, and practically speaking, any fiber with a diameter of less than 3 microns should be considered suspect.
Next is the parameter of length. It should be realized that thin fibers with lengths up to 200 microns have been observed In human lung samples. Surely, such long, thin fibers cannot be fully engulfed by macrophages, which rupture In attempting phagocytosis,, and release cytoplasmic enzymes and other factors leading to flbrogenesis. On the other hand, shorter fibers which can be fully phagocytosed are less likely to damage macrophages, which may explain their relative Innoculty.
In 1978, German experimentalist Friedrich Pott published his well-known three-dimensional modal concerning the carcinogenic potency of fibers as a function of their size.
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This Is particularly significant for those who are concerned with the presence of fibers In the general environment, since It Is known that more than 95% of asbestos fibers found are shorter than 3 microns. Indeed, quoting again from the Concluding Remarks of the Lyon Symposium by Sir Richard Doll:
lt seems, therefore, that for practical purposes the best we can now do Is to work on the assumption that alt fibers that meet the criteria of the International Agency for Research on Cancer (IARC, 1986) for proven carcinogenicity In animals should be regarded as potentially carcinogenic to humans, but that we should base our estimate of potential risk on both the chemical constitution of the fibers and their size, counting only those fibers that are respirable and more than 5 pm longH (Richard Doll).
2- PHYSICO-CHEMISTRY
The results of the British group of researchers comparing the potency of fibrous erlonlte and crocldollte ware among the first Indications that physico-chemical parameters, In addition to size, were certainly operating In producing adverse biological effects.
Such difference In potency between asbestos fiber types became abundantly clear in the late seventies and in the eighties when a fairly large number of epidemiological studies were published from studies In workers In a variety of workplace settings. At the same time, the use of relatively recent analytical techniques for measuring the mineral lung burden was used, and reports also supported the concept of a much different potential between chrysotile asbestos and the amphlbole varieties, typically crocldollte and amoslte. I have tried to summarize these reports In the following 4 figures:
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3- DURABILITY
It Is Interesting to note that the mineral analysis of lung tissue had also provided precious Information regarding a possible pertinent parameter of Importance In biological potency of fibrous materials: durability, or persistence In lung tissues.
It should be noted that this difference In potency applies not only to mesothelioma and lung cancer, but also applies to asbestosis. Thus. Dr. J.C. Wagner showed that the proportional counts of the amphlbole fibers croddollta end amosite increase considerably with the severity of asbestosis whereas the proportional count of chrysotlle appears to be virtually unchanged, as shown In this figure.
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ASBESTOS CONTENT BY FIBER TYPE IN LUNG TISSUE: CORRELATION WITH SEVERITY OF ASBESTOSIS
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22.94 42.13 59.47 343.15 2550.29
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These and other observations led J.C. Wagner and his colleagues to state In 1987, at the Lyon IARC symposium:
...We believe, therefore, that chrysotlle Is the least harmful form of asbestos In every respect and that greater emphasis should be placed on the different biological effects of the various amphlbole fibers (J.C, Wagner).
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DOSIMETRY
So far, we have delt with the parameters of size and fiber types, and we can conclude that for fibrous materials, those which are of concern are fibers which are long, thin, and durable. But there Is yet another parameter which must be delt with: the dose.
In fact, we must return to the sets of data of difference In potency according to fiber type to appreciate the Importance of dose. One of the nagging problems which has puzzled many experimentalists for years was the apparent Inconsistencies between the effects reported from experimentation and those from epidemiology,
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Careful examination of the great majority of IN VITRO and IN VIVO experimental protocols to assess the biological effects of mineral fibers reveals that comparison of the effects (IN VITRO cytotoxicity, flbrogenlclty and tumour yield) has traditionally been' based on a gravimetric basis, l.e., comparing the effects produced by equal mass of tested minerals (for example: 50 vg/lOS celts; 20 mg dose by Intraperltoneal Injection; 20 mg/M3 by Inhalation, etc.
As I mentioned, the reported effects were often not consistent with epidemiological observations. In the recent years, development of sophisticated techniques for tissue mineral analysis
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has led to possible explanations of the Inconsistencies between animal experimental data and epidemiological evidence, pointing to the different durability of mineral fibers, and their different relative lifespan persltence between laboratory animals and man.
But there Is yet another explanation, which resides In the basis for reporting the observed effects, l.e., per equal mass vs equal number of fibers.
Contrary to experimental (animal) data, human experience of exposure to different asbestos fiber types and man-made mineral fibers shows:
a) an Impressive difference - In pathological potency between asbestos fiber types, chrysotlle being much less flbrogenic and carcinogenic, and having very little mesotheliomaproducing potential (If at all), compared to amphlboles.
b) Man-made mineral fibers, especially RockfSIag wools, have been positively correlated with excess Incidence of lung cancer In. production workers AT LOW EXPOSURE LEVELS, Indeed at exposure levels (*1 f/ml) where chrysotlle has been shown to produce no excess lung cancer (Copenhagen WHO 1986), It should be mentioned that there Is some uncertainty about the estimates of exposure In the early production phase of rock/slag, and that there may have been additional contributing factors (PAHs, arsenic, etc.) to the reported excess lung cancer mortality; all these sources may have contributed to. the observed hazard, but as Sir Richard Doll mentioned In his overview and conclusions of the 1986 Copenhagen meeting ...none has produced a quantitatively Similar hazard elsewhere, unless exposure was both Intense and prolonged.. (2)
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The problem Is that In spite of the human data, some regulatory agencies maintain that chrysotlle has the same potential as the other asbestos fiber types, and that man-made mineral fibers have lower pathogenic potential, BA5EO ON ANIMAL EXPERIMENTS USING EQUAL MASS DOSES.
Limited attempts to transform retrospectively gravimetric doses Into fiber number-doses have Indicated that If based on fiber number, the pathogenicity would show that ((fiber for fiber, chrysotlle would be seen as less pathogenic than the other asbestos fiber types, and possibly some other man-made mineral fibers as well.
For Instance, In a t978 publication (Brit. J. Cancer, 37: 673-688) by Davis et al., the authors report that rats submitted to dust clouds of chrysotlle, crocldolite and amoslte showed more lung fibrosis and tumours after Inhalation of chrysotlle, then with either amphlboles.
But, they state: a...it was found that the chrysotlle dust clouds used In this study contained many more fibers longer than 20 microns than either of the amphlbole dust clouds.
In 1986, J. Peto, using Wagner's 1984 animal data, made an analysis of effects per fiber rather than per unit mass relevant to the comparison of asbestos and man-made mineral fibers In the Induction of pulmonary tumours by Inhalation. The following table will Illustrate this.
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TABLE: LUNG TUMOUR DISTRIBUTIONe tRELATED ! . , TO CUMULATIVE DOSAGE
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The results shown Indicate that a similar mass of chrysotlla produced -a greater tumour Incidence than man-made mineral fibers, but that the risk per fiber may have been similar for chrysotlle and glass wool, and possibly greater for rock wool. (All groups had been exposed to 10 mg/M, but the fiber count was .more than 10 times higher for chrysotlle than for rock wool or glass wool). While there Is some scepticism In the scientific community about Pete's analysis. It would be most desirable to have more relevant experimental data.
Also in 1986, Goldsmith, J.R. Indicated that abased on fiber or particle counts, man-made mineral fibers appear to be more potent thBn asbestos with regard to chronic pulmonary diseases.
In a more recently published IN VITRO study on the compBrlson of mass vs number of fibers In the cytotoxic response of Chinese hamster lung V79 cells to erlonlte, crocldollte and chrysotlle, especially for fibers L >8 microns, W <0.25 microns, the UICC chrysotlle fibers emerge as the least potent. Their data show that both samples of erionite required fewer fibers than UICC crocidotlte, and that UICC chrysotlle required a significantly higher number of fibers than the other three tested materials to produce similar cytotoxicity. For Instance, the LDS(J values (In fiber number) for V79 cytotoxicity shows the following: erionite samples: *1.1 X 10: crocldollte: 6.28 X 10; chrysotlle: 388.8 X 10. For fiber lenghts equal to or smaller than 5 microns, the difference Is even more pronounced. The following table will illustrate this.
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The next 3 tables will Illustrate that equal masses of different materials may contain vastly different numbers of fibers; and this means that comparison of potency between different materials should be made on the basis of fiber number, not on mass of matarlal. An Illustration of the Importance of this Is the comparison of experimental effects between aramld fibers and chrysotlla fibers.
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Table 1. Analysis o l mineral lib e r parameters by means o! transmission electron
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KEVLAR (10 <1 <50 H) INFLATION (ILO Wo r kin g Document. Ap r il 1 7 -2 5 . 1989)
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Of course, these observations do not rule out other Important factors In possible reasons for a gradient In fiber potency, such as chemical differences In fiber types, durability (persistence In tissues), and possibly others.
Presently, TLVs for asbestos fiber types ere In fiber number almost everywhere, whereas gravimetric standards (from *5 to 10 mg/M5) are the current rule for man-made mineral fibers, although some man-made mineral fiber companies have recently cautioned their customers to observe low levels In terms of fiber numbers.
In the meantime, carefully planned animal experimentation, where doses are measured In fiber numbers, and where results are expressed In effects/fiber number, would certainly help to support the contention that If chrysotlle must be controlled to such low levels as 1 or 0.5 f/ml, so must the man-made fibers be controlled at the same levels (and possibly lower levels In some cases). These man-made fibers are used/proposed as asbestos substitutes In a large number of applications: friction materials, thermal Insulation, flber-relnforced plastics and resins, gaskets and Joints, etc.
In conclusion, I think we can now say with a fair degree of confidence that:
1- For the purpose of biological assessment, fiber size, fiber types (physico-chemical parameters) and durability should always be taken Into consideration.
2- For the purpose of experimental comparison of biological potency of different fibrous materials, dose applied to In vitro and In vivo models should be In fiber numbers rather than In mass.
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3- For the purpose of regulatory actions, all long, thin and durable fibers should be controlled whether they are natural or synthetic, whether they are mineral or organic.
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