Mineral Fibers: Chemical. Physicochemical. and Biological Properties

J . s. HA RING TON,^ A . c. ALL IS ON,^

AND

D . v . BADAM13

I . Introduction . . . . . . . . . . . . . . . I1. Chemical and Physicochemical Properties . . . . . . A. Classification of Fibers . . . . . . . . . . B . Types of Asbestos . . . . . . . . . . . . C . Origin and Geographic Distribution of Different Types of D. Industrial Uses of Asbestos . . . . . . . . . E . Serpentine (Chrysotile) Asbestos . . . . . . . F . Amphibole Asbestos . . . . . . . . . . . G . Synthetic Asbestos . . . . . . . . . . . H . Identification and Estimation of Asbestos . . . . . I . Glass Fibers . . . . . . . . . . . . . I11. Biological Properties of Mineral Fibers-In Vitro Effects . A. Hemolysis . . . . . . . . . . . . . . B . Cytotoxic Effects of Respirable Dusts on Cultured Cells IV . Biological Properties of Mineral Fibers-In Vim Effects . . A. Identification of Asbestos Fibers in Tissues . . . . B. The Asbestos Body and the Ferruginous Body . . . C. Fibrogenic Effects of Mineral Fibers in Animals . . . D . Fibrogenic Effects in Man . . . . . . . . . E . Carcinogenic Effects in Animals . . . . . . . . F. Carcinogenic Effects in Man . . . . . . . . . V. General Discussion of Biological Effects of Asbestos . . . A. Hemolysis . . . . . . . . . . . . . . B. Cytotoxicity . . . . . . . . . . . . . C . Fibrogenic Effects . . . . . . . . . . . . D . Carcinogenic Effects . . . . . . . . . . . E . Conclusion . . . . . . . . . . . . . . VI . Summary . . . . . . . . . . . . . . References . . . . . . . . . . . . . . .

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292 294 294 295 297 299 302 312 319 320 322 323 323 335 354 355 356 359 363 366 372 383 383 384 384 385 388 389 391

1 Cancer Research Unit of the National Cancer Association of South Africa. South African Institute for Medical Research. Johannesburg. South Africa . Clinical Research Centre. Medical Research Council. Harrow. Middlesex. England . Research and Engineering Division. TBA Industrial Products Ltd., Rochdale. England .

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1. Introduction We are living in an age when there is increasing awareness of our environment, including the effects of various types of air pollution. Among the most important occupational air pollutants are particles of coal, quartz, and fibers of asbestos that are inhaled by miners and exposed industrial workers. It has long been known that inhalation of asbestos, like quartz, leads to a fibrogenic reaction in the lung, which is termed asbestosis (Lynch and Smith, 1935; Doll, 1955). In 1960 a new danger was revealed: chronic exposure to the type of crocidolite asbestos mined in the northwestern Cape Province of South Africa was associated with a high incidence of an otherwise rare type of malignant tumor, mesothelioma of the pleura or, more rarely, of the peritoneum (Wagner et al., 1960). It has since become clear that not only asbestos miners but also persons working with asbestos industrially have an increased incidence of lung cancer of two types : mesothelioma and bronchogenic carcinoma. Epidemiological studies in several countries have defined further the lung cancer risk in relation to occupation, fiber type, and other factors such as cigarette smoking. Exposure to asbestos has become one of the major cancer-producing occupational hazards, when fiber is handled without adequate precautions. Concurrently the carcinogenic effects of asbestos fibers in experimental animals have been investigated. All asbestos types implanted in the pleural cavity have induced mesotheliomas, and some are carcinogenic after inhalation. At one time it seemed possible that chemicals associated with asbestos fibers, including polycyclic hydrocarbons and trace metals, might play an important role in asbestos carcinogenesis. This now seems unlikely, although an exception should perhaps be made in the case of magnesium ions, which have been found in certain circumstances, e.g., hemolysis, to be markedly active. Recently attention has focused on the role in cancer induction of the length, diameter, and shape of the fibers, which are indirectly controlled to a large extent by chemical composition. The size and shape of asbestos fibers have a marked influence on their site of deposition and retention in the lungs. Asbestos and other fibers of similar dimensions (e.g., glass and aluminum oxide) readily induce mesotheliomas after implantation in the pleural cavity. These observations are of academic interest as well as importance in occupational medicine. Like the remarkable findings of Oppenheimer and his colleagues (1961) on the carcinogenic effects produced by the subcutaneous implants of chemically inert plastic films, these observations focus

[BIOLOGICAL EFFECTS OF ASBESTOS] 1

I

IBIOMEDICAL

GEOLOGY CHEMISTRY PHYSICO- CHEMISTRY

ASPECTS

1

IN VlVO STUDIES ANIMALS

M

E TYPE

OF

CELL USED

EFFECT OF FIBER USED

PROTECTION

L

WORKING GROUPS

FIG.1. Scope of research on the biological effects of asbestos.

-t

PREVENTION

I

E.3

(0

W

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V.

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attention on the physicochemical properties of the agents in question-in this case the length and diameter of fibers-rather than on their chemical composition. How such agents induce malignancy is a t present unknown, but since the problem has been identified it is a challenge for future research. Cancer-inducing fibers are often incompletely ingested by cells and effects on regulatory mechanisms at the plasma membrane may be involved. I n addition to observations in animals, effects of quartz particles and asbestos fibers on cultured cells have been studied, especially macrophages and mesothelial cells, which are in vivo targets for asbestos. Interactions of fibers with model membrane systems, especially erythrocyte membranes, have been extensively documented, and it is now possible to provide reasonable explanations of these interactions. Although some of the information about effects of asbestos has been reviewed elsewhere, notably a t meetings held a t the New York Academy of Science (Whipple, 1965) and the International Agency for Research on Cancer (1973), much of the relevant work has been published in a variety of specialist journals concerned with geology, crystallography, chemistry, cell biology, cancer, and occupational medicine. No general review has been published. We have attempted to summarize the main properties of the different asbestos types that are relevant to their biological activity and what is known of their effects on model cellular systems as well as experimental animals and man. Not all the aspects can be comprehensively covered in the space available, but the recent references quoted as well as the papers contributed to the International Agency for Research on Cancer (IARC) Working Croup Meeting in Lyon (Bogovski et al., 1973) should allow readers to obtain information on the current state of knowledge. An indication of the wide extent covered by research on the technology and biological effects of asbestos is given in Fig. 1. Detailed attention has been given to chemical and physicochemical properties of asbestos (extreme left, Fig. 1) and its biological effects (right, Fig. 1).The reader is referred t o a bibliography of the world’s literature on asbestos, abstracted and indexed for 1960 to 1968, by Williams (1969).

II. Chemical and Physicochemical Properties A. CLASSIFICATION OF FIBERS Man has used naturally occurring organic fibers such as cotton, silk, and jute for thousands of years. Since the synthesis of nylon in the 1930s, a whole range of synthetic man-made organic fibers, such as polyesters (Terylene, Dacron) and polyacrylics (Courtelle, Orlon, and Acrylan), and

MINERAL FIBERS

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others have also been widely utilized. Inorganic fibers, however, have a relatively short history of usage. Although asbestos was known to the ancient Chinese, the Egyptians, and Romans, it became a n important industrial material only in the late nineteenth century because of a happy coincidence-the arrival of the steam engine had established the need for insulation and packings and a forest fire in Canada had laid bare vast deposits of asbestos. The increasing need for cheap insulation also led to the development of staple fibers spun from rocks and blast furnace slags to produce rock wool and “mineral wool.” In the past 40 years, glass fibers have also been widely used both as textiles and for reinforcing plastics in a variety of applications. In the past 20 years, over a hundred nonmetallic and inorganic fibers have been synthesized (McCreight et al., 1965; Carroll-Porczynski, 1969) but only a few (for example, carbon fibers, boron fibers, silicon carbide whiskers, and aluminosilicate fibers) have shown promise of practical application. Because a mineral is generally defined as a naturally occurring crystalline structure, the only true mineral fibers are the different varieties of asbestos. So-called mineral wool is really a type of glass wool. This review is, therefore, essentially devoted to asbestos [for more detailed treatment of the subject, see Hodgson (1965) and Speil and Leineweber (1969)], but some reference will be made t o glass fibers both for completeness and because recent experiments with glass fibers are being used to define some fiber properties that are of biological importance.

B. TYPESOF ASBESTOS Before describing briefly the different types of asbestos, it might be useful t o place in perspective where asbestos fits into the mineral kingdom. About a quarter of all known minerals, including many precious and semiprecious stones, are silicates, and more than nine-tenths of the earth’s crust is composed of them (Bragg and Claringbull, 1965). The atoms form tetrahedral arrangements comprising a silicon atom a t the center and oxygen atoms at each of the four corners. They are extremely stable and exist in the form of discrete groups, chains, double chains, sheets and three-dimensional structures. This pseudo polymerization is achieved by linking the tetrahedra in different ways, for example, by sharing the oxygens a t the corners, edges, or faces of the tetrahedra, as seen in Fig. 2. About thirty mineral silicates can crystallize with a fibrous habit. Some of these are referred to as asbestos minerals. The nonfibrous crystals with the same composition form separate nonasbestos mineral systems, for example, crocidolite is the fibrous form of riebeckite, and amosite is the fibrous form of grunerite. The main varieties of asbestos, in order of

J. S. HARINGTON, .4.C. ALLISON AND D. V. BADAMI

296

A

0

c -

Silicon 0 Oxygen

FIG.2. Diagram showing the different struct,ures t,hat, can be formed by linking the silicon-oxygen tetrahedra: (A) single chains; (B) double chains (amphiboles) ; a.nd (C) sheet,s ( c h r y s d c ) . Asbestos Arnohibole minerals

I

Serpentine (Chrysotile) Mg,(Si,O,\ (OH),

i Riebeckite (Crocidolite) N~Fe,2+Fe~'[Si80z2] (OH, F),

Grunerite (Amosite) (FeZ+),(FeZt, Mg), [Si80,,] (OH),

I Anthophyllite (Mg,Fez+),[Si80zz](OH, F),

FIG.3. Classification of the major typcs of asbestos.

297

MINERAL FIBERS

TABLE I

CHARACTERIZATION OF THE MAJOR TYPES OF ASBESTOS Characteristics Basic composition

Chrysotile (white)

Crocidolite (blue)

Amosite (brown)

Deep green Silky, soft Excellent

Hydrated silicate of iron and sodium Na2Fe32+F e P [Sis 0 2 2 1 (OH, Fh Blue Harsh Fair

Hydrated silicate of iron and magnesium (Fe2+)a(Fez+, Mg)3 [Sis 0 2 2 1 (OH)Z Mid-brown Coarse Poor

Flexible, heat resistant, stiff, strong, alkali resistant

Flexible, heat resistant, stiff, strong, acid resistant

Brittle long fibers, acid resistant

Hydrated magnesium silicate

Approximate formula Mg&051(0H)r Color of crudc rock Texture of fiber Flexibility and spinning properties Major properties

decreasing commercial importance, are chrysotile, crocidolite, amosite, and anthophyllite. Another type of asbestos, tremolite, often occurs in association with talc. Mineralogically, asbestos is divided into two classes : serpentine and amphibole (Fig. 3). The former is a sheet silicate (Fig. 2C), whereas the latter is built up of double chains of tetrahedra (Fig. 2B). Chrysotile is the principal asbestos member of the serpentine family, whereas all other asbestos minerals belong to the amphibole group. Table I summarizes the chemical composition and properties of chrysotile, crocidolite, and amosite. The reader is referred to Deer et al. (1963) for details of other types of asbestos. C. ORIGINAND GEOGRAPHIC DISTRIBUTION OF DIFFERENT TYPES OF ASBESTOS Chrysotile accounts for approximately 90% of the world production of asbestos. Although this fiber is found in several parts of the world (Fig. 4), the major deposits are in Canada, USSR, and Rhodesia. The Thetford district of Quebec is the main source of chrysotile in Canada, but new deposits have been opened up at Cassiar in British Columbia and Clinton Creek in the Yukon. Most amphibole asbestos is mined in South Africa, primarily crocidolite and some amosite. Some crocidolite is also found in Western Australia and Bolivia. Finland is the major source of anthophyllite. Most chrysotile fibers are found in metamorphosed ultramafic rocks of

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J. S. HARINGTON, A. C. ALLISON AND D. V. BADAMI

FIG.4. Main asbestos mining countries of the world (1970). Countries are numbered in order of highest production (metric tons) : 1. 2. 3. 4. 5. 6. 7.

8. 9. 10. 11. 12. 13.

U.S.S.R. Canada South Africa China Italy U.S.A. Rhodesia Swaziland Japan Cyprus Finland Brazil Yugoslavia

1,900,000 1 ,500,000 290,000 173,000 119,000 114,400 80,000 39,000 33,000 26,000 14,000 13,000 12,000

14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

India Greece Bulgaria Taiwan Egypt Turkey South Korea Phillipines Australia France Mozambique Argentine Portugal

10,000 8,000 3,550 3,500 3,000 1,700 1,400 1,200 637 500 500 320 190

igneous origin that were altered to serpentine by hydrothermal action. Then, changes of pressure in the earth's crust caused an irregular network of cracks in the rocks, and hot ground waters were forced into the cracks under pressure. This was followed by a slow process of dissolution from the walls, and recrystallization in the form of a close-packed assembly of fibers generally running across the veins. Chrysotile asbestos is usually worked relatively near the surface by open-cast pit methods. Once the overburden has been cleared, explosives are used t o release large tonnages of rock and fiber, the latter accounting for only a few percent of the parent rock. In recent years, however, some mines

MINERAL FIBERS

299

have reached a depth beyond which it is uneconomical to work as open pits, and underground mining techniques have been introduced. Amphibole (derived from the Greek amphibolos meaning “ambiguous”) asbestos is found in metamorphosed sedimentary strata. It is not generally found in the same deposits as its massive nonfibrous counterparts. Crocidolite (from the Greek word meaning “knap of woollen cloth”) and amosite (derived from Asbestos Mining Co., South Africa) occur in what are described as “banded ironstones” of the Transvaal series with typical horizons of about 10 ft in thickness stretching across hundreds of miles. Amphibole fibers generally occur in steeply dipping or folded ore bodies and some mines operate a t a maximum depth of 1300 ft.

D. INDUSTRIAL USES OF ASBESTOS 1. Primary Manufacture

Crude asbestos, together with associated mother rock is conveyed to sorting stations, where waste rock is rejected and the ore undergoes a series of crushing and grinding operations. Fiber bundles of widely different lengths are inevitably mixed together. Subsequent screening results in a rough separation into grades but such screening is too imperfect to remove all the shorter fibers from the longer grades and even the lower grades contain a few long fibers. There are a number of laboratory methods of classifying the fibers, including dry sieving methods such as the Quebec box and Rotap tests and wet classification tests such as the Bauer-McXett and T 6 N Classifiers (Asbestos Textiles Institute Handbook, 1967). Another widely used method is based on the measurement of weight mean length. This is obtained by sorting or classifying fiber bundles into length fractions, each of which is weighed. The weight of each group is multiplied by its average length and the sum total of t,hese products is divided by the total weight to give the weight mean length. Using this method, the industrial uses of asbestos fibers can broadly be described as follows : less than 2 mm in fire-resistant paints; 2-5 mm in asbestos cement products, asbestos paper, molded plastics, and filter sheets; 5-10 mm in asbestos textiles such as felts, yarns, cloths, and cloth-based laminates, insulation mattresses, asbestos cement, and spraying; greater than 10 mm in specialized textiles, superior performance laminates, and mattress fillings. A unique feature of asbestos is its ability to be “opened” to varying degrees in ball or air-jet mills to produce specific surface areas which can be varied from about 1 m2/grn to about 20 m2/gm (cf. surface area of 0.7 m2/gm for cotton and 0.3 m2/gm for nylon). Fibers for textile applications receive

300

J. S. HARINGTON, A. C . ALLISON AND D. V. BADAMI

a more exacting treatment to eliminate uneven lengths and odd pieces of rocks of unopened fiber. 2. Secondary Manufactwe

The graded fiber undergoes special processes depending on ultimate application. Asbestos is used industrially because of a combination of useful properties. High tensile strength and stiffness, high temperature resistance, and incombustibility are attributes of all types of asbestos, but the different varieties vary most critically in chemical properties. The major use of chrysotile is in asbestos- cement because it has a high alkali resistance, whereas crocidolite is used in insulation and lead-acid battery cases because of its high resistance to chemical action. Rosato (1959) and Carroll-Porczynski (1969) have described the uses of asbestos in detail, and some of the major applications are briefly outlined in the following. a. Conventional Textile Processing. Batches of asbestos fibers are opened, cleared, and blended by beating in an air stream. The fibers are then fed into a carding engine where they are formed into a web by the combing action of rollers covered with a wire brush type of material. Usually a percentage of organic fibers is incorporated into the web in order to provide extra strength during processing. The web is then divided into strips, called slivers, that are wound onto bobbins. The slivers are then twisted into yarns on spinning frames. Although normal weaving processes are carried out with asbestos yarn, since asbestos fibers are relatively short and have very low extensibility, it has been necessary to develop special expertise over many years to work with asbestos fibers. b. Recent Developments i n Asbestos Textiles. Since asbestos fibers have broad length and diameter distributions, it is inevitable that the textile processes mentioned are dusty and shed a proportion of fibers. The finer of the fibers become airborne, and some of them may be inhaled with consequences discussed in detail later. The carding and weaving processes have traditionally been very dusty, although imaginative use of ventilation, enclosing of dusty operations, and mechanization of handling have now enabled dust levels to be controlled below recognized threshold values. The asbestos textile industry has recently also developed processes designed to minimize the amount of airborne dust produced during use by treating the textiles with a filmforming polymer in low concentrations (Heron, 1972). This treatment reduces the dust by a factor of 4 or 5 (Holmes, 1972). Dust production can also be reduced by dampening the fibers with an oil-water emulsion. Even more striking are recent developments of dispersion-based chrysotile asbestos textiles. This aspect has been reviewed by Heron and

M I N E R I L FIBERS

301

Huggett (1971). In essence, the process involves the preparation of an aqueous dispersion of finely divided asbestos fibers in the presence of suitable additives, and the subsequent formation of this into continuous filaments that can be spun into yarn and then treated to remove the additives. Many surfactants are said to open the chrysotile slowly, with only mild agitation from a pump (Novak, 1953); once formed such dispersions are stable almost indefinitely. The suspension properties or viscosity of these dispersions is complex and depends on fiber length, degree of opening, temperature, and other factors. Finally, such a dispersion can be extruded into a coagulating bath (Rex et al., 19.59) containing a polyvalent metal salt so as to produce continuous filaments. At this stage the yarn still contains a considerable amount of organic material that has to be removed either by extraction or heat treatment. S o t only does this wet process eliminate the carding operation but it also produces smoother and more regular asbestos yarns which arc 99% inorganic. Figure 5 shows electron micrographs of replicas of conventional and dispersion-based yarns and the uniformity of the latter can be clearly seen. Measurements, both in

FIG.5. Electron replica micrographs of (A) dispersion-based asbestos yarn; (B) conventional yarn.

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laboratory simulation tests and in actual lagging operations, have shown that products from dispersion-based textiles are less dusty than equivalent conventional products by almost an order of magnitude (Holmes, 1973). c. Asbestos Cement. The asbestos fiber is used to reinforce Portland cement. A suitable grade of fiber is mixed with cement and a considerable excess of water. The water is rapidly drained off, leaving a thin layer of cement with the fiber, which is then transferred to a forming bowl or mandrel where the necessary thickness is built up from a series of layers. This material is used for a great variety of structural purposes such as the fabrication of roof and wall cladding, rainwater and soil pipes, flue pipes, cisterns, cable conduits, and troughs. d. Other AppZications. In addition to textiles and cement, asbestos is used in a host of other applications that require incombustibility and protection against fire. Asbestos fibers are used not only for heat and acoustic insulation, but because of their unique properties of friction and wear they form a major constituent of automotive brake and clutch linings. Since asbestos fibers have very much higher modulus (stiffness) than glass fibers, they are being increasingly used for reinforcing both thermosetting and thermoplastic polymers. The structure and properties of chrysotile, crocidolite, and amosite will be discussed in further detail below.

E. SERPENTINE (CHRPSOTILE) ASBESTOS 1. Crystal Structure

It has already been mentioned that chrysotile has a sheet silicate structure. Sheet silicates are formed by linking three corners of each tetrahedron in the basal plane to neighbors (see Fig. 2, Section 11, B) and include a large number of common minerals, for example, the micas, talc, pyrophyllite, and most clays. All have a flaky structure, easy cleavage, and a pseudohexagonal symmetry based on the silicate (SizOs)sheet symmetry. In the micas, two silicate sheets are placed together with the vertices of the tetrahedra facing inward and joined together by aluminum, magnesium, or iron atoms, depending on the type of mica. Pairs of such sheets are held together by an arrangement of either potassium or sodium atoms. Talc, Mg6(Si8020)(OHI), also has a double silicate sheet as in mica but no intermediate alkali atoms are present. Some other clay minerals, on the other hand, are characterized by the kaolinite layer that consists of a single sheet of silicate together with a layer of A1-0, OH octahedra. When the silicate layer is bonded to a magnesium hydroxide layer instead, the resulting structure is termed a serpentine mineral, the fibrous variety of

303

MINERAL .FIBERS

v- -w b

CSI

o.Mg

d

0.0

.=OH

FIG.6. Schematic diagram showing the atomic arrangement in chrysotile.

which is chrysotile. However, the interatomic dimensions in the Si-0 and Mg-OH layers are slightly different and their bonding together results in the curving of the layers, with the silicon-oxygen sheets on the inner side and the Mg-OH (brucite) layers on the outside (Fig. 6). The curved sheets form scrolls and cylinders, which are referred to as fibrils (Figs. 7 and 8),

FIG.7. High-resolution electron micrograph of a transverse section of a bundle of chrysotile fibrils. (From Yada, 1967; reproduced by permission of the author and of the editor, Acta Crystallogruphicu.)

304

J. S . H-IRISGTOK, .I. C . ALLISOX AND D. V . BhDAMI

Fro. 8. Electron microgrttpli of ultrasonically dispersed specimen of clirysot ile, showing flcsible indiridtinl fihrils as well a4 bundles of fibrils.

and very large numbers of them together form the fiber bundles seen by the naked eye. In some nonfibrous forms of serpentine, the layers fit together in complex zig-zag and corrugated forms. Whittaker (1935) developed a detailed theory of cylindrical lattices to explain the X-ray diffraction effects observed from chrysotile, and electronmicroscopic studies by Yada (1967) show clearly the Swiss roll structure of the ultimate fibrillar unit of chrysotile (Fig. 7). When very finely divided chrysotile is examined in the electron microscope, individual fibrils can be seen threading their way through the field of view (Fig. S). It is generally believed that the lower photographic intensity observed along the center of the fibril indicates an actual lower density due to the fibrils being hollow. Indeed, the apparent tubular morphology is used by many electron microscopists as the unique feature identifying chrysotile. The tube is real in many cases (Fig. 9) but commonly it is partially filled with hydrated magnesium silicate. A large number of published electron micrographs of chrysotile also show clear evidence of electron beam decomposition, which can be recognized by the appearance of a dark central zone that may or

11IIlr;ERIL FIBERS

305

may not have a bubbled appearance. Decomposition can be confirmed by the loss in crystallinity, resulting, in turn, in a loss of the diffraction pattern. A considerable amount of work has been carried out t o determine whether or not the center of the fibrils is hollow or filled either completely or partially with a noncrystalline material of the same chemical composition. This uncertainty arose because measurements of density (= 2.55 gm/cm3) indicated a near theoretical density, but lateral packing of hollow fibers would be expected to lead to a void volume of 20 to 30% and, hence, to a lower density. However, recent density measurements (Huggins and Shell, 1965) indicated the presence of G to 15% of voids, thus partially reconciling the various observations. It is currently accepted that the fibers are partially filled, but for a detailed analysis of this position the reader should refer t o the discussion by Whittaker and Zussman (1971). A. L. Rickards (unpublished, 1971) has found supporting evidence from electron micrographs of heat-treated chrysotile specimens that there is some interfibrillar material as well as intrafibrillar material.

FIG.9. Electron micrograph of a sperial grade of chrysotile fibrrs from Coalinga, New Idria, U.S.A.

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J. S . HARINGTON, A. C . ALLISON AND D. V. BADAMI

2. Fibril Dimensions

a. Fibril Length. As mentioned earlier, mean fiber length is an important property that determines the commercial value of a grade of asbestos (Asbestos Textiles Institute . Handbook, 1967). There has been little information} however, about the length of the individual fibrils that make up the macrobundles of fibers. Atkinson et al. (1971) have recently attempted to measure fibril lengths using electron microscopy. Direct measurements proved impossible as, at the magnification necessary to resolve individual fibrils, the lengths of fibrils far exceeded the field of view. Hence a statistical technique was developed, based on counting the number of fibrils that passed right through the field of view with no ends visible at all and those with only one end visible. From these measurements it was possible to calculate that average fibril lengths ranged from 1 to 2 mm for most commercial grades, in direct proportion to their macrobundle lengths (Fig. 10). Measurements based on viscosity and the novel phenomenon of reduction of friction drag agreed with the electron-microscopic results. b. Fibril Diameter. A wide range of fibril diameter values has previously been reported by using electron microscopy, X-ray diffraction techniques, and surface area measurements. Since these differences could have been due both to differences in techniques and to materials, Atkinson and his associates (1971) undertook direct electron-microscopic measurements of 100-200 fibrils in each sample and found that over a wide range of samples, ranging from low to high grade and from various localities including East Canada and Africa, the mean diameters were in the range 30-38 nm (300-380 A) (Fig. 11). The mean fibril diameters of the longer spinning 4.

fibril length

(mml

3.

2.

’.

k dp .

$9

/:

/!

o

electron microscope drag reduction

307

MINERAL FIBERS

0

10

20

30

40

50

60

70

80

nm

Cassiar AAA

W7R

Kaapsch Hoop

Shabani nonsiky

--

Shabani silky

o 1

.

10

20

30 40

50 6 0

70

80

nm

fibril diameter

FIG.11. Distribution of fibril diameters for various grades of chrysotile.

grades were found t o be about 20% higher than for the corresponding shorter grades of fiber. Using the above data of average fibril length of 1-2 mm and average fibril diameter of 300-380 d, it can be seen that the fibrils have an aspect ratio (length/diameter) of about 100,000:1.

3. Surface Area and Surface Charge The ability of asbestos fibers, in particular chrysotile, to subdivide into successive smaller bundles allows a whole range of specific surface areas to be obtained. This is important for many commercial applications such as filtration and reinforcement. On the assumption that all the fibrils in a fiber of a commercial grade, such as Cassiar AC.65, could be separated into individual units, and assuming only the external surface to be available, the

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ultimate specific surface area of chrysotile is approximately 100 m2/gm. Actual commercial grades of fiber, on the other hand, have surface areas ranging from 10 to 20 m2/gm. Dispersion opened fibers do, however, have surface areas of 30-50 m2/gm. It may be seen from Fig. 6 (Section 11, E, 1) that the ideal external surface of chrysotile is a layer of magnesium hydroxide. When models with correct ionic radii are built up, it is clear that the outer layer is effectively a close-packed layer of hydroxyl groups. Pundsack (1955) determined the pH of a suspension of chrysotile in Cop-free distilled water to be 10.33. However, some of the dispersion-based asbestos textiles appear to have localized acidic areas, indicating perhaps partial stripping of the magnesium hydroxide layer. The surface properties of chrysotile play an important role in its performance in most commercial applications, in particular in aqueous dispersions in the presence of surface-active agents. Chrysotile has a positive charge in neutral aqueous suspension due to the release of surface hydroxyl ions. Martinez and Zucker (1960) measured zeta potentials of chrysotile using a streaming potential method and in the presence of aqueous potassium chloride solution. An equilibrium value of 93 mV was obtained but this was largely dependent on pH. Furthermore, Martinez (1971) has stated that this value was high by a factor of 2. Highly alkaline solutions produced negative potentials, whereas in more acidic media the potentials were positive. R. B. Gettins, C. RI. Freedman, and F. J. Mallon (unpublished, 1971) using electrophoresis, measured zeta potentials of chrysotile in aqueous suspensions containing anionic surface-active agents. Values obtained were obviously those for chrysotile together with adsorbed surfactant and ranged from - 100 to -25 mV; this relatively wide range is due to the varying quantity of electrolyte present (sodium sulfate).

+

4. Chemical Composition

The idealized composition of chrysotile, Mga(SizOs)(OH)4, is made up of approximately 43.5% SiO,, 43.5y0 MgO, and 13% H2O. Although some mined chrysotile approximates closely to such a composition, both substitutional impurities and macroscopic inclusions of associated minerals are common and often amount to 10 to 20y0,and occasionally in very low grades (by length) as high as 4oQ/,, depending on the geographic origin of the fiber. Iron and aluminum are the most common impurities; others are calcium, chromium, nickel, manganese, sodium, and potassium. Gosseye and Hahn-Weinheimer (1971) have recently reported a wide variation in major impurities, based on results from analyzing about sixty samples from various mines. Iron content varied from 1.0 to 15.5%, aluminum from 0.09

MINERAL FIBERS

309

to 0.90%, sodium from 0.01 to lo%, and calcium from 10 to 4400 ppm. Because of the wide variation in physical and chemical characteristics of asbestos fibers, a set of standard Union Internationale Contre le Cancer (UICC) samples was prepared in 1966, and much of the work reported in Sections I11 to V of the present review is based on these samples (Rendall, 1970; Timbrell, 1970). In comparison with the foregoing data, the iron content of the UICC samples ranges from 2 to 3%, aluminum from 0.3 to 0.40/,, and the sodium content is 0.03%. Little has been done to indicate clearly the degree of substitution in the chrysotile lattice. By using chrysotile irradiated with thermal neutrons and studying the solubility characteristics of the fiber in 1N hydrochloric acid, Morgan et al. (1971a) concluded that iron, chromium, cobalt, and scandium are all incorporated in the brucite layer. Studies of magnetically separated irradiated fractions again showed the presence of chromium and cobalt in the magnetic fraction but no scandium. Thus scandium is clearly associated with chrysotile, probably because the ionic sizes of scandium and magnesium are comparable. There is less clear evidence for the generally assumed substitution of silicon by Fez+and magnesium by Fe3+.Since the substituted ions vary considerably in size, they can influence the strains resulting in the chrysotile lattice and, hence, some of the physical characteristics. Otouma (1971) concluded that with less than 0.35% of oxide of the substitutive elements in the outer (octahedral) sheet the fibers become thinner and larger in surface area. Considerable effort has been devoted to the analysis of minerals associated with chrysotile fibers. These are made up of hydrated minerals (brucite, chlorite, talc), carbonates (calcite, magnesite, dolomite), and a diverse group consisting principally of magnetite, chromite, and quartz. Other serpentine minerals such as a lizardite and antigorite occur less often. Many of these minerals are found intimately intergrown with the fiber bundles, but commercial processes of fiber separation also help to separate associated minerals. Even in the purer grades of chrysotile, other minerals (magnetite, brucite, and magnesite) are commonly found. Whereas magnetite can be magnetically separated, brucite and magnesite are generally present in the commercial fibers and can be estimated by thermogravimetric analyses. Harington (1965) reported that virgin chrysotile was not associated with any primary oil or organic matter but that, like other forms of asbestos, it absorbed from jute bags an appreciable amount (70-85’%) of oils, two of which were found to be weakly carcinogenic. Commins and Gibbs (1969) found that samples of chrysotile asbestos stored in polythene bags contain traces of benzo[a]pyreneand 3,3‘, 5,5 -t-butyldiphenoquinone, derived from one of the antioxidants used in polymerization of ethylene.

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J. S. HARINGTON, A . C. ALLISON -4ND D. V. BADAMI

Gibbs and Hui (1971) found the organic content of commercially milled Canadian chrysotile to range from 0.5 to 20.0 mg/100 gm of fiber, depending on source and grade. These yields exceeded those from field specimens in all cases but one and indicated contamination by mining and milling processes. Samples were obtained from ore entering dryers, ore leaving dryers, and milled fiber prior to bagging. Contamination was found to occur during crushing and drying. Infrared and gas-chromatographic examination showed n-alkanes to be the major constituents. The amounts of polycyclic aromatic hydrocarbons present in chrysotile were fouild to be exceedingly low, being approximately 1/10,000 of the levels in smoke from the rural areas of England and Wales (Commins, 1958). However, the amounts of polycyclic aromatics associated with oil-fired dryers may be less than those with coal-fired dryers used previously. Although Harington (1962) found no benzo[a]pyrene in African chrysotiles, Reimschussel (see Speil and Leineweber, 1969) reported this hydrocarbon in African chrysotiles but not in Canadian and U.S. chrysotiles. Since Harington examined virgin samples and Reimschiissel studied commercial fibers, again some of the benzo[a]pyrene could have been introduced during processing or shipping of the fiber.

5 . Adsorption Young and Healey (1954) studied the adsorption of several vapors on chrysotile (e.g., nitrogen, argon, carbon monoxide, and acetylene) and found surface areas of 9.7 m2/gm for a 7R Canadian fiber, whereas ammonia and water vapor gave surface areas of 17.6 m2/gm. They concluded that this was due t o the extremely polar nature of water and ammonia molecules, which could apparently gain access to more of the surface available. With an increasing emphasis on dispersion-based textiles, there has been a greater interest in the study of adsorption from solutions on chrysotile. Gettins and Mallon (1971) have studied the adsorption of common surfactants, for example, dodecylbenzenesulfonate and sodium laurate. Adsorption proceeded rapidly and equilibrium was reached in a few minutes. The complete adsorption isotherm indicated that the amount adsorbed increased rapidly at low solution concentrations and thereafter remained virtually a t a constant level over a wide range of solution concentration. From the known surface area of the fiber and the equilibrium coverage, they calculated that each dodecylbenxenesulfonate molecule occupied 30.8 A which compared well with a value of 30 A (calculated from the atomic dimensions) for a vertically oriented molecule. They further concluded that only about 5-10% of the molecules were chemisorbed,

MINERAL F I B E R S

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whereas the rest of the molecules were physisorbed with the polar heads directed away from the fiber surface. 6. Chemical Decomposition of Chrysotile

All types of asbestos resist prolonged attack by strong alkalis, and it has long been known that chrysotile is attacked by aqueous acids that react with the hydroxyl layers. The magnesium atoms are then free to diffuse out, leaving a siliceous residue. Eventually the chrysotile lattice is completely destroyed although the fibrous morphology is often retained. Faust and Nagy (1965) found that chrysotile is completely destroyed after treatment with I N HC1 a t 95°C for 1 hour. Monkman (1971) studied the rates of attack of various acids on bundles of fibers. The degree of fiber opening and, hence, surface area, have a marked effect on the rate of reaction. Atkinson and Rickards (1971), by using highly opened chrysotile, eliminated the complexities arising from penetration between bundles and were able to study the attack of the fibrils themselves. The rate of attack was measured by using X-ray diffraction as a function of temperature, acid type, and concentration to estimate quantitatively the residual chrysotile lattice. Electron micrographs clearly showed that the reaction boundary moves inward as the reaction proceeds, and i t was also shown by electron diffraction that the residual silica retains a sheet structure. Clark and Holt (1960) found that by continuous extraction with hot water, chrysotile could be decomposed and that the extracts contained orthosilicic acid and magnesium hydroxide. They suggested that the residual silica was probably colloidal in size and in the form of minute flakes.

7. Thermal Decomposition of Chrysotile All asbestos minerals, in spite of their high fusion temperature, break down a t temperatures below 1000°C, depending on the species. Different aspects of their progressive thermal decomposition can be followed by a number of techniques : thermogravimetric analyses, differential thermal analysis, infrared spectroscopy, X-ray diffraction, and electron microscopy. The first stage in the decomposition of chrysotile is dehydration, followed by dehydroxylation (Ball and Taylor, 1963; Brindley and Hayami, 1965). Although there are suggestions that this can commence a t temperatures as low as 200"-25O"C, clear onset of dehydroxylation is evident between 550"-600°C. Chrysotile is fully dehydroxylated by about 8OO0C,the residue being an amorphous phase. On further heating to about 825OC, recrystallization occurs with the formation, according to the theoretical scheme, of

312

J. S. HARINGTON, A. C. ALLISOK AND D. V. BADAMI

forsterite (MgzSi04)and silica. But silica has not been detected as an independent phase. At about 1100°C, some enstatite (MgSiO,) is formed. However, this picture is only a general description, the actual transformations are far more complex. By using infrared spectroscopy, Daykin (1971) has shown that the onset of forsterite can be detected even before complete dehydroxylation is observed. Donor-acceptor mechanisms have been postulated to explain the dehydroxylation process. Since many laboratory samples of asbestos, including the UICC samples, are produced by hammer milling, it would be useful to note that both the dissipation of mechanical energy and consequent local rise of temperature affect the subsequent thermal behavior of chrysotile (Martinez, 1961). Harris (1971) concluded that the surface layers of chrysotile fibers were very easily distorted during grinding. With continued grinding, the X-ray diffraction pattern of the chrysotile lattice disappeared completely. Another example of dissipation of much larger amounts of mechanical energy, of course, is the application of brakes to stop moving automobiles. Automobile brake linings contain chrysotile asbestos in amounts ranging from 30 to 50% by weight. However, when the wear debris is examined in the electron microscope, very few asbestos fibers can be seen (Lynch, 1968; A. L. Rickards, unpublished, 1971). On the other hand, A. M. Langer (personal communication, 1973) has observed (with very high magnification in transmission electron microscopy) many asbestos fibers in wear debris. The large stresses and consequent rise in temperature not only destroy the crystal structure of chrysotile but in general, even the fibrous morphology is destroyed. Both the structure and composition of thc wear debris is extremely complex.

F. A~IPHIBOLE ASBESTOS The amphiboles constitute a large and important group of rock-forming minerals, with a wide variation in composition, but having certain relationships in their optical properties and crystal structure that have led mineralogists to classify them together. They are often associated with granite and other deep-seated igneous rocks as well as with metamorphic rocks. Because of the wide variations in composition, species names are applied to idealized compositions known as end members. The three main subgroups are (1) iron-magnesium amphiboles, ( 2 ) calcium amphiboles, and ( 3 ) alkali amphiboles. Mg), (Si802,) (OH),], The first subgroup includes grunerite [ (Fe2+)4(Fe2+, the fibrous form of which is known as amosite asbestos. Tremolite is representative of the second class, and the best known alkali amphibole is riebeckite, the asbestos form of which is crocidolite [NazFe32+Fe23+ [Si800pB]

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(OH,F)2]. Massive riebeckite granite is of quite common occurrence (including some in the United Kingdom), and massive grunerite occurs in the United States but these do not contain fibers of commercial value. Only in a very few places, mainly in South Africa and Western Australia, do the amphiboles crystallize in a fibrous form, and, as mentioned earlier, these are not normally associated with their massive counterparts, unlike chrysotile that is invariably found with rocks of the same composition. 1. Crystal Structure It has already been mentioned that the amphiboles possess structures built up of double chains or ribbons of linked tetrahedral groups of atoms having the unit composition (SilOll)nalong the fiber axis. They are laterally bonded by planes of cations and also some hydroxyl ions rising up to 2% in some amphiboles (Fig. 12). In both crocidolite and amosite, the cations are mainly ferrous and ferric iron. The cleavage planes are parallel to the silica chains since it is more difficult to break the Si-0 bonds than the other bonds in the structure. Thus, cleavage takes place in a zig-zag manner (line A-A in Fig. la), the resultant surface being made up essentially of an ordered

FIG.12. Schematic diagram showing structure of amphiboles. permission of Cape Asbestos Co., London.)

(Reproduced by

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J. S. HARINGTON, A. C. ALLISON AND D. V. BADAMI

FIG.13. (top) Electron micrograph of ultrasonidly dispersed specimen of crocidolit3 pm are fibrogenic (Vorwald et al., 1951). 5. Short fibers are as lethal as long ones (Halt et al., 1965b). 6. Long fibers are more fibrogenic (IV. Klosterkotter, personal communication to Ilr. Gilson, 1965, in Vigliani, 1968). 7. Long fibers are fibrogenic; small part,icles remain in macrophages (\\-ebster, 1966). a F r o m Vigliani, 1968; reproductd by permission of the author and of the rditor, Medicina del Lavoro.

short-fiber chrysotile. On the other hand, Burger and Engelbrecht (1970a) reported that fiber length was not nearly as important a deciding factor in fibrogenicity when the fibers were injected into the pleural cavities of rats. Both long and short fibers of chrysotile produced a progressive fibrosis, a result apparently a t variance with that of Davis (1972a). Recent studies support the contention that longer fibers are more fibrogenic than shorter, because essentially they are less well phagocytozed and transported away (Hilscher et al., 1970; Beck, 1971; Friedrichs et al., 1971; Hilscher, 1972; Timbrell, 1972a, b). Transport begins with fibers measuring 20 pm and increases with decreasing fiber length. Also, short fibers are found almost always intracellularly (see Timbrell and Skidmore, 1968) whereas longer ones are seldom incorporated by cells (Friedrichs et al., 1971). I n general, then, the sites of deposition and clearance from the lung influence the way in which fibers of different lengths exert their biological effects. I n experiments where the pleural cavity is used, the fibers are artificially deposited in a confined space; in the lung, long-fibers deposited by respiration would be difficult t o mobilize while short ones can be phagocytozed by macrophages and carried away (Davis, 1972a). Short-fibers would also penetrate more efficiently to the lower parts of the lung. Davis also points out that long fibers could cause considerable irritation during constant respiratory movements while short ones would be aggregated into compact masses and probably encapsulated soon afterwards. Timbrell and Skidmore (1968) exposed rats and guinea pigs to clouds of long- and short-fiber amosite. Twice as much dust was retained in the lungs after exposure to the short-fiber cloud than to the long-fiber one, this

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J. S. HARINGTON, A. C . ALLISON AND D. V. BADAMI

being due to deeper penetration of the former. I n animals that had died more than a year after exposure, lesions consistent with early asbestosis were seen in the long-fiber group but no progression had occurred in the short-fiber group. One result is a t variance with the hypothesis that long fibers are more fibrogenic than short: Holt et al. (1965a, b) reported considerable fibrosis in the lungs of guinea pigs treated with very fine chrysotile, crocidolite, amosite, and anthophyllite. On this basis, they suggested that long-fiber dust did not cause more severe lesions. The experimental evidence regarding fiber length and progressive fibrosis can be summarized as follows: longer fibers are probably more effective than shorter fibers in the production of asbestosis in experimental animals. Fiber diameter has received considerable attention and appears to play an important part in deciding how deeply penetration into the lung can occur (Timbrell and Skidmore, 1971; Timbrell, 1972). In addition to the foregoing work, it has been shown that elimination from the lung is more efficient for certain forms of asbestos than others. Wagner and Skidmore (1965) found that chrysotile was eliminated from the lungs of rats 3 times as rapidly as amosite during the period after exposure had ceased. Using UICC standard reference samples, Wagner (1970) reported 6 times as much amosite as chrysotile in the lungs of rats a t the end of exposure, and similar observations were made by Morris et al. in 1965. When injected into the pleural cavity of hamsters, harsh chrysotile (hydrophobic in character) produced thicker granulomatous and fibrous pleural adhesions and more rapid development of mesotheliomas than soft chrysotile (hydrophilic) (Smith et al., 1973). The two forms of fiber used were comparable in length although the harsh one consisted of thicker bundles. The different sizes of the samples and their surfaces and charges, and trace metal contents, were associated only in terms of time of response. It was felt that the hydrophilic character of the more active form, the soft chrysotile, may have acted as a barrier inhibiting biological interaction. With regards to prevention of asbestosis in experimental animals, PVPNO-well known for its effective preventive action against fibrosis by quartz (Schlipkoter and Brockhaus, 1961; Schlipkoter et al., 1963; Schlipkoter and Beck, 1965; Chiappino et al., 1967) and coal-containing quartz (Hilscher and Schlipkoter, 1973; Wellcr and Ulmer, 1973)-has littlc cffect on various forms of asbestos. Thcre is a possibility of some reduction in the cffect of asbcstos on animals (Robock et al., 1969b; Davis, 1970b; Klostcrkotter and Itobock, 1970) but this is not dramatic. Poly-p-dimcthylaminostyrene-N-oxidc, a polymcr with an antiquartz cffect similar to that of PVPNO (Chiappino et al., 1967), docs not secm to have as yet been tested experimentally against asbestos fibrosis ncithcr in viiro nor in vivo.

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D. FIBROGENIC EFFECTS IN MAN

It was first clearly recognized in the 1920s that asbestosis, a diffuse interstitial fibrosis of the lungs, is caused by occupational exposure to asbestos although the first case of diffuse pulmonary fibrosis from exposure to asbestos was reported by Murray in 1907 (see Wright, 1969, for a brief review of asbestosis). The Senior Medical Inspector’s Advisory Panel established in 196.5 by H.M. Factory Inspectorate concluded that there is an increasing incidence of the disease in Britain, for which the likely explanation is a greater use of asbestos and greater numbers of people employed in industry over the previous 20 years. S o evidence was found that the overall attack rate had decreased in industry over this period, although this was observed in some textile mills where conditions had improved. Asbestosis appears to be confined to those industries in which asbestos is extensively used. Because they are occupational diseases, asbestosis and its associated malignancies can be prevented. The report of the Advisory Panel emphasizes that care should be taken to control the discharge of dust-laden air from factories and the dispersal of dust from waste dumps. Another possibility of prevention may lie in the replacement of one type of asbestos with another, although this would apply more to the asbestos malignancies than t o asbestosis (Harington, 1967). It would appear that all forms of asbestos fiber used in industry are capable of inducing pulmonary asbestosis. Epidemiological aspects have been analyzed in several countries, especially since the time of the UICC Working Group on Asbestos and Cancer mcht in New York in 1964 (Whipple, 1965). The importance of fibrr type on the risk of drvdoping asbestosis (and malignancy) was rec0gnizc.d. Comparativr studics of mining and other populations exposed t o only onr type of fiber were recommended (Gilson, 1966). Among the countries regarded suitable for such studies were the following: Australia, crocidolite; Canada, chrysotile; Cyprus, chrysotile; Finland, anthophyllite; Italy, chrysotilc; South Africa, amositc, chrysotilc, crocidolitr; United States, chrysotile, trrniolitc; and the Soviet Union, chrysotile. Since 1965, three more international conferences on the biological effects of asbestos have extended awareness of human exposure in industrial populations t o this mineral. These are the Second International Conference onGthe Biological Effects of Asbestos held in Dresden in 1965, the International Conference on Pneumoconiosis held in Johannesburg in 1969 (Shapiro, 1970), and the Working Group Meeting on the Biological Effects of Asbestos xhich took place in Lyon in 1972 (Bogovski et al., 1973; Gilson

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J. S. HARINGTON, A. C. ALLISON AND D. V. BADAMI

TABLE VII GEOGRAPHIC ORIGINAND TYPESOF ASBESTOS FIBERFIBROGENIC TO MAN Country

Fiber type

Source

Australia (Western) Bulgaria

Crocidolite Anthophyllite, tremolite, chrysotile Not specified Chry sotile Chrysotile Not specified

McNulty (1968, 1970) Zolov et al. (1968)

Anthophyllite, tremolite Anthophyllite

Kiviluoto (1965) Noro et al. (1968). Meurman and Kiviluoto (1968); Kiviluoto and Meurman (1970); Meurman et al. (1973); Ahlman et al. (1973) Avril and Champeix (1970) McVittie (1965) Smither (1965)

Canada (Quebec) Cyprus East Germany (Dresden area) Finland

France Great Britain

Chry sotile Not specified Chrysotile, crocidolite, amosite Chrysotile, some amosite, little crocidolite

Cartier (1968) McDonald (1973) McDonald (1973) ltoitzsh (1968)

Smither and Lewinsohn (1972)

Italy (northern)

Not specified Chrysotile

Vigliani et al. (1968) Vigliani (1969, 1970)

Rhodesia

Chrysotile

Gelfand and Morton (1970)

Southern Africa

Crocidolite, amosite; chrysotile (Swaziland) Crocidolite, amosite; chrysotile (Swaziland) Crocidolite, amosite

Sluis-Cremer (1965)

Massive fibrosis: crocidolite (northwestern Cape), amosite and/or northeastern Transvaal crocidolite Mixed dust fibrosis (asbestos as one component)

Webster (1969, 1970) Sluis-Cremer and du Toit (1973) ; Sluis-Cremer (1970) Solomon et al. (1971)

Goldstein and Webster (1971)

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MINERhL FIBERS

TABLE V I I (continued) Country

Fiber t,ype

Source

United States

Insulation asbestos, mainly chrysotile Not specified Predominantly chrysotile, amosite, crocidolite occasionally used Not specified Not specified

Selikoff et aZ. (1965a,b)

(San Francisco) (New York State)

Enterline (1 965) Hueper (1965) Enterline (1968) Mancuso and El-Attar (1968) Cooper and Balzer (1968)

Amosite, chrysotile, fibrous glass Asbestos type not Kleinfeld (1968) specified, commercial talc (mixhre of t remolite, anthophyllite, serpentine, and free silica) Insulation materials Selikoff et aZ. (1970) (amosite, chrysot>ile); fibrous glass, plastic, and other materials Chrysotile, crocidolite lhterline and Weill (1973) (silica) Chrysotile, amosite, Cooper and Miedema crocidolite, and (1973) accompanying materials such as magnesium carbonate, calcium silicate, and diatomaceous earth

1972, 1973a). The extensive bibliography of Williams (1969, pp. 12-71) should also be referred to Table VII, by no means exhaustive, summarizes information on the type of fiber implicated in causing asbestosis in various countries. In many instances it has not been possible t o specify in precise terms the type of fiber to which workers or other populations have been exposed. This is not surprising in view of the present inadequate information regarding type of fiber, dose, and duration of exposure and industrial processes involved. Smither and Lewinsohn (1973) point out that of seventy-one papers reviewed by them between 1964 and 1970, one-half was specific about type of occupation, the other half referring nonspecifically to

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J. S. HARINGTON, A. C. ALLISON AND D. V . BADAMI

“asbestos workers.” Type of fiber was qualified in only a third of the papers, the particular textile operation in use in only 20%, and the actual dust levels to which the workers had been exposed, in 14%. The information summarized in Table VII reinforces the view that all types of asbestos fiber, when mined, milled, or used in industry in sufficient amounts are fibrogenic to man. It is in some circumstances possible to be reasonably specific about type of exposure, for instance, to anthophyllite in Finland and t o some extent chrysotile in the United States and Canada, although in most circumstances the likelihood of mixed e x p o h e is great. Regarding asbestosis and cigarette smoking, Hammond and Selikoff (1972) concluded that the latter may increase the risk of death from asbestosis, although to a much lesser extent than death from bronchogenic cancer. The important issue of air pollution by asbestos and health hazards related to this has been dealt with recently. Reitze et al. (1972) drew attention t o hazards associated with the spraying of inorganic fiber containing asbestos (over 40,000 tons of such material were produced in the United States in 1970). Selikoff et al. (1972a) discussed air pollution by asbestos, using material from direct and indirect occupational groups, neighborhood contamination groups, and the general community. However, Rickards and Badami (1971) found only trace amounts (10-4-10-10gm/ mm3) of chrysotile in urban air near a large asbestos textile factory in Britain. Holmrs (1972, 1973) has recently discussed sampling methods in relation to occupational and general environmental situations. Trace quantities (10-6-10-8 gm per sample of single-dose vial) of chrysotile asbestos wcrc found in one-third of samples from two sets of seventeen widely used parentrral drugs (Nicholson et aZ., 1972). Howevcr, recent work by Rickards (1973) suggests much lower values of chrysotile (10-7-10-9 gm/liter) in similar drugs. Although thc significance of this observation is not yct clear (Gilson, 1973a), i t would sccm purdent to have such materials filtercd out a t a suitablc stage. Earlicr observations by House (1964), Groves (1965), and Brown et al. (1965) draw attention to cell culture, solutions, and virus growth becoming affected by asbestos fibers after filtration of media through asbestos pads. Finally, health hazards caused by asbestos and precautions to minimize or abolish these have becn rcvicwed by Smither and Cross (1972) and others are listed in the bibliography of Williams (1969, pp. 109-116).

E. CARCINOGENIC EFFECTS IN ANIMALS I n his Wyers Memorial Lecture, Gilson (1966) stated that a t the time of the earlier work on experimental asbestosis, the association between

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asbestos exposure and cancer had not been well established and little attention was therefore paid to asbestos as a carcinogen. I n 1941, Nordmann and Sorge had found that half of a 100 mice subjrcted to asbestos dust over a 7-13 week period showed abnormal epithelial growth of the bronchial murous membrane; of the 10 animals that survived the experiment, 2 developed carcinoma of the bronchus. A failure to produce malignancy in a large experiment in which mice were exposed to asbestos was reported by Lynch et al. (19.57). Asbestos of an undisclosed type, cut to lengths of 0.5 t o 1 cm, induced sarcomas in rats after subcutaneous and intraperitoneal implantation. T w o other silicates, augite and tremolite, failed to produce tumors under the same conditions (Schmahl, 1968). That the results of Schmahl’s work were probably due to an Oppenhcimer offect-the induction of sarcomas in certain species of animals after apparently inert films of plastic, glass, and other materials have been implanted subcutaneously-is indicated by the high incidence of sarcomas obtained by Nothdurft and Mohr (1958) and by Nothdurft (1960, 1961) who implanted quartz or quartz glash platvs into rats. Oppcmheimer et al. (1961) induced sarcomas with glass discs, but powdercd glass was found to be inert. On the basis of this finding, Nothdurft postulatcd that quartz and glass discs or films are not chemical carcinogens and behaved in a distinct fashion when implanted. Further work on glass revicwd by Bischoff and Bryson (1964) does not seem to alter this contcntion. The association of pleural mesothelioma with human exposure to crocidolite in South Africa (Wagner et al., 1960) stimulated further experimental inveqtigations of the induction of bronchogenic cancer and pleural and peritoneal mesotheliomas in experimental animals. 1. Bronchogenic Cancer The inhalation route of fiber administration to animals is clearly the most realistic as it most closely parallels the human situation (Wagner and Berry, 1972). Nevertheless, the technique requires skill and efficient equipment (Timbrel1 et al., 1968, 1970a). Perhaps for these reasons, comparatively few tests for carcinogenicity in the lungs of experimental animals have been made. In one investigation, one-third of a group of rats given chrysotile by inhalation and surviving 16 or more months had primary malignant tumors of the lung. Over a half of these were adenocarcinomas, and the remainder fibrosarcomas and squamous cell carcinomas; one mesothelioma was also found (Gross el al., 1967~).The actual carcinogens responsible for these effects were ascribed by the authors to increased amounts of trace metals

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3. S. HARINGTON, A. C. ALLISON AND D. V. BADAMI

introduced in or on the fiber during hammer milling of the specimens. The content of nickel increased by 82%, cobalt by 145%, and chromium (chrome) by 34%. A later report (Gross et al., 1970a) described a further series of primary bronchogenic cancers which had been induced in rats dusted with chrysotile. Again, most of the malignant tumors were adenocarcinomas, and the carcinogenic action was ascribed to contaminant trace metals. Studies of cocarcinogenesis between various forms of asbestos and hydrocarbon carcinogens have shown clearly that chrysotile can augment considerably the numbers of malignant tumors produced by the polycyclic hydrocarbon, benzo[a]pyrene. A similar effect had been described earlier when Shabad et at. (1964) induced lung tumors in rats by mixing benzo[a]pyrene with India ink, whereas with the carcinogen alone they were unable to do so. Saffiotti et at. (1965) induced lung tumors in hamsters by combinations of iron oxide and benxo[a]pyrene but not by the latter alone. Studies by Miller et al. (1965) suggest that some type of combined carcinogen and cocarcinogen reaction of the type mentioned in the foregoing may be a property of certain types of asbestos and not of other types. The results of these may help to explain the more potent activity of crocidolite than that of amosite. Miller and his associates found that intratracheal injection of amosite did not increase the yield of tracheobronchial tumors induced in hamsters by benzo[a]pyrene,indicating a weak or negligible promoting property for this type of asbestos. Thcy found that amosite apparently promoted benzo[a]pyrene carcinogenesis, but too few animals were used for the results to be significant. More extensive studies (L. Miller, personal communication) have shown that chrysotile effectively promotes the carcinogenic effect of benzo[a]pyrene. Crocidolite has not yet been tested in this type of experiment (see Harington et at., (1967). More recently, VBsamae (1971) has confirmed the promoting action of chrysotile established by Miller et al. in 1965. Intratracheal injection of benzo[a]pyrene together with chrysotile (UICC standard reference sample) resulted in a considerably higher yield of malignant lung tumors in rats: 35 epidermoid carcinomas compared to 12 induced by benzo[a]pyrene alone. Chrysotile alone induced 2 malignant tumors-a reticulosarcoma and a mesothelioma. Pylev (1972) obtained a similar effect to the above with chrysotile and benzo[a]pyrene. However Pott et al. (1972), found that the rate of tumors that developed after the intraperitoneal injection of chrysotile in rats was not distinctly influenced by the addition of benzo[a]pyrene. No animal experimentation has apparently yet been carried out to test the suggested effect of cigarette smoking on the development of bronchogenic carcinoma in man (Hammond and Selikoff, 1972) although such lines of

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369

approach have been occasionally mentioned (Selikoff et al., 1967; Harington, 1973). It was a t one time thought that organic matter, including polycyclic hydrocarbons found in or on asbestos due to geological and/or industrial processing or contamination (Harington, 1962, 1965; Harington and Smith, 1964; Harington and Roe, 1965; Roe et al., 1965) might in some way contribute to the carcinogenic role of asbestos. The extensive experiments of Wagner and Berry (1969), Wagner et al. (1970), and Wagner (1972b) have shown, however, that asbestos from which organic matter has been removed by exhaustive extraction with hot benzene is as active as native (unextracted) fiber in inducing mesotheliomas in rats by intrapleural inoculation. More recent work on organic matter on asbestos has shown that the organic content of commercially milled Canadian chrysotile ranges from 0.5 to 20.0 mg/100 gm fiber, depending on source and grade of fiber (Gibbs and Hui, 1971). Infrared spectral analyses and gas chromatographic separation showed n-alkanes to be significant contaminants of the fiber. It was found that during the distribution of UICC samples for animal experiments the fibers were contaminated with constituents of the polythene in which the fibers were packed and also oxidation products formed catalytically by the fiber reacting with antioxidant constituents in the plastic covers or bags. One such product is 3 ,3’ ,5 ,5’-t-butyldiphenoquinone (Commins and Gibbs, 1969; Gibbs, 1969, 1970). The biological significance of this substance has not yet been evaluated although it has not been suggested that the use of polythene for bulk packaging of commercial fibers constitutes a potential health hazard. Other studies have shown that jute oil is absorbed to a considerable extent from jute bags in which asbestos is stored (Harington, 1965). Such mineral oil is a potent incomplete carcinogen of the tumor-promoting type and also a complete carcinogen (Roe et al., 1967). 2. Pleural and Peritoneal Mesotheliomas

A number of experiments followed the preliminary report by Wagner (1962) that crocidolite and chrysotile could induce mesothelial tumors in animals after the intrapleural inoculation of fiber. In 1965, Peacock and Peacock described a similar effect in fowls after crocidolite and amosite had been inoculated, although it was not possible to determine the relative carcinogenicity of each type of fiber. In 1965, too, Wagner induced mesotheliomas with chrysotile and crocidolite. Peacock and Peacock (1963, 1968) described the carcinogenicity of chrysotile, crocidolite, amosite, and

370

J. S. HARINGTON, A. C. ALLISON AND D.

V.

BADAMI

tremolite in fowls and mice, and Smith et al. (1968) induced pleural mesotheliomas in hamsters with amosite and chrysotile. I n the latter study, carcinogenic activity of the two forms of asbestos was not observed a t a dose level at which the fiber was fibrogenic. Comprehensive experiments by Wagner and his colleagues (1970) showed that rats given amosite, chrysotile, and crocidolite from which organic matter had been removed by prior extraction with benzene all induced appreciable proportions of pleural mesotheliomas. Amosite produced fewer mesotheliomas than did chrysotile and crocidolite, because of a longer induction period. Samples of chrysotile from seven different Canadian mines all produced mesotheliomas. When different doses of asbestos were applied, the risk of developing a mesothelioma a t a given age of the animal could be taken as being proportional to dose. Wagner and Berry (1969) later found that in a total of 337 mesotheliomas induced after the intrapleural inoculation of fibsr into rats, a large proportion was due to chrysotile, crocidolite, amosite, anthophyllite, and brucite. For chrysotile and crocidolite, a relationship between number of inesotheliomas and dose of fiber was found. Of the UICC reference samples used, crocidolite was the most carcinogenic followed by amosite, anthophyllite, chrysotile B (Canadian), and chrysotile A (Rhodesian). Carcinogenicity was apparently unrelated to content of iron, chromium, cobalt, nickel, or scandium nor to the presence of organic matter on the fiber; these features were reviewed by Harington (1973). A relationship between carcinogenicity and size distribution of fibers was found. The UICC amphibole samples tested had diameter distributions which, in decreasing order of fincness, were crocidolite, amosite, and anthophyllite. Thus for a given weight of asbestos inoculated into the pleural cavity, anthophyllite provided fewer fibers than amosite which, in turn, provided fewer fibers than crocidolite. Of these fibers, only a small proportion of anthophyllite would be below the threshold diameter, whereas the proportion of amosite would be somewhat larger and that of crocidolite larger still. This classification of the amphiboles is in the same order as the efficiency with which they produced the inesotheliomas in the experiment. Wagner and Berry concluded that it was difficult to assess the state of chrysotile fibers in animals and to compare this with that of the amphiboles. Nevertheless, as they point out, their findings are consistent with the proposition that mesotheliomas are associated with the implanatation of fine fibers in cells. I n this context, they suggest that the fibrous nature of the materials used appears to be a major factor in production of mesotheliomas: the finer the fiber, the more tumors are produced. Chemical composition of asbestos fibers appears to be a minor factor, a t

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least according to contemporary evidence. This seems consistent with the hypothesis t h a t carcinogenicity is related t o the ability of fibers to interact with the cell membrane without destroying the cell. Thus, the fibrous nature of the asbestos materials is probably a major factor in hheir production of mesothelioinas. New light has been thrown upon the problem by Stanton and Wrench (1972) and Stanton (1973) who concluded that the carcinogenicity of asbestos, glass, and aluminum oxide (AlaOa) is primarily rclated to the length and diamet,er of fibers rather than to physicochemical properties. If the length and diameter of asbestos are important, it would be expected that fibers of similar dimensions but, different composition, and if sufficiently durable, should also induec malignant tumors. This was found to be the case. The following fibers produced an incidence of mesothclioma greater t,han 50% after implantation in tlhe pleura of rats: thc UICC standard reference samples of crocidolite and chrysotile A; two samples of fine fibrous glass with dianictcrs of 3 pni or less; and aluminum oxide whiskers. All these samples arc composed almost entirely of fibers having in common a predominancc of fibcrs below 5 pm in diameter. The A1,03 fibers are of particular intercst because they are totally different) from asbestos and glass, both in internal structure and chemical composition, yet their size distribution is reniarkably like that of UICC crocidolitc. Of particular significance in this work are the contrasting results given by work on the active fibrous and inactive nonfibrous forms of Al2O3.This reemphasizes t,he importance of fiber sizo and shape in carcinogenic activity. Exceptionally pure, chemically invrt. fibers composed of materials free of asbestos and glass seem tjo carry thc! same carcinogenic hazard for the pleura as do asbestos and glass. Pot)t and Friedrichs (1972) found glass fibers (of unspecified size) to bc carcinogenic when inoculated intraplcurally into rats. Stanton and Wrench (1972) concluded from their work that contaminants such as hydrocarbons and trace metals are unlikely to cont’ributein any significant way to the final effect. The essential featurc for carcinogenicity seenis to be “a durable fibrous shape, perhaps in a narrow range of sizt:.” Using asbestos-impregnated fibrous glass pledgets (meshn-orks of long, intertwined flexible strands of glass coated with a heat-cured phenol formaldehyde resin measuring 30 x 20 x 3 mm and 45 nig by w i g h t ) , Stanton et al. (1969) induced sarcomas of the pleura and pcricardiuni in 74% of t,rested rats. The fibrous glass alonc caused only slight reaction. I t remains to be seen whether the results obtained by St,anton and his colleagues can be ctxplained in tcrnis of an Opponheimer effect, namely, the induction of sarcomas in certain aninials after the subcutaneous implanta-

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tion of apparently inert mineral or synthetic films (Oppenheimer et al., 1955). Detailed analyses and review of such “solid state carcinogenesis” have been provided by Bischoff and Bryson (1964) and Bryson and Bischoff (1967), of which the first report (Bischoff and Bryson, 1964, p. 93)) deals with the carcinogenic effects of intact asbestos fibers and glass sheets.

F. CARCINOGENIC EFFECTS IN MAN Two main types of malignancy are associated with human exposure to asbestos: primary bronchogenic carcinoma of the lung and diffuse mesothelioma of the pleura or peritoneum. 1. Bronchogenic Carcinoma

Shortly after asbestosis had been related to occupational exposure to asbestos, it was suggested that the disease might be complicated by the development of bronchogenic cancer, but this association was only generally accepted in the 1950s when it mas found to be very strong. More recently, mesotheliomas of the pleura and peritoneum have been found to be associated in many cases with asbestos exposure, and since 1966 mesothelioma has been a scheduled industrial disease in Britain (such a disease is recognized by the relevant authority as one capable of causing disability and which must be notified for possible compensation.) I t is generally accepted that there is an excess incidence of bronchogenic cancer in those dying with asbestosis. The lung tumor may be the actual cause of death or an incidental finding at autopsy (Senior Medical Inspector’s Advisory Panel, 1967). The association was first suggested by Gloyne (1933) in Britain and by Lynch and Smith (1935) in the United States. Analyses of past and present data point to a rising proportion of cases with asbestosis and bronchogenic cancer and more recently with mesothelial tumors of the pleura (Gilson, 1966). Recent studies (Demy and Adler, 1967; Newhouse and Wagner, 1969; Bohlig and Hain, 1972) and reviews by Wright (1969) and Wagner et al. (1971) emphasize these connections. Epidemiological features of asbestos cancers have been described by O’Donnell and Mann (1957), Mancuso and Coulter (1963), Oettl6 (1964), Buchanan (1965), Selikoff et al. (1965a, b, 1968a, b), Mancuso and El-Attar (1968), and Webster (1969). The association between asbestosis and bronchogenic cancer is strong. The percentage of cases of asbestosis dying of this cancer ranges from 14 to 20% [see Williams (1965) and Harington (1967) for references] and may even be as high as 50% (O’Donnell and Mann, 1957; Buchanan, 1965). Thus, in persons with asbestosis, the death rate for cancer a t this one site

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exceeds that for cancers of all sites in those not exposed to asbestos. In a recent analysis, Selikoff et al. (1973) found bronchogenic carcinoma accounted for approximately 45% of fatal neoplasms among asbestos insulation workers. Clear proof of the association first came in a study of mortality in a defined population of men employed in t,he textile industry (Doll, 1955; see Gilson, 1966; Wright, 1969). In general, it seems at the present time that in British asbestos workers there has been no excess of bronchogenic cancer in the absence of asbestosis (Senior Medical Inspector’s Advisory Panel, 1967). This experience seems to indicate that bronchogenic carcinoma is a complication of asbestosis rather than a result of exposure to asbestos. I n the United States, an excess mortality from bronchogenic carcinoma may exist in the comparative absence of asbestosis in certain groups of workers exposed to asbestos (Mancuso and Coulter, 1963; Selikoff et al., 1964, 1967). In South Africa, bronchogenic carcinoma seems to occur in all South African asbestos areas and the percentage of cases is similar to those exposed to Cape crocidolite and aniosite (Webster, 1973). Some measure of prevention of this cancer, a t least when it is associated with asbestosis, may be achieved when the risk of the latter is reduced by improved ventilation procedures and precautions taken against inhalation of asbestos (Knox et al., 1965; Elmes and Simpson, 1971). The effect of cigarette smoking in relation to bronchogenic cancer and exposure to asbestos has been considered. The habit enhances the risk of developing bronchogenic cancer in workers exposed to asbestos, but no association between development of mesothelioma and the habit has emerged to date (see Gilson, 1973a). Selikoff et al. (1968a) concluded that asbestos insulation workers with a history of regular cigarette smoking had 8 times the risk of men who neither worked with asbestos nor smoked cigarettes. This effect was confirmed in a further study (Hammond and Selikoff, 1972) : exposure to asbestos does not seem to lead to a n extremely high risk of bronchogenic cancer among nonsmokers. Cigarette smoking did not increase the risk of mesothelioma development, also confirming the 1968 findings of Selikoff and co-workers. A new study by Hammond and Sclikoff (see Selikoff, 1973) shows that, of 9590 asbestos insulation workers, all with a history of cigarette smoking, studied over the 5-year period 1967-1971, where 25 deaths from bronchogenic cancer were expected, 134 deaths occurred. These results were underlined by a long-term study (still in progress) of mortality of female asbestos workers in Britain (Newhouse et al., 1972) in some of whom the smoking habits are known. In a comparison of 1300 male and 480 female asbestos factory workers whose smoking habits and mortality from

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bronchogenic cancer over a 10-year period were recorded, Berry et al. (1972) reported that no significant excess in deaths was found in workers (whether smokers or nonsmokers) with low-to-modcrate exposure. Among workers who smoked and who were severely cxposcd, however, the excess was highly significant. 2. Carcinoma of the Gastrointestinal Tract

A raised incidence of cancer of the gastrointestinal tract in a group of insulation workers in the United States has been described (Mancuso and Coulter, 1963; Hammond et al., 1965; Mancuso and El-Attar, 1967, 1968) but was not confirmed’ by two British studies (Doll, 1955; Buchanan, 1964; see Senior Medical Inspector’s Advisory Panel, 1967). 3. Diffuse Mesothelioma of the Pleura and Peritoneum

Historical accounts of the discovery of the association between exposure to asbestos and the development of mesothelioma are to be found in the Wyers Memorial Lecture of Gilson (1966), thc memorandum of the Senior Medical Inspector’s Advisory Panel on Problems Arising from the Use of Asbestos (1967), and in reviews by Wright (1969) and Wagner et al. (1971). The occurrence of cancers of the ovary, peritoneum, or pleura in association with asbestos was reported in 1933 by Gloyne, in 1946by Wyers, and in 1960 by Keal. Gilson writes that when Dr. C. A. Sleggs, working in a hospital in Kimberley in the northwestcrn Cape of South Africa, drew attention to cases with pleural effusions who did not respond to therapy for tuberculosis (which is frequent in the region), attention was first directed to diffuse mesothelioma of the pleura. In due course, biopsies showed this tumor to be present. In 1960, Wagner et al. associated this tumor with exposure t o asbestos. By 1963, Wagner had collected 120 cases of mesothelioma of the pleura, confirmed by biopsy or autopsy. Primary peritoneal tumors had also been found. A large proportion of cases had been exposed to crocidolite in the northwestern Cape. More than half of the cases had never worked in the industry but had lived in thc vicinity of mines and mills. At the present time, 360 pleural mesotheliomas have been recorded in South Africa (Webster, 1973). I n 1964, OettIB showed that people in the northwestern Cape have a distinct risk of developing lung canccr; this is not evident in the northeastern Transvaal where amositc and Transvaal crocidolite are mined. KO cases of mesothelioma in British workers exposed to amoiste (mined and milled, with some crocidolite, almost cxclusivcly in the northeastern Transvaal) were reported by Enticknap and Smither in 1964. To date,

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only a few cascs of mcsothelioma with possiblc past exposure to amosite in this region have been reported. This is not due to differences in the commercial production of northwestern Cape crocidolite and northeastern Transvaal amosite or to other factors studied (Sluis-Cremer, 1965; Harington, 1967; Harington et al., 1971r; Sluis-Cremer and du Toit, 1972). Workers exposed to crocidolitc in th(. northwestern Cape arc thus a t greater risk than arc those exposed to ainositr and crocidolite in thc northeastern Transvaal, a t least with regard to mcmthelioma. Suggestions have been made that such differences in activity in man could be exploited as a preventivc measure (Harington, 1967; Senior Medical Inspector’s Advisory Panel, 1967). Since the discovery of the association between the developmcnt of mesothelioma and exposure to asbestos, a large number of reports has been published. The subject has been st,udied intensively in the United Kingdom (for references, sce Gilson, 1966; Wagner et al., 1971; Wagner, 1972a) and in the United States by Selikoff and his colleagues (1965a, 1968a, b, 1972a, bj, Mancuso and Coulter (1963), and Mancuso and El-Attar (1967, 1968). Other countries where thc dismse has been found and described are South Africa, Australia, Canada, East and West Germany, Italy, and France. Four intcrnational confcrcnces have greatly clxtended our understanding of almost all aspects of thc disease; namely, the UICC Working Group on ,isbestos and Canrer, Biological Effects of Asbestos, New York, 1965 (Whipple, 1965), thc Sccond International Conferencc on the Biological Effects of Asbestos, Dresden, 1968, the Intcrnational Conference on Pnrumoconiosis, Johannesburg, 1969 (Shapiro, 1970), and the Working Group of the Intrrnational Agency for Rcscarch on Cancer, Lyon, 1972 (Bogovski el al., 1973). Onc of the important features emerging from this information is that exposure to asbestos from nhich mesotheliomas may arise may be of slight degree or remote in time. Exposure may have occurred in homes, or simply from living in thc vicinity of asbestos factorirs or mills (Newhouse and Thompson, 1965). These exposures mainly took place about 30 to 40 years prior to the onset of disease, during a period when regulations to control asbt.stos factories were not in existence and the surrounding rnvironment could have been polluted duc to lack of such control. Workers carrying out lagging in ships in confined spaces and fellow workers using dusty overalls (Gilson, 1966) in such adversc circumstances may also be a t some risk. A second significant fcature, as mcntioned above, is thc apparent rarity of the disr.ase in thc northeastern Transvaal n-hcre amosite and some crocidolittl are minrd (Sluis-Cremer, 1965; Webster, 1969; Harington et al., 1 9 7 1 ~ ;Webster, 1973; Sluis-Crcnirr, 1970; Sluis-Crcmer and du Toit,

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1973). Selikoff et al. (1973), howcver, found both bronchogenic cancer and mesothelioma in considerable excess in a group of workmen exposed solely to amosite in the United States. Further work on the situation apparently prevailing in the northeastern Transvaal of South Africa may help to resolve these differences. In Finland where anthophyllite is found mesothelioma is virtually unknown (Kiviluoto, 1965; Meurman, 1966; Meurman et at., 1973), although pleural plaques in persons exposed to this type of fiber are common. Plaques (and asbestosis) are also common in South Africa both in the regions where the incidence of mesothelioma is low and where it is high Timbrell (1972) points out that the dose of fiber to the larger airways of the lung may be sufficient to produce asbestosis in both of the South African regions, but there could be a marked difference in effect between the fibers of the two localities if penetration of the subregions of the lung is a n important factor in the production of mesotheliomas. Chrysotile seems to be implicated in the production of mesotheliomas (see Enticknap and Smither, 1964; Elwood and Cochrane, 1964), and in the United States this type of asbestos may be actively involved as an etiological agent (Selikoff et al., 1965a, b; Mancuso and El-Attar, 1968). By 1965 in Swaziland, where chrysotile is mined and milled, no cases of mesotheliomas had been reported (Gilson, 1966); this is also the position in Rhodesia where the same type of fiber is mined. Pooley’s study (1973b) may bear relevance to this. Lung tissue from 120 cases of mesothelioma from four countries was examined by electron microscopy for fiber types and the results compared to those from a control group of 135 nonmesothelioma cases. Larger numbers of asbestos fibers were found in the mesothelioma group, and, of these, the more predominant fiber detected was of the amphibole variety. Powdered asbestos has been used in human patients to stimulate pleural adhesions after pleurectomy in some cases since the 1940s, and untoward effects do not seem to have been encountered. Chrysotile was the type of asbestos used in surgery by Helwig et al., in 1965. a. Diameter Characteristics of Certain Respirable Asbestos Fibers. Timbrell et al. (1970b) noted that fiber diameter could be useful in distinguishing exposure t o the same (or different) types of fiber and in different geographic localities. Timbrell pointed out in 1965 that a common factor of the two main deposition mechanisms is particle free-falling speed. For a fiber, this is determined predominantly by the diameter and not by the length. If the diameter of an asbestos fiber is less than about 3.5 pm, the fiber stands a good chance of escaping deposition and of penetrating deeply into the lung. The more symmetrical a fiber is, the greater its chance of penetrating. The limitation on the lengths of the fibers that reach the pulmonary air spaces is

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imposed by the nasal hairs and by the small diameters of the respiratory bronchioles. This approach proved interesting when Timbrell et al. (1971) showed that fiber diameter distributions of crocidolite and amosite from the Transvaal differ from those of crocidolite from the northwestern Cape of South Africa (Fig. 32). These differences are evident by both optical and electron microscopy (Timbrell, 1972b). Specimens of asbestos from the crocidolite mines of the northwestern Cape and from the northeastern Transvaal show distinct differences (Timbrell et al., 1971; Timbrell, 1972b). This evidence has since been confirmed in South Africa (R. E. G. Rendall, personal communication) (Figs. 33-36). Timbrell and his colleagues (1971) suggested that this could explain the clear association between exposure to northwestern Cape crocidolite and the development of mesothelioma (Wagner et al., 1960) and the rarity of this tumor in the Transvaal (Sluis-Cremer, 1965; see Harington, 1967; Harington et al., 1971c; Webster, 1973). Electron and optical microscopy have shown that for a given mass of comminuted asbestos, northwestern Cape crocidolite produces 30 times as many fibers as do crocidolite and amosite from the Transvaal (Timbrell et al., 1971). It could also be expected that Transvaal fibers are less likely to become airborne and would settle more rapidly during production or from tailing dumps. And, finally, because of the greater aerodynamic size, most

50.00 10 00

I4 , 0 01

a025

, , ,(,,, 005 00801

,

02

fiber diameter

, , , ,,,

05 (pm)

08

FIG.32. Measurements of fiber diameters of asbestos from eleven crocidolite mines in the northwestern Cape and from different levels in two crocidolite and three amosite mines in the Transvaal. (A) Northwestern Cape (crocidolite) ; (B) Transvaal (amosite, crocidolite). [Rsdrawn from Figure 1, Timbrell et al., 1971; published by permission of the authors and of the editor, Nature (London).]

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J. S. HARINGTON, A . C . ALLISON A N D D. V. BADAMI

of the Transvaal fiber would reach the periphery of the lung much less efficiently than the shorter northwestern Cape type. These differences are likely to have an important effect on the ease of penetration into the lung periphery and pleura where mesothelial tumors develop. This important aspect is therefore dealt with in some detail in the following. b. Deposition and Fate of Asbestos Fihers in the Lung. The influenccs of length and diameter, and shape, on the respirability of fibrous particles have been discussed from a theoretical point of view by Timbrell (1972b), Timbrel1 and Skidmore (1971), specifically for glass, and theoretically by Beeckmans (1970). Timbrell (197213) concluded that deposition by sedimentation is controlled primarily by fiber diameter becausc the falling speed of a fiber is mainly dependent on its diameter and is less affected by its length. I n fine airways, however, interception becomes an important mechanism of deposition for long fibers, especially where airways branch. Chrysotile fibers, in particular, are readily deposited by interception, mainly a t bifurcations, since their curvature increases the collision cross-section area. The great majority of the fibers deposited on the trachea, bronchi, and bronchioles are carried away by the mucociliary escalator, to be ingested

FIG.33. Optical micrograph of typical crocidolite fibers collected from the air in an asbestos mill in the northeastern Transvaal, Sout,h Africa. Magnification: X247.

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FIG.34. Optical micrograph of typical crocidolite fibers collected from the air in an asbestos mill in the northwestern Cape, South Africa. Magnificat.ion: X247.

and voided, whereas the majority of the fibers penetrating to the alveoli are retained within the lungs. Timbrell et al. (1971) and Timbrell (197213) have suggested that differences in the intrinsic diameter (and hence respirability) of the forms of crocidolite mined in the northwestern Cape of South Africa and in Australia can account for the higher incidence of mesotheliomas there than in the crocidolite-mining area of the northeastern Transvaal of South Africa. Timbrell et al. (1970a) reported that each of the fiber types appears to possess a fiber diameter that is unique: anthophyllite fibers are significantly thicker than amosite fibers, which, in turn, are significantly thicker than crocidolite fibers. Tremolite fibers tend to be short and stubby. The relationship between fiber length and diameter and capacity to induce mesotheliomas after intrapleural implantation has been discussed in Section IV, E, 2. Despite the importance of fiber shape or diameter, there has been little investigation of the effect of these parameters on respirability in animals. Wagner and Skidmore (1965) and Morris et aE. (1965) have described experiments in which rats were exposed to airborne chrysotile and amphibole asbestos over a period of 6 weeks. At the termination of the exposure, the silica contents of the animals’ lungs were measured, and more

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J. S. HARINGTON, A. C. ALLISON AND D. V. BADAMI

dust was found in animals exposed to amosite than in those exposed t o chrysotile. The results of experiments of this type cannot be related to initial patterns of deposition except in a general way, as clearance processes have been removing material from the lung since the start of the exposure and it is known that many factors, including lung loading, can affect the rate of clearance. Evans et al. (1972) have recently studied the deposition and clearance of UICC crocidolite asbestos made radioactive by irradiation in a reactor. Using brief “nose only” exposures, the distribution of deposited material between the upper and lower respiratory tract can be quantified. Clearance of material deposited in the lower respiratory tract can be followed, either

FIG.35. Electron micrograph of typical crocidolite fibers collected from the air in an asbestos mill in the northeastern Transvaal, South Africa. Magnification: X2125.

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p!

* a FIG.36. Electron micrograph of typical crocidolitc fibers collected from the air in an asbestos mill in the northwestern Cape, South Africa. Magnification: X2125.

by serial killing or by integrating the long-term component of fecal excretion. Finally, the distribution of fiber within the conducting airways and the lung parenchyma can be investigated by radioautographic techniques. ,It is possibIe to make these measurements with onIy a few milligrams of fiber, so that comparative studies can be made on dust samples collected from factories or mining operations. An average of 35% of inhaled asbestos was deposited, especially at bifurcations of smaller bronchioles. Fibers in the lung parenchyma tended to be concentrated at the ends of alveolar ducts and at the entrances to alveolar sacs although some

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fibers were found in the alveoli. These fibers are shorter and thinner (< 10 pm in length) than those deposited in the bronchioles (> 5 pm). After 30 days, about 30% of deposited crocidolite remained within the lungs, the remainder having been excreted in the feces. Comparable studies with other fiber types, especially chrysotile, are awaited with interest. Clearance mechanisms by pulmonary macrophages (supplemented by those in blood circulation) have been investigated (Rasche and Ulmer, 1965, 1966). That asbestos fibers migrate from initial sites of injection, usually along lymphatic pathways, has been shown (Kanazawa et aE., 1970). Pleural “milky spots,” in which small numbers of asbestos fibers were found during the later stages of the experiment, could perhaps provide the nidus from which both pleural plaques and pleural mesotheliomas could subsequently develop (Kanazawa et al., 1970). No mesotheliomas, as reported by Roe et al. (1965, 1967), were found.

4. Conclusions Several reviews on the asbestos cancer problem (Gilson, 1966; Selikoff et al. 1967; Wright, 1969; Wagner et al., 1971; Wagner, 1972a, b) have pointed to quite distinct differences in epidemiological aspects of the major cancer patterns arising from exposure to asbestos. The Report of the Advisory Committee to the Director of the International Agency for Research on Cancer, Lyon, France, listed the following seven points (see Gilson , 1973a) : 1. All major types of asbestos arc able to cause lung cancer although there are clear differences in risk with type of fiber and nature of exposure. Since exposure to asbestos and response are related, there is no excess risk when occupational exposure has been low. 2. All commercial types of asbestos except anthophyllite may be responsible for the induction of mesothelioma. The risk is greatest with crocidolite, less with amosite, and apparently less with chrysotile. With the last two, there seems to be a greater risk in manufacturing than in milling. Some cases of mesothelioma have no known association with exposure to asbestos. 3. There is evidence of an association of development of mesotheliomas with air pollution near crocidolite mines and factories using mixed fibers. There is no excess risk from air pollution near chrysotile and amosite mines. 4. There is a t present no evidence of any cancer risk to the general public from asbestos in the air, water, beverages, food, or in fluids used for administration of drugs. 5. Cigarette smoking enhances the risk of developing bronchogenic

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cancer in workers exposed to asbestos. No association between cigarette smoking and development of mesothelioma has been demonstrated. 6. There is at present no evidence of lung damage or fibrosis due to asbestos affecting the general public. 7. Pleural plaques are associated with past exposure to all commercial types of asbestos though not all pleural plaques are related to asbestos.

V. General Discussion of Biological Effects of Asbestos From the results of extensive researches on the biological effects of asbestos carried out during the past 5 years, some generalizations can be made with confidence. These will be listed in the following pages. Other correlations are less certain, and, in some cases, no general conclusions can yet be reached. To compare the biological effects of different fiber types, two main in vitro models have been used: hemolysis and cytotoxicity for cultures of macrophages. In vivo comparisons have been made of fibrogenesis and carcinogenesis in man and experimental animals.

A. HEMOLYSIS With asbestos minerals, there is a clear positive correlation between the magnesium-silicon ratio of different fiber types and their hemolytic activity. Since the silicon content is approximately constant, this is essentially a correlation between the magnesium concentration of fibres and their hemolytic potency. However, with other particles, for example, silica and glass fibers, magnesium is not required for hemolysis. This difference may be related to the chemical nature of the membrane constituents with which particles interact. In the case of silica this appears to be mainly phospholipid in the presence of cholesterol, whereas in the case of asbestos, membrane sialoglycoproteins are also involved. There is likewise a positive correlation between the amount of protein adsorbed to particles under standard conditions and their hemolytic potency. As discussed in the next section, a positive correlation has also emerged between the hemolytic potency of different asbestos fiber types and their cytotoxicity for macrophages in culture. With nearly symmetric particles, such as various forms of silica, titanium dioxide, and other minerals, capacity to induce fibrogenic reactions is related to their hemolytic and cytotoxic potencies. In contrast, the hemolytic and cytotoxic activities of various mineral fibers are poorly correlated with their capaciLy to stimulate collagen synthesis or to induce malignancies in viuo. As discussed in the following, fiber length and diameter rather than chemical composition are related to fibrogenic and carcinogenic potency.

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B. CYTOTOXICITY Two types of cytotoxicity can be distinguished. An early lytic reaction can occur within minutes of adding asbestos to macrophages or other cells. This is inhibited by the presence in the medium of decomplemented serum, but may actually be accelerated by complement-sufficient serum. Early cytotoxicity is thought to be due to interaction of asbestos fibers with plasma membranes. Delayed cytotoxic reactions, occurring many hours after incubation of macrophages with asbestos, are associated with selective release of lysosomal hydrolases into the medium and are attributed to interaction of ingested asbestos particles with the membranes surrounding secondary lysosomes. Most authors agree that of all the types of asbestos fibers, greatest cytotoxicity is shown by chrysotile. This is true of both early and late cytotoxicity. Other forms of asbestos show some cytotoxic effects. A claim that crocidolite is highly cytotoxic was discussed in Section 111, B, 3. Information on the relationship between cytotoxicity and fiber length is still scanty, but would be worth obtaining since short fibers ( > 5 pm) are completely ingested by macrophages, whereas long fibers (es,C. J., Bailey, A.. J., Brynne, C. J., and Lcvene, C. I. (1972). Riochirn. Riophys. Acta 278, 372. Bcck, E. G. (1970). Nordrhein-\Vest,falcn District Res. Rep. No. 2083. West, deutschcr Verlag, Koln Opladen. Beck, E. G. (1971). I n Discussion of paper by Beck et al. (1971a). Beck, E. G., Sack, J., and Bruch, J. (1967). Fortschr. Staublungenjorsch. 2, 481. Bcck, E . G., Rruch, J., Friedrichs, K. H., Hilschcr, W., and Pott, F. (1971a). In “Inhalrd Particles 111” (W. H. Walt,on, cd.), Vol. I, p. 477. Unwin, London. Beck, E. G., Holt,, P. F., a.nd Nasrallah, E. T. (1971b). Brit. J . Intl. Med. 28, 179. Beck, E. G., Holt, P. F., and Mmojlovic, N. (1972). Brit. J . Z n d . M e d . 29, 280. Beeckmans, J. M. (1970). Int. J. Environ. Stud. 1, 31. Berman, H. (1932). Amer. Mineral. 17, 313. Berman, H., and Larsen, E. 9. (1931). Amer. Mineral. 16, 140. Berry, G., Newhouse, M. L., and Turok, M. (1972). Lancet 2, 476. Bey, E., and Harington, J . S. (1971). J. Exp. Med. 133, 1149. Bischoff, F., and Bryson, C. (1964). Progr. Exp. Tumor Res. 5, 85. Bogovski, P., Gilson, J. C., Timbrell, V., and Wagner, J. C., eds. (1973). “Biological Effects of Asbestos,” Sci. Publ. 8. Int. Agency Res. Cancer, Lyon.

392

J. S. HARINGTON, A. C. ALLISON AND D. V. BADAMI

Bohlig, H., and Hain, E. (1973). In “Biological Effects of Asbestos,” p. 217. I n t . Agency Res. Cancer, Lyon, France. Bragg, W. L., and Claringbull, G. F. (1965). “Crystal Structure of Minerals.” Bell, London. Brindley, G. W., and Hayami, R. (1965). Mzneral. Mag. 35, 189. Brown, E. (1957). J . Cell. Comp. Physiol. 50, 49. Brown, F., Cartwright, B., and Newman, J. F. E. (1965). Nature (London) 205, 310. Bryson, G., and Bischoff, F. (1967). Progr. Exp. Tumor Res. 9, 77. Buchanan, W. D. (1964). Znt. Congr. Occup. Health, Proc., lith, 196s p. 617. Buchanan, W. D. (1965). Ann. N . Y . Acad. Sci. 132, 507. Burger, B. F., and Engelbrecht, F. M. (1970a). S . A f r . Med. J . 44, 1268. Burger, B. F., and Engelbrecht, F. M. (1970b). S . Afr. Med. J . 44, 1271. Carlin, R. L. (1961). J . Amer. Chem. SOC.83, 3773. Carroll-Porczynski, C. Z. (1960). “Manual of Man-made Fibres.” Astex Publ. Co., Guildford, England. Carroll-Porczynski, C. Z. (1969). “Advanced Materials.” Astex Publ. Co., Guildford, England. Cartier, P. (1968). Znt. Conf. Biol. Efects Asbestos, 2nd, Dresden, 1968 pp. 109-112. Charache, P., Macleod, C. M., and White, P. (1962). J . Gen. Physiol. 45, 1117. Chatgidakis, C. B. (1963a). Med. Proc. 9, 383. Chatgidakis, C. B. (1963b). Brit. J . Ind. hfed. 20, 236. Cherry, R. J. (1972). Chem. Phys. Lipids 8, 393. Chiappino, G., Marchisio, M. A,, Peruzzo, G. F., and Vigliani, E. C. (1967). Fortschr. Staublungenforsch. 2, 205. Clark, S. G., and Holt, P. F. (1960). Ann. Occup. Hyg.3, 22. Commins, B. T. (1958). Int. J . Air Pollut. 1, 14. Commins, B. T., and Gibbs, G. W. (1969). Brit. J . Cancer 23, 358. Comolli, R . (1967). J . Pathol. Bucteriol. 93, 241. Comunith Europea del Carbone e I>ell’Acciaio, Alta Autorith. (1967). “Collezione di igiene e di medicina del lavoro,” No. 6. Cook, G. M. W., Heard, 1).H., and Seaman, Cr. V. F. (1960). Nature (London) 188,1011. Cooke, W. E. (1924). Brit. Med. J . 2 , 578. Cooper, W. C., and Balzer, J. L. (1968). Int. Conf. Biol. Egects Asbestos, Znd, Dresden, 1968 pp. 151-160. Cooper, W. C., and Miedema, J. (1973). In. “Biological Effects of Asbestos,” p. 173. Int. Agency Res. Cancer, Lyon, France. Cossette, M., Lemonde, J., and Massey, D. G. (1971). Zn “The Physics and Chemistry of Asbestos Minerals,” Commun. pp. 1-3. Institute of Natural Sciences, Louvain University, Belgium. Davis, J. M. G. (1964). Brit. J . Exp. Pathol. 45, 634. Davis, J. M. G. (1967). Brit. J . Exp. Pathol. 48, 379. Davis, J. M. G. (1970a). Exp. Mol. Pathol. 12, 133. Davis, J. M. G. (1970b). Exp. MoZ. Pathol. 13, 346. Davis, J. M. G. (1971). Brit. J . Exp. Pathol. 52, 238. Davis, J. M. G. (1972a). Brzt. J . Exp. Pathol. 53, 190. Davis, J. M. G. (1972b). Brit. J . Exp. Pathol. 53, 652. Davis, J. M. G., and Gross, P. (1973). I n “Biological Effects of Asbestos,” p. 238. Int. Agency Res. Cancer, Lyon, France. Davis, J. M. G., Gross, P., and de Treville, R. T. P. (1970). Arch. Pathol. 89, 364.

MINERAL FIBERS

393

Ihykin, C. W. (1971). I n “The Physics and Chemistry of Asbestos Minerals,” Abstr. Pap. 2 : 6. Institute of Natural Sciences, Louvain University, Belgium. Deer, W. A,, Howie, R. A., and Zussman, J. (1962-3). “Rockforming Minerals,” Vol. 2(1963) and 3(1962) Longmans, Green, New York. Ilemy, N. G., and Adler, H. (1967). Amer. J . Roentgenol., Radium Ther. Nucl. M e d . 100, 587. Ilognon, A., and Simonot,, Y. L. (1951). C.R. SOC.Riol. 145, 1615. Doll, R. (1955). Brit. J . Znd. Med. 12, 81. Editorial. (1973). Lancet 1, 815. Elmes, P. C . , and Simpson, M. J. C. (1971). Brit. J . Ind. Med. 28, 226. Elwood, P. C., and Cochrane, A. 1,. (1964). Brit. J . Z n d . Med. 21, 304. Enterline, E. (1965). Ann. N . Y . Acad. Sci. 132, 156. Enterline, E. (1968). Int. Conf. Biol. Eflects Asbestos, 2nd, Dresden 1968 pp. 113-118. Enterline, E., and Weill, H. (1973). I n “Biological Effects of Asbatos,” p. 179. Int. Agency Res. Cancer, Lyon, France. Enticknap, J. B., and Smither, W. J. (1964). Brit. J . Znd. Med. 21, 20. Evans, J. C., Evans, P. J., Holmes, A,, Hounam, It. F., Jones, D. M., Morgan, A., and Walsh, M. (1972). U . K . At. Energy Auth., Res. Group, Rep. R7082, 1. Eylar, E. H., Madoff, M. A., Brody, 0. V., and Oncley, J. L. (1962). J . Biol. Chem. 237, 1992. Fahr, and Feigel, (1914). Muenchen. Med. Wochenschr.61,625. Faust, G. T., and Nagy, B. (1956). Amer. Mineral. 41, 819. Fedoseev, A. I)., Grigor’eva, L. F., Chigareva, 0. G., and Romanov, 1). P. (1970). Amer. Mineral. 55, 854. Friedrichs, K. H., Hilscher, W., and Sethi, S. (1971). Int. Arch. Arbeitsmed. 28, 341. Gardner, L. U. (1938). I n “Silicosis and Asbestosis” (A. J. Lanza, ed.), p. 257. Oxford Univ. Press, London and New York. Gelfand, M., and Morton, S.A. (1970). I n “Pneumoconiosis” (H. A. Shapiro, ed.), p. 204. Oxford Univ. Press, London and New York. Gettins, R. B., and Mallon, F. J . (1971). In “The Physics and Chemistry of Asbestos Minerals,” Abstr. Pap. 4:l. Tnst,itut,e of Nat#ural Sciences, Loiivain Universit,y, Belgium. Gibbs, G. W. (1969). Anaer. Ind. Hyg. Ass. J . 30, 458. Gibbs, G. W. (1970). I n “Pneumoconiosis” (H. A. Shapiro, ed.), p. 165. Oxford Univ. Press, London and New York. Gibbs, G. W., and Hui, H. Y. (1971). Amer. Ind. Hyg. Ass., J . 32, 519. Gilson, %J. C. (1965). Ann. N.Y . Acad. Sci. 132, 9. Gilson, J. C. (1966). Trans. SOC.Occup. Med. 16, 62. Gilson, J. C. (1972). Union Znt. Contre Cancer, Bull. Cancer 10, 3. Gilson, J. C. (1973a). “Asbestos Cancers-Man” (from Report of The Advisory Committee t,o Direct.or). Int. Agency Kes. Cancer, Lyon, France. In Bogovski et al. (1973), p. 341. Gilson, J. C. (1973b). I n “Biological Effects of Asbestos,” p. 5. Int.. Agency Res. Cancer, Lyon, France. Gloyne, S. R. (1933). Tubercle 14, 550. Goldie, H. (1938). C.R. Soc. Bid. 129, 1090. Goldstein, B., and Webster, I. (1971). I n “Inhaled Particles 111” (W. H. Walton, ed.), Vol. 11, p. 705. Unwin, London. Goldstein, B., and Webster, I. (1972). Ann. N . Y . Acad. Sci. 200, 306.

394

J. S. HARINGTON, A . C . ALLISON A N D D. V. BADAMI

Gosseye, A., and Hahn-Weinheimer, P. (1971). I n “The Physics and Chemistry of Asbestos Minerals,” Abstr. Pap., 1 : l . Inst,itute of Nat>uralSciences, Louvain University, Belgium. Qoverna, M., and Rosanda, C. (1972). Brit. J . Ind. Med. 29, 154. Cranata, A., and Chmano, 11. (1963). Med. Lavoro 54, 81. Gross, P., and de Treville, R. T. P. (1968). Arch. Environ. Health 15, 638. Gross, P., Cralley, L. J., and de Treville, 11. T. P. (1967a). Amer. Ind. Hyg. Ass. J . 28, 541. Gross, P., de Villiers, A. J., and de Treville, lt. T. P. (1967b). Arch. Pathol. 84, 87. Gross, P., de Treville, 11. T. P., Tolker, E. B., Kaschnk, M., and Babyak, M. A. (1967~). Arch. Environ. Health 15, 343. Gross, P., de Treville, R. T. P., Cralley, L. J., and I)avis, J. M. G. (1968). Arch. Paihol. 85, 539. Gross, P., de Treville, R. T. P., and Cralley, 1,. J . (1970a). I n “Pneumoconiosis” (H. A. Shapiro, ed.), p. 220. Oxford Univ. Press, London arid New York. Gross, P., de Treville, R . T . P., and Haller, M. N. (1970b). Arch. Environ. Health 20,571. Gross, P., Tuma, a., and de Treville, It. T . P. (1970~)Arch. . Environ. Health 21, 38. Groves, M. J . (1965). Lancet 2, 344. Gye, W. E., arid Purdy, W. J. (1922). Brit. J . Exp. Pathol. 3, 75. Hammond, E. C., and Selikoff, I. J. (1973). I n “Biological I3ffect.s of Asbest,os,” p. 312. Int’. Agency lies. Cancer, Lyon, France. Hammond, E. C., Selikoff, I. J., and Churg, J. (1965). Ann. N . Y . Acarl. Sci. 132, 519. Harington, J. 6 . (1962). Nature (London) 193,43. Harington, J. S. (1963). Med. Lavoro 54, 769. Haringt,on, J. S. (1965). Ann. N . Y . Acad. Sci. 132, 31. Harington, J. S. (1967). I n “The Preverit,ioriof Cancel” (R.. IV. Raven and F. J . C. Ror, eds.), Chapter 31, p. 207. Butterwort.h, London. Haringt,on, J. S. (1972). Ann. N . Y . Acad. Sci. 200, 816. Harington, J. S. (1973). I n “Biological Effects of Asbestos,” p. 304. Int. Agency Res. Cancer, Lyon, France. Harington, J. S., and Miller, K. (1971). Environ. Res. 4, 118. Haringt,on, J. S., and Roe, F. J . C. (1965). Ann. AT. Y . Acad. Sci. 132, 439. Harington, J. S., and Smith, M. (1964). S. A f r . J . Sci. 60, 283. Harington, J. S., and Sutt,on, 1 ) . A. (1963). Med. Lavoro 54, 701. Harington, ,J. S., Roe, F. J. C., and Walters, M. (1967). S. Afr. Mecl. J . 41, 800. Harington, J. S., Kanaeawa, K., Birbeck, M., Carter, R., and Roe, F. J. C. (1968). Int. Conf. Rial. Effects Asbestos, 2nd, Dresden, 1968 pp. 235-239. Harington, J. S., Miller, K., and Macnab, G. (1971a). Environ. Res. 4, 95. Haringt,on, J. S., Macnab, G., Miller, K., and King, P. (1971b). Med. Lavoro 62, 171. Harington, ,J. S., Gilson, J. C., and Wagner, J. C . (1971~).Nature (London) 232, 54. Haringt,on, .J. S., Ritchie, M., King, P. C., and Miller, K . (1973). J . Pathol. 109, 21. Harley, J. I)., and Margolis, J. (1961). Nutu.re (London) 189, 1010. Harris, A. M. (1971). I n “The Physics and Chemist.ry of Asbestos Minerals,” Abstr. Pap. 3:2A. Institute of Natural Sciences, Loiivain University, Belgium. Harris, A. M., and Grimshaw, R.. W. (1971). I n “The Physics and Chemistry of Asbestos Minerals,” Abstr. Pap. 3:ZB. Irist,itute of Nat,ural Sciences, Louvain Universit,y, Belgium. Harris, C. M., Kokot,, E., Lenxer, 8. L., and Lockyer, T . N. (1962). Chem. Ind. (London) p. 651.

MINER-XL FIBERS

395

Helwig, J., Ash, R., Friedman, S., I>aught.ridge, G., and Johnson, J. (1965). J . Anaer. Med. Ass. 194, 253. Hendry, N. W.(1965). Ann. N . Y . Acatl. Sci. 132, 12. Heppleston, A. G. (1969). Brit. hfed. Bull. 25, 282. , 496. Oxford Hepplcston, A. G. (1970). I n “Pneumocaoniosis” (H. A. Shapiro, ~ d . ) p. Univ. Press, London and New York. Heppleston, A. G., and Styles, J . A. (1967). Nature (London) 214, 521. Heron, G. F. (1972). British Patent 1,299,191. Heron, G. F., and Hugget.t, li. (1971). I n “The Physics and Chemistry of Asbestos Minerals,” Abstr. Pap. 4 2 . Institute of Natural Sciences, Louvain Universit,y, Belgium. Hilscher, W.(1972). Zentralbl. Allg. Pathol. Anal. 116, 413. Hilscher, W., and Gchlipkoter, H. W. (1973). A n n . N . Y . Acad. Sci. 200, 166. Hilscher, LV,,%hi, S., Friedrichs, K . H., and Pott,, F. (1970). Xaturwissenschaften 57, 356. Hodgson, A. A. (1965). Ro?y.Inst. Chem., Lett. Ser. No. 4,p. 1. Hodgson, A. A,, Freeman, A. G,, arid Taylor, H. F. W. (1965). Mineral. Mag. 35, 5. Holmes, S. (1965). A n n . iV. Y . Acad. Sci. 132, 288. Holmes, S. (1972). See Smither and Cross (1972). Holmes, S. (1973). I n “Biological Effects of Asbestos,” p. 109. Int. Agency Res. Cancer, Lyon, France. Holmes, A., Morgan, A,, and Sandells, F. ,J, (1971). Amer. I n d . Hyg. ASS., J. 32, 281. Holt,, P . F., and Lindsay, H. (1969). J . Cheni. Soc., B p. 54. Holt,, P. F., and Nasrallah, E. T. (1966). Nature (London) 211, 878. Holt,, P. F., Mills, J., and Young, 1). K . (1965a). A n n . iV. Y . Acad. Sci. 132, 87. Halt,, P. F., Mills, J., and Young, 1). K. (1965b). J . Pathol. Racteriol. 87, 15. Holt,, P. F., Lindsay, H., and Nasrallah, E. T. (1967). Xature (London) 216, 611. House, JV. (1964). Nature (London) 201, 1242. Hueper, W . C. (1965). Ann. N . Y . Acad. Sci. 132, 184. Huggins, C. FV., and Shell, H. R.. (1965). Anter. hi‘ineral. 50, 1058. Inglot, A. I)., and Wolna, E. (1968). Riocliem. Pharmacol. 17, 269. Jones-Williams, W. (1960). J . Pathol. Rackviol. 79, 193. Kanazawa, K., Birbeck, M. S. C., Carter, 11. L., and Roe, F. J. C. (1970). Brit. J . Cancer 24, 96. Keal, E. E. (1960). Lancet 1, 1211. King, TI. (1961). Trans. Roy. Soc. S. Aust. 84, 119. Kiviluoto, It. (1965). A n n . iV. Y . Acad. Sci. 132, 235. Kiviliiot,o, R., and Meurman, L. (1970). I n “Pneumoconiosis” (H. A. Shapiro, ed.), p. 190. Oxford Univ. Press, London and New York. Kleinfeld, (1968). Int. Cortj. Biol. E$ects Asbestos, 2nd, Dresden, 1968 pp. 38-39. Klosterkott,er, W. (1968). Int. Cons. Riol. E$ects Asbestos, d n d , Dresden, 1968 pp. 47-52. Klosterkotter, W., and Robock, K . (1967). Silikoseber. ,~rordrhein-Westfalen6, 33. Klosterkottcr, JV., and Itobock, K . (1970). Arbeitsmed. Sozialmed.; Arbeitshyg. 36, 111. Knox, J . F., I>oll, R. S., and Hill, I . I>. (1965). A n n . N . Y . Acad. Sci. 132, 526. Koshi, K., and Sakabe, H . (1966). Znd. Health 4, 16. Koshi, K., Hyashi, H., Hamada, A,, and Hakabe, H. (1961). Bull. X a t . Inst. Ind. Health, Kawasaki 6, 10. Koshi, K., Hayashi, H., and Rakabc, H . (1968). Ind. Health 6, 69. Koshi, K., Hayashi, H., and Sakabc, H. (1969). Znd. Health 7, 66.

396

J. S. HARINGTON, -4. C. ALLISON .4ND D. V. BADAMI

Laamanen, A,, Noro, L., and Raunio, V. (1965).Ann. N . Y . Acad. Sci. 132, 235. Landsteiner, K., and Jagic, N. (1904).Wien. Klan. Wochenschr. 17,63. Langer, A. M. (1974).In press. Langer, A. M., and Pooley, F. D. (1973).I n “Biological Effects of Asbestos,” p. 119. Int. Agency Res. Cancer, Lyon, France. Langer, A. M., Rubin, I., and Selikoff, I. J. (1970).I n “Pneumoconiosis” (H. A. Shapiro, ed.), pp. 57-69.Oxford Univ. Press, London and New York. Langer, A. M., Baden, V., Hammond, E. C., and Yelikoff, I. J. (1971a). I n “Inhaled Part,icles 111” (W. H. Walton, ed.), Vol. 11, p. 683.Unwin, London. Langer, A. M., Selikoff, I. J., and Sastre, A. (1971b). Arch. Environ. Health 22,348. Langer, A. M., Rubin, I . B., and Selikoff, I . J. (1972a).J.Hislochem. Cytochem. 20, 723. Langer, A. M.,Ilubin, I. B., Selikoff, I . J , and Pooley, F . 1). (197213).J . Hislochem. Cytochem. 20, 735. Langer, A. M., Ashley, R., Baden, V., Berkley, C., Hammond, E. C., Mackler, A. D., Maggiore, C. J., Nicholson, W. J., Rohl, A. N , Rubin, I. B., Sastrr, A., and Selikoff, I. J. (1973).J . Occup. Med. 15, 287. Liebling, R. S., and Langer, A. M. (1972).Arner. Mineral. 57, 857. Lowenstein, K.L. (1966).I n “Composite Materials” (L. Holliday, ed.), p. 128.Elsevier, Amsterdam. Lynch, J. It. (1968).J . Air Pollut. Contr. Ass. 18, 824. Lynch, K.M., and Smith, W.A. (1935).Amer. J . Cancer 24, 56. Lynch, K.M., McIver, F. A . and Cain, J. R. (1957).A M A Arch. Znd. Health 15, 207. McDonald, J. C. (1973).I n “Biological Effects of Asbestos,” p. 153. Int. Agency Res. Cancer, Lyon, France. McDonald, A. I)., Harper, A., El-Attar, A. A , and McDonald, J. C. (1970).Cancer 26, 914. McEwen, J., Finlayson, A,, Mair, A,, and Gibson, A. A. M. (1970).Brit. Med. J . 4,575. MacLean Smith, J., Wootton, I. I). P., and King, E. J. (1951).Thorm 6, 127. Macnab, G., and Harington, J. S. (1967).Nature (London) 214, 522. McNulty, J. C. (1968).Int. Conf.Biol.Effects Asbestos, 2nd, Dresden, 1968 pp. lO(t107. McNulty, J. C. (1970).I n “Pneumoconiosis” (H. A. Shapiro, ed.), p. 201.Oxford Univ. Press, London and New York. McCreight, L. R., Ranch, H. W., Sr., and Sutton, W.H. (1965).“Ceramic and Graphite Fibers and Whiskers.” Academic Press, New York. McVittie, J. C. (1965).Ann. N . Y . Acad. Sci. 132, 128. Makarova, T.A., Korytkova, E. N., and Nesterchuk, N. I. (1971).I n “The Physics and Chemistry of Asbestos Minerals,” Abstr. Pap. 1:7.Institute of Natural Sciences, Louvain University, Belgium. Mancino, I)., and Arienzo, R. (1967a).Boll. Sac. Ital. E d . Sper. 43, 1752. Mancino, I)., and Arienzo, R. (1967b).Boll. Sac. Ital. Biol. Sper. 43, 1754. Mancino, D., and Arienzo, R. (1967~). Riv. Anat. Patol. Oncol. 31, Suppl., 49-50. Mancino, D., and Arienzo, It. (1967d).Luv. Urn. 19,297. Mancuso, T.F.,and Coulter, E. J. (1963). Arch. Enuiron. Health 6, 210. Mancuso, T.F., and El-Attar, A. A. (1967). J . Occup. Med. 9, 147. Mancuso, T. F.,and El-Attar, 1.A. (1968).Int. Conf. Biol.Effects Asbestos, 2nd, Dresden, 1968 pp. 161-166. Marchand, F.(1906).Deut Ges. 17, 223. Marchisio, M. A., Davis, J. S., and Parazzi, E. (1970).Med. Lavoro 61, 211. Marks, J. (1957). Brit.J.Ind. Med. 14, 81.

MINERAL FIBERS

397

Maroudas, N. G. (1972). Exp. Cell Res. 74, 337. Maroudas, N. G., O’Neill, C. H., and Stanton, M. F. (1973). Lancet 1, 807. Martinez, E. (1961). Amer. Mineral. 46, 901. Martinez, E. (1971). I n “The Physics and Chemistry of Asbestos Minerals,’, Discussion. Institute of Natural Sciences, Louvain University, Belgium. Martinez, E., and Zucker, G. (1960). J. Phys. Chem. 64,924. Mellors, A., and Tappel, A. L. (1967). J . Lipid Res. 8, 479. Meurman, L. 0. (1966). Acta Pathol. Microbiol. Scand., Suppl. 181, 327. Meurman, L. O., and Kiviluoto, R. (1968). Int. Conf. B i d . E$ects Asbestos, %nd,Dresden, 1968 pp. 135-138. Meurman, L. O., Kiviluoto, R., and Hakama, M. (1973). I n “Biological Effects of Asbestos,” p. 199. Int,. Agency Ites. Cancer, Lyon, France. Miller, K., and Harington, J. S. (1972). Brit. J. Exp. PathnE. 53, 397 Miller, L., Smith, W. E., and Berliner, S. W. (1965). A n n . N. Y. Acad. Sci. 132,489. Monkrnan, L. J. (1971). I n “The Physics and Chemistry of Asbestos Minerals,” Abstr. Pap. 3 :2. Institute of Natural Sciences, Louvain University, Belgium. Morgan, A., and Cralley, L. J. (1973). In “Biological Effects of Asbestos.” p. 113. Int. Agency Res. Cancer, Lyon, France. Morgan, A., and Holmes, A. (1970). I n “Pneumoconiosis” (H. A. Shapiro, ed.), pp. 52-56. Oxford Univ. Press, London and New York. Morgan, A,, Holmes, A., and Gold, C. (1971a). Enuiron. Res. 4, 558. Morgan, A., Holmes, A., and Lally, A. E. (1971b). In “The Physics and Chemistry of Asbestos Minerals,” Abstr. Pap. 2:8. Institute of Natural Sciences, Louvain University, Belgium. Morgan, A,, Lally, A. E., and Holmes, A. (1972). U.K. At. Energy Auth., Res. Group, Rep. R7188. Morris, T. G., Roberts, W. H., Silverton, R. E., Skidmore, J. W., Wagner, J. C., and Cook, G. W. (1965). I n iiInhaled Part.icles and Vapours 11” (C. N. navies, ed.), p. 205. Pergamon, Oxford. Munder, P. G., Ferber, E., Modolell, M., and Fischer, H. (1967). Fortschr. Staublungenforsch. 2 , 129. Murray, H. M. (1907). “Report of the Departmental Committee for Industrial Diseases.” HM Stationery Office, London. Nadler, S., and Goldfischer, S. (1970). J. Histachem. Cytochenz. 18, 368. Nash, T., Allison, A. C., and Harington, J. S. (1966). Nature (London) 210, 259. Newhouse, M. L., and Thomson, H. (1965). Ann. N. Y . Acad. Sci. 132, 579. Newhouse, M. L., and Wagner, J. C. (1969). Brit. J. Ind. Med. 26,302. Newhouse, M. L., Berry, G., Wagner, J. C., and Turok, M. E. (1972). Brit. J. Ind. Med. 29, 134. Nicholson, W. T., and Pundsack, F. L. (1973). In “Biological Effects of Asbestos,” p. 126. Int. Agency Res. Cancer, Lyon, France. Nicholson, W. J., Maggiore, C. J., and Selikoff, I. J. (1972). Science 177, 171. Nordman, M., and Sorge, A. (1941). Z. Krebsforsch. 51, 168. Noro,.L. (1968). Amer. Ind. Hyg. Ass., J . 29, 195. Noro, L. et al. (1968). Ink Conf. Biol.Efects Asbestos, 2nd, Dresden, 1968 pp. 13*135. Nothdurft, H. (1960). K l . Med. 3, 80. Nothdurft,, H. (1961). Sarkomerzeugung bei Ratten durch implantiert,e Fremdkorper Reprint 8, p. 262. C. F. Boehringer and Sohne Gmbh, Mannheim. Nothdurft, H., and Mohr, H. J. (1958). Naturwissenschaften 45, 549.

398

J. S. HARINGTON, A. C. ALLISON AND D. V. BADAMI

Nourse, L. D., Nourse, P. N., Botes, H., and Schwartx, H. (1974). Environ.. Res. (in press). Novak, I. J. (1953). British Patent 689,692. O’Donnell, W. M., and Mann, R . H. (1957). Amer. J. Pathol. 33, 610. O-ttlB, A. G. (1964). J . Nut. Cancer Inst. 33, 383. Oldham, P. 1). (1973). I n “Biological Effects of Asbestos,” p. 45. Tnt. Agency Res. Cancer, Lyon, France. Oppenheimer, B. S., Oppenheimcr, E . T., Uanishefsky, I., %out, A. P., and Eirich, F. It. (1955). Cancer Res. 15, 333. Oppenheimer, B. S., Oppenheimer, E. T., Stout, A. P., Danishefsky, I., and Willhit,e, M. (1959). Acta Unio Int. Contra Cancrum 15, 660. Oppenheimer, E. T., Willhit,e, M., I)anishefsky, I., and Stout., A. P. (1961). Cancer Res. 21, 132. Otouma, T. (1971). I n “The Physics and Chemistry of Asbestos Minerals,” Abstr. Pap. 15 . Institute of Natural Sciences, Louvain Universit,y, Belgium. Parazzi, E., Pernis, B., Secchi, G. C., and Vigliani, E. C . (1968a). Med. Lavoro 59, 561. Parazzi, E., Secchi, G. C., Pernis, B., and Vigliani, E. C. (1968b). Arch. Environ. Health 17, 850. Peacock, A., and Peacock, P. R. (1963). Brit. Em p. Cancer Campaign, Annu. Rep. Part 11, p. 534. Peacock, P. R., and Peacock, A. (1965). Ann. N . Y. Acad. Sci. 132, 501. Peacock, P. It., and Peacock, A. (1968). Int. Conf. Biol. Effects Asbestos, 2nd, Dresden, 1968 pp. 327-235. Pernis, B., and Castano, P. (1971). filed. Lavoro 62, 120. Policard, A. (1962). J . Clin. Pathol. 15, 394. Ponder, E. (1932-1933). Proc. Roy. Soc. Ser. R 112, 298. Pooley, F. D. (1973a). I n “Biological Effects of Asbestos,” p. 50. Int. Agency Res. Cancer, Lyon, France. Pooley, F. 11. (1973b). In “Biological Effects of Asbestos,” p. 222. Int. Agency Res. Cancer, Lyon, France. Pooley, F. D., Oldham, P., Chang-Hyun, U. M., and Wagner, ,J. C. (1970). I n “Pneumoconiosis” (H. A. Shapiro, ed.), p. 108. Oxford Univ. Press, London and New York. Pott,, F., and Friedrichs, K. H. (1972). Naturwissenschaften 59, 318. Pott,, F., Kuth, F., and Friedrichs, K. H. (1972). Zentralbl. Bakteriol., Parasifenk. Infektimskr. Abt. 1 :drig. 155, 463. Pundsack, F. L. (1955). J. Phys. Chen. 59,892. Pylev, L. N. (1972). Vop. Oncol. p. 40. Quagliano, J. V., Fujita, J., Franz, G., Phillips, I). J., Walmsley, J. A., and Tyrel, S. V. (1961). J . Amer. Chem. SOC.83, 3770. Rajan, K. T. and Evans, P. H. (1973). I n “Biological Effects of Asbestos,” p. 94. h t . Agency Res. Cancer, Lyon, France. Rajan, K. T., Wagner, J. C., and Evans, P. H. (1972). Na.ture (London) 238, 346. Rasche, B., and Ulmer, W. T. (1965). Med. Thor. 22, 516. Rasche, B., and Ulmer, W. T. (1966). Klin. Wochenschr. 44,841. Rcitze, W. B., Nicholson, W. J., Holaday, D. A,, and Selikoff, I. J. (1972). Amer. Znd. Hyg.Ass., March, 178. Rendall, R . E. G. (1970). I n “Pneumoconiosis” (H. A. Shapiro, ed.), p. 23. Oxford Univ. Press, London and New York.

399

MINER.4L FIBERS

RCX,W. G. IT.,Wilke, S., and Wilkr, W.(1959). British Patent 824,446. ltichards, R. J., and Morris, T. G. (1973). LiJe Sci. (in press). Richards, R. J., Wusteman, F. S., and Ljodgson, K. S. (1971). Life Sci. 10, 1149. Ilickards, A. L. (1972). Anal. Chem. 44, 1872. Rickards, A. L. (1973). Anal. Chem. (in prrss). Itickards, A. L., and Badami, D. V. (1971). Nature (London) 234, 93. Robock, K., arid Klosterkotter, LV, (1971a). I n “Inhaled Part,icles 111” (W. H. Walton, d . ) , pp. 453 arid 465. Unwin, London. Itobock, K., arid Klosterkotter, W. (19711n). Int. Pneumoconiosis ConJ., dth, f 9 7 f . Bucharest. Preprint, pp. 2-10. Itobock, K., and Klosterkotter, W. (1973). Staub-Reinhalt. Lzr]t. 33, 279. Itobock, K., Klosterkott,er, W., aiid Scharpeiiseel, F. (1969a). Silikoseber. NorrlrheinWeslfalen 7, 145. Ilobock, K., Klosterkot,t,er, W.,and Kiichler, M. (1969b). Silikoseber. NordrheinWestfalen 7, 169. Kobock, K., Klost,erkotter, JV., and I)ellbriigger, H. (1971). Silikoseber. NordrheinWestfalen 8, 119. Iloe, F. J . C., Walters, M. A,, aiid Harington, J. S. (1965). Int. J. Cancer 1, 491. Koe, F. J . C., Carter, R , L., and Taylor, \V. (1967). Brit. J. Cancer 21, 694. Roitzsch, E. (1968). Int. Conf. Biol. Effects Asbestos, 2nd, Dresden, 1968 pp. 93-94. Itosato, D. V. (1959). “Asbestos, it,s Indust,rial Applications.” VanNostrand-Reinhold, Princeton, New Jersey. Ross, R., Everett, N. B., and Tyler, It. (1970). J. Cell B i d . 44, 645. Roy, TI. M., and Roy, R. (1954). Amer. M i n . 39, 957. Saffiot,t,i,V., Cefis, F., and Shubik, P. (1965). Int. Conf. Lung Tumours Anim., 1965. Saito, H. (1963). J. Chem. Soc. J a p . , Ind. Chem. Sect. 66, 18. Schlipkoter, H. W. (1968). /n.t. Conf. Biol. Effects Asbestos, %d, Dresden, 1968 pp. 67-74. Schlipkot,er,H. W., and Beck, E. G. (1965). filed. Lavoro 56, 485. and Brockhaus, A. (1961). Klin. Wochenschr. 39, 1182. Schlipkoter, H. W., Schlipkiiter, H. JV., Dolgner, R., and Brockhaus, A. (1963). Ger. Med. Mon. 8, 509. Schmkhl, 11. (1958). 2. Krebsforsch. 62, 561. Schmahl, I). (1968). Int. Conf. Biol. Effects Asbestos, 2nd, Dresden, 1968 pp- 55-36. Schnitzer, R. ,J., and Bunescu, G. (1970). Arch. Environ. Health 20, 481. Schnitzer, It. J., and Pundsack, F. L. (1970). Environ. Res. 3, 1. Schnitzer, R. J., Bunescu, G., and Baden, V. (1971). Ann. N. Y. Acad. Sci. 172, 757. Secchi, G. C. (1968). N e d . Lavoro 50, 294. Seechi, C . C., and Rezzonico, A. (1968). filed. Lavoro 59, 1. Seeman, P., and Weinstein, J. (1966). Riochem. Pharmacol. 15, 1737. Selikoff, I. J. (1973). J. Amer. Med. Ass. 223, 336. Selikoff, I. J., Churg, J., and Hammond, E. C. (1964). J. Amer. Med. ASS.188, 22. Selikoff, I. J., Churg, J . , and Hammond, R. C. (1965a). N . Engl. J . Med. 272, 560. Selikoff, I. d., Churg, J., and Hammond, E. C. (1965b). Ann. N. Y. Acad. Sci. 132,139. (1967). Amer. Selikoff, I. J., Bader, R. A,, Bader, M. E., Churg, J., and Hammond, E. J . Med. 42, 487. Selikoff, I . J., Hammond, E. C., and Churg, J . (1968a). J . Amer. Med. Ass. 204, 106. Relikoff, I. J., Hammond, E. C., and Churg, J . (196813). Int. Conf. Riol. Eflects Asbestos, 2nd, Dresden, 1968 pp. 283-288. Selikoff, I. J., Hammond, E. C., and Churg, J. (1970). I n “Pneumoconiosis” (H. A. Shapiro, ed.), p. 180. Oxford Univ. Press, London and New York.

c.

400

J . S. HARINGTON, A . C . -4LLISON AND D. V. BADAMI

Selikoff, I. J., Nicholson, W. J., and Langer, A. M. (1972a). Arch. Environ. Health 25, 1. Selikoff, I. J., Hammond, E . C., and Churg, J. (1972b). Arch. Environ. Health 25, 183. Selikoff, I. J., Hammond, E. C., and Seidman, M. (1973). I n “Biological Effects of Asbestos,” p. 209. Int. Agency Res. Cancer, Lyon, France. Senior Medical Inspector’s Advisory Panel. (1967). “Problems Arising from the Use of Asbestos,” Memo. Ministry of Labour, H.M. Factory Inspectorate, H.M. Station ery, Office, London. Shabad, L. M., Pylev, L. N., and Kolesnichenko, T. S. (1964). J . Nut. Cancer Znst. 33, 135. Shapiro, H. A., ed. (1970). I n “Pneumoconiosis.” Oxford Univ. Press, London and New York. Sheherbatskaya, V. A. (1957). T r . Vses. Konf. Med. Radiol., 1966 p. 266. Simson, F. W., and Strachan, A. S. (1940). Publ. S. Afr. Inst. Med. Res. 9, 95. Singer, S. .J., and Nicolson, G. L. (1972). Science 175, 720. Skavlem, J. H., and Ritterhoff, R. J. (1946). Amer. J . Pathol. 22, 493. Sluis-Cremer, G.K. (1965). Ann. N . Y . Acad. Sci. 132, 215. Sluis-Cremer, G.K. (1970). Environ. Res. 3, 310. Sluis-Cremer, G. K., and du Toit, R. S. J. (1973). In “Biological Effects of Asbestos,” p. 160. Int. Agency Res. Cancer, Lyon, France. Smith, B. A., and Davis, J. M. G. (1971). J . Pathol. 105, 153. Smith, W. E. (1969). Cancer Res. 9, 712. Smith, W. E., and Yazdi, E. (1969). Proc. Amer. Ass. Cancer Res. 10, 84. Smith, W.E., Hubert, I)., Miller, L., Badollet, M. S., and Churg, J. (1968). Znt. Conf. Biol. Effects Asbestos, 8nd, Dresden, 1968 pp. 59-60. Smith, W. E., Langer, A . M., Badollet, M. S.,Miller, L., Hubert, D., Hayt,on, T., and Churg, J. (1973). In press. Smither, W. J. (1965). Ann. IV. Y . Acad. Sci. 132, 166. Smither, u .J., and Cross, A. A. (1972). Trans. Znst. Mar. Eng. M, 35. Smither, W. J., and Lewinsohn, H. C. (1973). Zn “Biological Effects of Ashestos,” p. 169. Int. Agency Res. Cancer, Lyon, France. Solomon, A., Goldstein, B., Webster, I., and Sluis-Cremer, G. K. (1971). Environ. Res. 4,430. Speakman, K . (1971). Zn “The Physics and Chemistry of Asbestos Minerals,” Abstr. Pap. 2:l. Institute of Natural Sciences, Louvain University, Belgium. Speil, S., and Leineweber, J. P. (1969). Environ. Res. 2, 166. Stalder, K. (1965). Reitr. Silikose-Forsch. 86, 1. Stalder, K. (1966). Naturwissenschaften 53, 706. Stalder, K., and Stober, W. (1965). Nature (London) 207, 874. Stanton, M. F. (1973). I n “Biological Effects of Asbestos,” p. 289. Int. Agency Res. Cancer, Lyon, France. Stanton, M. F., and Wrench, C. (1972). J . Nat. Cancer Inst. 48, 797. Stanton, M. F., Blackwell, R., and Miller, E. (1969). Amer. Ind. Hyg. Ass., J . 30, 236. Steinberg, J. (1973). J . Cell Sci. 12, 217. Stewart, M. J., and Haddow, A. C. (1929). J . Pathol. Bacteriol. 32, 172. Suzuki, M. D., and Churg, J. (1969). Amer. J . Pathol. 55, 79. Suzuki, M. D., and Churg, J. (1970). Environ. Res. 3, 107. Rzentei, E.(1967a). Fortschr. Staublungenforsch. 6, 149. Szentei, E. (1967b). Fortschr. Staublungenforsch. 2, 157. Szentei, E., and Dolgner, R. (1966). Naturwissenschaften 53, 705.

MINERAL FIBERS

40 1

Timbrell, V. (1965). Ann. N. Y . Acad. Sci. 132, 255. Timbrell, V. (1970). In “Pneumoconiosis,” (H. A. Shapiro, ed.), p. 25. Oxford Univ. Press, London and New York. Timbrell, V. (1972). In “Assessment of Airborne Particles” (T. T. Mercer, P. E. Morrow, and W. Stober, eds.), Chapter 22, p. 429. Thomas, Springfield, Illinois. Timbrell, V. (1973). In “Biological Effects of Asbestos,” p. 13. Int. Agency Res. Cancer, Lyon, France. Timbrell, V., and Skidmore, J. W. (1968). Znt. COT$.Biol. Eflects Asbestos, 2nd, Dresden, 1968 pp. 52-56. Timbrell, V., and Skidmore, J. W. (1971). In “Inhaled Particles 111” (W. H. Walton, ed.), Vol. I, p. 49. Unwin, London. Timbrell, V., Hyett, A. W., and Skidmore, J. W. (1968). J . Nut. Cancer Znst. 11, 273. Timbrell, V., Skidmore, J. W., Hyett, A. W., and Wagner, J. C. (1970a). Aerosol Sci. 1, 215. Timbrell, V., Pooley, F. D., and Wagner, J. C. (1970b). In “Pneumoconiosis” (H. A. Shapiro, ed.), p. 120. Oxford Univ. Press, London and New York. Timbrell, V., Griffiths, D. M., and Pooley, F. D. (1971). Nature (London) 232, 55. Utidjian, M. D., Gross, P., and de Treville, R. T. P. (1968). Arch. Enuiron. Health 17, 327. Vigliani, E. C. (1968). Med. Lavoro 59, 401. Vigliani, E. C. (1969). Med. Lavoro 60, 325. Vigliani, E. C. (1970). In “Pneumoconiosis” (H. A. Shapiro, ed.), p. 192. Oxford Univ. Press, London and New York. Vigliani, E. C., Gheszi, I., Maranzana, P., and Pernis, B. (1968). Znt. Conf. Bid. Eflects Asbestos, 2nd, Dresden, 1968 pp. 147-150. Vorwald, A. J., Durkan, T. M., and Pratt, P. C. (1951). Arch. Znd. Hyg. Occup. Med. 3 , l . VBsamae, A. (1971). Annu. Rep. Znt. Agency Res. Cancer, 1971 p. 46. Wagner, .J. C. (1958). Staublungenerkrankungen, Rer, Arbeitsmed. Tag., 1956 3, p. 566. Wagner, J. C. (1960). Proc. Pneiimoconiosis Conf.,Johnnnesburg (A. J. Orenstein, ed.), p. 373. Churchill, London. Wagner, J. C. (1962). Nature (London) 196, 180. Wagner, J. C. (1963). Brit. J. Ind. filed. 20, 1 . Wagner, J. C. (1965). Ann. N. Y. Acad. Sci. 132, 505 (in Discussion). Wagner, J. C. (1970). In “Hygiene Standard for Airborne Amosite Asbestos Dust from the Committee of Hygiene Standards of the British Occupat,ional Hygiene Society,” p. 6. Wagner, J. C. (1972a). Ann. Occup. Hyg. 15, 61. Wagner, J. C. (1972b). Recent Results Cancer Res. 39, 37. Wagner, J. C., and Berry, G. (1969). Brit. J. Cancer 23, 567. Wagner, J. C., and Berry, G. (1973). In “Biological Effects of Asbestos,” p. 85. Int. Agency Res. Cancer, Lyon, France. Wagner, J. C., and Skidmore, J. W. (1965). Ann. N . Y. Acad. Sci. 132, 77. Wagner, J. C., Sleggs, C. A,, and Marchand, P. (1960). Brit. J . Znd. Med. 17, 260. Wagner, J. C., Berry, G., and Timbrell, V. (1970). In “Pneumoconiosis” (H. A. Shapiro, ed.), p. 216. Oxford Univ. Press, London and New York. Wagner, J. C., Gilson, J. C., Berry, G., and Timbrell, V. (1971). Brit. Med. Bull. 27, 71. Wagner, M. M. F. and Wagner, J. C. (1972). J. Nut. Cancer Res. 49, 81.

402

J. S. HARINGTON, A. C . ALLISON AND D. V. BADAMI

Webster, I. (1966). S. Afr. Pneumoconiosis Rev. No. l., p. 25 (report of work of Pneumoconiosis Research Unit, Johannesburg). Webster, I. (1969). Int. Congr. Occup. Health, Proc., 16th, 2969 p. 211. Webster, I. (1970). I n “Pneumoconiosis” (H. A. Shapiro, ed.), p. 209. Oxford Univ. Press, London and New York. Webster, I. (1973). I n “Biological Effects of Asbestos,” p. 195. Int. Agency Res. Cancer, Lyon, France. Weissmann, G., and Rita, G. A. (1972). Nature (London), New Bid. 240, 167. Weller, W., and Ulmer, W. T. (1973). Ann. N . Y . Acad. Sci. 200, 624. Whipple, H. E., ed. (1965). “Biological Effects of Asbestos,” Vol. 132. N. Y. Acad. Sci., New York. White, C. D. (1967). Nature (London) 215, 875. Whittaker, E. J. W. (1955). Acta Crystallogr. 8, 261, 265, and 726. Whit,taker, E. J. W., and Zussman, J. (1971). I n “The Elect,ron Optical Investigation of Clays” (J. A. Gard, ed.), p , 166. Mineral. SOC.,London. Williams, S. (1969). “Asbestosis. A Bibliography of the World’s Literature Abstracted and Indexed 1960-1968” (submitted t o University of South Africa as partial requirement for degree of Bachelor in Library Science). Pneumoconiosis Research Unit,, C.S.I.R., P. 0. Box 1038, Johannesburg. Williams, W. J. (1965). Arch. Environ. HeaZth 10, 44. Working Group on Asbestos and Cancer. (1965). Arch. Enuiron. Health 11, 221. Wright, G. W. (1969). Amer. Reu. Resp. Dis.100, 467. Wyers, H. (1946). Thesis presented t o the University of Glasgow for the Degree of Doctor of Medicine (from Gilson, 1966). Yada, K. (1967). Acta Crystallogr. 23, 704. Yang, J. C. (1961). Amer. Mineral. 46, 748. Young, G. J., and Healey, F. H. (1954). J. Phys. Chem. 58, 881. Zajusz, K., Paradowski, Z., and Dudsiak, Z. (1968). Med. Proc. 19, 20. Zolov, C., Burilkov, T., and Babadschov, L. (1968). Int. Conf. RioZ. Eflects Asbestos, 2nd, Dresden, 1968 pp, 107-109.