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.I Asbestos: Scientific Developments and co I Implications for Public Policy --4 O J. A. J.B. T. Mossman, Bignon, M. Corn, Seaton, B. L. Gee o cn CO cn Is 4=- i Physico-Chemical Characteristics of Asbestos Asbestos is a commercial term for a group of fibrous minerals often associated with the development ofpulmo "Asbestos" is a broad commercial term for a group of natural!) nary interstitial fibrosis (asbcstosis), lung cancer, and occurring hydrated silicates that crystallize in a fibrous h^bit. Thi malignant mesothelioma in occupationally exposed indi legal definition ofa fiber as promulgated by the EPA and other U.S viduals. The pathogenicity of different forms of asbestos regulatory agencies is one that possesses a 3:1 aspea ratio varies--long, thin amphibole fibers are most pathogenic, However, this definition has been criticized by mineralogists (4). particularly in the induction of mesothelioma. Available Asbestos fibers in ores arc'not respirable until released and madi data do not support the concept that low-level exposure airborne during mining and processing. The family of asbesto: to asbestos is a health hazard in buildings and schools. minerals can be subdivided into serpentine and .amphibole fiber The concentration of asbestos fibers in aft, type of asbes (Fig. 1). rhiysnrile. which accounts for over 90% of the world' tos, and size ot tibers must be considered in evaluation of production of asbestos, is the most common fibrous serpentine potential health risks. whereas the amphiboles. a chemically diverse group ofless industri ally important minerals, include the fibrous minerals and emcidnlitr amosiie anrhnphyllirc ashesrrw. artinolite asbestos, and tremolit< asbestos. Trcmolite, actinolite and anthophyllite, which occur ii sbestos engenders both bear and panic in U.S. both fibrous and nonfibrous forms, have been only rarely mined fo Asociety. Observation that asbestos-containing materials use as commercial asbestos. Both the fibrous and nonfibrous form (ACM) have been used in schools, buildings, and hospitals, of these amphibole minerals are sometimes found as contaminant and the Asbestos Hazard Emergency Response Act (AHERAo)f, caommercial deposits of chrysotile, talc, vermiculite, and othc mandate from the Environmental Protection Agency (EPA) mthinaetrals (4). The nonfibrous forms of rypridnlire and amositc ar requires inspection of the nation's public and private schools for referred to as ricbcdcitc and gnineritc, respectively. asbestos, have resulted in the explosive growth of asbestos identifica The various types of asbestos fibers differ in their chemica tion and removal companies. By EPA estimates, extension of EPA composition, morphology, and durability. Therefore, the biologi requirements to approximately 733,000 public and commercial effects should be considered individually for each fiber type. Idcntifi buildings containing asbestos will cost S53 billion, discounted at cation of specific types of asbestos in air samples requires sophisti 10% over 30 yean (I). Because of uncertainties regarding the ealed technology such as transmission electron microscopy, x-ra amount of asbestos and its condition in these buildings, estimates diffraction, or energy dispersive x-ray spectroscopy. The rod-lik for removal of asbestos are as high as S100 to SI50 billion (2). amphiboles appear to penetrate the peripheral lung more readil Asbestos was shown to cause asbcstosis at the turn of the century. Its association with the causation of lung and pleural tumors in asbestos miners and workers was demonstrated in the 1950s and 1960s, respectively (3). An important issue is whether these diseases Table 1. Summary statistics for average airborne fiber concentrations in U.l schools (88) and buildings (89). The data used in the calculation of eac statistic are the avenge concentrations (expressed as number offibers great! are also hazards to the general population exposed to airborne levels of asbestos in schools and other buildings. Does available evidence support the concept that asbestos causes disease in the nonoccupational environment? What are the mechanisms of asbestos-induced than 5 iim in length per cubic centimeter of air) in a building (for index samples) or the concentration outside each building [for outdoor sample (89)]. By visual inspection, category 1 buildings contained no asbesto containing material (ACM), category 2 buildings contained ACM in primi ify good condition, and buildings in category 3 showed at least one area > fibrogenesis and carcinogenesis? Most importantly, have recent data been adequately considered in formulating policies in the United States for regulation and banning of asbestos? In this article, we summarize recent developments and discuss their implications for significantly damaged ACM. In the study on public buildings, 387 index and 48 outdoor air samples were evaluated. No asbestos fibers were ierecte in 83% of the 387 samples. The sample size is given in parentheses beloeach heading. public policy. B. T. Masurian is a member of the Department of Pathology of the University of Vermont, College of Medicine, Burlington, VT 05405. J. Bignon is director of the Unite INSERM dc Rcthcrchc sur U Biopathdogic ct U Toxicologic rulmotuuc ct Renale, CretcU, France. M. Com is director of the Division of Environmental Health Engineering, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205. A. Seaton is director of the Institute of Occupational Medicine, Edinburgh, Scotland EH8 9SU. J. B. L, Gee u a director ofthe WinoKMcr Chest Clinic and manta of the Department of Internal Medicine, YaJc University School of Medicine, New Haven, CT 06510. Statistic Schools (71) Outdoor air (48) Median Mean SD 0.00024* 0.00053 0.00000 0.00039 0.00096 Public buildings Category 1 (6) Category 2(6) Category 3 (37) 0.00010 0.00099 0.00198 0.00040 0.00059 0.00052 0.00058 0.00073 0.00072 80th pcivcntilc * 0.00045; 90th percentile -- 0.00083. 394- SCIENCE, VOL. Z+ ST0053465 Fig. 1, Oauifigtion and morphology of asbenoa fiben. The burned photograph* are scanning election mkrograpna of Union Internationale Conor Ic Cancer ref erence tample* of diryaodlc A (left) and oraddotite asbestos (right) (field ofview ia -12 |un in both photographs). The amphiboica are decided in Older of their relative indumial importance. Serpentine I Chrysolite MO.St.O^lOH), Asbestos I Ampdibola I Crociddite NaIlFe3'yF9J')3SisOwlOHti Amosits (Fe.Mg)7Sis02I10H)j Anthophytlite Tremolits Actinoiile (Mg.FtTSi,0MIOH)j CajMgjSijOjj/OHI* C*2(Mg.FelJSi,Oj2tOH>2 than chrysodle fiben, which are curly, can occur in bundles, and can be intercepted at airway bifurcations (Fig. 1). Hie chemical makeup ofeach fiber type is complex, and fiben may consist ofa variety of trace metals and organic compounds acquired in ores or during processing. Asbestos is attractive to industry because of its resistance to heat and chemicals, high tensile strength, and lower cost compared to .man-made materials. Although use of spray-on asbestos as a fire proofing material or insulation has been banned in this country, as well as in several European countries, asbestos is incorporated currently into cement construction materials (roofing, shingles, and cement pipes), friction materials (brake linings and dutch pads), jointing and gaskets, asphalt coats and sealants, and other similar products. As a result of these applications, an estimated 20% of buildings including hospitals, schools, and other public and private structures contain ACM (1). Asbestos in buildings does not sponta neously shed fibers, but physical damage to ACM by decay, renovation, or demolition can cause release ofairborne fibers {S). Diseases Associated with Occupational Exposure to Asbestos Occupational exposure to asbestos can cause four types of disor ders: asbestosis; lung cancer; mesotheliomas ofthe pleura, pericardi um, and peritoneum; and benign changes in the pleura (2). Asbestosis, a pulmonary interstitial fibrosis with excessive deposition of collagen, caused progressive lung stiffening, impaired gas exchange, disability, and death in many workers exposed before the enforce ment of occupational standards. Lung cancers, that is, tumors arising in tracheobronchial epididia] or alveolar epithelial cells, have occurred in asbestos workers in most cases 20 or more years after their first exposure to asbestos. In general, lung cancers have been found in asbestos workers who are smokers and only rarely in nonsmokers (6). A number of epidemiologic studies have indicated that the relation between the development of lung cancers and cumulative exposure to asbestos is approximately linear, but wide variations in slope of the line occur apparently related to fiber type and industrial usage (7). Death rates from lung cancers in asbestos workers, as measured by standard mortality ratios (SMRs), die observed mortality of a cohort divided by the mortality ofa control population, are lowest in chrysotilc miners and workers manufac turing friction materials. In contrast, lung cancer deaths are higher in those mining and working with amphibolc asbestos. Textile workers in a South Carolina plant in which chrysodle was used exhibited a striking increase in lung cancers with duration of exposure when compared to Canadian chrysodle miners and millers. Solvents and oils in textile production might act as cocardnogcns in the development of these lung tumors (7). Diffuse malignant mesothelioma is a fatal tumor arising from mcsodielial cells or underlying mesenchymal cells in the pleura, pericardium, and peritoneum (8). The time between diagnosis and initial occupational exposure to asbestos commonly exceeds 30 years. Smoking evidently does not enhance risk of mesothelioma in asbestos workers (J). Although mesotheliomas are extremely rare malignancies, that u, only 1648 were recorded from 1973 to 1984 in one survey covering approximately 10% of the U.S. population (9), they may account for as much as 18% of the proportional mortality in aocidolitc workers (10). Mesotheliomas also have been observed after household exposure of family members of asbestos workers and in individuals living in close proximity to asbestos mines (II). Although mesothelioma has been considered by some as a disease pathognomonic of exposure to asbestos, approximately 20 to 30% of mesotheliomas occur in the general population In adults not exposed occupationally to asbestos (12). Mesotheliomas are rarely found in children. Diagnosis of mesotheliomas is a challenge as the tumor may resemble mctastascs ofocher tumor types occurring in the pleura or peritoneum and assume a wide variety of microscopic appearances. Thus, death certificates may either underestimate (because these tumors are attributed to cancers of the gastrointestinal tract and other organs) {13) or overestimate die incidence of mesotheliomas. In France, mesotheliomas are overestimated by a factor of 3 on death certificates in comparison to the mesothelioma registry (14). A number of benign pleural changes that rarefy cause functional impairment have been observed in asbestos workers. These include pleural effusions, pleural fibrosis, pleural plaques, that is, accumula tions of acellular collagen on the diaphragm and chest wall, and pseudorumors or infoldings of the lung often associated with plaques. These pleural changes may reflect exposure to asbestos but have no demonstrated relation to die development ofmesothelioma. Tumors of the gastrointestinal tract, larynx, and other organs including the kidney, ovary, pancreas, pericardium, eye, and lym phatic system, have been reported in some cohorts of asbestos 19 JANUARY 1990 ARTICLES 19) ST0053466 workers (IS, IS). In general, the enhanced SMRs for these turnon arc not statistically distinguishable from normal SMRs and have not been confirmed in most cohorts. Both laryngeal and gastrointestinal tumors have other etiologies such as smoking, alcohol, diet, and intestinal polyposis that confound the interpretation of epidemio logic data. The Amphibolc Hypothesis The association ofmesothelioma with asbestos exposure was lint described in 1960 in the northwest Cape area ofSouth Africa where long, thin croddolite fibers were mined (IS). Since then, an increased incidence of mesothelioma has been repotted in a number of occupational settings including factories that presumably used only chrysotile. Within the past decade, sophisticated technology has allowed examination of the types of fibers in the lung tissue of these workers. Results revealed that many chrysotilc-exposed work ers showed an appreciable lung burden of amphibolc fibers, which were used for brief periods in the workplace (17). The persistence of amphibolcs in human lungs may be attributed to their increased ability to penetrate the peripheral lung, lack of clearance, or durability. In contrast, chrysotile has been found post-mortem in smaller amounts than expected in the hmgs of asbestos workers (IS). It disappears with time most likely because magnesium and silica are leached from the fibers (19). Recently, the lung content of asbestos and nonasbestos fibers has been compared in diagnosed cases of mesothelioma, lung cancer, and cardiovascular disease (controls) from the western coast of France, a region containing shipyards (20). The number ofamphibolc fibers (crocidolite and amosite) was significantly higher in lungs from mesothelioma patients, whereas numbers of chrysotile and nonasbestos fibers were simitar in all groups. These data suggest that the lung burden of chrysotile and nonasbestos fibers bears no relation to the occurrence of these cancers. Several recent studies indicate that the risk of pleural mesothelio ma is lower where chrysotile is used without admixture or contami nation by amphibolcs (21). For example, a gradation of death rates from mesothelioma has been observed in both male and female asbestos-exposed cohorts. Mesothelioma has been responsible for approximately 6 to 8% of the proportional mortality in men working with mixtures containing crocidolite or amphibolc (crodd olite or amosite) in comparison to less chan 1% of the proportional mortality in men working with chrysotile (IP). In Female cohorts, the proportional mortality from mesothelioma was highest for amphibolc exposure (10.6%) and lowest for chrysotile exposure (0.2%). Thus, these dan suggest chat amphibolcs are the major cause of mesotheliomas in asbestos workers. Chrysotile miners and millers in Quebec who were supposedly exposed only to chrysotile have developed few mesotheliomas (22). However, recent fiber analyses on the lungs of both these workers and chrysotile factory workers showed the presence of tremolite (2J). This amphibolc in the fibrous form has been implicated as the causative agent of mesotheliomas and lung cancers in miners exposed to vermiculite heavily contaminated with tremolite (24). Although tremolite composes less than 1% of the asKotos dust in the Quebec mines and mills, die relarive ratio of tremolite to chrysotile fibers in the lungs of Canadian miners and millers is related directly to their risk of developing mesothelioma (2S). For the reasons above, the few mesotheliomas observed in Canadian chrysotile workers appear to be attributable to fibrous tremolite, an observation compatible with other evidence that amphibolcs are the most pathogenic asbestiform minerals. Likewise, recent data on London asbestos factory workers show diat the severity ofasbestosis and carcinoma ofthe lung (as wed as n> lioma) correlates with the lung burden of croddolite and a asbestos and that the proportions of chrysodle and nooa.fibers are decreased in comparison to matched control pattern A British cohort exposed since 1970 to chrysotile at airbonu not exceeding 0.S to 1.0 fiber per cubic centimeter in the nu rure of friction materials showed no excess of deaths fron cancer, ocher asbestos-related tumors, or chronic respiratxxy i (27). These and other data (7, 17, 21, 2S) suggest that ampf are more potent than chrysotile in the induction of fibmk disease and associated lung cancers. Experimental Models of Asbestos-Induced Lung Disease Several studies have shown that mesotheliomas arc induce dosage-dependent fashion after intrapleural and intraperiront jection of asbestos and other asbestos-like fibers into rodents Chrysotile was as carcinogenic as the amphibolcs by these rou administration. However, differences have been observed bet the carcinogenicity of fibrous and nonfibrotu materials. For c pie, in one study, fibrous tremolite was carcinogenic after . pleural injection, whereSs nonfibrous tremolite was noncarcino at identical concentrations (SO). Although the natural rou. exposure to fibers by inhalation was circumvented in these ex menu, they were usdul in indicating that fibers longer than I and less than 0.25 |xm in diameter have the most marked cargenic potential, that is, the "Stanton hypothesis.* These data been supported by the results of inhalation studies in rats in u short (5 |un in length) and long fiber preparations ofamosite chrysotile asbestos have been compared (SI). In contrast to batches of amosite and chrysotile asbestos containing many . fibers, short fibers of amosite produced neither asbestosis pulmonary tumors. Short chrysotile produced a small amoun asbestosis and malignancies, but these were attributed to contam don of the short chrysotile preparation by longer fibers. Fewer I than short fibers of both types were present in the lungs of all ra the terminarion of exposure, but, regardless ofsize, fewer chryst fibers remained in the lung. These results support the obscrvati that chrysotile fibers, in comparison to amphibolc fibers, are dei more rapidly from human lungs (17). This phenomenon and lim. alveolar penetradon of curly duysodle bundles (rather than tl inherent absence of carcinogenicity) may account for the appar lack of association of chrysotile fibers with the development mesothelioma in human cohorts. The exorbitant costs of. inhalation experiments with anin preclude long-term studies to determine the carcinogenic pdten of asbestos at low-level exposures. The development ofmalignant in rodents approaches the 2- to 3-year life-span of these anirr (J2), a period of too brief to reflea the consequences of the loi term solubility of chrysotile in the human lung. Mechanisms of Asbestos-Induced Inflammation and Fibrogcncsis Both epidemiologic and experimental data support the concept a threshold for chrysotile-induccd pulmonary fibrosis. In a she model of asbestosis, inflammation and histopathologic evidence . disease were not observed after less than 100 mg of chrysotile we injected into the trachea of the sheep (3J). After brief, inteninhalation of chrysotile, the sheep accumulated alveolar macn phages (AMs) at areas ofdeposition offibers (4). These cell types ai 296 SCIENCE, VOL. 14 rwed as "effector" cells of disease as they produce a mixture of >roblast growth factors, chemoucric factors, and fibroneedn. ostaglandins, plasminogen activator, a hcat-stablc factor similar to jteiet-dcrived growth factor (PDGF), lysosomal enzymes, and rive oxygen metabolites, one or more of which may cause olifcration or functional impairment of neighboring epithelial Us and fibroblasts in the lung, were released after exposure ofAMs asbestos in vitro (35). These substances might mediate both acute id chronic inflammatory reactions in man and animals after halation of asbestos. In support of this hypothesis, AM-derived owth factor (AMDGF), PDGF, superoxide (Of), and HjOj ere spontaneously released from AMs recovered by bronchoalvcor lavage from patients with asbestosis (35). Similarly, AMs lavaged om both mice and sheep that had an earlier intratracheal injection 7 duysotile released enhanced amounts of a growth factor that imulated proliferation of a human embryonic lung cell line (WT 3) (37). In one study, AMs from both normal individuals and patients id) idiopathic pulmonary fibrosis expressed a 4.2-kilobasc messencr RNA complementary.cd c-rir, a proto-oncogene coding for the B tain of PDGF (33). The amounts were approximately fourfold ighcr from AMs of patients with pulmonary fibrosis. Because DGF is mitogenic to mesenchymal cells, which possess functional DGF receptors, elevated levels of PDGF in lung tissue or fluids ould induce lung fibroblasts to divide or to produce exorbitant mounts of collagen, the hallmark of the fibrotic lesion. Quiescent iiman mesothelfal cells also undergo DNA synthesis after exposure s PDGF and a broad speesrum of other growth factors (39). Within the past few years, several laboratories have focused on cove oxygen spedes (AOS) as causative agents of both isbestosis nd asbestos-related maligrunties. Increased amounts of superoxidc Of) have been produced after rodent AMs were exposed in vitro o long asbestos fibers, whereas generation was minimal after hotter fibers and nonfibrous particles were introduced (40). Smaller ibets and particles are incorporated into phagolysosomes by AMs, vhcreas longer fibers arc incompletely phagocytoscd, a process iberating more AOS. The observation that exogenous administration of scavengers of \OS prevents asbestos-induced cell death to cultures of tracheal rpithelial cells and lung fibroblasts (4t) suggests that AOS are minutely related to asbestos toxicity even in the absence of AMs. ?ibers may induce generation of AOS after phagocytosis or by txaacdlular mechanisms. For example,' recent studies with asbestos n cdl-free systems have demonstrated by electron spin resonance dut chrysolite, croddolite, and amosire generate AOS in the presence of HjOj or physiological saline (42). Under these circumitmces.iFe2* on the surface of the fiber appears to drive a modified Haber-Wciss (Fenton) reaction that results in production of the toxic hydroxyl radical (OH-) from H2O1 and Of. These reactions result in lipid peroxidation, which is prevented by incubation of asbestos with the iron chelator, desfcrroxaminc (43). At high concentrations, AOS are cytotoxic to cells of the respira tory tract, but at low concentrations they induce functional changes in rodent lung fibroblasts chat may be critical to the pathogenesis of asbestos-induced fibrotic lung disease. For example, after addition of xanthine and xanthine oxidase (a chemical generating system produdng Of), rat lung fibroblasts in vitro produced increased amounts of cell-assodatcd collagen in a pattern similar to that observed after their exposure to crocidolire asbestos (40, 44). In an inhalation model of rapid-onset asbestosis, osmotic pumps contain ing polyethylene glycol (PEG)-conjugated catalase, the enzyme scavenging H2O1, were implanted subcutaneously into rats before they were exposed to crocidolire for 20 days (45). This procedure boosted levels of catalase in the sera and lungs of these animals and ameliorated both the inflammation and the severity and extent of fibrotic lesions that normally develop after inhalation of asbestos. This study was the first successful experimental approach to the prevention of asbestos-associated lung disease. Moreover, the results support the concept ofa cause and effect relation between AOS and the development of asbestosis. Mechanisms of Asbestos-Induced Carcinogenesis Carcinogenesis is a multistage process that classically has been described in rwo stages (46). The "initiation'* stage corresponds to a heritable genetic change (point mutation) induced in a cell by a carcinogenic substance. It is followed by the "promotion" stage, a scries of events in which the initiated cell undergoes proliferative and genotypic changes conferring the malignant phenotype. During the past few years, the identification of a number of protooncogenes has resulted in a new understanding of the successive genetic events involved in the process of malignant transformation. Increased expression of these genes may cause the production of growth factors or growth-factor receptors. Loss ofother genes (antioncogenes) also appears to contribute to the carcinogenic process. These findings indicate that the distinction between genetic and epigenetic events in carcinogenesis is not simple, especially because chromosomal rearrangements or deletions associated with point mutation and activation or loss of genes can happen at any stage in the process of cell transformation. Whether the multistage model is directly applicable to asbestosassociated carcinogenesis is unclear. Unlike most carcinogens, asbes tos docs not cause base substitution and frameshift mutations in bacterial-mutation assays (47). Of the 23 agents designated as group 1 human carcinogens by the International Agency for Research on Cancer (IARC), only asbestos and conjugated estrogens were nongenotoxic as defined by both the Ames test and rodent bonemarrow assays for detection of chromosomal aberrations or micronucleated erythrocytes (48). Although asbestos was weakly muta genic in Chinese hamster lung cells (49), it was not mutagenic in liver epithelial cells or in Syrian hamster embryo (SHE) fibroblasts (50). Asbestos did not cause morphologic transformation of C3H 10T1V2 cells (51), but transformed both BALB/c#3T3 and SHE fibroblasts (52). Glass fibers and nonfibrous silica (albeit at much higher concentrations) also were active in the SHE bioassay. In this system, longer, thinner fibers were more potent in the induction of transformation and chromosomal anomalies, an observation consist ent with the increased malignant potential ofthese fibers in compar ison to shorter fibers or particles after their administration intraplcurally, intrapcritoncally, or by inhalation to rodents (29, 30). In these and other in vitro studies, the biologic effects of fiber types have been assessed comparatively on a mass (milligrams of fibers per dish) rather than a numerical (numbers offibers ofa given size per dish) basis. Cytotoxicity and cytogenetic effects of chiysotile, crocidolire, and crionite (an aluminosilicate fiber) recently were compared in Chinese hamster lung fibroblasts (V79 cells) (53). Numbers of chrysoriic fibers required to produce cytotoxic or cytoge netic changes were several orders of magnitudes higher in comparison to crionite, the most potent fiber, or croddolite, a fiber ofintermediate potency. These results are consistent with the higher tumorigenic potential of crionite in rodent inhalation experiments (54). In some studies, asbestos appears to augment the mutagenic and carcinogenic effects of chemical carcinogens and radiation. For example, both crocidolire and chrysotile increased the frequency of mutation and transformation in rodent epithelial cells and fibro blasts exposed to beruo[a)pyrene (BaP) (50) and radiation or radon 19 JANUARY 1990 ARTICLES 297 mesoois 1 ST0053468 alpha particles (51). However, synergistic effects ofasbestos and BaP wen not observed in two studies with SHE and rat mesothelial cells, respectively (52, 55). The paniculate nature of asbestos and its capacity to bind nucleic adds has prompted transfection studies in which asbestos was used as a vchidc for introducing DNA or RNA. into a number ofcell lines (56). Under these circumstances, asbestos was intermediate in rank in comparison to a number of other insoluble facilitators including calcium phosphate, talc, and kaolin, none of which have been associated with the induction of cancer. After addition to human or rat mesothelial cells, both chrysodle (in tats) (57) and amositc (in humans) (58) have caused ancuploidy and altered growth characteristics after repeated passaging. Injection of tat mesothelial cells into nude mice after a single exposure to chrysodle did not cause tumors in animals, but multiple exposures (36 times) to chrysodle and repeated passaging resulted in tumorigenic cell populations (57). In contrast, human mesothelial cells displaying chromosomal abnormalities and growth alterations after duplicate exposures to cytotoxic concentrations ofamosite were not tumorigenic in nude mice (58). Asbestos promoted the proliferation of mesothelial cells both in organ cultures of human mesochclium exposed to asbestos in vitro and in mice given intraperitoneal injections of asbestos (59). Asbestos fibers come in contact with the chromosomes of rat mesothelial cells (60) and the mitotic apparatus of V79 (53) and SHE (61) cells in vitro. These interactions might induce chromo somal misaggregation or abnormalities. Several investigators have examined chromosomal aberrations in human mesotheliomas, but changes appeared inconsistent from tumor to tumor. The most common abnormalities involved inversions, translocations, and de letions of chromosomes I, 3, 7, 9, 17, and 22 (62). Constitutively enhanced expression ofthe PDGF-B gene, the proto-oncogene c-rii, was observed in human mesothelioma cell lines when compared to normal human mesothelial cells (55). In comparison to human mesothelial ceils, human bronchial epithelial cells in vitro are relatively resistant to asbestos. In one study, concentrations of chrysodle, crocidolitc, or amositc asbestos approximately ten times as high as that required for mesothelial cells were required to achieve a comparable increase in toxicity (as measured by a 50% decrease in colony-forming efficiency of human bronchial epithelial cells) (64). In another study, ancuploidy was not increased significantly over a range of concentrations of either crocidolitc or chrysodle asbestos (55). This latter observation and the demonstration that insertion of asbestos into rat tracheal grafts can cause the development of carcinomas following insertion of subcarcinogcnic amounts of the polycyclic aromatic hydrocarbon, dimethylbcnzo[ii]anthracene (55), suggest that asbestos is a pro moter in the development of lung cancers. In support of this concept, both crocidolitc and chrysodle asbestos induced a number of biochemical and proliferative alterations in both rodent and human tracheal epithelial cell and organ cultures that were similar to those observed in mouse skin that had been treated with the tumor promoter 12-0-tetradecanoylphorbol-13-acetatc (TPA) (57). The repertoire of these asbestos-associated proliferative changes, which were masked in tracheal epithelial cells in a high-serum containing medium or by addition of transforming growth factor-type B (TGF-PO (68), included enhanced incorporation of JH-thymidinc, increases in colony-forming efficiency, and the development of squamous metaplasia, that is, conversion of differentiated mucoci liary cells to keratinizing cells resembling epidermis. Induction of ornithine decarboxylase (ODC), a rate-limiting enzyme in the biosynthesis of polyamines that is increased in mouse skin after exposure to TPA but not after addition of nonrumor promoting phorbol derivatives, also occurred in a dosage-dependent fashion in tracheal epithelial cells exposed to long, thin, asbestos and glass fibers. In contrast, nonfibrous particles and shorter fibers did not increase ODC activity at similar concentrations (59). Until quite recently, it was unclear how asbestos triggered proliferation in tracheal epithelial cells. However, several pieces of data suggest that mechanisms ofcell signaling by asbestos are similar to those observed with TPA, a soluble tumor promoter that binds directly to protein kinase C (PKC), a calcium- and phospholipiddependent enzyme that activates a limb of the phosphoinositidc signal-transduction pathway (70). Mitogenic concentrations of cro cidolitc asbestos caused increased accumulation of diacylglycerol in tracheal epithelial cells (71) and subsequent activation of PKC (72), presumably by activation of membrane phospholipases. The in creased production of inositol oris- and tetrakisphosphates appeared responsible for the generation of diacylglycerol, which preceded increased cell division. Abrogation of aotidolite-induced ODC activity in tracheal epithelial cells by inhibitors of PKC and calcium channel antagonists (59) suggests that PKC is related causally to asbestos-associated cell proliferation. Mechanisms other than tumor promotion by asbestos also may explain interactions between smoking and asbestos; these mecha nisms could be important in the development of lung cancers in asbestos workers (7, 75). For example, smoking impaired clearance of amositc asbestos from rodent. Iungs and increased retention of fibers in airway epithelial cells (74). Both cigarette smoke, and asbestos induced AOS in a synergistic fashion in vitro and damaged isolated bacteriophage DNA (75). AOS liberated from asbestos fibers also catalyzed the oxidation of6-hydroxybenzo[d]pyrcne to a more mutagenic and carcinogenic radical (75). Because crockfolite and chrysodle asbestos adsorbed BaP and acted as vehicles to increase both uptake of these lipophilic carcinogens and formation of DNA adducts in tracheal epithelial cells (77), fibers might facilitate the initiation of lung turnon by BaP. Public Policy The available experimental and epidemiological data indicate that both fiber type and size are important determinants of the pathoge nicity of asbestos. Although asbestos has caused disease in the workplace (78) and such occurrence has resulted in calls for regula tions to protect worken (79), recent epidemiologic data are concor dant with the suggestion that exposure to chrysodle at current occupational standards does not increase the risk of asbestosassociated diseases (17, 21, 27, 28). Unlike most other countries, particularly in the European community, which have more stringent requirements for regulation and importation of amphiboles, federal policy in the United States does not differentiate between different' types of asbestos. Does airborne asbestos present a risk to the health of individuals in schools and other buildings.1 The available data do not indicate that asbestos-associated malignancies or functional impairment will occur as a result of exposure to most airborne concentrations of asbestos in buildings. First and foremost, the levels of airborne asbestos in buildings, even with damaged ACM, are magnitudes lower than concentrations in the unregulated workplace in the past and approximately 1/100 of the permissible exposure of 0.2 fibers per cubic centimeter of air in the U.S. workplace (80). Before the enforcement of occupational standards, workplace concentrations of 100 or more fibers per cubic centimeter of air were not uncommon (81). In contrast, surveys of asbestos in schools and public buildings show that che mean airborne concentrations arc several thousand fold lower (Table 1). With few exceptions, the type of asbestos fiber found predominantly in buildings is duysotile. Accumulating evi 298 SCIENCE, VOL. Z47 dence .indicates chat this asbestos type is probably not associated with the occurrence of mesotheliomas at low levels ofexposure. For example, recent analyses on the fiber concentrations in lungs of asbestos workers showed that chrysotile workers with mesothelioma had 400 times the median lung fiber burden in comparison to workers exposed to amphiboles. Data indicate thac mesotheliomas in chtysocile workers appeared at lung burdens comparable to diat required for the development of asbestosis, a disease associated with occupational exposure to asbestos in the past unregulated workplace (82). Transmission electron microscopy of air samples is essential fur the identification and quantitation of finer asbestos fibers. In the United States and United Kingdom, the direct transmission electron microscopy method is advocated to determine airborne asbestos fiber concentrations in buildings. In France, the indirect transmis sion electron microscopy technique is used, and concentrations are expressed on a mass (milligram) basis. The limit for detection of fibers by phase-contrast microscopy is approximately 0.01 fibers per cubic centimeter ofair, a concentration higher than that reported in most schools and buildings (Tabic 1). Moreover, phase-contrast microscopy cannot be used to identify types of fibers (asbestos or nonasbestos) or to detect fibers less than 0.5 pm in diameter, twice the diameter offibers associated with the greatest biological activity and induction of tumors in rodents (diameters 0.25 tun, that is, Stanton fibers) (29, 30). Such long, thin asbestos fibers are rarely found in air samples of buildings (81, 83). As shown in Table ], fiber concentrations from recent studies in buildings are comparable to levels in outdoor air, a point surely relevant to assessing the health risks ofasbestos in buildings. Airborne concentrations ofasbestos in buildings reported in the 1970s were somewhat higher, presumably because of earlier, less sophisticated sampling and analytical tech niques. Recent epidemiologic studies ofdeaths from mesothelioma in the general population also suggest that risk from asbestos in buildings is miniscule (9,10,84). In comparison to lung cancers (an average of 130,000 cases per year in the United States, largely attributed to smoking), an estimated 1,500 cases of mesothelioma per year occur in the U.S. population (8S). The data on death rates from pleural or peritoneal mesotheliomas over the past 10 to 20 years indicate that mesotheliomas are increasing in males oyer 65 yean ofage who have a past occupational history ofexposure to asbestos (84). By contrast, death fates from mesothelioma in females of all ages have declined slightly or remained constant. Thcs^results support the concept that asbestos in buildings is not an important risk factor, as one would expect increased mesotheliomas in both males and females in this case. A recent French study did not shorw increased risks of asbestosassodated malignancies, pleural plaques, or functional impairment of the lung (effects clearly present in asbestos workers) in persons exposed for 10 yean to airborne asbestos in buildings (86). Al though this survey is still in progress, no mesotheliomas have been observed to date among approximately 15,000 permanent occu pants. Although the validity of extrapolating from high to low dose levels has never been confirmed empirically in the evaluation of asbestos, calculated lifetime risks from mesotheliomas and lung cancers attributable to asbestos in schools and other buildings have appeared in recent years (85, 87). The linear dose-response equations in these models have been used with the assumption chat there is no threshold for disease, a hypothesis which is open to question. Moreover, the range of estimated risks varies from study to study. With the exception of one analysis (85), differences between the pathogenic potential of chrysodles and amphiboles have not been considered in these assessments, and the importance of fiber size has been ignored. Regardless, examination of combined data from Table 2. Estimates of risk from asbestos exposure in schools in comparison to other risks in U.S. society. Data from six published risk estimates (87) in which total deaths (lung cancer and mesotheliomas) attributable to asbestos exposure over a lifetime were estimated pit 1 million students exposed to 0.00024 fibers per cubic centimeter air (the mean airborne concentration in schools. Table 1) for live school yean, beginning at age 10. Estimates indicate that the annual rate is 0.005 to 0.093 deaths per million students for an average life expectancy of 75 years. Modified with permission from Weill and Hughes (90). Cause Asbestos exposure in schools Whooping cough vaccination (1970 to 1980) Aircraft accidents (1979) High school football (1970 to 1980) Drowning (ages 5 to 14) Motor vehicle accident, pedestrian (ages 5 to 14) Home accidents (ages 1 to 14) Long-term smoking Annual rate (deaths per million) 0.005 to 0.093 1 to 6 6 10 27 32 60 1200 published risk estimates shows that risks of asbestos-related total deaths (both lung cancers and mesotheliomas) due to exposure in schools are magnitudes lower than commonplace risks in modemday society (Table 2). The AHERA ruling of 1986 brought asbestos to the attention of the U.S. public and instilled fears in parents that their children would contract asbestos-related malignancies because of high levels of airborne asbestos fibers in schools. Panic has been fueled by unsupported concepts such as the "one fiber theory," which main tains that one fiber of inhaled asbestos will cause cancer. As a result of public pressure, asbestos often is removed haphazardly from schools and public buildings even though most damaged ACM is in boiler rooms and other areas which are inaccessible to students or residents (1). The removal ofpreviously undamaged or encapsulated asbestos can lead to increases in airborne concentrations offibers in buildings, sometimes for months afterwards (>3), anl can result in problems with safe removal and disposal. Asbestos abatement also has led to the exposure of a large new cohort of relatively young asbestos removal workers. While these people should be protected by careful regulation of the circumstances ofremoval, they are often exposed under suboprimal working conditions. As a result of the AHERA ruling, public and private schools arc required to inspect for asbestos and inform parents if ACM are present. Although the law does not require or set standards for che removal of asbestos, schools, often with little expert advice, must submit a management plan detailing how they will deal with damaged asbestos and can be fined a maximum of$5000 per day for lack of compliance to deadlines. The EPA has recommended bulk sampling of ACM to determine the presence of asbestos and visual inspection to determine the course of action, rather chan measure ment ofairborne levels offibers--data thac are far more important in determining the need, if any, for removal of ACM. The available data and comparative risk assessments (Table 2) indicate chat chrysotile asbestos, the type of fiber found predomi nantly in U.S. schools and buildings, is not a health risk in the nonoccupational environment. Clearly, the asbestos panic in the U.S. must be curtailed, especially because unwarranted and poorly controlled asbestos abatement results in unnecessary risks to young removal workers who may develop asbestos-related cancers in later decades. The extensive removal of asbestos has occurred less fre quently in Europe. Prevention (especially in adolescents) of tobacco smoking, che principal cause of lung cancer in the general population, is both a more promising and rational approach to eliminating lung rumors 19 JANUARY 1990 ARTICLES 299 ST0053i>69 I i than asbestos abatement. Even acknowledging chat brief, intense exposures to asbestos might occur in custodians and service workers in buildings with severely damaged ACM, worker education and building maintenance will prove far more effective in risk prevention for these workers. RPERNCBS AND NOTES 1. 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In 1971, the Occupational Safety and Health Administration (OSHA) passed legislation restricting airborne asbestos in the workplace to five fibers greater than 5 pm in length per cubic centimeter air over an 8*hour time-weighted average. In 1986, this standard was reduced to 0.2 fiber) per cubic ccndmccer air. 81. J. M. G. Davis and J. C McDonald, Br. J. hd. Med. 45, 505 (1988). 82. A. Churg and J. L. Wright, in NorvOccupational Exposure to Mineral Fibres, J. Bignon, J. Peto, R. Satacch, Eds. (International Agency for Research on Cancer, Lyon, 1989), pp. 314-318. 83. G. J. Burden and S. A.M.T. JaBrey, Am. Oaup. Hyg. 30,185 (1986); M. Com, in Proceedings ofthe Symposium on Health Aspects ofExposure to Asbestos in Buddings, J. D. Spcngkr, H. Ozkaynak, J. F. McCarthy, H. Lee, Eds. (Harvard Univ. Press, Cambridge, MA, in press); D. G. Massey and G. Foumicr-Masscy, Hewoii Med. J. 46, 153 (1987); R. N. Sawyer, A. N. Rohl, A- M. Langer, Emnmt. Res. 36, 46 ST0053470 300 SCIBNCE, VOL. 247 (1985). 84. V, Hendcnon and P. EncrrSne, J. AM. Cam hat. 79, 31 (1987). 88. ;. R. Hughs and H. Wall, Am. Rrr Kafir. DU. 133, S (1986). 86. 5. Cardkr cf at., A#i6. Borhom. Hoohk 42, 303 (1987). 87. Naoonal Research Council, Couniroc on Nonoccupaoooal Hcakh Aista of Asbtsufcroi Fiber*. Adtmifmt fitn: NsafoM Hooim Kltkt (N*nool Acadcntf Proa, Wsshingou. DC, 1984); Report to die U5. Consumer Product Sifay Camaniaaaon by die Chtonic Hoard Adriaory Pand on Aabcetoa (Coraumer Product Safer? Camniaaion, Washington, DC, 1983); AirMiw AcUatm HnUk Aaamrat Uptime (Environmental Proeocnon Agency, Waahingaon, DC, 1986); E. D. Acheron and M. J. Gardner, Aabnaac The Cmnt UmH joe Adnm (Her JAsfSCy1* Scadoncry Office, London, 1983); Report on niamra ofbeahh and aaFoy aridng firm the uee of tetntoe in Orario (Ontario Royal Cornmuoon, Ontario - Mtrnroy of die Aatomey General, Toconao, 1984); L Dot and J. Petti, Aaknat- tjhrr m HroJtf of Exporter la Atfatat (Her Majcaty*r Surionery Office, London, 1985). 88. M. Com, K. E. Dump, D. McFce, R_ Lot, in peepantian. 89. Batidlc Columbus Division, Price Associates, Alliance Technologic* Corporation, Energy Technology Conauhanta and Midwest Reaeaadi InatituK. Asrusv Aaims 11 Panic OtmUhtp (EPA Caen. So. 6142-4294, draft report for die Eipoaure Evahaacian Division, 1989). 90. U WdJ and J. M. Hughs, Am. Rat. PuUit HooUt 7.171 (1986). 91. We ehanJt 1. Sabcna, V. Kdlcher, anti M. Bergeron. Research in die laboratory of 8.TJM. baa been supported by grants from die Narional Cancer Inatseurr (ROl CA33501), National Insotureof Environmental Health Scienczs (ROI ES03S78), National Heart, Lung, and Blood Institute (R01 HL39469 and SCOR gram 14212), and American Cancer Society (BC 415). We also that* H.CW. for her hdphil comments. ST005347I griming and Human Memory Systems Endel Tulvtng and Daniel L. Schacte^l Pruning is a. nonconsddlis form of human memory, which is concerned- with^'perceptual identification of words and objects and wiugh has only recently been and memory, one that is dot procedural, semantic, or episodic It has come to be known as priming (2). Its function is to improve identification of peraeptual objects. Priming is a type of implicit memoty; it does nor involve explicit or conscious recollection ofany recognized as separate from other forms of memory or memory aystems. It is currently under interne experimen tal scrutiny. Bvidence is converging for the proposition that priming is an expression of i perceptual representa previous experiences. It has affinities to both procedural and seman tic memory. PjCming resembles procedural memoty in that it enhances perceptual skills. It also resembles semantic memoty in that it involves cognitive representations ofthe world and expresses itself tion system that operates at a pr&-*cmantic level; it in cognition rather than behavior. emerges early in development, and access to it lacks the The pe&otypicai priming experiment consists of two stages. In kind offlexibility characteristic of other cognitive memo the fimfstudy) stage, the subject is presented with a stimulus object ry systems. Conceptual priming, however, seems to be (target). Target stimuli may comprise words, line drawings of based on the operations of semantic memoty. objects, drawings of faces, and the like. In the second (test) stage, wjtlch may follow the first after an interval that can vary from seconds to months, the subject is given reduced perceptual informa tion about the object and asked to name or categorize it. Reduced emory was traditionally thought to bb a unitary cues may consist of initial letters or graphemk fragments of words, Mfaculty ofthe mind. Recently, however, many researched partially obliterated words or figures, originally presented faces in a have adopted the hypothesis that memory consists or a more highly schematized form, or tachisroscopic presentation of number of systems and subsystems with different operating sdtjimmueli-. Priming is said to have been demonstrated if the probability teristks. The problem ofwhat these systems and their propenoffbtharee,identification of the previously encountered targets is in and how they are related to one another, now occupies thfc center creased, or the latency of the identification response is reduced, in stage in research on memory. comparison with similar measures for nonstudied control items. The One broad, as yet tentative, organizational scheme diiitinguishes difference between performance on the target items and the nonstu procedural, semantic, and episodic memoty (J). Procedural memory died items provides a measure of the magnitude of the priming underlies changes in skillful performance and approbate respond effect ing to stimuli; semantic memory has to do with aaguisition and use Although priming and other kinds of implicit memoty have been of factual knowledge in the broadest sense; and episodic memory reported from rime to time, systematic attempts to explore it began enables people to remember personally experienced events. The about 10 years ago (J). One ofthe triggers for the study ofpriming domain ofprocedural memory is behavior, whereas that ofsemantic turned out to be experiments by Warrington and Wciskrantz (6) and episodic memory is cognition or thought. Cognitive memory showing that densely amnesic patients, who were severely impaired systems have the capability ofmodeling the external world--that is, in their ability to remember recently seen information, exhibited of noting representations of objects, events, and relations among near-normal learning when they were tested by methods that tapped them--whereas procedural memory docs not have this capability. what we now know is priming. A second stimulus for the study of Evidence is accumulating about yet another category of learning priming lay in research concerned with the nature of and access to lexical representations (S). A third source of influence was the E. Tuhring ! oorvmrty ppofe--or cr (he Univorhcy of Toronto, Toronto, Canada, M55 1AL 6. L Schactcf u a proftxor of Mythology at the Uruvcniry of Amooa, Tuoon, AZt 1S721. growing interest in the classification of memory into distinctive categories such as episodic and semantic memory (6) and procedural and declarative memory (7): 19 JANUARY 1990 ARTICLES 301