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r-':.ieed is a pi-'cio.cf<U service 5y Pfizer Laccratcr1-- Pfizer L_os PLAINTIFF'S EXHIBIT Viiluineij Iwue 1 PROBLEMS IN MEDICAL PRACTICE Nortin M. Hadler, MD,.Editor William B. Bjittn, MD,JI), (apcihior Fiber Toxicology and Occupational Health: The Integration of Research And Health Programs William B. Bunn. MD. JD, MPH Senior Director. Health. Safety and Environment; and Vic e President. Manvilte Sales Corporation Denver. Colorado Joel R. Bender, PhD, MD Vice President. Health. Safety and Environment Ovsens-Corntng Fiberpas Toledo. Ohio l he potential toxic consequences involved in the manufacture and use of manmade fibers (especially fiber glass and other man-made vitreous fibers) in voke the sense that we have been here before. But the manmade fibers are physicochemically unique: they differ from the mineral fibers and from each other. Unlike the problems associated with asbestos, in which the untoward properties became apparent only after the long and widespread use of the min eral. there is continuing and worldwide investigation of the epidemiology and toxicology of many of the manmade fi bers. The questions recently raised about the advisability of removing remainant asbestos from the environ ment has focused the attention of phy sicians and scientists on the potential for a new epidemic of occupational and environmental lung diseases caused by the newer fibers. Background There is growing contention about the nsk of exposure to asbestos and the rationale for asbestos removal. This was recently pointed out by an article in Sci ence (1990:247.294) by Brooke T. Mossman and her colleagues. They raised the question of whether there is a potential for a third wave of asbestosrelated disease among persons neither engaged in manufacturing asbestos nor among its end users. The article was hotly debated in the letters to the edi tor of that publication. The paper concerned the relative risks of removing chrysotile (the pre dominant form), crocidolne, and other forms of asbestos from buildings. The Editor's Comment It is premature to write an epilogue for the chronicle of asbestosis. There are chapters yet to be written and precepts begging formulation. But Lite lessons already at hand need to be indelibly taken to heart by every physi cian and by every member of society. It is clearly established that exposure to amphibole asbestos fibers imparts an important risk for fibrosing lung disease, and an important and specific risk for mesothelioma. Furthermore, there is little room for debate regarding the synergy for bronchogenic carcinoma when such an exposure coincides with cigarette smoking. To establish these tenets as "facts" required more than a genius for clinical investigation: it required zeal and perseverance on behalf of the worker at risk1 to convince the skeptic and overcome the inertia inherent in any attempt to shift moneys from profits to welfare. We have come that far. Asbestos exposure in the industrial setting is regulated: no more than two fibers m 10 mL of air is permissible. Furthermore, we have held perpetra tors of exposure accountable after the "fact" for events that occurred before the fxi --levels of accountability measured in tens of billions of dollars (Continued on page 2) 1 Editor's Comment (Connnueu jm page ti that drove such corporations as Johns Manvdle and Raybestos into bank ruptcy to deal with the process.1 Such is our collective guilt. But here the issue doesn't rest The same zeal drives extrapolations from these "facts": 1. What stochastic imperative defines the "permissable risk1 How does one balance cost with conscience? 2. Most asbestos mined is not amphibole but serpentine fibers: more particularly. 90% or more of the world's asbestos mining yields chrysocle, a serpentine fiber. These fibers have far less toxicity than amphibole fibers. In fact, it has been argued that the risk is negligible1 and that our national mandate to remove asbestos from public buildings is a waste of money and. possibly, a hazard* regardless of the fiber. These issues engender debates that are fueled by emotion1 wherein con viction supplants data. But conviction supplants data of necessity. Epidemi ology can cope with rate events but only if they cluster or if they are qualitatively unique. Otherwise, so much goes on in any complex system, such as a population of people, that all manner of influences perturb the likelihood of a rare event*'' The lingering debates about asbestos will rage unai ail spleens are vented, and data is not likely to come to the rescue. Knowing the asbestos saga, how can we be prescient regarding other and new fibers that are taking their places in our environment? Addressing that question was my charge to Dr. Bunn and his co-authors. Dr. Bunn, my co editor, and Dr. Bender are responsible for health and environment at two of the largest fiber manufacturers in the US. If any of us needs to learn lessons from the asbestos story, they do. We want to share their insights. Nortin M. Hadler, MD, FACP Professor of Medicine and Microbiology/Immunology University of North Carolina at Chapel Hill Chapel Hill, North Carolina References 1 Nicholson WJ. Perkel G. Selikoff IF: Occupational exposure to asbestos: popula tion at risk and projected mortality--1980-2030. Am J Ind Med 1982.3:239-311. 2. Morgan WKC: The adversary system: Cui bono? Ann Intern Med 1982.97:919921. 3. Mossman BT. Gee JBL: Asbestos-related diseases. N Engl J Med 1989:320:17211730. 4. Mossman BT. Bignon J. Com M, et al: Asbestos: scienufic development and implications for public policy. Science 1990,247:294--301. 3 The Association of Occupational and Environmental Clinics: Lener to the Editor (in response to Reference 3). N Engl J Med 1991;324:195-196. 6. Femstem AR: Scientific standards in epidemiologic studies of the menace of daily life. Science 1988;242:1237-1263. 7 Diamond GA. Forrester JS: Clinical trials and statistical verdicts: probable grounds for appeal. Ann Intern Med 1983;98:385-394. authors questioned current risk-assess ments on the grounds they were too conservative; the public faces a greater hazard in removal, they said, than in maintenance. Furthermore, the cost of removal programs, estimated at over SI00 billion, might be better spent on primary asbestosis-prevention programs. Finally, there was some concern raised regarding the potential toxicity of as bestos substitutes. The debate extended beyond Science and rapidly reached the public. It is un likely the issue will soon be resolved scientifically; but, we may assume, even without such resolution, asbestos will be removed and the ban on asbestosrelated products will continue, with or without modification. Medical (and legal) practitioners will have to adopt positions in this debate: asbestosis and other pneumoconioses are ' *Ticult to diagnose in the early stag and often occur in the setting of other insults, such as smoking. Epidemiologic methods are less pow erful in such a circumstance. Society and medicine both are wont 10 draw causal inferences from prominent indi vidual cases. The result is that anecdote and emouon drive political, regulatory, and judicial activity at least as effecnvely as does science. The recent quandary faced by physi cians over asbestos-related disease in troduces the need for the medical com munity to understand pulmonary toxic ity and fiber (or particulate) toxicology. These issues are not only controversial today, but. it must be re-emphasized, developing technology will have future impact. The pneumociiniii't > in historical perspcctise Asbestosis. the scarring of the lung, was known early ui the 20th Century and perhaps as early as the 1890s. Because of the need to insulate ships rapidly dur ing World Wars I and II. its incidence increased gready. Although the associa tion of asbestos exposure and lung can cer (lung tumors and mesothelioma) was once a matter of debate, the recogni tion of the association occurred during the 1950s and '60s. The most-recent research concerns the reduction of nonoccupationai exposures stemming from removal of asbestos-containing products from buildings. Perhaps the greatest lesson to be learned is that it is imperative mat we anticipate the health effects of exposure to fiber. We still do not fully under stand fiber toxicity, but the past hun dred years of scientific scrutiny and pub lic response must serve to guide con sideration of other naturally occurring or man-made fibers and particulates. The recognition of the relationship to cancer in the '50s and '60s spurred a reaction that included regulations by the Occupational Safety and Health Admin istration (OSHA) and. in the '70s. liti gation that has been going on since. In the '80s, concern for a low level of risk led to the removal of asbestos from pub lic schools and other buildings and to a ban on asbestos-containing products. These latter measures have led to the current scientific debate. Fibers are not the only fibrogemc pul monary toxins. For example, that crys talline silica causes lung scarring has been known since the time oi Hippocrates. Silicosis gained general at tention after the Gauley Bridge inci dent in 1937. resulting in acute Siltcoitv. 2 r;jetton in a group of miners ' "hat anen.ion led to social reform in .cupattonal health regulations and compen sation (primarily Worker's Compensa tion) for stlicoQc disease processes. Coal workers' pneumoconioses have been well recognized since the early 1300s. but it took a century to awaken the public conscience--and then only after the Farmington mine disaster of 1968. The high-water mark of mine safety in the US was reached with the enactment of the Black Lung Act of 1969. Other pulmonary diseases, such as bysstnosis and berylliosis, have been the subject of reguladon. litigation, and debate for many yean. issue is somewhat clouded by the tact that other fibers--including asbestos-- are present in these areas. In animals, enonite appears to be a more-potent mesoihehomogenic agent than is asbes tos. No consensus ha> been reached on acceptable levels of occupational expo sure to the fiber. >o no recommenda tions have been made, nor have defini tive regulatory reviews been conducted for erionite. wollastomte. or attapulgite. \\ ollaslonilc In such products as ceramics, insula tion. and wallboard. wollastomte-- a monocalcium silicate fiber--is used seful for assessing ns hazards. Overall. : data suggests that two risk-profiles exist, one for origin the other for liber length. The data on exposure is vari able. but dust levels for certain opera tions approach the standards for nui sance dust 115 mg/mJ total. 5 mg/m1 respirable). MAN-MADE VITREOLS FIBERS For more than 50 years, the man-made vitreous fibers (MMVFs) have been pro duced and used in a wide variety of applications. They are synthetic, mor- THE EPIDEMILOGY AND TOXICOLOGY OF FIBERS " Man-made fibers have similar irritant effects the extent of which Natural fibers Asbestos is a naturally occurring min eral fiber the toxicologic and epi demiologic effects of which have been depends on the diameter and flexibility of the fiber." well documented. Standards for work place exposure and work practices exist in most developed countries. However, as an asbestos replacement. It is a game, and amorphous; the family is there is a need to evaluate the risk posed durable fiber, but tt has less tensile sometimes referred to as "man-made by other naturally occurring fiben (eg. strength than asbestos. Toxicologic stud mineral fibers" (MMMFs). but, techni enonite). A body of information is ies of wollastonite are limited; the only cally, MMVF is more correct. These emerging on these fiben, but specific inhalation study in animals failed to pro fibers are all created from molten regulations exist in only a few countries. duce a significant tumor-response. masses of raw material under highly F.riunite Injection and in vitro studies suggest controlled conditions. Fiber glass is one that wollastonite is less toxic than MMVF. which also includes rock/slag Zeolite is a naturally occurring, crystal asbestos. Epidemiologic studies of the (mineral) wool and refractory ceramic line. hydrated aluminosilicate; erionite neoplastic potential of wollastonite have fiber (RCF). is a crystalline, fibrous form. It is found not been conducted, and studies of its Much more is known of the epide naturally in the western United States. fibrotic potential are limited. miology of vitreous fibers th2it is known Turkey, South Afnca. and elsewhere. Overall, the health studies of wollas of other man-made fibers or non Enonite has very limited commercial tonite are sparse. Exposure levels vary asbestos natural fibers. In addition, application, but exposure occurs widely with the application and the in chronic inhalation and other toxicologic because it is a contaminant in the min dustry; fiber levels of up to 40 to 50 testing has been performed. Specific ing and manufacture of other zeolites fibers/cc (f/cc) have sometimes been standards do not exist in the United (which do have commercial value, as reported. States (except as nuisance dust), but molecular sieves and in ion-exchange processes). Enonite can produce tumors, particu Attapulgite broader standards are currently under consideration and multiple international A fibrous aluminum silicate and mag .bodies have already reviewed the sci larly mesothelioma, in mice and rats that nesium silicate, attapulgite is used as a entific literature on man-made vitreous inhale it. Villages near Turkish erionite thickening agent and an absorbent, as fibers. deposits have been found to have high incidences of mesotheliomas, but the in pet liner. It is mined primarily in ;he United States. The fibers are short and relatively thin, although the size varies Fiber Silas' Two basic forms of fiber glass are in with the geographic region of the general use; wool-type fibers and tex `Ai Gauley Bndge. West Virginia, workers were exposed lo high levels of crystalline silica when tunnelling through a mountain with a high quartz content. The minimum exposure necessary to produce silicosis was then thought to oe two yean, but a num ber of workers with less than two yean' exposure developed an acute pulmonary process and many died. The event led to the recognition of acuie silicosis and trig gered a deeper scrutiny of ihe chronic ef deposit. The effeci of attapulgite in ani mals has varied significantly from study to study. These differences appear to be related to '.he origin of the fiber. Inhalation studies in animals suggest that the longer the fiber the greater the toxietty. This result is consistent with injection and in vitro studies, although there is considerable variability. The epidemiologic data on anapulgite tile fibers. Fiber glass was originally developed in the early 1930s for use in home panel filters and home insulation; textile fibers appeared commercially in the late 1930s. followed by fine-diameter glass fibers in the early 1940s. Wool fiber-glass is generally used in thermal and acoustical insulation. These products include air-duct msulJtion. pipe insulation. veiuilation-sy\iem air- fects of crystalline silica. I is very limned and does not yield data filters, roof insulation, and insulation lor 3 hums?, automobiles, aircraft, cooling trations of airborne glass fiber may, like s essmg agents." They concluded p'unces. ami refrigerators. exposure to dust, produce a nonspecific, th-i "fiber exposure, either alone or in Glass fibers are also manufactured with transitory, lung condition usually mani combination wnh other exposures, mjv diameters of less than one p. This fine- fested by coughing or wheezing. The have contributed to the elevated risk diameter material is produced in the effects subside soon liter the worker is More-recent studies have shown sev United Slates in limited quantities that eral potential confounders in the min- constitute less than I ^ of the total fiber j erai wool industry." The authors also glass producnon. Special-purpose, tine fi ber is limited to use in specialty filter pa "Esposurc to reported that "no excess of the same magnitude was evident for glass-wool pers. battery components, and sophisti cated aerospace insulations. fiber glass production." Also, "there was no evi dence of an increased risk for pleural Textile fiber-glass finds wide application as a component of curtains, industrial fab does not tumors or nonmalignant respiratory dis eases." rics. electrical yams, roofing shingles, and reinforcement for plastics, papers, rubber, sensitize the Inng The University of Pittsburgh compre hensive mortality study of over 16.000 and other materials. It is generally not of respirable size. nor produce workers, many with long-term exposure (up to 40 years), was undertaken at 17 Health effects of fiber glass allergic rcut lion." fiber-glass-and mineral-wool-manufac turing plants (14.800 fiber-glass work Skin irritation. Fiber glass may irritate the ers in II plants). The original report, skin of some workers in glass-fiber published in 1982. covered mortality manufacturing facilities and of some work from the 1940s to the end of 1977. The ers who fabricate or install fiber-glass-con- removed from exposure, and there same group of workers was followed taining materials. The skin irritation and should be no further effect on the through 1982 (reported in October. possible inflammation is a mechanical re worker's health and well-being. Expo 1986. with additional analyses in June. action to sharp broken ends of fiber that sure to fiber glass does not sensitize the 1987). The 1987 report contained, for rub or become embedded in the outer lung nor produce allergic reaction. the first time, local area mortality sta layer of the skin. Skin reactions vary di tistics for each of the plants. The study rectly with the size and the stiffness of the fiber those with diameters greater than 4 F.pidemiiilopic studies was further updated through 1985. with publication in 1990. Through 1982, to 5 p are more likely to cause irritation Respiratory system diseases are the pri malignant respiratory disease had than are fmer-diameter fibers. When the mary subjects of most epidemiologic caused no statistically significant excess diameter is less than 1.0 p, the fibers usu smdies involving fiber glass and other of deaths in any of the 11 fiber-glass ally do not cause skin irritation. Normally, MMVFs. Tens of thousands of workers plants, nor in any grouping that distin the irritation does not persist for long, and have been employed in manufacturing guished those plants on the basis of it can usually be relieved by using mild fiber glass since its initial development glass-wool or textile production (textile soap and warm water to gently wash the over 50 years ago. and two major stud fibers are referred to as "glass filament" exposed areas. Most workers find that any ies have addressed the mortality of in the manuscript and by IARC). irritation experienced when first working workers engaged in thai production. The update through 1985. however, v ith fiber glass lessens over time. Allergic Researchers at the Universiry of Pitts did show a statistically significant excess contact dermatitis has not been associated burgh studied the mortality of almost of deaths from respiratory cancer among with exposure to fiber glass, but there have 15.000 workers from II fiber-glass- workers employed m glass-wool and been reports of allergic reactions to the manufacturing facilities. This study has mineral-wool plants. To see if the data uncured-resin finishes that are used in been expanded to include over 30.000 were consistent with a cause-effect some fiber-glass products. workers from 14 such facilities. The first relationship specific for exposure to Some persons may be more affected by results from the enlarged study will be glass fibers, the researchers investigated irritation from fiber glass than are others, available in 1992. In Europe, research possible associations of excess cancer and a few may be forced to seek other ers at the International Agency for deaths with length of employment, dose t>pes of employment. The vast majority Research on Cancer (IARC) have con resppnse. time from initial employment, of workers, however, can control skin irri ducted a five-country study of mortality and the manufacture of still-finer glass- tation by using appropriate work practices. among almost 12,000 workers at six fibers (microfibers). There were no sta Man-made fibers have similar irritant ef plants manufacturing fiber glass. An tistically significant findings in support fects the extent of which depends on the update of this study is under way. of a relationship between respiratory diameter and flexibility of the fiber. In 1984. Saracci el al published their disease and exposure to glass fibers. study of the mortality of 23.609 work A recent case-control study was un Upper respiratory irritation. Some work ers (including 11.852 workers produc dertaken in which those workers were ers may experience a temporary upper res ing fiber glass) in 13 European facto studied who had manufactured fiber piratory irritation manifested as a scratchi ries producing MMVFs. There were glass and who had participated in the ness or burning of the nose or throat. This 2.836 deaths. That study was updated University of Pittsburgh study. The in is especially likely if. during the manufac by Simonato et al in 1986. The authors terview portion of the later study ture or handling of glass-containing prod reported that, compared to regional showed that smoking is the most-im ucts. more than 3 to 5 f/cc are released rates, glass workers suffered no excess portant nonworkplace factor in lung and if they are of large diameter (more (han 5 to 6 p). Like skin imianon. upper respiratory irritation is a mechanical reac tion to sharp, broken fibers. mortality from lung cancer. However, they did report an "excess of lung can cer among rock wool/slag-wool workers employed during a.i early technological cancer among the fiber-glass-manufacruring employees. Smoking at the New ark. Ohio, plant in 1955 was significantly greater than in the rest of the US. sug Accidental exposures to high concen phase before the introduction of dusi- gesting that cigarettes could accoum lor 4 >ome oi die excess uu'ig cancer previ ously reported in the University 'httsburgh study. Other than the statistically significant standardized mortality rate, no note worthy mortality findings--such as from nonmalignant respiratory disease or mesotheliomas--were associated with exposure io fiber glass. Morbidity among fiber-glass workers has also been studied. None of the mayor studies reported a consistent pat tern of respiratory disease: nor was any impairment found of the respiratory function of manufacturing workers, even among those with extensive exposure. In the most-comprehensive study. Weill reported on the respiratory health of 1.089 workers at five fiber-glass and rwo mineral-wool plants in the United States during 1979 and 1980. The researchers noted that the sub jects were generally healthy. However, small opacities did show on the chest x-rays of some workers. In summariz ing their findings, the authors noted that, in general, "the minimal evidence of respiratory effects detected in the in vestigation. which cannot, at present, be considered clinically significant, is en couraging concerning the question of potential health effects of exposure to man-made vitreous fiber." A follow-up study with controls, reported by Weill in 1985 and 1990. found no adverse pul monary effects associated with work in the MMVF industry. F.\|)ct imcntiil MiJtlic> Researchers have studied the effects of surgically implanting fibrous material in the pleural and abdominal cavities of animals and of injecting fibers directly into the trachea. In 1977. it was found in such work that tissue changes, including cancer and scarring, were produced by specialty glass-fibers with diameters of less than l .0 p. Other fiber-glass compo sitions. including those used in building insulation, did not produce such results. These experiments are valuable in the study of the mechanisms of tissue reac tions. but. because they are based on the introduction of large amounts of fiber by routes that bypass normal body-defensemechanisms, they do not justify the con clusion that inhalation of glass fiber is hazardous to workers. As a consequence, several inhalation studies in animals were initiated at independent research cen ters. Commercially available fiber-glass products and, more recentty, specially prepared fibers with carefully specified lengths and diameters were used. None of these studies demonstrated tumor in duction or fibrosis by fibrous glass. Ktsk evaluation International and US agencies have con ducted a number of reviews of the health aspects of glass fibers. These agencies included the National Institute for Occupational Safety and Health (1977). the World Health Organization (1984), and the National Academy of Sciences (1984). Recently, (here have been two additional major reports pre pared on the health effects of glass fibers. In 1986. the International Agency for Research on Cancer (IARC) reviewed man-made mineral-fibers. After review ing the epidemiologic data on over 400 deaths from lung cancer among the 27.000 fiber-glass workers in the Euro pean study (by Simonato et al) and the US study (by Enterline and Marsh), the 1987 IARC working group of the World Health Organization stated that the evi dence was inadequate to conclude that either glass wool or glass filaments were carcinogenic to humans. No evidence of fibrosis or other morbidity was found by the IARC panel. Despite seven negative inhalation studies in animals, implantation of microfibers of two special-purpose glasses induced cancer. This is the basis for the determination by the IARC that glass wool is "2B"--a possible human carcinogen. Continuous-filament fiber glass was designated "Group 3"--it is "not classifiable as to human carcino genicity." In 1987. a second major, international evaluation of the safety of glass fibers by the World Health Organization (WHO), led to the report of the Inter national Programme on Chemical Safety (IPCS): "The overall picture indicates that the possible risk of cancers among the general public is very low. if there is any at all. and should not be a cause for concern if the current low level of exposure continues." The IPCS does allow the weighting of evidence, and the inhalation studies in animals were given greater weight in their analysis. In 1988. the US Environmental Pro tection Agency announced its agree ment with the IPCS conclusion when it stated that the evidence for the carci nogenicity of fiber glass "is considered inadequate." Mineral wool The fibers known as "mineral wool" are produced by spinning or blowing mol ten basalt or the slag obtained from refining ores. These latter consis: of meraJ silicates--silicates of aluminum, boron, calcium, iron, sodium--and vari ous metal oxides. Depending on the source. ;ne average iioer Oiameier ranges from 3 to 15 q. Major application In the early 1900s. mineral wool was developed as insulation. The fiber is generally supplied in three basic forms: loose wool, wool bonded into a ban or blanket, and acoustical tile and panels. Today, mineral wool is widely used io control temperature and sound. Its major applications are in commercial insulation, acoustical control products, pipe insulation, and insulation for auto mobiles, ships, mobile homes, refrigera tors. domestic cooling appliances, and a wide variety of other appliances and equipment. Health effects The skin, eye, and upper respiratory ir ritations of mineral wool are similar to those of fiber glass. Animal studies Several inhalation studies with animals have been done ?t independent research centers. Commercially avail able mineral-wool was used. In rwo of these studies, the animals were exposed to high concentrations of fiber for one year or more and then allowed to live out the rest of their lives. Compared to the controls, none of the test animals demonstrated fibrogenesis. carcino genesis. or permanent changes of the respiratory system; nor did the expo sure reduce life expectancy to a signifi cant degree. Other studies of implanted, injected, or instilled mineral wool have shown that virtually all fibrous materials can. at very high dosages and regardless of physical or chemical makeup, have adverse effects. However, evidence from other experiments indicates that mineral wool is attacked by the fluids normally present in the lung. This may cause fragmentation into shorter fibers that may be biologically less active or may even lead to the total disappeajance of very fine fibers Kpideminluck studio* thousands of workers have been em ployed in plants that manufactured min eral wool during the 50 years since us development. A number of epi demiologic studies of workers have been done, but the rwo major mortality stud ies were those discussed above in ihe fiber-glass section. The excess lung can cer found in slag- and rock-wool work ers was the most-disturbing finding, but that excess might be relaied to early production phases and to con'iKindmg 5 exposures 10 such carcinogens as lead, nd no effects were found in tne iung- TIMA TiermaJ Insuiauon Mar.uiactur- asbestos, or arsenic. In addition, ihc .uncnon tests of nonsmokers Among . mg A iianoni Groups of rats were jiudies were difficult 10 control for other current and former cigarette smokers, I exposed for six hours per day. five Ja>s a factors--smoking, for example--that the results of lung function ie\is were week, to J0mg/m: of four different types could have contributed to the excess. consistent with minimal obsimcnon of RCF' kaolin, zircomx high punry. or associated with cigarene smoking and "after service" lie. a kaolin-based, ce- Udr.Ktnrs ceramic liber also, but to a lesser exieni. wuh expo i ramie liber, containing 27'T crystalline There are ihree broad categories of sure to ceramic fiber. Some symptoms - silica that had previously been exposed io refractory ceramic fiber iRCF): kaolin- of dry cough and breathlessness were high temperatures). Approximately 200 based fibers, in which the clay is also found. to 250 f/cc were greater than 5 |i in length. obtained by mining; blends of alumina, Small opacities were present on I}% Hamsters were exposed only to kaolin silica, and a refractory metal oxide leg, of 594 chest x-rays. Primarily, these RCFs. In both the rat and the hamster rirconiaj: and high-punty products that were related to age and to smoking hab studies, positive controls inhaled 10 mg/ are a blend of aJumina and silica pro its and there was some evidence of an mJ of chrysotile asbestos and negative cessed to limit the levels of impurities association with time spent in the controls received filtered air. that are found in other RCF products. industry (but not with cumulative A total of 35^ ofthe hamsters exposed The fibers are produced by spinning exposure to RCF). It is not clear what to the kaolin RCF-fibers developed molten mixtures. The average diameter the long-term biological significance mesotheliomas. A nonmalignant me- of the fibers produced in this manner may be of the small effects apparently sothelial proliferation was found in the is in the range of 1.2 to 3.5 p. Fiber related to ceramic fibers, and the study pleura of one of the asbestos-exposed length can be varied from long fibers is likely to be continued. hamsters; negative-control hamsters had down to p-sized. Results from the US study will soon no lung lesions. Cytologic examination of the lungs of the kaolin-exposed hamsters revealed pulmonary fibrosis in the termi "Recent studies on animals nal airways and pleura. In the RCF-exposed rats, pathological may affect studies revealed lung turnon (some be nign), pulmonary tumors, and the risk evaluation for RCFs." mesotheliomas. In asbestos-exposed rats, benign and malignant lung tumors were reported; the final results are not yet available. Cytologic examination of the Major application rats sacrificed at one year showed that be available. Preliminary reports indi exposure to kaolin RCF. zirconia RCF. Applications vary, but ail are used in cate a decrease in pulmonary function high purity RCF. "after service" RCF. high-temperature, specialty environ that is not clinically significant and a and asbestos all resulted tn pulmonary ments. Blankets are used primarily as possible increase in pleural plaques fibrosis. After the first year, the fibrosis furnace and kiln-wall liners; loose fiber among RCF-exposed workers. The progressed more slowly. is used as a filler in packing voids and latter findings may have been con expansion joints; custom-molded shapes founded by exposure to asbestos. Risk euiluation are widely used in metal molding and as furnace combustion-chamber liners. Inhalation sludic' In 1987, IARC designated RCF as Group 2B, "possibly carcinogenic to hu There have been four known investiga mans," on the basis of animal studies. Health (.fleets tions of the effects that high concentra IPCS evaluated RCF with other Skin irritation and upper respiratory tions of airborne RCF have on animals. | MMVFs. Crystalline silica in the form irritation are largely the same as those In one. 48 rats were exposed to RCF by I of cristobalite has been classified by found with fiber glacs. inhalation for seven hours a day. five days I IARC as 2A. "probably carcinogenic io Uicr-sct \ ice effects RCF that has been in service at elevated a week, for 32 weeks. Fibers longer than 5 (jihad airborne levels of95 f/cc. Animals sacrificed at the end of the study had humans." MMN F rt"ukiti:iti' temperatures (greater than 1.800F) interstitial fibrosis in an average of 57c of Although no US regulatory guidelines will undergo partial conversion to cristo- the lung area; eight rats had pulmonary exist for any fibers, save asbestos, there balite. a form of crystalline silica that tumors, of which three were carcinomas: are multiple recommendations. NIOSH can cause silicosis. there was also one peritoneal (the National Institute for Occupabonal mesothelioma. Safety and Health) recommended a f.pkiemiolopic studies In contrast, inhalation work at Los 3 f/cc or 5 mg/m' guideline m 1977. There are no published reports dealing Alamos showed no cancer and little pul Fiber glass and mineral wool manufac with the health experience of people monary fibrosis in rats: 50 hamsters turers recommend a standard of 1 f/cc. who work with RCFs. Two investiga showed one mesothelioma but no fibrosis. based on irritation. The Safety and Health tions. one in Europe and the other in The exposures were conducted at 200 Committee of the Building and Trades the United States, are studying the f/cc. six hours a day. five days a week, for Department of the AFL-CIO also rec health of workers engaged in the manu 24 months. One of 157 control animals ommends a standard of I f/cc. An facture of RCFs. In October. 1989. a unexposed to fiber developed a sponta OSHA proposal is expected for fiber preliminary report from the European neous tumor. glass, mineral wool, and refractory ce study of over 650 RCF-plant workers In June. 1988. to help clarify some of ramic fibers over the next year Recent was made available. It noted that no the uncertainties, a two-year inhalation studies on animals may affect the nA evidence was found of pneumoconiosis study in rats and hamsters was begun by evaluation for RCFs. 6 Control of levels of respirable particles Polyolefin fibers the perspective and scientific overview or fibers is accomplished by a c >tna- The family ot polyolefin fibers consist hat will allow physicians to make oon of engineering changes, wot. prac of polypropylene, polyethylene, and ..iformed judgments about the risks cur tices. and protective equipment. In addi- polycarbonate fibers. The major uses are rently associated with man-made and uon. regular medical surveillance of ex in home furnishings such as rugs, mineral fibers. a posed populations is recommended. upholstery, curtains, and bedding. These fibers are generally not respirable even Special thanks to Thomas W i SYNTHETIC though fine fibers are used for light Hesterberg. PhD. Senior Toxicolo FIBERS weight, insulating clothing and for air filtration. gist. and Gerald R Chase. PhD Chief BiostansnaaniEpidemiologist, Aramid fibers There has been one subchronic inha of the Manviile Technical Center. Aromatic polyamides constitute the lation study with sized polypropylene Denver. Colorado They also contnb- i aramid fibers, which are durable and fibers; it showed biologic activity at 90 uted to this arrtcl- have high tensile strength. These fibers days, but no fibrosis. Variable, low lev generally fall outside the respirable range, but certain of them have fibrils that may break off and become respi rable. (t is not clear that fabrication gen erates either a fibrous or paniculate respirable component. Only a single experimental study of els of toxicity were found with injection and in vitro studies. No epidemiologic studies or data on workers exposed to polyolefin fibers have been published. SIMMARY This review of the scientific data shows Suggested Reading International Agency for Research on Can cer (lARCl. IARC Monographs on the Evaluation of Carcinogenic Risks to Hu mans. Man-Made Mineral Fibres and Ra don. Lyon, France. Vol 43. 1988. chrome exposure to aramid fibers has that, in terms of physiologic effects, International Programme on Chemical been conducted. Thin aramid fibers ar there are major differences from one Safety (IPCSl. Man-Made Mineral Fibres. a concentration of 100 f/cc produced man-made or natural fiber to the next. Environmental Health Criteria 77. World fibrosis and rai-speciiic rumors. Short term inhalation studies suggest that respirable organic fibers do generate a dssue response in animals; intraperitoneal injection studies have shown a slight increase in the incidence of tumors and of fibrosis. Exposures mea sured at manufacturing locations indi cate fiber levels ranging from undetect able to less than 1.0 f/cc. Carbon fibers The term "carbon fibers" refers to both Most of the data is reassuring, but we do need to reduce levels of exposure and to detect disease at an early stage. Personal risks and workplace protec tion-programs may become the subject of judicial or regulatory scrutiny. In that context, it is worth noting that, histori cally, the recognition of occupational pulmonary disease has come only after the fact, from the study of mortality pat terns. This retrospective approach is no longer morally or sociopolitically accept able. This paper, we hope, will supply Health Organization. Geneva. Switzerland. 1988. Bunn W, Hesterberg T, Chase G. et al: Man-made mineral fibers. In Medical Toxi cology of Hazardous Materials. Sullivan J. Kriegel G (ed). Williams and WUJcins. Bal timore (in press). US Environmental Protection Agency (USEPA). Health Hazard Assessment of Nonasbestos Fibers. Health and Environ mental Review Division. Office of Toxic Substances. Washington. DC. 1988. carbon and graphite fibers. They are synthetic fibers prepared by the high- MEDILEGAL BULLETINtemperature processing of poly- acrylonme, pitch, or rayon. They are characterized by light weight, high ten sile strength, and flexibility. The aver age diameter of the fiber is 5 to 8 p. but up to 25% of the fibers are respi rable by humans. Regulation of the Manufacture and Use There have been two short-term Of Potentially Hazardousmhaiadon studies, one subchronic and one chronic, of carbon-based fibers. SubstancesUnfortunately the studies were con ducted with materials that had large pro portions of paniculate matter or fibers that were not respirable by rats. William B. Bunn, NtD, JD, MPH Lnjecdon studies have not shown a Senior Director, Health. Safety and Environment; and significant increase in tumors, but in Vice President. Manviile Sales Corporation vitro tests have shown both genotoxic Denver, Colorado and cytotoxic effects. Dermal studies have not shown statistically significant increases in tumors. There have been only limited stud In the United States, the evaluation and regulation of the health effects of standards for full evaluation and regu latory review; appropriate testing is ies of exposed populations, and epi demiologic data is not available for risk assessment. What data there is on re spirable carbon-fibers in the occupa tional setting indicates only minimal exposure. commercial products is both intensive and comprehensive; internationally, scrutiny is increasing. Before a new commercial product is introduced, it undergoes several levels of review. For pharmaceuticals, pesticides, and consumer products, there are specific mandated before a new product can be approved. For chemicals, petroleum products, and other new commercial introductions, regulatory review is required by the Toxic Substances Con trol Act (TSCA). Regulatory authorities may also require special studies ot po- 7 I lervil exposure. This evaluation of r sible exposure and toxicity is intei 10 provide on assessment of risk and 10 lead 10 recommended practices that u.ill minimize that nsk to workers, downline manufacturers and distributors, and users. Specific labels may be required by the agencies involved. The review extends to current prod ucts going into new uses or to new mar kets. For example, significant new use regulation (SNUR) requires review of significant new uses of a product: spe cial review is required of materials manufactured in foreign countries when the products first enter commerce in the United States. Because of the natural origin of the raw materials, most fibers have gener ally been thought to be excluded from TSCA-mandated review. However, a joint committee of industry and gov ernment has been formed to review test methods for the evaluation of the health effects of fibers and to consider guide lines for testing fibers entering com merce. This group is being coordinated through the Chemical Industry Insti tute of Toxicology. Once a product enters ihe market place. multiple health and safety regu lations. from multiple regulatory agen cies. apply. Which regulatory agency is primary is usually determined by the circumstances of exposure, although there is substantial overlap and integra tion of regulatory functions: workers ex posed to a potentially toxic substance are an Occupational Safety and Health Administration (OSHA) responsibility; the Environmental Protection Agency <EPA) regulates exposure of ihe gen eral public. The role of OSHA OSHA directives include communica tion. general training, and specified methods of compliance. A permanent function of OSHA is to assure adequate communication of the potential hazards from ihe manufacturer of the product to the worker. The Hazard Communi cation Standard mandates a written pro gram. including the labelling of prod ucts and work areas, the preparation of ! material safety data sheets, and training relauve to specific hazards Specific sub- I stances are regulated by imposing exI posure limns for engineering controls and respiratory protection: work prac tice requirements: medical monuonng and surveillance standards: unj other : substance-specific conditions. The role of EPA The scope of EPA's functions is exten sive and growing. In addition 10 iniual review by the Office of Toxic Substances (OTS) under the authority conferred by the TSCA, a comprehensive program has evolved dedicated to reducing the risks associated with various particular media. For example, standards have been derived for dean water, clean air. the treatment and disposal of solid and liquid hazardous waste (under the au thority of RCRA [the Resource Con servation and Recovery a ;t| and. sub sequently. remediation under CERCLA [the Comprehensive Environmental Re sponse. Compensation, and Liability Act[). Therefore, each emission from a manufacturer or user of a product is regulated. The liability is retrospective, joint, and several lie. any and all parties are liable). EPA is also required to communi cate with communities that may be af fected by storage and use of potentially hazardous substances through Title III of the Superfund Amendments and Reauthorization Act (SARA). The EPA also controls the quantities of chemi cals that may be emitted, generates repons to encourage the reduction of waste, and develops Indoor Air Quality (1AQ) programs to protect the public from untoward exposures. The inten tion is to provide comprehensive, cradlelo-grave regulation of potentially haz ardous substances. Other venues In addition to federal law. state and local laws regulate occupational and environ mental exposures. States have laws requinng special labelling and impos ing resnrictions on release of substances. California, for examaple. has its Propo sition 65 and "Toxic Hot Spots" regula- t'^"s. Other states have implemented i own regulations, but most state and local regulations follow federal guidelines; even when they do. how ever. the implementation time or expo sure limitations may be substantially dif ferent. The US government mandates diligent, ongoing review of federal, stale, and local statutes. International regulations pose unique problems for exporters and multina tional corporations. The European Community has implemented regula tions similar to the comprehensive regu latory structure in the US. Elsewhere in the world, health standards are rap idly expanding and evolving. In addition to this regulatory frame work. a second area of legal control is exercised through the ton system. Over ihe years, case law has evolved a senes of precedents that impose significant liabilities on corporations (and individu als) that do not adequately test prod ucts. assess risk, communicate possible risks, and recommend work practices to assure the safety of persons exposed to the product. There is increasing rec ognition of a duty not only to inform but to perform a product-stewardship role. Strict standards of liability for poten tially hazardous products, and punitive damages for failure to institute effec tive programs, make this area of law-- and medicine--particularly challenging. The multitude of regulatory standards, the development of common-law expec tations. and the increase in worker and consumer awareness will make the 1990s a period of tremendous challenge for health professionals working with manufacturers, workers, and consum ers. The combination of expanding sociopolitical concerns and new tech nologies and materials means the prob lems wilt increase, not lessen. Health professionals, then, must engage in nsk evaluation and communication. This process begins with the recognition of the complexity and comprehensive nature of the regulations and includes a sensitivity (and an action-oriemed approach) to both worker and consumer protection. MPI Medical Publications, Inc. 3422 Old Capitol Trail Wilmington. DE 19808 Occupational Problems in Medical Practice"* is produced by MPI under a special pant. 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