Critical Reviews in Toxicology

Our medical research library holds 51 studies published in Critical Reviews in Toxicology (1982–2025). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 43 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Informa Healthcare
• Published: 1980 to the present, England
• Language: English
• ISSN: 1040-8444 (print), 1547-6898 (electronic)
• Continues: CRC Critical Reviews in Toxicology
• Its record in the NLM Catalog

2020s

• A risk assessment of mechanics who changed chrysotile asbestos containing brakes and other vehicle components in the 1950s-early 2000s era: an update on the 2004 evaluation. D.W. Brew, M.E. Stevens, A.M. Langer, et al. 2025;55(10):932-981. Review PubMed · Publisher

  Abstract

  For the past 50 years, there has been an ongoing interest in understanding the potential health hazards, if any, to vehicle mechanics who worked with asbestos-containing brakes in the 1950s-early 2000s era. Two reviews have been published on this topic, one by Langer (2003) ("Reduction of the biological potential of chrysotile asbestos arising from conditions of service on brake pads") and another by Paustenbach, et al. (2004) ("Environmental and occupational health hazards associated with the presence of asbestos in brake linings and pads (1900 to present): a 'state-of-the-art' review"). This analysis is an update on those papers since a considerable amount of research has been published over the past 20 years on this topic. The following important aspects are addressed in this review: new information on the toxicology of chrysotile, toxicology studies of brake dust associated with grinding, additional epidemiology studies and meta-analyses published on auto mechanics of the era, previously unfound data on how brakes (during the era when chrysotile was used) were manufactured, and new work describing the transformation of chrysotile to various degradation products during vehicle braking. This update also addresses questions about the health hazards associated with asbestos in vehicle clutches, transmissions, and gaskets. The exposure data indicate that the airborne concentrations of chrysotile fibers associated with vehicle mechanic work when asbestos was in auto brakes were, on average, less than 0.04 f/cm3 (8-h TWA) and the average lifetime cumulative dose was in the vicinity of 0.5-3 f/cm3-year for mechanics of that era. Although many of these fibers may have no toxicity due to thermal degradation and the conversion to degradation products, 31 epidemiology studies have evaluated the risks of mesothelioma for vehicle mechanics of this era and all but one indicate that there was no increased incidence of this disease in these workers. The weight of evidence continues to indicate that the asbestos-related health risks to vehicle mechanics from asbestos-containing components were de minimis. The risks associated with take-home and bystander exposure of a mechanic were also addressed and they were found to pose a de minimis or zero health risk to those potentially exposed. Based on our evaluation, there is no indication that asbestos from asbestiform tremolite was present at detectable concentrations in bulk samples of brakes or in the air during brake work. The recent U.S. Environmental Protection Agency (EPA) risk assessment of 2024 on chrysotile and their views of the hazards of asbestos-containing brakes were discussed. Their analyses did not alter our views that exposures to mechanics posed no increased risk of asbestos related disease. The latest knowledge about the role of genetic susceptibility on the development of mesothelioma is also addressed.

• Review of epidemiological and toxicological studies on health effects from ingestion of asbestos in drinking water. J. Go, N. Farhat, K. Leingartner, et al. 2024;54(10):856-894. Systematic review PubMed · Publisher

  Abstract

  Asbestos is a group of naturally occurring fibrous minerals that were commonly used in the construction of cement pipes for drinking water distribution systems. These pipes deteriorate and can release asbestos fibers into drinking water, raising concerns about potential risk to human health. The objective of this work was to synthesize human, animal, and in vitro evidence on potential health risks due to ingested asbestos in drinking water and evaluate the weight of evidence (WoE) of human health risk. A systematic review of epidemiological evidence was conducted, along with critical review of animal and in vitro evidence, followed by WoE evaluation that integrated human, animal, and in vitro evidence. The systematic review included 17 human studies with health outcomes mostly related to various cancer sites, with the majority focusing on the gastrointestinal system. The WoE evaluation resulted in very low levels of confidence or insufficient evidence of a health effect for cancers in 15 organ systems and for three non-cancer endpoints. While eight studies reported possible associations with stomach cancer in males, few high-quality studies were available to verify a causal relationship. Based on high-quality animal studies, an increased risk for cancer or non-cancer endpoints was not supported, aligning with findings from human studies. Overall, the currently available body of evidence is insufficient to establish a clear link between asbestos contamination in drinking water and adverse health effects. Due to the lack of both high-quality epidemiological studies and a validated kinetic model for ingested asbestos, additional research on this association is warranted.

• An updated evaluation of reported no-observed adverse effect levels for chrysotile, amosite, and crocidolite asbestos for lung cancer and mesothelioma. E.M. Beckett, A. Abelmann, B. Roberts, et al. 2023;53(10):611-657. Review PubMed · Publisher

  Abstract

  This analysis updates two previous analyses that evaluated the exposure-response relationships for lung cancer and mesothelioma in chrysotile-exposed cohorts. We reviewed recently published studies, as well as updated information from previous studies. Based on the 16 studies considered for chrysotile (<10% amphibole), we identified the "no-observed adverse effect level" (NOAEL) for lung cancer and/or mesothelioma; it should be noted that smoking or previous or concurrent occupational exposure to amphiboles (if it existed) was not controlled for. NOAEL values ranged from 2.3-<11.5 f/cc-years to 1600-3200 f/cc-years for lung cancer and from 100-<400 f/cc-years to 800-1599 f/cc-years for mesothelioma. The range of best-estimate NOAELs was estimated to be 97-175 f/cc-years for lung cancer and 250-379 f/cc-years for mesothelioma. None of the six cohorts of cement or friction product manufacturing workers exhibited an increased risk at any exposure level, while all but one of the six studies of textile workers reported an increased risk at one or more exposure levels. This is likely because friction and cement workers were exposed to much shorter chrysotile fibers. Only eight cases of peritoneal mesothelioma were reported in all studies on predominantly chrysotile-exposed cohorts combined. This analysis also proposed best-estimate amosite and crocidolite NOAELs for mesothelioma derived by the application of relative potency estimates to the best-estimate chrysotile NOAELs for mesothelioma and validated by epidemiology studies with exposure-response information. The best-estimate amosite and crocidolite NOAELs for mesothelioma were 2-5 f/cc-years and 0.6-1 f/cc-years, respectively. The rate of peritoneal mesothelioma in amosite- and crocidolite-exposed cohorts was between approximately 70- to 100-fold and several-hundred-fold higher than in chrysotile-exposed cohorts, respectively. These findings will help characterize potential worker and consumer health risks associated with historical and current chrysotile, amosite, and crocidolite exposures.

• Projection of future numbers of mesothelioma cases in the US and the increasing prevalence of background cases: an update based on SEER data for 1975 through 2018. B. Price. 2022;52(4):317-324. Review PubMed · Publisher

  Abstract

  Historically, mesothelioma, which is almost exclusively a cancer of the pleura or peritoneum, has been referred to as a sentinel disease for asbestos exposure meaning that the disease is an epidemiologic marker for asbestos. This description of mesothelioma often has been misinterpreted to mean that the only risk factor for mesothelioma is asbestos. In addition to a few risk factors other than asbestos, in the US, background mesotheliomas, i.e. mesothelioma cases that are a consequence of spontaneous tumor formation, are the most prevalent number of cases after asbestos-associated cases.1 My analysis of SEER data for 1973 through 2005 published in 2009 projected that around 2040 virtually all mesothelioma cases in the US will be background cases. The update here, which is based on the most current SEER data, 1975 through 2018, and the same methods used in 2009 shows that the pattern of mesothelioma incidence is unchanged. Further, in general agreement with the analysis published in 2009, after 2040 virtually all mesothelioma cases, currently estimated to be approximately 1600 per year, will be background cases.

• The health effects of short fiber chrysotile and amphibole asbestos. D.M. Bernstein. 2022;52(2):89-112. Review PubMed · Publisher

  Abstract

  The potential toxic effects of short chrysotile and amphibole asbestos fibers with lengths <5 to ∼10 µm have been debated over the years. This stems from the large database of epidemiology, toxicology, and in-vitro studies, each of which often provides different information in understanding and differentiating the effects of short fibers. The epidemiology studies in which the cancer potency estimates were based upon relatively high exposure concentrations provide a conservative assessment that shorter fibers would have little if any effect, especially under controlled exposure or environmental conditions that may occur today. The QSAR models have shown that fiber aspect ratio and Mg content are excellent predictors of cancer potency and that short fibers/particles of amphibole would have no effect. The studies of motor vehicle mechanics and in particular workers who serviced chrysotile containing brakes with the majority of the fibers being short provides evidence that motor vehicle mechanics, including workers who were engaged in brake repair, are not at an increased risk of mesothelioma. Several inhalation toxicology studies clearly differentiated that short chrysotile and amphibole asbestos fibers did not produce a significant carcinogenic effect in the lung or pleural cavity. Because of dosing and lack of sensitivity to biosolubility, in vitro studies can be difficult to interpret; however, a number have differentiated short chrysotile and amphibole asbestos fibers from long fibers. Integral to understanding the importance of fiber length in determining possible health effects is an understanding of the biological and physiological function of the respiratory system. Short asbestos fibers, like innocuous dust, can be cleared through the tracheobronchial ciliated mucous transport, phagocytized by macrophages and cleared via the bronchial tree, and can also be removed through the lymphatic system. While the first two methods can remove them from the lung, with lymphatic transport through one-way valves, fibers are removed from the active area of the lung where the fiber-related disease has been shown to develop and can accumulate in lymphatic sumps and lymph nodes. While short asbestos fibers are present in most occupational or environmental exposures, the large body of studies strongly supports that they do not contribute to the health effects of asbestos exposure.

• A critical review of the 2020 EPA risk assessment for chrysotile and its many shortcomings. D. Paustenbach, D. Brew, S. Ligas, et al. 2021;51(6):509-539. Review PubMed · Publisher

  Abstract

  From 2018 to 2020, the United States Environmental Protection Agency (EPA) performed a risk evaluation of chrysotile asbestos to evaluate the hazards of asbestos-containing products (e.g. encapsulated products), including brakes and gaskets, allegedly currently sold in the United States. During the public review period, the EPA received more than 100 letters commenting on the proposed risk evaluation. The Science Advisory Committee on Chemicals (SACC), which peer reviewed the document, asked approximately 100 questions of the EPA that they expected to be addressed prior to publication of the final version of the risk assessment on 30 December 2020. After careful analysis, the authors of this manuscript found many significant scientific shortcomings in both the EPA's draft and final versions of the chrysotile risk evaluation. First, the EPA provided insufficient evidence regarding the current number of chrysotile-containing brakes and gaskets being sold in the United States, which influences the need for regulatory oversight. Second, the Agency did not give adequate consideration to the more than 200 air samples detailed in the published literature of auto mechanics who changed brakes in the 1970-1989 era. Third, the Agency did not consider more than 15 epidemiology studies indicating that exposures to encapsulated chrysotile asbestos in brakes and gaskets, which were generally in commerce from approximately 1950-1985, did not increase the incidence of any asbestos-related disease. Fourth, the concern about chrysotile asbestos being a mesothelioma hazard was based on populations in two facilities where mixed exposure to chrysotile and commercial amphibole asbestos (amosite and crocidolite) occurred. All 8 cases of pleural cancer and mesothelioma in the examined populations arose in facilities where amphiboles were present. It was therefore inappropriate to rely on these cohorts to predict the health risks of exposure to short fiber chrysotile, especially of those fibers filled with phenolic resins. Fifth, the suggested inhalation unit risk (IUR) for chrysotile asbestos was far too high since it was not markedly different than for amosite, despite the fact that the amphiboles are a far more potent carcinogen. Sixth, the approach to low dose modeling was not the most appropriate one in several respects, but, without question, it should have accounted for the background rate of mesothelioma in the general population. Just one month after this assessment was published, the National Academies of Science notified the EPA that the Agency's systematic review process was flawed. The result of the EPA's chrysotile asbestos risk evaluation is that society can expect dozens of years of scientifically unwarranted litigation. Due to an aging population and because some fraction of the population is naturally predisposed to mesothelioma given the presence of various genetic mutations in DNA repair mechanisms (e.g. BAP1 and others), the vast majority of mesotheliomas in the post-2035 era are expected to be spontaneous and unrelated in any way to exposure to asbestos. Due to the EPA's analysis, it is our belief that those who handled brakes and gaskets in the post-1985 era may now believe that those exposures were the cause of their mesothelioma, when a risk assessment based on the scientific weight of evidence would indicate otherwise.

• Potential airborne asbestos exposures in dentistry: a comprehensive review and risk assessment. A.M. Ierardi, C. Mathis, A. Urban, et al. 2021;51(4):301-327. Review PubMed · Publisher

  Abstract

  Chrysotile was formerly used in the manufacture of casting ring liner (CRL) and periodontal dressing powder (PDP). The purpose of this study was to describe the potential for airborne asbestos exposure among dental professionals who may have used these products and to assess their risk of asbestos-related disease (ARD). Task-specific exposure data associated with CRL and PDP were identified and compared to regulatory standards for asbestos and health-based benchmarks. Personal airborne fiber concentrations ranged from 0.008-3.5 f/cc by PCM (duration: 3-420 minutes) for CRL (tearing, placement), and from <0.0044-<0.297 f/cc by PCM (duration: 5-28 minutes) for PDP (mixing). Eight-hour time-weighted average (TWA) exposures were calculated using the reported task-based airborne fiber concentrations and associated sampling durations. For CRL tasks, the upper-bound calculated 8-hour TWA of 0.022 f/cc (tearing, placement) did not exceed regulatory standards for asbestos (≥0.1 f/cc). All samples collected during the mixing of PDP resulted in non-measurable fiber concentrations. The greatest estimated cumulative asbestos exposure for dental professionals using CRL (tearing, placement) of 0.33 f/cc-years is well below "best estimate", published chrysotile no-observed-adverse-effect-levels (NOAEL) for ARD (lung cancer = 89-168 f/cc-years; pleural mesothelioma = 208-415 f/cc-years). As such, the use of asbestos-containing CRL and/or PDP is not expected to pose an increased risk of ARD among dental professionals. This conclusion is consistent with the lack of an increased risk of ARD reported in epidemiological studies of these occupations.

• Letter to the Editor regarding Bullock 2020. D. Egilman, B. Castleman, T. Bird. 2020;50(10):953-954. Letter · Comment PubMed · Publisher

• Perspectives on the knowledge of asbestos disease in the United States - what was known, by whom, and when. W.H. Bullock. 2020;50(8):673-676. Review PubMed · Publisher

  Abstract

  Historical research on asbestos disease can be traced back to the early twentieth Century. The majority, if not all of the early research was conducted outside the United States. There are a number of historical time-lines published that chronical these studies. However, what these time-lines do not address is how widespread this information was, who had access to it, and who may have been furthering this research here in the United States. To address these questions, we can look to the writings of early pioneers in occupational medicine like Alice Hamilton and Carey P. McCord from that era to determine the extent that asbestos disease was mentioned or being discussed. Based on the works of Dr. Hamilton and Dr. McCord, the dissemination and penetration of knowledge about asbestos within the medical and industrial hygiene communities during the first half of the twentieth Century in the United States were very limited or non-existent.

• Response to Letter to the Editor from Egilman, Castleman and Bird (2020) concerning Bullock (2020), Perspectives on the knowledge of asbestos disease in the United States - what was known, by whom and when. W.H. Bullock. 2020;50(10):955-956. Letter · Comment PubMed · Publisher

2010s

• An updated evaluation of potential health hazards associated with exposures to asbestos-containing drywall accessory products. N.F.B. Jacobs, K.M. Towle, B.L. Finley, et al. 2019;49(5):430-444. Review PubMed · Publisher

  Abstract

  Following a previously published (2012) evaluation of the potential health hazards related to the use of asbestos-containing drywall accessory products, additional information regarding asbestos exposures during the use of accessory products, as well as studies of chrysotile asbestos risk as a function of exposure, have been published in the peer-reviewed literature. The purpose of this analysis is to update the original evaluation with this new information. It was previously estimated that a professional drywaller performing joint compound-associated tasks could have a lifetime cumulative chrysotile exposure of 12-26 f/cc-year. Using conservative assumptions regarding airborne asbestos levels during different drywalling tasks, task duration, and job tenure, we found that a range of 4.3-36.3 f/cc-year is a plausible estimate of a career drywaller's cumulative asbestos exposure from historical joint compound use. The estimated range for bystander exposures would be below (sometimes significantly below) this range depending on the frequency and duration of work near drywallers. Further, the estimated drywaller and bystander total fiber exposures were well below a recently published "no-observed adverse effect level, best estimate" for predominately chrysotile exposures of 89-168 f/cc-year for lung cancer and 208-415 f/cc-year for mesothelioma. We also determined that, even if the chrysotile or possibly talc ingredients in the drywall products had contained asbestiform tremolite, the cumulative tremolite exposures would have been well below a recently published tremolite no-effect level of 0.5-2.6 f/cc-year. Based on our calculations, typical drywall work using asbestos-containing drywall accessory products is not expected to increase the risk of asbestos-related lung cancer or mesothelioma. These conclusions are consistent with the lack of epidemiological evidence that drywall work resulted in an increased incidence of asbestos-related disease in the drywall trades.

• Critical review of the evidence for a causal association between exposure to asbestos and esophageal cancer. M.K. Peterson, I. Mohar, T. Lam, et al. 2019;49(7):597-613. Review PubMed · Publisher

  Abstract

  Esophageal cancers comprise about 1% of all cancers diagnosed in the US but are more prevalent in other regions of the world. Several regulatory agencies have classified asbestos as a known human carcinogen, and it is linked to multiple diseases and malignancies, including lung cancer and mesothelioma. In a 2006 review of the epidemiological literature, the Institute of Medicine (IOM) did not find sufficient evidence to demonstrate a causal relationship between asbestos exposure and esophageal cancer. To reevaluate this conclusion, we performed a critical review of the animal toxicological, epidemiological, and mechanism of action literature on esophageal cancer and asbestos, incorporating studies published since 2006. Although there is some evidence in the epidemiological literature for an increased risk of esophageal cancer in asbestos-exposed occupational cohorts, these studies generally did not control for critical esophageal cancer risk factors (e.g. smoking, alcohol consumption). Furthermore, data from animal toxicological studies do not indicate that asbestos exposure increases esophageal cancer risk. Based on our evaluation of the literature, and reaffirming the IOM's findings, we conclude that there is insufficient evidence to demonstrate a causal link between asbestos exposure and esophageal cancer.

• Dose-response modeling of NLRP3 inflammasome-mediated diseases: asbestos, lung cancer, and malignant mesothelioma as examples. L.A. Cox. 2019;49(7):614-635. Review PubMed · Publisher

  Abstract

  Can a single fiber of amphibole asbestos increase the risk of lung cancer or malignant mesothelioma (MM)? Traditional linear no-threshold (LNT) risk assessment assumptions imply that the answer is yes: there is no safe exposure level. This paper draws on recent scientific progress in inflammation biology, especially elucidation of the activation thresholds for NLRP3 inflammasomes and resulting chronic inflammation, to model dose-response relationships for malignant mesothelioma and lung cancer risks caused by asbestos exposures. The modeling integrates a physiologically based pharmacokinetics (PBPK) front end with inflammation-driven two-stage clonal expansion (I-TSCE) models of carcinogenesis to describe how exposure leads to chronic inflammation, which in turn promotes carcinogenesis. Together, the combined PBPK and I-TSCE modeling predict that there are practical thresholds for exposure concentration below which asbestos exposure does not cause chronic inflammation in less than a lifetime, and therefore does not increase chronic inflammation-dependent cancer risks. Quantitative examples using model parameter estimates drawn from the literature suggest that practical thresholds may be within about a factor of 2 of some past exposure levels for some workers. The I-TSCE modeling framework explains previous puzzling aspects of asbestos epidemiology, such as why age at first exposure is a better predictor of lifetime MM risk than exposure duration. It may be a valuable tool for risk analysts when LNT assumptions are not justified due to inflammation response thresholds mediating dose-response relationships.

• The toxicology of chrysotile-containing brake debris: implications for mesothelioma. C.A. Poland, R. Duffin. 2019;49(1):11-35. Review PubMed · Publisher

  Abstract

  The global use of "asbestos" in various commercial products has led to a wide range and pervasive legacy of disease. One such use of chrysotile asbestos was brake pads and was utilized commonly in automobiles and heavy vehicles. The result of incorporation of chrysotile into brake pads is associated with the exposure of mechanics fitting and servicing vehicles to liberated chrysotile fibers. Despite the proven exposure, the relative risk of malignant mesothelioma (MM) in this occupational population is broadly seen as low. The toxicity of particulates, including fibers such as chrysotile, is driven by a combination of dose and physicochemical properties. As such, it is plausible that chrysotile released from brake pads may have undergone modification, thereby altering the pathogenicity profile. The impact of high sheer stress causing shortening of long fibers, heat modification, binding of resin matrix to the fiber surface on the relative toxicity of brake debris with regards to MM is considered. It is apparent that released chrysotile can undergo significant modification, reducing the long fiber dose although not all modifications may lead to reduced toxicity.

• Correction to: Finley et al., Evaluation of tremolite asbestos exposures associated with the use of commercial products. 2018;48(5):416. PubMed · Publisher

• Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans. E.D. Kuempel, M.C. Jaurand, P. Møller, et al. 2017;47(1):1-58. Review PubMed · Publisher · Free full text

  Abstract

  In an evaluation of carbon nanotubes (CNTs) for the IARC Monograph 111, the Mechanisms Subgroup was tasked with assessing the strength of evidence on the potential carcinogenicity of CNTs in humans. The mechanistic evidence was considered to be not strong enough to alter the evaluations based on the animal data. In this paper, we provide an extended, in-depth examination of the in vivo and in vitro experimental studies according to current hypotheses on the carcinogenicity of inhaled particles and fibers. We cite additional studies of CNTs that were not available at the time of the IARC meeting in October 2014, and extend our evaluation to include carbon nanofibers (CNFs). Finally, we identify key data gaps and suggest research needs to reduce uncertainty. The focus of this review is on the cancer risk to workers exposed to airborne CNT or CNF during the production and use of these materials. The findings of this review, in general, affirm those of the original evaluation on the inadequate or limited evidence of carcinogenicity for most types of CNTs and CNFs at this time, and possible carcinogenicity of one type of CNT (MWCNT-7). The key evidence gaps to be filled by research include: investigation of possible associations between in vitro and early-stage in vivo events that may be predictive of lung cancer or mesothelioma, and systematic analysis of dose-response relationships across materials, including evaluation of the influence of physico-chemical properties and experimental factors on the observation of nonmalignant and malignant endpoints.

• History of knowledge and evolution of occupational health and regulatory aspects of asbestos exposure science: 1900-1975. C.A. Barlow, J. Sahmel, D.J. Paustenbach, et al. 2017;47(4):286-316. Review PubMed · Publisher

  Abstract

  The understanding by industrial hygienists of the hazards of asbestos and appropriate ways to characterize and control exposure has evolved over the years. Here, a detailed analysis of the evolution of industrial hygiene practices regarding asbestos and its health risks, from the early 1900s until the advent of the national occupational health and safety regulatory structure currently in place in the US (early-to-mid 1970s) is presented. While industrial hygienists recognized in the early 1900s that chronic and high-level exposures to airborne concentrations of asbestos could pose a serious health hazard, it was not until the mid-1950s that the carcinogenic nature of asbestos began to be characterized and widespread concern followed. With the introduction of the membrane filter sampling method in the late 1960s and early 1970s, asbestos sampling and exposure assessment capabilities advanced to a degree which allowed industrial hygienists to more precisely characterize the exposure-response relationship. The ability of industrial hygienists, analytical chemists, toxicologists, and physicians to more accurately define this relationship was instrumental to the scientific community's ability to establish Occupational Exposure Levels (OELs) for asbestos. These early developments set the stage for decades of additional study on asbestos exposure potential and risk of disease. This was followed by the application of engineering controls and improved respiratory protection which, over the years, saved thousands of lives. This paper represents a state-of-the-art review of the knowledge of asbestos within the industrial hygiene community from about 1900 to 1975.

• Weight of evidence analysis for assessing the genotoxic potential of carbon nanotubes. P. Møller, N.R. Jacobsen. 2017;47(10):867-884. Review PubMed · Publisher

  Abstract

  Carbon nanotube (CNT) is a nanomaterial that has received interest because of its high-tensile strength and low weight. Although CNTs differ substantially in physico-chemical properties, they share high aspect ratio which resembles that of asbestos and other fibers causing lung cancer and mesothelioma. One type of multi-walled CNTs (i.e. MWCNT-7) has been classified as possibly carcinogenic to humans by IARC (Group 2B) based on experimental animal data, whereas other types of MWCNTs and single-walled CNTs (SWCNT) could not be classified due to lack of data from epidemiologic studies and insufficient mechanistic evidence. Damage to DNA is considered to be a key mechanistic step in the development of fiber-induced cancer. Thus, the genotoxic potential can be a cornerstone in the evaluation of hazards of CNTs. The present study used a weight of evidence (WoE) analysis to evaluate the genotoxicity of different types of CNTs. Genotoxicity endpoints close to cancer (mutations and chromosome aberrations) and animal models had highest weight in the WoE analysis. Eight CNT materials out of 130, which had been assessed in several studies, were evaluated in the WoE analysis. The results demonstrated that MWCNT-7 has strongest WoE for a genotoxic hazard among the MWCNTs. Two types of SWCNTs have a similar WoE for genotoxicity as MWCNT-7. Several reference materials from the Joint Research Centre have less WoE for genotoxicity. The WoE analysis demonstrates a difference in genotoxicity for CNTs, but further research is required to unravel the physico-chemical characteristics that govern the differences in genotoxic hazard.

• A review of exposure and toxicological aspects of carbon nanotubes, and as additives to fire retardants in polymers. A. Christou, A.A. Stec, W. Ahmed, et al. 2016;46(1):74-95. Review PubMed · Publisher

  Abstract

  Carbon nanotubes (CNTs) have attracted considerable interest due to their unique physical, chemical, optical and electrical properties opening avenues for a large number of industrial applications. They have shown potential as fire retardant additives in polymers, reducing heat release rate and increasing time to ignition in a number of polymers. Relevant work on the types, properties and applications has been reviewed particularly considering their application in fire situations. There are concerns over the health risks associated with CNTs and many papers have likened CNTs to the health problems associated with asbestos. There are contradictions relating to the toxicity of CNTs with some papers reporting that they are toxic while others state the opposite. Directly comparing various studies is difficult because CNTs come in many combinations of size, type, purity levels and source. CNTs can potentially be released from polymers during the combustion process where human exposure may occur. While this review has shed some light regarding issues relating to toxicity under different fire scenarios much more thorough work is needed to investigate toxicity of CNTs and their evolution from CNT-polymer nanocomposites in order to reach firm conclusions.

• An updated evaluation of reported no-observed adverse effect levels for chrysotile asbestos for lung cancer and mesothelioma. J.S. Pierce, P.S. Ruestow, B.L. Finley. 2016;46(7):561-86. PubMed · Publisher

  Abstract

  Although consumption of chrysotile asbestos has decreased since the 1970s, the latency period of asbestos-related cancers is thought to be at least 20-30 years, and therefore the potential health risks associated with historical exposures is still actively researched. This analysis represents an update to a previous paper in which we evaluated the exposure-response relationships for lung cancer and mesothelioma in chrysotile-exposed cohorts. Here, we review several recently published studies as well as updated information from previous studies. For each of the 14 studies considered, we identified the "no-observed adverse effect level" (NOAEL) for lung cancer and/or mesothelioma. NOAEL values for lung cancer ranged from 1.1 to <20 f/cc-years to 1600-3200 f/cc-years, and for mesothelioma ranged from 100-400 f/cc-years to 800-1599 f/cc-years. The range of "best estimate" NOAELs was estimated to be 89-168 f/cc-years for lung cancer and 208-415 f/cc-years for mesothelioma. None of the six cohorts of cement or friction product manufacturing workers exhibited an increased lung cancer risk at any exposure level, while all of the five studies of textile workers reported an increased risk at one or more exposure levels. This is likely because friction and cement workers were exposed to much shorter chrysotile fibers. Of the seven cases of peritoneal mesothelioma reported in the included studies, none were observed in the analyses of cement or friction product manufacturing workers in the absence of crocidolite exposure. These findings will help characterize potential worker and consumer health risks associated with historical and current chrysotile exposures.

• The legacy of the F344 rat as a cancer bioassay model (a retrospective summary of three common F344 rat neoplasms). R.R. Maronpot, A. Nyska, J.E. Foreman, et al. 2016;46(8):641-75. Review PubMed · Publisher · Free full text

  Abstract

  The Fischer 344 (F344) rat was used by the National Toxicology Program (NTP) for over 5 decades for toxicity and carcinogenicity studies. However, in 2006, the NTP decided to switch to a different rat stock due largely to high background control incidences of Leydig cell tumors (LCTs) and mononuclear cell leukemia (MNCL), also known as large granular lymphocytic (LGL) leukemia. In the current review, we aim (1) to provide a summary of NTP bioassays with treatment-associated effects involving MNCL and LCTs in addition to male F344-specific tunica vaginalis mesothelioma (TVM); (2) to describe important pathobiological differences between these F344 rat tumor responses and similar target tissue-tumor response in humans; and (3) to present the NTP reasons for switching away from the F344 rat. We show that due to the highly variable background incidence of F344 MNCL, more reliance on historical control data than is usual for most tumor responses is warranted to evaluate potential effect of any chemical treatment in this rat strain. The high spontaneous incidence of LCTs in the testes of male F344 rats has made this tumor endpoint of little practical use in identifying potential testicular carcinogenic responses. TVM responses in F344 rats have a biological plausible relationship to LCTs unlike TVM in humans. Given their high spontaneous background incidence and species-specific biology, we contend that MNCL and LCT, along with TVM responses, in F344 rat carcinogenicity studies are inappropriate tumor types for human health risk assessment and lack relevance in predicting human carcinogenicity.

• Health effects of World Trade Center (WTC) Dust: An unprecedented disaster's inadequate risk management. M. Lippmann, M.D. Cohen, L.C. Chen. 2015;45(6):492-530. Review PubMed · Publisher · Free full text

  Abstract

  The World Trade Center (WTC) twin towers in New York City collapsed on 9/11/2001, converting much of the buildings' huge masses into dense dust clouds of particles that settled on the streets and within buildings throughout Lower Manhattan. About 80-90% of the settled WTC Dust, ranging in particle size from ∼2.5 μm upward, was a highly alkaline mixture of crushed concrete, gypsum, and synthetic vitreous fibers (SVFs) that was readily resuspendable by physical disturbance and low-velocity air currents. High concentrations of coarse and supercoarse WTC Dust were inhaled and deposited in the conductive airways in the head and lungs, and subsequently swallowed, causing both physical and chemical irritation to the respiratory and gastroesophageal epithelia. There were both acute and chronic adverse health effects in rescue/recovery workers; cleanup workers; residents; and office workers, especially in those lacking effective personal respiratory protective equipment. The numerous health effects in these people were not those associated with the monitored PM2.5 toxicants, which were present at low concentrations, that is, asbestos fibers, transition and heavy metals, polyaromatic hydrocarbons or PAHs, and dioxins. Attention was never directed at the very high concentrations of the larger-sized and highly alkaline WTC Dust particles that, in retrospect, contained the more likely causal toxicants. Unfortunately, the initial focus of the air quality monitoring and guidance on exposure prevention programs on low-concentration components was never revised. Public agencies need to be better prepared to provide reliable guidance to the public on more appropriate means of exposure assessment, risk assessment, and preventive measures.

• A review and critique of U.S. EPA's risk assessments for asbestos. S.H. Moolgavkar, E.L. Anderson, E.T. Chang, et al. 2014;44(6):499-522. Review PubMed · Publisher

  Abstract

  U.S. Environmental Protection Agency (EPA) recently conducted a risk assessment for exposure to Libby amphibole asbestos that is precedent-setting for two reasons. First, the Agency has not previously conducted a risk assessment for a specific type of asbestos fiber. Second, the risk assessment includes not only an inhalation unit risk (IUR) for the cancer endpoints, but also a reference concentration (RfC) for nonmalignant disease. In this paper, we review the procedures used by the Agency for both cancer and nonmalignant disease and discuss the strengths and limitations of these procedures. The estimate of the RfC uses the benchmark dose method applied to pleural plaques in a small subcohort of vermiculite workers in Marysville, Ohio. We show that these data are too sparse to inform the exposure-response relationship in the low-exposure region critical for estimation of an RfC, and that different models with very different exposure-response shapes fit the data equally well. Furthermore, pleural plaques do not represent a disease condition and do not appear to meet the EPA's definition of an adverse condition. The estimation of the IUR for cancer is based on a subcohort of Libby miners, discarding the vast majority of lung cancers and mesotheliomas in the entire cohort and ignoring important time-related factors in exposure and risk, including effect modification by age. We propose that an IUR based on an endpoint that combines lung cancer, mesothelioma, and nonmalignant respiratory disease (NMRD) in this cohort would protect against both malignant and nonmalignant disease. However, the IUR should be based on the entire cohort of Libby miners, and the analysis should properly account for temporal factors. We illustrate our discussion with our own independent analyses of the data used by the Agency.

• A systematic review of occupational exposure to synthetic vitreous fibers and mesothelioma. P. Boffetta, K. Donaldson, S. Moolgavkar, et al. 2014;44(5):436-49. Systematic review PubMed · Publisher

  Abstract

  Objective: We investigated whether available epidemiological and toxicological data suggest an increased risk of mesothelioma among workers exposed to synthetic vitreous fibers (SVF).

  Methods: We conducted a systematic review of epidemiological studies on the risk of mesothelioma among workers exposed to SVF, and toxicological studies on SVF and mesothelioma.

  Results: Seven cohort studies were conducted among workers employed in production of rock/slag wool, glass wool, or continuous glass filament in the United States, Canada, and Europe. Of the six deaths from mesothelioma identified in these studies, three had exposure to asbestos. A review of death certificates in a study of rock wool production workers identified one additional probable death. A formal comparison with expected deaths is not feasible. Four community-based case-control studies were identified, of which three reported an increased risk among SVF-exposed workers. The number of cases not exposed to asbestos was less, and residual confounding from asbestos exposure misclassification may explain the association in these studies. The toxicology review of SVF suggested that they present a low hazard mostly due to their low biopersistence, typically with a half-life in rat studies of tens of days compared to amphibole asbestos which has a half-life of 400-500 days.

  Conclusions: The combined evidence from epidemiology and toxicology provide little evidence that exposure to SVF increases the risk of mesothelioma.

• Toxicological and epidemiological studies on effects of airborne fibers: coherence and public [corrected] health implications. M. Lippmann. 2014;44(8):643-95. Review PubMed · Publisher

  Abstract

  Airborne fibers, when sufficiently biopersistent, can cause chronic pleural diseases, as well as excess pulmonary fibrosis and lung cancers. Mesothelioma and pleural plaques are caused by biopersistent fibers thinner than ∼0.1 μm and longer than ∼5 μm. Excess lung cancer and pulmonary fibrosis are caused by biopersistent fibers that are longer than ∼20 μm. While biopersistence varies with fiber type, all amphibole and erionite fibers are sufficiently biopersistent to cause pathogenic effects, while the greater in vivo solubility of chrysotile fibers makes them somewhat less causal for the lung diseases, and much less causal for the pleural diseases. Most synthetic vitreous fibers are more soluble in vivo than chrysotile, and pose little, if any, health pulmonary or pleural health risk, but some specialty SVFs were sufficiently biopersistent to cause pathogenic effects in animal studies. My conclusions are based on the following: 1) epidemiologic studies that specified the origin of the fibers by type, and especially those that identified their fiber length and diameter distributions; 2) laboratory-based toxicologic studies involving fiber size characterization and/or dissolution rates and long-term observation of biological responses; and 3) the largely coherent findings of the epidemiology and the toxicology. The strong dependence of effects on fiber diameter, length, and biopersistence makes reliable routine quantitative exposure and risk assessment impractical in some cases, since it would require transmission electronic microscopic examination, of representative membrane filter samples, for determining statistically sufficient numbers of fibers longer than 5 and 20 μm, and those thinner than 0.1 μm, based on the fiber types.

• Health risk of chrysotile revisited. D. Bernstein, J. Dunnigan, T. Hesterberg, et al. 2013;43(2):154-83. Review PubMed · Publisher · Free full text

  Abstract

  This review provides a basis for substantiating both kinetically and pathologically the differences between chrysotile and amphibole asbestos. Chrysotile, which is rapidly attacked by the acid environment of the macrophage, falls apart in the lung into short fibers and particles, while the amphibole asbestos persist creating a response to the fibrous structure of this mineral. Inhalation toxicity studies of chrysotile at non-lung overload conditions demonstrate that the long (>20 µm) fibers are rapidly cleared from the lung, are not translocated to the pleural cavity and do not initiate fibrogenic response. In contrast, long amphibole asbestos fibers persist, are quickly (within 7 d) translocated to the pleural cavity and result in interstitial fibrosis and pleural inflammation. Quantitative reviews of epidemiological studies of mineral fibers have determined the potency of chrysotile and amphibole asbestos for causing lung cancer and mesothelioma in relation to fiber type and have also differentiated between these two minerals. These studies have been reviewed in light of the frequent use of amphibole asbestos. As with other respirable particulates, there is evidence that heavy and prolonged exposure to chrysotile can produce lung cancer. The importance of the present and other similar reviews is that the studies they report show that low exposures to chrysotile do not present a detectable risk to health. Since total dose over time decides the likelihood of disease occurrence and progression, they also suggest that the risk of an adverse outcome may be low with even high exposures experienced over a short duration.

• Letter to the Editor re Bernstein et al: Health risk of chrysotile revisited. Crit Rev Toxicol, 2013; 43(2): 154-183. M.M. Finkelstein. 2013;43(8):707-8. Letter · Comment PubMed · Publisher

• Oxidatively damaged DNA in animals exposed to particles. P. Møller, P.H. Danielsen, K. Jantzen, et al. 2013;43(2):96-118. Review PubMed · Publisher

  Abstract

  Exposure to combustion-derived particles, quartz and asbestos is associated with increased levels of oxidized and mutagenic DNA lesions. The aim of this survey was to critically assess the measurements of oxidatively damaged DNA as marker of particle-induced genotoxicity in animal tissues. Publications based on non-optimal assays of 8-oxo-7,8-dihydroguanine by antibodies and/or unrealistically high levels of 8-oxo-7,8-dihydroguanine (suggesting experimental problems due to spurious oxidation of DNA) reported more induction of DNA damage after exposure to particles than did the publications based on optimal methods. The majority of studies have used single intracavitary administration or inhalation with dose rates exceeding the pulmonary overload threshold, resulting in cytotoxicity and inflammation. It is unclear whether this is relevant for the much lower human exposure levels. Still, there was linear dose-response relationship for 8-oxo-7,8-dihydroguanine in lung tissue without obvious signs of a threshold. The dose-response function was also dependent on chemical composition and other characteristics of the administered particles, whereas dependence on species and strain could not be equivocally determined. Roles of cytotoxicity or inflammation for oxidatively induced DNA damage could not be documented or refuted. Studies on exposure to particles in the gastrointestinal tract showed consistently increased levels of 8-oxo-7,8-dihydroguanine in the liver. Collectively, there is evidence from animal experimental models that both pulmonary and gastrointestinal tract exposure to particles are associated with elevated levels of oxidatively damaged DNA in the lung and internal organs. However, there is a paucity of studies on pulmonary exposure to low doses of particles that are relevant for hazard/risk assessment.

• Resisting the urge to act on random patterns: a reply to Schenker et al. D.W. Berman, L.A. Cox, D.A. Popken. 2013;43(7):609-10. Review PubMed · Publisher

• Response to Murray M. Finkelstein, letter to the editor re Bernstein et al: Health risk of chrysotile revisited. Crit Rev Toxicol, 2013; 43(2): 154-183. D. Bernstein, J. Dunnigan, T. Hesterberg, et al. 2013;43(8):709-10. Letter · Comment PubMed · Publisher

• Evaluation of take home (para-occupational) exposure to asbestos and disease: a review of the literature. E.P. Donovan, B.L. Donovan, M.A. McKinley, et al. 2012;42(9):703-31. Review PubMed · Publisher

  Abstract

  The potential for para-occupational (or "take-home") exposure to a number of chemicals has been recognized for over 60 years. We conducted a literature review in order to characterize reported cases of asbestos-related disease among household contacts of workers occupationally exposed to asbestos. Over 200 published articles were evaluated. Nearly 60 articles described cases of asbestos-related disease thought to be caused by para-occupational exposure. Over 65% of these cases were in persons who lived with workers classified as miners, shipyard workers, insulators, or others involved in the manufacturing of asbestos-containing products, with nearly all remaining workers identified as craftsmen. 98% of the available lung samples of the persons with diseases indicated the presence of amphibole asbestos. Eight studies provided airborne asbestos concentrations during (i) handling of clothing contaminated with asbestos during insulation work or simulated use of friction products; (ii) ambient conditions in the homes of asbestos miners; and (iii) wearing previously contaminated clothing. This review indicates that the literature is dominated by case reports, the majority of which involved household contacts of workers in industries characterized, generally, by high exposures to amphiboles or mixed mineral types. The available data do not implicate chrysotile as a significant cause of disease for household contacts. Also, our analysis indicates that there is insufficient information in the published literature that would allow one to relate airborne asbestos concentrations in a workplace to those that would be generated from subsequent handling of contact with clothing that had been contaminated in that environment. Ideally, a simulation study could be conducted in the future to better understand the relationships between the airborne concentrations in the workplace and the fiber characteristics that influence retention on fabric, as well as the concentrations that can be generated by handling the contaminated clothing by the persons in the home.

• Evaluation of tremolite asbestos exposures associated with the use of commercial products. B.L. Finley, J.S. Pierce, A.D. Phelka, et al. 2012;42(2):119-46. Review PubMed · Publisher

  Abstract

  Tremolite is a noncommercial form of amphibole mineral that is present in some chrysotile, talc, and vermiculite deposits. Inhalation of asbestiform tremolite is suspected to have caused or contributed to an increased incidence of mesothelioma in certain mining settings; however, very little is known about the magnitude of tremolite exposure that occurred at these locations, and even less is known regarding tremolite exposures that might have occurred during consumer use of chrysotile, talc, and vermiculite containing products. The purpose of this analysis is to evaluate the exposure-response relationship for tremolite asbestos and mesothelioma in high exposure settings (mining) and to develop estimates of tremolite asbestos exposure for various product use scenarios. Our interpretation of the tremolite asbestos exposure metrics reported for the Thetford chrysotile mines and the Libby vermiculite deposits suggests a lowest-observed-adverse-effect level (LOAEL) for mesothelioma of 35-73 f/cc-year. Using measured and estimated airborne tremolite asbestos concentrations for simulated and actual product use, we conservatively estimated the following cumulative tremolite asbestos exposures: career auto mechanic: 0.028 f/cc-year; non-occupational use of joint compound: 0.0006 f/cc-year; non-occupational use of vermiculite-containing gardening products: 0.034 f/cc-year; home-owner removal of Zonolite insulation: 0.0002 f/cc-year. While the estimated consumer tremolite exposures are far below the tremolite LOAELs derived herein, this analysis examines only a few of the hundreds of chrysotile- and talc-containing products.

• Letter to the Editor regarding the Donovan et al. (2011) article. D. Egilman, J.H. Schilling. 2012;42(2):169-72; author reply 173-83. Letter · Comment PubMed · Publisher

• Potential health hazards associated with exposures to asbestos-containing drywall accessory products: A state-of-the-science assessment. A.D. Phelka, B.L. Finley. 2012;42(1):1-27. Review PubMed · Publisher

  Abstract

  Until the late 1970s, chrysotile asbestos was an ingredient in most industrial and consumer drywall accessory products manufactured in the US. In 1977, the Consumer Product Safety Commission (CPSC) issued a ban of consumer patching compounds containing "respirable, free-form asbestos" based on their prediction of exceptionally high rates of asbestos-related diseases among individuals using patching compounds for as little as a few days. Although hundreds of thousands of workers and homeowners handling these products may have experienced exposure to asbestos prior to the ban, there has been no systematic effort to summarize and interpret the information relevant to the potential health effects of such exposures. In this analysis, we provide a comprehensive review and analysis of the scientific studies assessing fiber type and dimension, toxicological and epidemiological endpoints, and airborne fiber concentrations associated with joint compound use. We conclude that: 1) asbestos in drywall accessory products was primarily short fiber (< 5 µm) chrysotile, 2) asbestos in inhaled joint compound particulate is probably not biopersistent in the lung, 3) estimated cumulative chrysotile exposures experienced by workers and homeowners are below levels known to be associated with respiratory disease, and 4) mortality studies of drywall installers have not demonstrated a significantly increased incidence of death attributable to any asbestos-related disease. Consequently, contrary to the predictions of the CPSC, the current weight of evidence does not indicate any clear health risks associated with the use of asbestos-containing drywall accessory products. We also describe information gaps and suggest possible areas of future research.

• Evaluation of bystander exposures to asbestos in occupational settings: a review of the literature and application of a simple eddy diffusion model. E.P. Donovan, B.L. Donovan, J. Sahmel, et al. 2011;41(1):52-74. Review PubMed · Publisher

  Abstract

  This article presents a review of the publicly available information as it relates to airborne asbestos concentrations at varying distances from a source in an occupational environment. Personal and area samples collected 5-75 feet from the primary worker from workplace surveys conducted in the 1970s and area samples collected 5-50 feet from the primary worker during more recent simulation studies were identified, compiled, and analyzed. As expected, airborne asbestos concentrations generally decreased with distance from the worker who performed a given task. Based on this review, however, the authors found that no systematic research to quantitatively relate fiber concentration with distance from the source (including consideration of fiber length, dilution ventilation, and initial momentum of the particle) has been conducted to date. A simple mathematical model was therefore used, and the results were considered, along with available published data comparing exposure data for both workers and persons/areas near workers. From this analysis, the authors offer guidance for estimating airborne asbestos concentrations at distance from a source. Based on the available data and our modeling results, the authors propose the following approach as a rule of thumb: for persons 1-5 feet from the source, airborne asbestos concentrations can be roughly approximated at 50% of the source concentration; 35% at >5-10 feet, 10% for >10-30 feet, and less than 1% at distances greater than 30 feet. This approach should be helpful for bracketing the range of likely exposures to bystanders being evaluated in asbestos-related dose-reconstruction analyses.

• Comparing milled fiber, Quebec ore, and textile factory dust: has another piece of the asbestos puzzle fallen into place?. D.W. Berman. 2010;40(2):151-88. Review PubMed · Publisher

  Abstract

  Results of a meta-analysis indicate that the variation in potency factors observed across published epidemiology studies can be substantially reconciled (especially for mesothelioma) by considering the effects of fiber size and mineral type, but that better characterization of historical exposures is needed before improved exposure metrics potentially capable of fully reconciling the disparate potency factors can be evaluated. Therefore, an approach for better characterizing historical exposures, the Modified Elutriator Method (MEM), was evaluated to determine the degree that dusts elutriated using this method adequately mimic dusts generated by processing in a factory. To evaluate this approach, elutriated dusts from Grade 3 milled fiber (the predominant feedstock used at a South Carolina [SC] textile factory) were compared to factory dust collected at the same facility. Elutriated dusts from chrysotile ore were also compared to dusts collected in Quebec mines and mills. Results indicate that despite the substantial variation within each sample set, elutriated dusts from Grade 3 fiber compare favorably to textile dusts and elutriated ore dusts compare to dusts from mines and mills. Given this performance, the MEM was also applied to address the disparity in lung cancer mortality per unit of exposure observed, respectively, among chrysotile miners/millers in Quebec and SC textile workers. Thus, dusts generated by elutriation of stockpiled chrysotile ore (representing mine exposures) and Grade 3 milled fiber (representing textile exposures) were compared. Results indicate that dusts from each sample differ from one another. Despite such variation, however, the dusts are distinct and fibers in Grade 3 dusts are significantly longer than fibers in ore dusts. Moreover, phase-contrast microscopy (PCM) structures in Grade 3 dusts are 100% asbestos and counts of PCM-sized structures are identical, whether viewed by PCM or transmission electron microscope (TEM). In contrast, a third of PCM structures in ore dusts are not asbestos and only a third that are counted by PCM are also counted by TEM. These distinctions also mirror the characteristics of the bulk materials themselves. Perhaps most important, when the differences in size distributions and PCM/TEM distinctions in these dusts are combined, the combined difference is sufficient to completely explain the difference in exposure/response observed between the textile worker and miner/miller cohorts. Importantly, however, evidence that such an explanation is valid can only be derived from a meta-analysis (risk assessment) covering a diverse range of epidemiology study environments, which is beyond the scope of the current study. The above findings suggest that elutriator-generated dusts mimic factory dusts with sufficient reliability to support comparisons between historical exposures experienced by the various cohorts studied by epidemiologists. A simulation was also conducted to evaluate the relative degree that the characteristics of dust are driven by the properties of the bulk material processed versus the nature of the mechanical forces applied. That results indicate it is the properties of bulk materials reinforces the theoretical basis justifying use of the elutriator to reconstruct historical exposures. Thus, the elutriator may be a valuable tool for reconstructing historical exposures suitable for supporting continued refinements of the risk models being developed to predict asbestos-related cancer risk.

• Industrial-grade talc exposure and the risk of mesothelioma. B. Price. 2010;40(6):513-30. Review PubMed · Publisher

  Abstract

  Industrial-grade talc deposits are complex mixtures of mineral particles and may vary substantially in composition across small geographical areas. Typical industrial-grade talc includes amphibole cleavage fragments, platy talc, serpentine minerals, talc in fibrous form, and a minor presence of transitional fibers. Industrial-grade talc was erroneously determined to be an asbestos-containing material due to an unintended consequence of Occupational Health and Safety Administration's (OSHA's) method for measuring airborne asbestos mandated in 1972. This error was repeated, most notably, by the National Institute for Occupational Safety and Health (NIOSH) in, 1980 for talc mined in northern New York State (NYS) by RT Vanderbilt Company (RTV). Subsequent exposure studies of northern NYS talc conducted through the, 1980s and one study published after, 2000 relied on the conclusion that talc was an asbestos-containing material to infer a causal relationship between talc and mesothelioma. The present review included (1) publications concerning talc's cancer-causing potential issued by organizations concerned with occupational and public health; (2) talc exposure studies and animal and cellular studies of RTV talc; (3) mesothelioma rates in northern NYS; and (4) mesothelioma mortality among RTV mining employees. The review indicated that failure to correctly identify the mineral characteristics of talc resulted in misleading reports concerning the carcinogenic potential of talc. However, the collective data from animal and cellular studies, mesothelioma rates in northern NYS, exposure studies, and a mortality analysis of RTV mining employees do not support a causal relationship between RTV talc and mesothelioma. This conclusion is applicable to all mineral components in RTV talc and to other industrial-grade talcs and mineral aggregates with the same components.

• Letter to the editor: "Comparing milled fiber, Quebec ore, and textile factory dust: has another piece of the asbestos puzzle fallen into place?" by D. Wayne Berman. J.M. Dement, L.T. Stayner. 2010;40(8):749-51; author reply 752-7. Comment · Letter PubMed · Publisher

• Review of carbon nanotubes toxicity and exposure--appraisal of human health risk assessment based on open literature. K. Aschberger, H.J. Johnston, V. Stone, et al. 2010;40(9):759-90. Review PubMed · Publisher

  Abstract

  Carbon nanotubes (CNTs) possess many unique electronic and mechanical properties and are thus interesting for numerous novel industrial and biomedical applications. As the level of production and use of these materials increases, so too does the potential risk to human health. This study aims to investigate the feasibility and challenges associated with conducting a human health risk assessment for carbon nanotubes based on the open literature, utilising an approach similar to that of a classical regulatory risk assessment. Results indicate that the main risks for humans arise from chronic occupational inhalation, especially during activities involving high CNT release and uncontrolled exposure. It is not yet possible to draw definitive conclusions with regards the potential risk for long, straight multi-walled carbon nanotubes to pose a similar risk as asbestos by inducing mesothelioma. The genotoxic potential of CNTs is currently inconclusive and could be either primary or secondary. Possible systemic effects of CNTs would be either dependent on absorption and distribution of CNTs to sensitive organs or could be induced through the release of inflammatory mediators. In conclusion, gaps in the data set in relation to both exposure and hazard do not allow any definite conclusions suitable for regulatory decision-making. In order to enable a full human health risk assessment, future work should focus on the generation of reliable occupational, environmental and consumer exposure data. Data on toxicokinetics and studies investigating effects of chronic exposure under conditions relevant for human exposure should also be prioritised.

• The carcinogenicity of dietary acrylamide intake: a comparative discussion of epidemiological and experimental animal research. J.G. Hogervorst, B.J. Baars, L.J. Schouten, et al. 2010;40(6):485-512. Review PubMed · Publisher

  Abstract

  Since 2002, it is known that the probable human carcinogen acrylamide is present in commonly consumed carbohydrate-rich foods, such as French fries and potato chips. In this review, the authors discuss the body of evidence on acrylamide carcinogenicity from both epidemiological and rodent studies, including variability, strengths and weaknesses, how both types of evidence relate, and possible reasons for discrepancies. In both rats and humans, increased incidences of various cancer types were observed. In rats, increased incidences of mammary gland, thyroid tumors and scrotal mesothelioma were observed in both studies that were performed. In humans, increased risks of ovarian and endometrial cancers, renal cell cancer, estrogen (and progesterone) receptor-positive breast cancer, and oral cavity cancer (the latter in non-smoking women) were observed. Some cancer types were found in both rats and humans, e.g., endometrial cancer (observed in one of the two rat studies), but there are also some inconsistencies. Interestingly, in humans, some indications for inverse associations were observed for lung and bladder cancers in women, and prostate and oro- and hypopharynx cancers in men. These latter observations indicate that genotoxicity may not be the only mechanism by which acrylamide causes cancer. The estimated risks based on the epidemiological studies for the sites for which a positive association was observed were considerably higher than those based on extrapolations from the rat studies. The observed pattern of increased risks in the rat and epidemiological studies and the decreased risks in the epidemiological studies suggests that acrylamide might influence hormonal systems, for which rodents may not be good models.

2000s

• The inhalation toxicology of p-aramid fibrils. K. Donaldson. 2009;39(6):487-500. Review PubMed · Publisher

  Abstract

  The pandemic of lung disease caused by asbestos has cast suspicion on any industrial fibrous material that can become airborne in respirable form in workplaces, such that the respirable fibres might be inhaled. Fibre toxicology arose as a sub-specialty of particle toxicology to address the specialised nature of fibre effects and has evolved substantially in the last 25 years. It has yielded valuable information on the dosimetry, structure-activity relationships, and mechanism involved in toxicological effects of a range of fibrous materials, including asbestos, other naturally occurring fibrous materials, and synthetic vitreous fibres. A robust structure/activity paradigm has emerged from this research that highlights fibre length, thinness, and biopersistence as major factors in determining the pathogenicity of a fibre. p-Aramid is a manufactured fibre composed of synthetic polyamide (poly paraphenylene terephthalamide) manufactured on a commercial scale since 1970 by polymerisation and spinning steps. It is used as an advanced composite and in fabrics, body armour, friction materials, etc. Respirable fibrils of p-aramid can be released from the fibres during working and can become airborne. A considerable body of research has been carried out into the hazard posed by inhaled p-aramid fibrils, and this review considers this body of literature and summarises the state-of-the-science in the toxicology of p-aramid fibrils in the light of the existing overarching fibre toxicology paradigm. The peer-reviewed studies demonstrate that p-aramid fibrils can be long and thin but that the fibrils are not biopersistent. Residence in the milieu of the lungs leads to fibre shortening, allowing efficient and complete phagocytosis and effective clearance. Subsequently the p-aramid hazard is low, and this is confirmed in animal studies. The mechanism of shortening of p-aramid fibrils is not well-understood, but may involve the action of macrophages on the fibrils following phagocytosis.

• Time trend of mesothelioma incidence in the United States and projection of future cases: an update based on SEER data for 1973 through 2005. B. Price, A. Ware. 2009;39(7):576-88. Review PubMed · Publisher

  Abstract

  The time trend of mesothelioma incidence and projections of future cases provide useful information for analyzing proposed public health interventions where asbestos exposure may be an issue, evaluating regulatory proposals, and estimating the remaining potential costs of programs to compensate individuals with asbestos-related diseases. We used the April 2008 release of Surveillance, Epidemiology, and End Results (SEER) data, which covers 1973 through 2005, to analyze the time trends in age-adjusted mesothelioma incidence and to estimate an age and birth-cohort model to project the number of future mesothelioma cases. The increase in the number of SEER cancer registries from 13 to 17 in 2000 had little effect on the time pattern of age-adjusted mesothelioma incidence, and the pattern over time of pleural mesothelioma was indistinguishable from the pattern for total mesothelioma defined as sum of pleural and peritoneal cases. Our analysis suggests that the SEER registries viewed as a sample of the U.S. population over-represents high mesothelioma incidence, a fact that we accounted for in our projections. For 2008 we estimate approximately 2,400 cases, with asbestos the likely cause in 58%. We project that asbestos will no longer be a factor in mesothelioma cases after the year 2042. For 2008 through 2042, we estimate slightly more than 68,000 total cases, with asbestos the likely cause in 34%.

• A meta-analysis of asbestos-related cancer risk that addresses fiber size and mineral type. D.W. Berman, K.S. Crump. 2008;38 Suppl 1:49-73. Meta-analysis PubMed · Publisher

  Abstract

  Quantitative estimates of the risk of lung cancer or mesothelioma in humans from asbestos exposure made by the U.S. Environmental Protection Agency (EPA) make use of estimates of potency factors based on phase-contrast microscopy (PCM) and obtained from cohorts exposed to asbestos in different occupational environments. These potency factors exhibit substantial variability. The most likely reasons for this variability appear to be differences among environments in fiber size and mineralogy not accounted for by PCM. In this article, the U.S. Environmental Protection Agency (EPA) models for asbestos-related lung cancer and mesothelioma are expanded to allow the potency of fibers to depend upon their mineralogical types and sizes. This is accomplished by positing exposure metrics composed of nonoverlapping fiber categories and assigning each category its own unique potency. These category-specific potencies are estimated in a meta-analysis that fits the expanded models to potencies for lung cancer (KL's) or mesothelioma (KM's) based on PCM that were calculated for multiple epidemiological studies in our previous paper (Berman and Crump, 2008). Epidemiological study-specific estimates of exposures to fibers in the different fiber size categories of an exposure metric are estimated using distributions for fiber size based on transmission electron microscopy (TEM) obtained from the literature and matched to the individual epidemiological studies. The fraction of total asbestos exposure in a given environment respectively represented by chrysotile and amphibole asbestos is also estimated from information in the literature for that environment. Adequate information was found to allow KL's from 15 epidemiological studies and KM's from 11 studies to be included in the meta-analysis. Since the range of exposure metrics that could be considered was severely restricted by limitations in the published TEM fiber size distributions, it was decided to focus attention on four exposure metrics distinguished by fiber width: "all widths," widths > 0.2 micro m, widths < 0.4 microm, and widths < 0.2 microm, each of which has historical relevance. Each such metric defined by width was composed of four categories of fibers: chrysotile or amphibole asbestos with lengths between 5 microm and 10 microm or longer than 10 microm. Using these metrics three parameters were estimated for lung cancer and, separately, for mesothelioma: KLA, the potency of longer (length > 10 microm) amphibole fibers; rpc, the potency of pure chrysotile (uncontaminated by amphibole) relative to amphibole asbestos; and rps, the potency of shorter fibers (5 microm < length < 10 microm) relative to longer fibers. For mesothelioma, the hypothesis that chrysotile and amphibole asbestos are equally potent (rpc = 1) was strongly rejected by every metric and the hypothesis that (pure) chrysotile is nonpotent for mesothelioma was not rejected by any metric. Best estimates for the relative potency of chrysotile ranged from zero to about 1/200th that of amphibole asbestos (depending on metric). For lung cancer, the hypothesis that chrysotile and amphibole asbestos are equally potent (rpc = 1) was rejected (p < or = .05) by the two metrics based on thin fibers (length < 0.4 microm and < 0.2 microm) but not by the metrics based on thicker fibers. The "all widths" and widths < 0.4 microm metrics provide the best fits to both the lung cancer and mesothelioma data over the other metrics evaluated, although the improvements are only marginal for lung cancer. That these two metrics provide equivalent (for mesothelioma) and nearly equivalent (for lung cancer) fits to the data suggests that the available data sets may not be sufficiently rich (in variation of exposure characteristics) to fully evaluate the effects of fiber width on potency. Compared to the metric with widths > 0.2 microm with both rps and rpc fixed at 1 (which is nominally equivalent to the traditional PCM metric), the "all widths" and widths < 0.4 microm metrics provide substantially better fits for both lung cancer and, especially, mesothelioma. Although the best estimates of the potency of shorter fibers (5 < length < 10 microm) is zero for the "all widths" and widths < 0.4 microm metrics (or a small fraction of that of longer fibers for the widths > 0.2 microm metric for mesothelioma), the hypothesis that these shorter fibers were nonpotent could not be rejected for any of these metrics. Expansion of these metrics to include a category for fibers with lengths < 5 microm did not find any consistent evidence for any potency of these shortest fibers for either lung cancer or mesothelioma. Despite the substantial improvements in fit over that provided by the traditional use of PCM, neither the "all widths" nor the widths < 0.4 microm metrics (or any of the other metrics evaluated) completely resolve the differences in potency factors estimated in different occupational studies. Unresolved in particular is the discrepancy in potency factors for lung cancer from Quebec chrysotile miners and workers at the Charleston, SC, textile mill, which mainly processed chrysotile from Quebec. A leading hypothesis for this discrepancy is limitations in the fiber size distributions available for this analysis. Dement et al. (2007) recently analyzed by TEM archived air samples from the South Carolina plant to determine a detailed distribution of fiber lengths up to lengths of 40 microm and greater. If similar data become available for Quebec, perhaps these two size distributions can be used to eliminate the discrepancy between these two studies.

• An evaluation of reported no-effect chrysotile asbestos exposures for lung cancer and mesothelioma. J.S. Pierce, M.A. McKinley, D.J. Paustenbach, et al. 2008;38(3):191-214. Review PubMed · Publisher

  Abstract

  Numerous investigators have suggested that there is likely to be a cumulative chrysotile exposure below which there is negligible risk of asbestos-related diseases. However, to date, little research has been conducted to identify an actual "no-effect" exposure level for chrysotile-related lung cancer and mesothelioma. The purpose of this analysis is to summarize and present all of the cumulative exposure-response data reported for predominantly chrysotile-exposed cohorts in the published literature. Criteria for consideration in this analysis included stratification of relative risk or mortality ratio estimates by cumulative chrysotile exposure. Over 350 studies were initially evaluated and subsequently excluded from the analysis due primarily to lack of cumulative exposure information, lack of information on fiber type, and/or evidence of significant exposures to amphiboles. Fourteen studies meeting the inclusion criteria were found where lung cancer risk was stratified by cumulative chrysotile exposure; four such studies were found for mesothelioma. All of the studies involved cohorts exposed to high levels of chrysotile in mining or manufacturing settings. The preponderance of the cumulative "no-effects" exposure levels for lung cancer and mesothelioma fall in a range of approximately 25-1,000 fibers per cubic centimeter per year (f/cc-yr) and 15-500 f/cc-yr, respectively, and a majority of the studies did not report an increased risk at the highest estimated exposure. Sources of uncertainty in these values include errors in the cumulative exposure estimates, conversion of dust counts to fiber data, and use of national age-adjusted mortality rates. Numerous potential biases also exist. For example, smoking was rarely controlled for and amphibole exposure did in fact occur in a majority of the studies, which would bias many of the reported "no-effect" exposure levels towards lower values. However, many of the studies likely lack sufficient power (e.g., due to small cohort size) to assess whether there could have been a significant increase in risk at the reported no-observed-adverse-effects level (NOAEL); additional statistical analyses are required to address this source of bias and the attendant influence on these values. The chrysotile NOAELs appear to be consistent with exposure-response information for certain cohorts with well-established industrial hygiene and epidemiology data. Specifically, the range of chrysotile NOAELs were found to be consistently higher than upper-bound cumulative chrysotile exposure estimates that have been published for pre-1980s automobile mechanics (e.g., 95th percentile of 2.0 f/ cc-yr), an occupation that historically worked with chrysotile-containing friction products yet has been shown to have no increased risk of asbestos-related diseases. While the debate regarding chrysotile as a risk factor for mesothelioma will likely continue for some time, future research into nonlinear, threshold cancer risk models for chrysotile-related respiratory diseases appears to be warranted.

• Update of potency factors for asbestos-related lung cancer and mesothelioma. D.W. Berman, K.S. Crump. 2008;38 Suppl 1:1-47. PubMed · Publisher

  Abstract

  The most recent update of the U.S. Environmental Protection Agency (EPA) health assessment document for asbestos (Nicholson, 1986, referred to as "the EPA 1986 update") is now 20 years old. That document contains estimates of "potency factors" for asbestos in causing lung cancer (K(L)'s) and mesothelioma (K(M)'s) derived by fitting mathematical models to data from studies of occupational cohorts. The present paper provides a parallel analysis that incorporates data from studies published since the EPA 1986 update. The EPA lung cancer model assumes that the relative risk varies linearly with cumulative exposure lagged 10 years. This implies that the relative risk remains constant after 10 years from last exposure. The EPA mesothelioma model predicts that the mortality rate from mesothelioma increases linearly with the intensity of exposure and, for a given intensity, increases indefinitely after exposure ceases, approximately as the square of time since first exposure lagged 10 years. These assumptions were evaluated using raw data from cohorts where exposures were principally to chrysotile (South Carolina textile workers, Hein et al., 2007; mesothelioma only data from Quebec miners and millers, Liddell et al., 1997) and crocidolite (Wittenoom Gorge, Australia miners and millers, Berry et al., 2004) and using published data from a cohort exposed to amosite (Paterson, NJ, insulation manufacturers, Seidman et al., 1986). Although the linear EPA model generally provided a good description of exposure response for lung cancer, in some cases it did so only by estimating a large background risk relative to the comparison population. Some of these relative risks seem too large to be due to differences in smoking rates and are probably due at least in part to errors in exposure estimates. There was some equivocal evidence that the relative risk decreased with increasing time since last exposure in the Wittenoom cohort, but none either in the South Carolina cohort up to 50 years from last exposure or in the New Jersey cohort up to 35 years from last exposure. The mesothelioma model provided good descriptions of the observed patterns of mortality after exposure ends, with no evidence that risk increases with long times since last exposure at rates that vary from that predicted by the model (i.e., with the square of time). In particular, the model adequately described the mortality rate in Quebec chrysotile miners and millers up through >50 years from last exposure. There was statistically significant evidence in both the Wittenoom and Quebec cohorts that the exposure intensity-response is supralinear(1) rather than linear. The best-fitting models predicted that the mortality rate varies as [intensity](0.47) for Wittenoom and as [intensity](0.19) for Quebec and, in both cases, the exponent was significantly less than 1 (p< .0001). Using the EPA models, K(L)'s and K(M)'s were estimated from the three sets of raw data and also from published data covering a broader range of environments than those originally addressed in the EPA 1986 update. Uncertainty in these estimates was quantified using "uncertainty bounds" that reflect both statistical and nonstatistical uncertainties. Lung cancer potency factors (K(L)'s) were developed from 20 studies from 18 locations, compared to 13 locations covered in the EPA 1986 update. Mesothelioma potency factors (K(M)'s) were developed for 12 locations compared to four locations in the EPA 1986 update. Although the 4 locations used to calculate K(M) in the EPA 1986 update include one location with exposures to amosite and three with exposures to mixed fiber types, the 14 K(M)'s derived in the present analysis also include 6 locations in which exposures were predominantly to chrysotile and 1 where exposures were only to crocidolite. The K(M)'s showed evidence of a trend, with lowest K(M)'s obtained from cohorts exposed predominantly to chrysotile and highest K(M)'s from cohorts exposed only to amphibole asbestos, with K(M)'s from cohorts exposed to mixed fiber types being intermediate between the K(M)'s obtained from chrysotile and amphibole environments. Despite the considerable uncertainty in the K(M) estimates, the K(M) from the Quebec mines and mills was clearly smaller than those from several cohorts exposed to amphibole asbestos or a mixture of amphibole asbestos and chrysotile. For lung cancer, although there is some evidence of larger K(L)'s from amphibole asbestos exposure, there is a good deal of dispersion in the data, and one of the largest K(L)'s is from the South Carolina textile mill where exposures were almost exclusively to chrysotile. This K(L) is clearly inconsistent with the K(L) obtained from the cohort of Quebec chrysotile miners and millers. The K(L)'s and K(M)'s derived herein are defined in terms of concentrations of airborne fibers measured by phase-contrast microscopy (PCM), which only counts all structures longer than 5 microm, thicker than about 0.25 microm, and with an aspect ratio > or =3:1. Moreover, PCM does not distinguish between asbestos and nonasbestos particles. One possible reason for the discrepancies between the K(L)'s and K(M)'s from different studies is that the category of structures included in PCM counts does not correspond closely to biological activity. In the accompanying article (Berman and Crump, 2008) the K(L)'s and K(M)'s and related uncertainty bounds obtained in this article are paired with fiber size distributions from the literature obtained using transmission electron microscopy (TEM). The resulting database is used to define K(L)'s and K(M)'s that depend on both the size (e.g., length and width) and mineralogical type (e.g., chrysotile or crocidolite) of an asbestos structure. An analysis is conducted to determine how well different K(L) and K(M) definitions are able to reconcile the discrepancies observed herein among values obtained from different environments.

• Chrysotile as a cause of mesothelioma: an assessment based on epidemiology. C.M. Yarborough. 2006;36(2):165-87. Review PubMed · Publisher

  Abstract

  There has been a longstanding debate about the potential contribution of chrysotile asbestos fibers to mesothelioma risk. The failure to resolve this debate has hampered decisive risk communication in the aftermath of the collapse of the World Trade Center towers and has influenced judgments about bans on asbestos use. A firm understanding of any health risks associated with natural chrysotile fibers is crucial for regulatory policy and future risk assessments of synthesized nanomaterials. Although epidemiological studies have confirmed amphibole asbestos fibers as a cause of mesothelioma, the link with chrysotile remains unsettled. An extensive review of the epidemiological cohort studies was undertaken to evaluate the extent of the evidence related to free chrysotile fibers, with particular attention to confounding by other fiber types, job exposure concentrations, and consistency of findings. The review of 71 asbestos cohorts exposed to free asbestos fibers does not support the hypothesis that chrysotile, uncontaminated by amphibolic substances, causes mesothelioma. Today, decisions about risk of chrysotile for mesothelioma in most regulatory contexts reflect public policies, not the application of the scientific method as applied to epidemiological cohort studies.

• Potential pulmonary effects of man-made organic fiber (MMOF) dusts. D.B. Warheit, G.A. Hart, T.W. Hesterberg, et al. 2001;31(6):697-736. Review PubMed · Publisher

  Abstract

  In the first half of the twentieth century epidemiologic evidence linked elevated incidences of pulmonary fibrosis and cancer with inhalation of chrysotile and crocidolite asbestos, a family of naturally occurring inorganic fibrous materials. As the serpentine and amphibole forms of asbestos were phased out, synthetic vitreous fibers (SVFs; fiber glass, mineral wool, and refractory fiber) became increasingly utilized, and concerns were raised that they too might cause adverse health effects. Extensive toxicological research on SVFs has demonstrated that their pulmonary effects are directly related to fiber dose in the lung over time. This is the result of deposition (thin fibers deposit in the lower lung more efficiently than thick fibers) and lung-persistence ("biopersistence" is directly related to fiber length and inversely related to dissolution and fragmentation rates). In rat inhalation studies, asbestos was determined to be 7- to 10-fold more biopersistent in the lung than SVFs. Other than its effect on biopersistence, fiber composition did not appear to play a direct role in the biological activity of SVFs. Recently, the utilization of man-made organic fibers (MMOFs) (also referred to by some as synthetic organic fibers) has increased rapidly for a variety of applications. In contrast to SVFs, research on the potential pulmonary effects of MMOFs is relatively limited, because traditionally MMOFs were manufactured in diameters too thick to be respirable (inhalable into the lower lung). However, new developments in the MMOF industry have resulted in the production of increasingly fine-diameter fibers for special applications, and certain post-manufacturing processes (e.g., chopping) generate respirable-sized MMOF dust. Until the mid-1990s, there was no consistent evidence of human health affects attributed to occupational exposure to MMOFs. Very recently, however, a unique form of interstitial lung disease has been reported in nylon flock workers in three different plants, and respirable-sized nylon shreds (including fibers) were identified in workplace air samples. Whether nylon dust or other occupational exposures are responsible for the development of lung disease in these workers remains to be determined. It is also unknown whether the biological mechanisms that determine the respirability and toxicity of SVFs apply to MMOFs. Thus, it is appropriate and timely to review the current data regarding MMOF workplace exposure and pulmonary health effects, including the database on epidemiological, exposure assessment, and toxicology studies.

• Synthetic vitreous fibers: a review of toxicology research and its impact on hazard classification. T.W. Hesterberg, G.A. Hart. 2001;31(1):1-53. Review PubMed · Publisher

  Abstract

  Because the inhalation of asbestos, a naturally occurring, inorganic fibrous material, is associated with lung fibrosis and thoracic cancers, concerns have been raised about the possible health effects of synthetic vitreous fibers (SVFs). SVFs include a very broad variety of inorganic fibrous materials with an amorphous molecular structure. Traditionally, SVFs have been divided into three subcategories based on composition: fiberglass, mineral wool (rock, stone, and slag wools), and refractory ceramic fiber. For more than 50 years, the toxicologic potential of SVFs has been researched extensively using human epidemiology and a variety of laboratory studies. Here we review the research and its impact on hazard classification and regulation of SVFs. Large, ongoing epidemiology studies of SVF manufacturing workers have provided very little evidence of harmful effects in humans. Several decades of research using rodents exposed by inhalation have confirmed that SVF pulmonary effects are determined by the "Three D's", fiber dose (lung), dimension, and durability. Lung dose over time is determined by fiber deposition and biopersistence in the lung. Deposition is inversely related to fiber diameter. Biopersistence is directly related to fiber length and inversely related to fiber dissolution and fragmentation rates. Inhaled short fibers are cleared from the lung relatively quickly by mobile phagocytic cells, but long fibers persist until they dissolve or fragment. In contrast to asbestos, most of the SVFs tested in rodent inhalation studies cleared rapidly from the lung (were nonbiopersistent) and were innocuous. However, several relativley biopersistent SVFs induced chronic inflammation, lung scarring (fibrosis), and thoracic neoplasms. Thus, biopersistence of fibers is now generally recognized as a key determinant of the toxicologic potential of SVFs. In vitro dissolution of fibers in simulated extracellular fluid correlates fairly well with fiber biopersistence in the lung and pulmonary toxicity, but several exceptions suggest that biopersistence involves more than dissolution rate. Research demonstrating the relationship between biopersistence and SVF toxicity has provided a scientific basis for hazard classification and regulation of SVFs. For a nonhazardous classification, legislation recently passed by the European Union requires a respirable insulation wool to have a low lung-biopersistence or be noncarcinogenic in laboratory rats. U.S. fiberglass and mineral wool industries and the Occupational Health and Safety Administration (OSHA) have formed a voluntary Health and Safety Partnership Program (HSPP) that include: a voluntary permissible exposure level (PEL) in the workplace of 1 fiber/cc, a respiratory protection program for specified tasks, continued workplace air monitoring, and, where possible, the development of fiber formulations that do not persist in the lung. RCF manufacturers have implemented a Product Stewardship Program that includes: a recommended exposure guideline of 0.5 fibers/cc; a 5-year workplace air monitoring program; and research into the development of high-temperature-resistant, biosoluble fibers.

1980s

• Interspecies comparisons of lung responses to inhaled particles and gases. D.B. Warheit. 1989;20(1):1-29. Review PubMed · Publisher

  Abstract

  Two important challenges for inhalation toxicologists involve the elucidation of mechanisms of lung toxicity caused by inhalation of chemicals or particulate materials, as well as the extrapolation of animal data to humans. Because risk estimates of toxicity generally are dependent upon experimental data for which a variety of species are utilized, a fundamental knowledge of species similarities and differences in lung anatomy, physiology, biochemistry, cell biology, and corresponding disease processes is essential. In the present review, the known mechanisms of particle deposition and clearance among various species have been highlighted and related to structure/function relationships and pathogenetic responses to some selected inhaled toxicants. In the aggregate, there is remarkable homogeneity in form and function among the species. Morphologic aspects of the respiratory tract and lung defense mechanisms are qualitatively similar among species. On the other hand, quantitative differences between humans and experimental animals are known to exist with respect to deposition and mucociliary clearance of inhaled particulates, and these factors are likely to influence the dose that is delivered to specific target sites in the lung. It is interesting to consider that pathologic cellular events following asbestos, ozone, and nitrogen dioxide exposure are likely to occur at similar sites in humans, nonhuman primates, and rodents. In this respect, it has been demonstrated that the early lesions of asbestos-induced lung disease in both rats and humans are initiated at similar anatomical sites, i.e., the junctions of terminal airways and alveolar regions. PMs and complement-mediated mechanisms have been implicated in the development of asbestosis in rats; however, it remains to be determined whether complement activation plays an important role in human asbestosis, although pulmonary and interstitial macrophages clearly are associated with the fibrogenic process associated with this restrictive lung disease. The toxic pulmonary effects following ozone exposure have been well studied in rodents and nonhuman primates. It has been established that distal airway and alveolar epithelial cells are principal targets of oxidant pollutants, and this is well supported by dosimetry considerations, morphologic observations, and morphometric analyses. Chronic ozone exposure in rats and monkeys causes epithelial injury at the level of the terminal bronchiole and proximal alveolar regions of the lung.(ABSTRACT TRUNCATED AT 400 WORDS)

• Lung response to particulates with emphasis on asbestos and other fibrous dusts. K.P. Lee. 1985;14(1):33-86. Review PubMed · Publisher

  Abstract

  Many theories have been proposed to explain asbestosis and asbestos-related pulmonary disease. However, none of the theories give a completely plausible explanation for the pathogenesis. Recently, attention has been drawn to a theory that the fibrogenicity or carcinogenicity of fibrous dust particles is related to fiber diameter and length rather than to chemical properties. This theory may help partially elucidate the disease process but is still far from solving the enigma of pulmonary fibrosis or carcinogenesis. The theory cannot explain the absence of these pathological effects among fiberglass workers or experimental animals exposed by inhalation (even though mesotheliomas are induced by intrapleural implantation and fiber dimension-related fibrogenicity is demonstrated by intratracheal injection). Little information regarding the pulmonary response to manmade fibrous particles is available in animals following inhalation exposure. Attempts should be made to confirm the absence of adverse effects using animal inhalation experiments even though to this point there is no conclusive evidence that either lung cancer or pulmonary diseases can be produced among employees in manmade fiber industries. A new research trend seems concentrated on testing the durability of asbestos or manmade fibers. This is based on the concept that biological effects of fibrous particles are the result of relative durability and that particles which can be fragmented or shortened may be less pathogenic. In the last two decades, considerable understanding about pulmonary fibrosis and carcinogenesis of asbestos has been achieved by clinical and animal experiments. In vitro tests including cytotoxicity, hemolysis, immunology, and enzyme biochemistry have provided important information on the interrelationships among these various biological effects of asbestos.

• The mesothelium and its reactions: a review. D. Whitaker, J.M. Papadimitriou, M.N. Walters. 1982;10(2):81-144. Review PubMed · Publisher

  Abstract

  The origins, nature, and reactions of the mesothelium have intrigued investigators for over 100 years. Recently, the use of sophisticated techniques has clarified earlier impressions of its development, structure, and function. The structure of mesothelium reflects its functional properties, its long slender microvilli entrapping a layer of glycosoaminoglycans, providing a frictionless free surface between the parietal and visceral serosa. Transport requirements are met by various surface modifications and both inter- and intra-cellular mechanisms occur. The presence of stomatal openings in the mesothelial membrane has been established, and they may have a major role to play in the movement of cells to and from the serosal cavities. In addition, mesothelial cells can respond to situations of increased functional demand and during the course of inflammation, the mesothelium's fibrinolytic properties are of major importance in preventing the formation of adhesions and the enhancement of healing. Of all the unanswered questions the most significant is the nature, localization, and potentialities of mesothelial precursors. A mesodermal origin is readily acknowledged, but the healing process of damaged mesothelium is less clear. It seems probable that "mature" mesothelium is one source of cell renewal, but mesenchymal cells located in the submesothelial serosa are also strong contenders. Neoplastic mesothelium can adopt a spectrum of histological appearances, reflecting its mesodermal origins. In fact, overacceptance of this concept has erroneously led to the classification of other neoplasms arising in the serosal area as mesotheliomas. Although the ocogenic sequence is still obscure, asbestos is recognized as the major etiologic agent in malignant mesotheliomas. In 1955, Hartwell described differing impressions of the peritoneum as seen through the eyes of an anatomist, an histologist, and a surgeon. In this review on the mesothelium we have attempted to unravel some of its complexities as viewed by embryologists, electronmicroscopists, cell biologists, pathologists, and oncologists.

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