Asbestos is the generic name for a group of fibrous silicates present in nature, used in industrial processes and in the production of several products for domestic and environmental use.1–4 According to the chemical composition and physical properties, asbestos fibers are classified as serpentine (chrysotile or white asbestos), and amphibole comprising crocidolite (blue asbestos), amosite (brown asbestos), anthophyllite (yellow asbestos), tremolite (gray asbestos), and actinolite.2,3,5

It is well known that exposure to asbestos fibers can lead to diseases such as asbestosis (or diffuse interstitial pulmonary fibrosis), diffuse pleural fibrosis, rounded atelectasis (Blesovski's syndrome), malignant mesothelioma and also ovary, lung and laryngeal cancer. Currently, there is limited evidence in humans to establish the causal relationship between gastrointestinal cancer and asbestos exposure.1,3,6–8

The health hazard of asbestos depends on several factors such as its concentration in the air, the exposure time, the type and the size of the fibers, the respiratory rate associated with physical exertion and thermo-hygrometric conditions, the anatomical and functional conditions of exposed workers and there exists a tobacco smoke modulating effect.6

The unit measures used for asbestos exposure may vary. The ACGIH establishes threshold limit values in occupational health.9 On the one hand, fibers per cubic centimeter (f/cc or f/cm3), equivalent to fibers per milliliter (f/ml), is commonly used to measure exposure during a working day (about 8hours of duration) or during short-term exposures. These measures are compared with the permissible exposure limits (PEL, OSHA), the threshold limit values (TLV, ACGIH), the recommended exposure limits (REL, NIOSH) or the indicative occupational exposure limit values (IOELV, EU). On the other hand, fibers per milliliter and year (f/ml-y) is an exposure measure that represents the cumulative exposure to asbestos over a working life and is the measure that best reflects exposure intensity (exposure intensity equals the average concentration of asbestos in air multiplied by the duration of the exposure). Expressions such as fibers/milliliter-year (f/ml-y), fibers-year/milliliter (f-y/ml), fibers/cubic centimeter-year (f/cc-y) and fibers-year/cubic centimeter (f-y/cc) can be found in the literature. In order to analyze the effects of cancer, pulmonary fibrosis, mesothelioma and other pathologies, epidemiological studies tend to use this measure of cumulative exposure. Also, exposure units in millions of particles per cubic foot per year (mppcf-y) have been used.

The OSHA has set a PEL for asbestos at 0.1 fiber per cubic centimeter of air as an eight-hour time-weighted average (TWA), with an excursion limit (EL) of 1.0 asbestos fibers per cubic centimeter over a 30-minute period.10 Likewise, in Europe the 2009/148/EC Directive of the European Parliament and of the Council establishes the airborne concentration of asbestos in excess of 0.1 fibers per cubic centimeter as an 8-hour time-weighted average (TWA).11 For several years, this exposure limit has been adopted, with some variations, by several European countries.12,13

Although the exposure limit values have been lowered over the years, coinciding with the advances in scientific evidence on the harmful effects of asbestos, widespread social debate continues on the existence of a minimum level of intensity of exposure to asbestos below which exposure is safe and above which there is a likelihood of developing health damage. For that reason, continually reviewing and updating information on the health-effects exposure levels of asbestos is important. The aim of this study is to contribute to this debate, reviewing the best and the most recent scientific evidence available in the international literature on exposure levels for asbestos fibers and their relationship with established asbestos health effects.

An umbrella review14 was performed, retrieving systematic reviews and meta-analyses available in MEDLINE/PubMed, Google Scholar Academics bibliographic repository, the International Agency for Research on Cancer (IARC),3 the U.S. Agency for Toxic Substances and Disease Registry (ATSDR),15 the U.S. Environmental Protection Agency (EPA),16 the U.K. Health and Safety Executive (HSE)17 and the Canadian Institute for Work and Health (IWH).18

Several search strategies were tested using the usual connectors for keywords (AND, OR, NOT, etc.), obtaining final search engines to capture as many references as possible, filtered by “review AND systematic review AND meta-analysis”. The search was restricted to articles published in English from 1980 to March 2021. We included both human and experimental studies in animals.

An initial search strategy was carried out with a wide perspective and using search engines to capture all articles that analyzed the association between asbestos exposure and any known asbestos disease, including lung cancer, mesothelioma, asbestosis, diffuse interstitial pulmonary fibrosis, pleural plaques, diffuse pleural fibrosis, larynx and gastrointestinal cancer. Afterwards, different key words were incorporated to the search engines to restrict them to those articles that also incorporated variables that quantified exposure (fiber concentration, dose-exposure, exposure-response or dose-response). The syntaxes used in this review are shown in Supplemental text (syntaxes) in online Appendix.

Each of these syntaxes was applied independently and duplicate studies were eliminated. Titles and abstracts were screened using independent peer-review. A third expert resolved discrepancies and independently decided final inclusion for full text analysis. Only systematic reviews and meta- analyses evaluating exposure to asbestos fibers and its relationship to health effects were included in this umbrella review.

A first selection was based on reading the title, including those with the words “asbestos” and “pathology”, excluding those that were not of interest for the purpose of the study or were doubtful. The second selection was based on reading the abstracts, excluding those studies that did not analyze associations between asbestos exposure and the selected pathologies, or were not systematic reviews or meta-analyses. In a third phase, full texts were screened and articles that did not refer to the purpose of the study were excluded.

In a final stage, an evaluation of the methodological quality of the selected studies was performed by means of the AMSTAR (Assessment of Multiple SysTemAtic Reviews) instrument.19 The instrument is a reliable and valid measure for the evaluation of the methodological quality of systematic reviews and has proven good face and content validity.20 To report the results of this review, the evidence-based set of items for reporting systematic reviews stated by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) have been followed.21 This study has been registered at PROSPERO (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=185349).

The first finding is that all asbestos fibers have been associated consistently with lung cancer, mesothelioma and pulmonary fibrosis. In relation to laryngeal and ovarian cancer the causality of asbestos has also been demonstrated, but we did not find any systematic reviews or meta-analyses on these two pathologies to be able to draw conclusions about exposure levels. The evidence is, to date, less conclusive for gastrointestinal tumors.27

A second finding is that the risk, varies depending on the type of asbestos, the physicochemical characteristics of these fibers, the intensity of exposure and, for some pathologies, co-exposures with other carcinogens, especially tobacco. The studies clearly point that the greatest risk exists with exposure to amphibole fibers, followed by mixed fibers (amphibole and chrysotile), and finally, chrysotile. However, when analyzing the risk that occurs depending on the intensity of asbestos exposure, some studies suggest that for mesothelioma and lung cancer there may be a threshold below which there is no significantly increased risk of suffering the pathology, whereas other studies cannot conclude the existence of a threshold. What seems quite evident is that the exposure intensity required to produce mesothelioma may be lower than for lung cancer or pulmonary fibrosis (asbestosis).

The joint assessment of the analyzed systematic reviews and meta-analyses leads us to the conclusion that there is little risk of lung cancer or mesothelioma at daily exposure levels below 0.1 f/ml (daily environmental exposure limit value). However, most times the measures are reconstructions made decades after the exposure has taken place, which can have a large margin of error when applied to individual patients.33 Our findings could be explained at least in part by the carcinogenetic inflammatory mechanisms of asbestos. As a recent review has shown,34 asbestos and other fibers remain in the affected tissue for months to years, triggering a chronic inflammatory process and consequent release of high mobility group protein B1 and other cytokines that maintain this process which may ensue in cancer. This pathogenic mechanism could support the fact that low amounts of fibers, probably below 0.1 f/ml, are less likely to elicit a chronic inflammatory process. Other naturally occurring fibers are present in the environment and some of them (e.g. erionite) are as or more carcinogenic than asbestos.34,35

In any case, the most recent cutting-edge research shows that “safe” levels could vary greatly from one individual to another depending on the genetics of each individual. In this regard, for example, heritable mutations of the germline BAP1 and other tumor suppressor genes have been reported to increase susceptibility to asbestos carcinogenesis. It is estimated that 12% of mesotheliomas occur in carriers of these mutations.36,37

The occupational exposure limit values proposed by internationally renowned agencies have been drastically reduced over time. The ACGIH has adopted the current TLV of 0.1 f/ml for all types of asbestos.38 The limit values proposed by other agencies such as OSHA,10 NIOSH,39 CCOHS,40 HSE41 and UE-OSHA42 currently set an exposure limit value for eight-hour time-weighted average of 0.1 f/ml (with certain particularities). However, as both the ILO and the WHO have stated, there is no safe level of exposure to a carcinogen and, in concordance with them, we advocate for the global ban and eradication of all types of asbestos and demand the complete elimination of asbestos-related diseases as a global public health priority.43,44 This review, analyzed and synthesized the main results of 10 systematic reviews and available meta-analyses of the last 40 years that have examined asbestos exposure values that pose a threat to human health. Likewise, the fact that the first article included in the review was published in 1997 and the last in 2017 ensures that our review of reviews included all the reviews and meta-analyses published over the last 40 years.

None of the selected reviews scored low in the assessment of their methodological quality; some of them obtained intermediate quality scores (4 ≥ P ≤ 5) [22-27,30] and 50% of the reviews obtained middle 25,26or high quality scores (P ≥ 8),28,29,31 supporting a reasonably good quality of the included studies.

As any scientific study this one may have some limitations. It is possible in this type of studies, based on systematic search for scientific publications, to overlook unpublished studies (publication bias). Nevertheless, the fact that we included in our search those studies available on the websites of the leading institutions worldwide which have evaluated research on the health consequences of asbestos exposure, including IARC (WHO), NIOSH (USA), ACGIH (USA), ATSDR (USA), EPA (USA), IWH (Canada) and HSE (UK), it is unlikely that we have left out any major review or meta- analyses performed in recent years.

In summary, several studies provide a value for asbestos exposure below which no risk of lung cancer or mesothelioma would be observed 26,28,31and scientific evidence reported in the highest quality reviews and meta-analyses identified in this umbrella review (those with a 10 on the quality assessment), support that there is only limited evidence of the risk of lung cancer or mesothelioma at daily exposure levels below 0.1 f/ml (daily exposure environmental limit value). However, following the recommendations of the ILO and WHO, the best measure to prevent the negative health effects of asbestos exposure is its banning and eradication following strict cleaning protocols.43,44

Although the exposure limit values for asbestos have been lowered over the years, coinciding with the advances in scientific evidence on the harmful effects of asbestos, widespread social debate continues on the existence of a minimum level of intensity of exposure to asbestos below which exposure is safe and above which there is a likelihood of developing health damage.

This study contributes to this debate, reviewing the best and the most recent scientific evidence available in the international literature on exposure levels for asbestos fibers and their relationship with established asbestos health effects.

There is limited evidence of the risk of lung cancer or mesothelioma at daily exposure levels below 0.1 f/ml (VLA-ED). However, the best measure to prevent negative health effects of asbestos exposure is its banning and eradication following strict cleaning protocols.

Juan Alguacil.

J.M. Ramada Rodilla and F.G. Benavides have designed, planned and directed the study in all its stages. J.M. Ramada Rodilla prepared the first version of the manuscript. J.M. Ramada Rodilla, B. Calvo Cerrada, C. Serra Pujadas, G.L. Delclos and F.G. Benavides participated in the execution of the study, designing the search syntaxes, selecting the retrieved reviews and meta-analysis, applying the inclusion and exclusion criteria, and summarizing the main results in tables. All the authors have participated in the interpretation and discussion of the results and have critically reviewed the work, making relevant contributions at each stage of the study. All the authors have approved its final version and agree to its publication.

This review was funded by grants from Instituto de Salud Carlos III-FEDER (Grant Number PI16/00061) and the Barcelona Metropolitan Transport System (TMB).

No professional or person with interests of any kind with the funders (TMB and Instituto de Salud Carlos III-FEDER) participated in the design, development, analysis, conclusions and/or presentation of the results of this study. The authors declare their autonomy and independence to review and draw the most scientifically sound conclusions based on the best available evidence at present. The authors of this article declare that they have no other competing interests.