Review of refractory ceramic fiber (RCF) toxicity, epidemiology and occupational exposure

Abstract

This literature review on refractory ceramic fibers (RCF) summarizes relevant information on manufacturing, processing, applications, occupational exposure, toxicology and epidemiology studies. Rodent toxicology studies conducted in the 1980s showed that RCF caused fibrosis, lung cancer and mesothelioma. Interpretation of these studies was difficult for various reasons (e.g. overload in chronic inhalation bioassays), but spurred the development of a comprehensive product stewardship program under EPA and later OSHA oversight. Epidemiology studies (both morbidity and mortality) were undertaken to learn more about possible health effects resulting from occupational exposure. No chronic animal bioassay studies on RCF have been conducted since the 1980s. The results of the ongoing epidemiology studies confirm that occupational exposure to RCF is associated with the development of pleural plaques and minor decrements in lung function, but no interstitial fibrosis or incremental lung cancer. Evidence supporting a finding that urinary tumors are associated with RCF exposure remains, but is weaker. One reported, but unconfirmed, mesothelioma was found in an individual with prior occupational asbestos exposure. An elevated SMR for leukemia was found, but was absent in the highly exposed group and has not been observed in studies of other mineral fibers. The industry will continue the product stewardship program including the mortality study.

Keywords:

• Classification
• epidemiology
• refractory ceramic fiber
• toxicology
• pleural plaques occupational exposure
• Product Stewardship Program
• Recommended Exposure Guideline

Introduction

The most recent comprehensive review of refractory ceramic fibers (RCF) toxicology, epidemiology and exposure was published in this journal in 2010 (Utell & Maxim, 2010). Although no new chronic animal bioassays were conducted since the earlier publication, there are more recent data on occupational exposures and updates from the ongoing University of Cincinnati (UC) and other epidemiology studies that are noteworthy. Additionally, several other studies have been published that are relevant to assessing possible health risks of occupational exposure to RCF.

Hoffmann et al. (2017) suggests that the procedure for selection of papers to be included in a review article be made explicit. The papers and reports included in this article were identified based on the specific knowledge of the authors (useful for reports) and a sequence of Internet searches using PubMed and Google Scholar. For papers dealing specifically with refractory ceramic fiber, search terms included; ceramic fiber, synthetic vitreous fiber, man-made mineral fiber, Alumino Silicate wool, health effects, pleural plaques, spirometry, epidemiology, toxicology, lung cancer, mesothelioma, exposure, recommended exposure guideline, recommended exposure limit, occupational exposure limit, durability, dissolution rates, biopersistence and product stewardship. The focus of this article is on developments since 2010, but earlier years were included in the searches to discover any articles that might have been missed in the 2010 review.

Brief background

Composition and manufacture

RCF (CAS no. 142844-00-6), first invented in the 1940s, are amorphous fibers that belong to a class of materials termed synthetic vitreous fibers (SVFs), also called synthetic mineral fibers (SMFs), man-made mineral fibers (MMMFs) or man-made vitreous fibers (MMVFs), which also includes alkaline earth silicate (AES) wool, glass wool, rock (stone) wool, slag wool and special-purpose glass fibers. RCF are produced by melting (at ∼1925 °C) a mixture of alumina (Al₂O₃) and silica (SiO₂) in approximately equal proportions. Other inorganic oxides, such as Zr₂O₃, Cr₂O₃, B₂O₃ and TiO₂ are sometimes added to alter the properties (e.g. durability or maximum end-use temperature) of the resulting product (AFSSET, 2007; NIOSH, 2006). RCF can also be made by melting blends of calcined kaolin, alumina and silica. The molten material is made into fibers by either a blowing or a spinning process. Typical compositions of RCF and other SVFs are given in several sources (AFSSET, 2007; ATSDR, 2004; IARC, 2002; National Research Council, 2000; NIOSH, 2006). As manufactured, RCF are in the form of bulk fibers. Subsequent processing steps are used to convert the RCF into other physical forms such as a blanket, modules (folded blanket with hardware for rapid installation), paper, felt, board, vacuum formed shapes, textiles and as a putty or paste.

Physical properties

RCF have several desirable physical properties as a high-temperature insulating material. These include low thermal conductivity, low heat storage (low volumetric heat capacity), high thermal shock resistance, lightweight, good corrosion resistance and ease of installation (ERM, 1995). Depending upon the formulation, the maximum use temperature can be as high as 1430 °C (ERM, 1995; NIOSH, 2006; TIMA, 1993). For this reason, RCF (and certain other fibers) are also termed high-temperature insulating wools (HTIWs). These properties make RCF useful as a lightweight high-temperature insulation material.

RCF applications are principally industrial, where it is used as a furnace lining in the chemical, fertilizer, petrochemical, steel, glass, ceramic, cement, foundry, and forging industries (Mast et al., 2000a,b; Utell & Maxim, 2010). RCF is also used as fire protection for buildings and industrial process equipment, as aircraft/aerospace heat shields, and in automotive uses, such as catalytic converters, metal reinforcements, heat shields, brake pads, and airbags (Everest Consulting Associates, 1996; ERM, 1995 [focus on European applications]; Maxim et al., 1997). IARC (2002) noted that RCF production was approximately 1–2% of all mineral fibers as of that date.

Our current understanding of fiber toxicology (the so-called 3D paradigm of dose, dimension and durability; see Bernstein, 2007; Greim et al., 2014; Hesterberg & Hart 2001; Lippmann, 2014) indicates that fibers with greatest toxicological potential are those that are:

• Respirable, that has lengths l > 5 μm, diameters d ≤ 3 μm and aspect ratios l/d ≥3 (WHO) or ≥5 (NIOSH 7400 B),

• Sufficiently long (>20 μm) to impede clearance by alveolar macrophages and

• Biopersistent (not rapidly cleared from the lung by dissolution or breakage).

Refer Greim et al. (2014), Mast et al. (2000a,b) and Maxim et al. (2000) for length-diameter distributions of RCF in occupational exposures.

Figure 1 shows weighted half-times (days) of long (>20 μm) fibers from short-term inhalation studies for two types of amphibole asbestos (crocidolite and amosite) and several SVFs (including RCF) as measured by Hesterberg et al. (1998). RCF 1, one of three most common forms in the US and one of the fibers tested in the animal bioassays, was specially prepared to be rat respirable. However, later analysis (Maxim et al., 1997) showed that the particle to fiber ratio of RCF 1 was not representative of that found in workplace samples. RCF 1a was prepared from RCF 1 to match the particle to fiber ratio found in workplace samples. Additional information on RCF 1a has been published (Bellmann et al., 2001; Brown et al., 2000; Mast et al., 2000a,b]). As can be seen, RCF are more durable and biopersistent than several other SVFs, although very much less biopersistent than amphibole asbestos (see data from various sources summarized in Brown et al., 2005; Greim et al., 2014; Matsuzaki et al., 2015; Maxim et al., 2006). The averagely weighted half-time for RCF in rodents from several studies is approximately 50 days. There are no half-time data in humans, however, Lockey et al. (2012) noted that RCF can persist in human lung tissue for as much as 20 years.

Figure 1. Weighted half-times (days) in the pulmonary region for amphibole asbestos and selected SVFs (Greim et al., 2014; Hesterberg et al., 1998; Maxim et al., 2006).

Animal tests and hazard classification

The earliest animal study, published in 1956 (Gross et al., 1956) on male rats exposed by intratracheal injection, concluded that RCF was no more hazardous than a “nuisance dust”, but later studies conducted in the 1980s (Davis et al., 1984; Smith et al., 1987) and 1990s called this conclusion into question. Chronic nose-only studies on rats and hamsters conducted at the Research and Consulting Company (RCC) (then located in Geneva, Switzerland) indicated that nose-only inhalation exposure to high concentrations of RCF, resulted in fibrosis and tumors (for reviews and references see Greim et al., 2014; Mast et al., 1995a,b; McConnell et al., 1995; Mast et al., 2000a; NIOSH, 2006; Utell & Maxim, 2010). In 1988, an IARC Working Group reviewed the available evidence for RCF and placed RCF in Group 2B (possibly carcinogenic to humans). This classification was reaffirmed by a subsequent Working Group meeting in 2001 (IARC, 2002), which concluded that there was sufficient evidence in experimental animals but inadequate evidence in humans for the carcinogenicity of refractory ceramic fibers. Later analyzes, however, indicated that the RCC animal studies were compromised by overload, a factor that has made it difficult to derive accurate estimates of risk by extrapolation of animal study results (Brown et al., 2005; Drummond et al., 2016; Greim et al., 2014; Maxim et al., 2003; NIOSH, 2006; Utell & Maxim, 2010). Notwithstanding limitations of the animal studies, these results prompted concern that exposure to RCF might lead to similar health effects to those for various types of asbestos.

Harrison et al. (2015) provide a discussion of regulatory approaches in both the US and Europe. Useful discussions of RCF carcinogen classification and setting occupational exposure limits (OELs) in Europe can also be found in DECOS (2011), Greim et al. (2014) and SCOEL (2011). SCOEL recommended an OEL of 0.3 fibers/ml based on a calculated no-effect level for impact on lung function. OELs vary by country in Europe from 0.1 f/ml to 2.0 f/ml (Refer Table 3 of Harrison et al., 2015).

Product stewardship program

Beginning in the late 1980s, producers of RCF developed a unified and comprehensive industry-wide product stewardship program (PSP) to assess and control possible risks associated with the production and use of RCF-containing products. The PSP was developed and administered through a series of organizations including (in chronological order) the Thermal Insulation Manufacturers Association (TIMA), the Refractory Ceramic Fibers Coalition (RCFC) and the HTIW Coalition in the US and through similar organizations, including ECFIA in Europe and the Refractory Ceramic Fiber Association (RCFA) in Japan. This comprehensive multi-faceted program includes health research (epidemiology studies and medical surveillance), workplace monitoring, exposure assessment, development of workplace controls to reduce exposure in both production plants and end-user facilities, product research (to develop less biopersistent fibers), special studies (emissions, energy savings, waste generation rates and possible substitutes) and a communications outreach component [see Maxim et al. (2008) for more detail]. The voluntary PSP in the US has been conducted under regulatory agency oversight (from 1993 to 1998 by USEPA and from 2002 onwards by OSHA). Annual reports are written to OSHA summarizing PSP progress, exposure measurements and recent developments in toxicology and epidemiology. The most recent annual report to OSHA (Everest Consulting Associates, 2017) provides additional detail on the product stewardship program.

Epidemiology studies prior to 2010

The results of animal studies on the toxicity of RCF raised questions about possible adverse respiratory effects of exposure to these fibers in humans. These have been addressed in a series of epidemiology studies. Relevant summaries of epidemiology studies prior to 2010 are given in IARC (2002) and Utell & Maxim (2010). Additional comments are provided below.

One of the early epidemiology studies was reported by Chiazze et al. (1997). Costa & Orriols (2012) summarized the results of this study as follows:

Chiazze et al. (1997) carried out a case–control study in men with LC [lung cancer] from a cohort of 2933 workers at a continuous fiberglass filament factory [in Anderson, South Carolina]. They assessed the exposure to fiberglass, asbestos and RCF, among others. The risk for LC was lower in those exposed to RCF compared with the controls. [Material in square brackets added for clarity.]

Carel et al. (2007) reported on a multicenter case–control study in six Central and East European countries and the United Kingdom. Occupational and demographic data were collected from 2205 newly diagnosed male lung cancer cases and 2305 controls. The study did not find a carcinogenic effect of exposure to MMVF or RCF; however, the power of this study was low. The study found a significant association between asbestos exposure and lung cancer in the United Kingdom but failed to observe a similar association with asbestos exposure among subjects in other European countries.

Marchand et al. (2000) reported results of a case–control study of the relationship between occupational exposure to asbestos and man-made vitreous fibers (including RCF) and laryngeal and hypopharyngeal cancer. This study involved 315 incident cases of laryngeal cancer, 206 cases of hypopharyngeal cancer and 305 hospital-based controls with other types of cancer, all recruited in 15 hospitals in six French cities. These investigators concluded that exposure to asbestos resulted in a significant increase in the risk of hypopharyngeal cancer (OR =1.80, 95% CI: 1.08–2.99) and a non-significant increase in the risk of laryngeal cancer (OR =1.24, 95% CI: 0.83–1.90). Exposure to mineral wools was of borderline significance for the risk of hypopharyngeal cancer (OR =1.55, 95% CI: 0.99–2.41), and not significantly associated with the risk of laryngeal cancer (OR =1.33, 95% CI: 0.91–1.95). No significant results were observed for the other MMVFs including RCF.

The most comprehensive series of epidemiology studies on occupational RCF exposure was sponsored by the industry as part of the PSP and initiated at the UC in the US and at the Institute of Occupational Medicine (IOM) in Europe. The earlier results of morbidity (US and Europe) and mortality (US) studies have been described/reviewed in several publications (Burge et al., 1995; Cowie et al., 2001; LeMasters et al., 1998, 2003; Lockey et al., 1996, 1998, 2002; McKay et al., 2011; Trethowan et al., 1995; Utell & Maxim, 2010). Elements of these studies were also included in a study of Australian ceramic fiber production workers (Rogers et al., 1997). As of 2010, these studies indicated that occupational exposure to RCF resulted in:

• Respiratory symptoms (e.g. dyspnea, wheezing, chronic cough, chronic phlegm) “similar to those reported in other dust-exposed populations” (LeMasters et al., 1998);

• A statistically, but not clinically, a significant decrease in certain measures of respiratory function in one cross-sectional study (LeMasters et al., 1998) for certain subgroups (e.g. male current or former smokers);

• However, further longitudinal study (Lockey et al., 1998) revealed no excess decline in lung function;

• A statistically significant increase in the prevalence of pleural plaques (Lockey et al., 1996, 2002), but no evidence of parenchymal disease; and

• No increased deaths from lung cancer or, at that time, any cases of mesothelioma (LeMasters et al., 2003). The mortality study also found an unexpected, but statistically significant, association with cancers of the urinary organs (more below).

To summarize, the available epidemiological data from several studies as of 2010 indicated that symptoms were similar to other dust-exposed populations; there was evidence of minor decreases in certain measures of lung function and a dose-related increase in pleural plaques, but no interstitial fibrosis or elevated lung malignancy rates.

More recent results

Exposures

Exposure monitoring and using engineering controls and improved workplace practices for exposure reduction have been key elements of the PSP. Exposures are monitored (based on a stratified random sampling plan) at plants/facilities operated both by RCF producers and customers. Exposures to RCF at manufacturing locations can occur during fiber production, processing or converting (e.g. vacuum forming) or manufacture or assembly of other specific product forms (e.g. modules), packaging and warehousing. At customer facilities, exposures can result from many of the same activities (except fiber manufacture) and additionally when installing, repairing or removing after-service furnace linings.

Exposures vary by the type of work performed (the exposed population is divided into eight functional job categories [FJCs]) and other factors (e.g. the form of the product, type of engineering controls and industrial segment). Data on exposures by functional job category in the US and Europe for various time periods are provided in several publications (Burley et al., 1997; Everest Consulting Associates, 2017; Maxim et al., 1994, 1997, 1998, 2000, 2008; Rogers et al., 1997).

A useful summary statistic is the weighted average fiber concentration (fibers per milliliter, f/ml or fibers per cubic centimeter f/cc), calculated by taking the weighted average (weighted by the estimated number of workers in each FJC) of the measured 8-h time-weighted average (TWA) fiber concentrations.

Figure 2 shows the time series of a weighted average of measured fiber concentrations for RCF producers and customers in the US over the period from 1990 through 2016. (Similar data are collected for European producers and customers.) Respirators are worn for some jobs, but the data plotted in Figure 2 do not include any correction for the assigned protection factors of the respirators. There are some data to indicate that fiber concentrations were even higher in the years before 1990. Shown also in Figure 2 (dashed lines) are the recommended exposure guidelines (REGs) over this same time period. (The REGs were established on the basis of prudence and demonstrated feasibility rather than an explicit risk calculation.) The current REG, 0.5 f/ml, is numerically identical to the REL established by NIOSH. NIOSH (2006) wrote a criteria document containing a detailed discussion of the rationale for setting this REL. As can be seen:

Figure 2. Time trends in weighted average TWA fiber concentrations at RCF manufacturers and customers (Everest Consulting Associates, 2017).

• Exposures at both RCF manufacturing plants and customer facilities have decreased substantially over this period. Weighted average exposures are now substantially lower than the US industry REG of 0.5 f/ml.

• The gap between exposures at customer and manufacturer facilities (shown by the shaded area in Figure 2) has decreased over time to the point that weighted average exposures are nearly the same for both groups.

• The rate of decrease in weighted average fiber concentrations has slowed in recent years, suggesting that the limits of present control technologies are being reached.

Notwithstanding the flattening of the exposure trends in more recent years, there has been significant progress in reducing exposures, which has materially reduced the cumulative exposure of workers (fiber-years/ml) employed in this industry compared to what would have occurred without the exposure reductions resulting from the PSP. Figure 3 shows for both manufacturer and customer measurements (see the shaded areas) that the cumulative exposure of either the manufacturer or customer cohorts beginning in 1990 when the first integrated industry-wide stewardship program was developed would have been substantially larger but for the exposure reductions brought about by the product stewardship program. The general shapes of these curves will remain the same even if there are no further exposure reductions.

Figure 3. Graphs demonstrate cumulative exposure avoided by implementing the PSP program versus continued uncontrolled exposure at 1990 levels for manufacturer plants (left) and customers (right). Source: Everest Consulting Associates (2017).

Other exposure studies

Zhu et al. (2015a) explored the relationship between mass dust and fiber concentrations in a plant producing RCF. The authors found that there was a broad correlation between these two measures, but the relationship was not sufficiently accurate to enable reliable predictions. This finding is consistent with earlier studies conducted by RCF producers in the US and Europe. Simply stated, dust concentrations are not an adequate surrogate for fiber concentrations.

Zhu et al. (2015d) presented data on fiber and total dust concentrations for various production jobs in a factory in China. Gravimetric dust concentrations ranged from 0.63 to 16 mg/m³ and for fiber concentrations from 0.01 to 1.04 f/ml. Mean values for dust and fiber concentrations were 2.56 mg/m³ and 0.19 f/ml, respectively. This study adopted “reference values” of 5 mg/m³ and 0.5 f/ml for total dust and fiber concentrations, respectively. (The 0.5 f/ml reference value for fiber concentrations matches the industry REG and the NIOSH REL for RCF included in the HTIW Coalition PSP.) The authors also conclude that measurement of both total dust and fiber concentrations better reflects occupational exposures. The range and average fiber concentrations are broadly consistent with measurements made as part of the industry PSP, but differences in protocol preclude exact comparisons.

Epidemiology studies since 2010

Several relevant papers describing the results of epidemiology studies have been published since 2010. These are summarized below.

Wild et al. (2012) published a case–control study among males aged 40–79, including confirmed primary lung cancer cases from all hospitals of a study region consisting of four administrative districts in the Northern part of the French Lorraine region near the German and Luxembourgian borders. Cumulative occupational exposure indices for various materials, including RCF and other MMMFs, were obtained from the questionnaires. Attributable fractions were computed from multiple unconditional logistic regression models. A total of 246 cases and 531 controls were included. The odds ratios (ORs) adjusted on cumulative smoking and family history of lung cancer increased significantly with the cumulative exposure indices to asbestos, polycyclic aromatic hydrocarbons and crystalline silica, and with exposure to diesel motor exhaust. The authors also noted:

Neither RCF, MMMF, iron mining, stainless steel welding nor any other occupational exposure had any significant relation with lung cancer.

These results are consistent with the UC findings.

Lacourt et al. (2014) published a large case–control study aimed to test the hypothesis that there was an increased risk of pleural mesothelioma resulting from co-exposure to asbestos and RCF compared to asbestos exposure alone. Males were selected from a French case–control study conducted in 1987–1993 and from the French National Mesothelioma Surveillance Program in 1998–2006. Two population controls were frequency matched to each case by year of birth. Complete job histories were collected and occupational asbestos and RCF exposures were assessed using job exposure matrices. The dose–response relationships for asbestos exposure were estimated from an unconditional logistic regression model in subjects exposed to asbestos only and the second group of subjects exposed to both asbestos and RCF. The authors concluded that there is an increased risk of pleural mesothelioma resulting from co-exposure of asbestos and refractory ceramic fibers compared to asbestos exposure alone. The authors were somewhat guarded in noting:

Further investigations are needed to confirm and understand the mechanisms of the effect [sic] modification of asbestos exposure in the presence of co-exposure to RCF.

This finding was surprising because other epidemiology studies have not disclosed any significant increase in the incidence of mesothelioma among cohorts exposed to RCF alone. In addition, the Carel et al. (2007) study (though limited in sample size) reported results that were inconsistent with the findings of Lacourt. Specifically, Carel et al. (2007) wrote:

We did not find a carcinogenic effect of exposure to MMVF or for ceramic fibers. Also, no synergistic effect—that is departure from a multiplicative joint effect—of simultaneous exposure to asbestos and MMVF could be shown. [Emphasis added.]

The methodology of the Lacourt et al. (2014) analysis is similar to an earlier (Lacourt et al., 2013) study by many of the same authors that found a similar synergistic response between asbestos and mineral wool exposure. Carlsten & Georas (2014) reviewed the earlier Lacourt et al. (2013) paper and noted:

Lacourt and colleagues reported a case–control study investigating associations between pleural mesothelioma and occupational exposure to asbestos, mineral wool, and silica. A total of 1199 cases and 2379 control subjects were identified from different sources in France from 1987 to 1996 and 1998 to 2006. Although occupational exposure to asbestos is a well-known risk factor for pleural mesothelioma, the risks associated with mineral wool (which is used in insulation) and silica dust are less clear. The main finding was that occupational exposure to mineral wool was associated with a significantly increased OR for mesothelioma when adjusting for asbestos exposure (e.g. OR =2.5 for highest exposure group). No such associations were found for silica exposure in adjusted analyses, although a significantly higher OR was observed for silica exposure in the unadjusted subgroup analysis. These seemingly contradictory results could be the result of misclassification, the inability to independently separate exposures to the different compounds, or other factors, which were discussed in subsequent correspondence.

In the end, Carlsten and Georas concluded:

Taken together, these data suggest that more research is needed to understand how mineral wool and other fibers interact to increase risk of mesothelioma over time.

Boffetta et al. (2014) reviewed the evidence on occupational exposure to SVFs (including RCF) and also analyzed an earlier (2013) Lacourt et al.’s study on co-exposure to asbestos and mineral wool. They showed that the conclusion reached by Lacourt and colleagues was sensitive to possible misclassification of asbestos exposure. They found that even a very small misclassification of asbestos exposure (95% sensitivity and specificity) offset the risk from SVF exposure and wrote:

The fact that the elevated OR found in some of the case–control studies are reduced after adjusting for asbestos exposure and that they are not confirmed in cohort studies of production workers detracts from the credibility of a causal relationship between SVF exposure and mesothelioma risk. The combined evidence from epidemiologic studies leads to the conclusion that exposure to SVF is not likely to increase the risk of mesothelioma.

Boffetta et al. (2014) concluded:

The epidemiological literature reviewed here provides support for the notion that SVF do not cause mesothelioma and is in line with these toxicological arguments that SVF are not biopersistent. The evidence from epidemiology and toxicology is therefore consistent with the hypothesis that non-biopersistent SVF pose no risk of mesothelioma to humans.

Thus, the Lacourt findings for both mineral wool and RCF must be viewed with some caution.

Gérazime et al. (2015) published another case–control (retrospective) study of male workers. The authors used data from ICARE, a population based case–control study conducted in France. Detailed lifetime tobacco and alcohol consumption, as well as complete occupational history, were collected. Analyses were restricted to men and included 1867 cases of head and neck squamous cell carcinomas, 2276 lung cancer cases and 2780 controls. Occupational exposure to RCF was assessed through a specific job-exposure matrix. The authors estimated odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, residence area, tobacco smoking, alcohol consumption and cumulative exposure to asbestos with logistic models. The authors concluded that “although a moderate increase in risk cannot be excluded”, occupational exposure to RCF was not significantly associated with risk of head and neck cancer (OR = 0.83; 95% CI = 0.64–1.10) or lung cancer (OR = 0.91; 95% CI = 0.72–1.16). Results of this study (no statistically significant excess in head and neck or lung cancer) are consistent with the UC results.

UC mortality results since 2010

The UC mortality study is ongoing. The mortality study includes current and former male and female employees hired from 1952 through 1999 at two RCF manufacturing plants, one in New York and the other in Indiana who had at least 1-year RCF employment (see as LeMasters et al. [2003] for details). The latest published results of the prospective cohort study included all deaths as of 12/31/2015 (LeMasters et al. 2017). Participants (N = 1119) in the mortality study include current and former male and female workers at the New York (N = 818) and Indiana (N = 301) plants. The majority of workers are Caucasian (91%), male (84%) and current or former smokers (54%) and approximately half had self-reported prior asbestos exposure. The median age at death or time of follow up was 63.1 years, with a mean time since first exposure (latency) of 32.9 years and mean cumulative fiber exposure (CFE) of 46.1 fiber-months/cc At date of death or 12/31/2015, 87.3% had >20 years and 60.6% had >30 years time since first exposure. Exposure analyses enabled the identification of the most highly exposed subgroup in the cohort, workers (N = 285) with more than 45 fiber-months/cc RCF exposure.

Table 1 shows standardized mortality rates (SMRs) and two-sided 95% confidence intervals for deaths from malignant neoplasms (MNs) and selected other causes for both the entire cohort and most exposed group of RCF exposed workers in the latest update to the UC mortality study.

Table 1. SMRs and confidence intervals for full cohort (N = 1119) and most exposed group, abbreviated version, SMRs significantly elevated or reduced shown in boldface, excerpted from LeMasters et al. (2017).

Group	Full cohort (N = 1119)			>45 fiber-months/cc (N = 285)
Cause	Observed deaths	SMR	95% CI	Observed deaths	SMR	95% CI
All causes	234	0.73	0.64–0.83	93	0.79	0.64–0.97
All cancers	74	0.86	0.68–1.09	31	1.01	0.68–1.43
MN respiratory	24	0.83	0.53–1.24	8	0.75	0.32–1.48
MN trachea, bronchus, lung	23	0.83	0.53–1.25	8	0.78	0.34–1.55
MN urinary organs	8	1.80	0.78–3.55	6	3.62	1.33–7.88
MN kidney	4	1.72	0.47–4.39	3	3.60	0.74–10.52
MN bladder and other urinary	4	1.90	0.52–4.86	3	3.64	0.75–10.65
MN other & unspecified site	9	0.74	0.34–1.41	3	0.71	0.15–2.06
MN mesothelioma	1	2.86	0.07–15.93	1	7.85	0.20–43.76
MN lymphatic and hematopoietic	11	1.32	0.66–2.36	4	1.32	0.36–3.37
Leukemia	8	2.51	1.08–4.94	3	2.57	0.53–7.50
Benign and unspecified MN	1	0.94	0.02–5.26	0	0.00	0.00–9.67
Heart diseases	64	0.75	0.58–0.96	22	0.66	0.41–1.00
Other dis. circulatory system	15	0.68	0.38–1.13	5	0.59	0.19–1.39
Diseases respiratory system	25	1.01	0.65–1.49	12	1.26	0.65–2.20
Dis. genito-urinary system	2	0.35	0.04–1.26	1	0.47	0.01–2.60
Other and unspecified causes	8	0.76	0.33–1.50	2	0.57	0.07–2.06

NMN: malignant neoplasms; SMR: standardized mortality rates.

The pattern of SMRs is broadly similar to those reported earlier, but there are some differences related to kidney and bladder cancers and leukemia. Additionally, there was one reported, but unconfirmed mesothelioma in a worker with prior occupational exposure to asbestos – these points are discussed below.

LeMasters et al. (2017) also conducted a cancer incidence study. Since 2003 these investigators collected lung and urinary cancer incidence data using questionnaires for 1011 participants. There were four participants reporting respiratory cancers with 9.9 expected (Standardized Incidence Ratio (SIR) = 0.40) and two reporting urinary cancer with 6.4 expected (SIR = 0.31).

Kidney and bladder cancers

New data on the prevalence of urinary cancers that indicate elevated SMRs for these diseases remain, but [according to LeMasters et al. (2017)] might have been caused by other factors rather than RCF exposure. Known risk factors for these cancers, including cigarette smoking, obesity, certain drugs, medical conditions and treatments and exposures to many other toxicants are summarized in Tables A1 (kidney cancer) and A2 (bladder cancer) located in the Appendix. Most of these were not controlled for in the UC study. In reviewing the latest results, the UC investigators wrote:

…the strongest risk factor for bladder and renal cancers is cigarette smoking (McLaughlin et al., 2006; Zeegers et al., 2000); half of the bladder and renal cancer deaths in the current study were known smokers. In addition, three of the four bladder cancer deaths were millwrights with potential occupational exposures associated with bladder cancer, including exposure to polycyclic aromatic hydrocarbons (PAH) (Behrman, 2003; Kogevinas et al., 2003; Reulen et al., 2008; Spinelli, 1989).

In assessing the plausibility of a possible relationship between RCF exposure and urinary cancers, it is reasonable to examine whether exposure to other fibers or to asbestos has been linked to urinary cancers. SVFs are the logical fibers for comparison (see below), but one article (Lauriola et al., 2012) concluded that asbestos exposure was associated with a statistically significant increase in SMR for renal neoplasia. However, two meta-analyses have failed to demonstrate a significant association between kidney cancer and asbestos exposure (Goodman et al., 1999; Sali & Boffetta, 2000). In fact, if the observed and expected renal cancers in the Lauriola et al., study are pooled with those from the Sali and Boffetta paper, then the resulting SMR is not statistically significant.

Additionally, Kannio et al. (1996) reported the following data regarding bladder cancer and asbestos exposure among patients with bladder cancer admitted for diagnostic or surveillance purposes to the Surgery Clinic, Turku University Central Hospital (Turko, Finland) between October and December 1988:

Of the 28 primary bladder cancer cases in group 1, 17 (61%) had been exposed to asbestos at work. Of these, 16 (94%) were considered to have been definitely exposed. A crude OR of 2.8 (95% Cl = 0.9–8.4) was calculated for definite exposure to asbestos against no asbestos exposure and 2.4 (95% CI = 0.8–7.0) for the pooled category of definite to possible exposure against no asbestos exposure.

Although the odds ratios were elevated, the 95% CIs included 1.0 and, therefore, the elevations are not statistically significant.

Karami et al. (2011) investigated whether asbestos, as well as 20 other occupational dust exposures, were associated with renal cell carcinoma (RCC) risk in a large European, multi-center, hospital-based renal case–control study. The study included respondents from four Central and Eastern European countries (Moscow, Russia; Bucharest, Romania; Lodz, Poland; and Prague, Olomouc, Ceske-Budejovice and Brno, Czech Republic) between 1999 and 2003. In total, 1097 histologically confirmed RCC cases and 1476 controls were included in the study. These investigators found that among participants ever exposed to dust, significant associations were observed for glass fibers (OR: 2.1; 95% CI: 1.1–3.9), mineral wool fibers (OR: 2.5; 95% CI: 1.2–5.1) and brick dust (OR: 1.5; 95% CI: 1.0–2.4). Significant trends were also observed with exposure duration and cumulative exposure. No association between RCC risk and asbestos exposure was observed. (RCF was not included because of the small sample size.) The authors were careful to note the limitations of their study, but if the findings are correct, their results would provide a rationale for the contention that exposure to other SVFs, and potentially RCF, might be a risk factor for kidney or bladder cancer as reported in the UC studies. Among the reasons, why Karami et al. (2011) were cautious in claiming that exposure to SVFs might be a risk factor was the fact that their finding was not consistent with results from other epidemiology studies – a fact that prompted the authors to write (at various points in their article) the following cautionary remarks:

The lack of supporting evidence from cohort studies, therefore, reduces the plausibility of an association between RCC risk and exposure to both glass and mineral wool fibers.

Thus, it is unclear whether our findings of an association with glass and mineral wool fibers are real.

Our observed associations also require replication before meaningful inferences can be concluded.

Table 2 summarizes the reported links between exposure to SVFs and renal or bladder disease from cohort or case–control studies [most of which were not discussed or cited in the Karami et al. (2011) article] that underscore some of the limitations of this study. With very few exceptions, these study results do not support the contention that SVF exposure (at least glass wool or mineral wool exposure) is a risk factor in the malignant or non-malignant bladder or kidney disease. Although some of the studies summarized in Table 1 involved small sample sizes, there is more compelling evidence against this relationship in the various large well designed and executed cohort studies of Marsh and colleagues (Marsh et al., 1990, 2001a,b; Stone et al., 2004).

Table 2. Studies addressing links between exposure to man-made mineral fibers and either non-malignant or malignant kidney or bladder disease.

Increase in kidney or bladder disease	Stud y type	Population and dust/fiber exposure	Results	References
Yes	Cohort	2557 male workers in glass wool plant in Ontario, Canada.	The number of kidney cancers was nearly double that expected, both for plant-only and all workers. For the whole cohort, the 14 cases represented a significant excess (SIR =1.92; 95% CI [1.05, 3.21]). Study did not correct for smoking. Mortality from nephritis and nephrosis was significantly increased. Goldsmith & Goldsmith (1993) explored this issue by reviewing other literature and concluded that silica was likely to be the cause of the excess renal disease. Earlier study published 1984 showed cancer of genitourinary organs for plant only and total cohort of: Plant only: SMR =1.61; 95% CI [0.41, 4.39] and total: SMR =1.84; 95% CI [0.58, 4.43].	Shannon et al. (1984, 2005)
Yes	Case–control	Large hospital-based (CEERCC) study of renal cancer conducted across four Central and Eastern European countries.	Among participants ever exposed to dusts, significant associations with renal cell carcinoma (RCC) were observed for glass fibers (OR =2.1; 95% CI [1.1, 3.9]) mineral wool fibers (OR =2.5; 95% CI [1.2, 5.1]) and brick dust. Significant trends were observed with exposure duration and cumulative exposure.	Karami et al. (2011)
No	Cohort	5369 workers in mineral wool plant in Denmark.	Authors reported increase in cases of bladder cancer only among workers with ≥20 years since first employment. (4 bladder cancer cases compared to 1.6 expected O/E = 2.5; exact 95% CI [0.79, 6.03].) (p value reported in article 0.06 based on Chi-square test, improved p values are 0.1025 Mid-p exact tests or 0.1576 Fisher exact test.) No excess in kidney cancer found.	Olsen & Jensen (1987)
No	Case–control	Montreal multi-center of (inter alia) 100 kidney and 300 bladder cancer cases (1979–1983).	Study reported ORs for “synthetic fibers” [interpreted by Karami et al. (2011) to include glass and mineral wool] and kidney cancer OR =0.8; 95% CI [0.2, 2.8] and bladder cancer OR 1.6; 95% CI [0.9, 3.0]. Additional result for cases with substantial exposure (>15 years) for bladder cancer with borderline significance OR =2.1; 95% CI [1.0, 4.4].	Siemiatycki et al. (1986)
No	Cohort	Cohort of 941 workers in the glass wool producing industry in Finland was followed for deaths in 1953–1981.	SIR for bladder cancer =1.09; 95% CI [0.03, 6.06]. Kidney cancer included in “other” category with non-significant SIR.	Teppo & Kojonen (1986)
No	Cohort	3749 workers employed for at least 3 months in two Finnish glass factories (cohorts A and B) were followed up for cancer in 1953–1986 through the Finnish Cancer Registry.	SIR for kidney cancer (both sexes) = 0.35, based on 3 observed and 8.6 expected; 95% CI [0.07, 1.02]. SIR for bladder cancer (both sexes) = 0.97. Based on 9 observed and 9.3 expected; 95% CI [0.44, 1.84].	Sankila et al. (1990)
No	Cohort	Mortality and cancer incidence was investigated among 2807 workers employed for least 1 year before 1972 at 11 Swedish companies manufacturing prefabricated wooden houses. A total of 1068 workers were exposed to MMVF used for insulation.	Mortality: Bladder cancer SMR =0.98; 95% CI [0.26, 2.50] Kidney cancer SMR =0.47; 95% CI [0.099, 1.38]	Gustavsson et al. (1992)
No	Cohort	3539 male and female workers in three Swedish plants producing SVFs followed from 1952 to 1990.	SMR for bladder cancer =1.27; 95% CI [0.48, 2.77]. SMR for kidney cancer =1.4; 95% CI [1, 7.9].	Plato et al. (1995)
No	Cohort	22,002 production workers in man-made vitreous fiber production plants in Denmark, Finland, Norway, Sweden, United Kingdom, Germany and Italy, from 1982 to 1990.	There was no significant SMR for bladder cancer in the total cohort, those with ≥1 year employment or when partitioned among rock/slag wool, glass wool or continuous filament. (Total deaths from bladder cancer in entire cohort 35, SMR =1.07; 95% CI [0.74, 1.48].)	Boffetta et al. (1997)
No	Cohort follow up	A cancer incidence follow-up was conducted among 3685 rock-slag wool (RSW) and 2611 glass wool (GW) production workers employed for 21 year in Denmark, Finland, Norway, or Sweden and the standardized incidence ratios (SIR) were calculated on the basis of national incidence rates.	SIRs and 95% CIs for kidney cancer: Total SIR =0.50; 95% CI [0.28, 0.83] Rock/slag SIR =0.50; 95% CI [0.23, 0.95] Glass wool SIR =0.50; 95% CI [0.18, 1.09] SIRs and 95% CIs for bladder cancer: Total SIR =1.06; 95% CI [0.80, 1.38] Rock/slag SIR =0.91; 95% CI [0.62, 1.29] Glass wool SIR =1.39; 95% CI [0.88, 2.08]	Boffetta et al. (1999)
No	Cohort	11,373 male workers were who were employed for at least 1 year in the production of rock or slag wool (RSW), glass wool (GW) and continuous filament (CF) in 13 factories from seven European countries.	Increasing trend in mortality from non-malignant renal diseases. However, SMRs were not significantly elevated.	Sali et al. (1999)
No	Case–control	47 cases of nephritis or nephrosis from Owens Corning mortality surveillance system.	In this analysis, there was no consistent relation between respirable fiber exposure and either nephritis or nephrosis.	Chiazze et al. (1999)

Pooling the SMRs (Fixed effects model, see Morfeld et al., 2016) based on only the cohort studies listed in this table leads to the following pooled SMRs and corresponding 95% exact confidence intervals (http://www.openepi.com/SMR/SMR.htm) for bladder cancer – SMR =1.18.0, 95% CI [0.98, 1.41] and kidney cancer SMR =0.894, 95% CI [0.701, 1.124]. Neither result provides statistical evidence of elevated SMRs.

Leukemia

The latest UC mortality study results (Table 1) indicated an excess of leukemia deaths in the full cohort (four acute myeloid, two acute unspecified and two chronic lymphocytic). However, there was no significant excess of leukemia (all types) in the group with the highest exposures. The fact that there is no apparent exposure–response suggests that the observed increase in leukemia deaths in the cohort is related to other risk factors, rather than RCF exposure. Table A4 (Appendix) summarizes the literature on causes, contributing factors or risk factors for various types of leukemia. (As these cases were all in adults, this table does not address factors for childhood leukemia.) Included in this table are occupational, lifestyle-related, environmental, medical procedures, genetic disorders and family history risk factors for various subtypes of leukemia (most of which were not measured or controlled for in the UC study). Among the more likely explanations for this finding are occupational exposures to certain chemicals and lifestyle-related risk factors, such as smoking and obesity.

Although occupational exposures to certain chemicals have been attributed to leukemia, exposure to fibers has not been shown to be a risk factor for leukemia (see below) and such an effect is arguably implausible, given what is known about fiber toxicology and epidemiology. Occupational exposure to various fibers has been included in several studies of adverse health effects, but leukemia has not been the endpoint of concern because of the assumption that fiber exposures are more likely to be associated with malignant or non-malignant lung-related diseases. Nonetheless, several studies on health effects of exposure to other fibers (PVA, rock/slag wool, glass fibers and asbestos) present data relevant to other malignant diseases, including leukemia. Shown below is a short summary of these data by type of fiber.

• Polyvinyl alcohol (PVA): Morinaga et al. (1999) studied a cohort of male workers in a Japanese factory producing PVA. This small study (38 deaths among 454 PVA fiber exposed workers and 210 deaths among 2441 non-exposed workers) calculated SMRs and confidence intervals for several malignant diseases, including leukemia (ICD8 204–209). The calculated SMR and 95% confidence interval for leukemia among exposed workers were SMR = 0 and (95% CI; 0–5.52), respectively, whereas the non-exposed group actually had a higher SMR; SMR = 1.53 (95% CI; 0.49–3.57).

• Fiberglass (FG): Marsh et al. (2001a) performed the most comprehensive study on FG workers in the US, including 32,110 persons at risk and 935,581 person-years at risk. As with other fiber studies, the focus of this study was on malignant and non-malignant lung diseases. Nonetheless, the study reported observed fatalities (199) for “all lymphatic and hematopoietic tissue diseases (ICD 200–209)”, including leukemia. The SMRs were not elevated when compared to either US or corresponding local county rates. For example, the SMR and corresponding confidence interval compared to US national rates were SMR = 0.92 and (95% CI; 0.8–1.06), respectively.

• Rock-slag wool (RSW): Marsh et al. (1996) published results of a large epidemiological study of workers exposed to rock-slag wool (RSW) in the US. Although the focus of this study was on respiratory cancers, data were available on lymphopoietic cancers (ICD8 200–209), including leukemia. Two cohorts were included and SMRs were not significantly elevated for either cohort.

• Man-made mineral fibers (MMMFs) (Countries other than the US): Several authors have reported results for various MMMFs, including fiberglass, rock and slag wool in countries other than the US.

  • Claude & Frentzel-Beyme (1984) studied a cohort of workers in a German rock-wool factory; the exposed and reference cohorts included male employees, consisting of 2096 males in the former and 1778 males in the latter group. The calculated risk ratio for “leukemia and lymphatic system (200–207)” was 0.57 (95% CI; 0.1 – 3.37).

  • Simonato et al. (1986) reported results of a study of 24,609 workers in 13 European factories (Denmark, Finland, Germany, Italy, Norway, Sweden and the UK) that produced continuous filament, glass wool, rock wool and slag wool. Based on 17 leukemia deaths (both sexes) the calculated SMR and confidence interval were 0.80 and (95% CI; 0.47–1.28), respectively.

  • Plato et al. (1995) reported a follow-up study of 3539 workers (74, 043 person-years) in three Swedish plants producing fiberglass or rock wool. The calculated SMR and 95% confidence interval for deaths from leukemia were 0.89 and (95% CI; 0.33 – 1.93), respectively.

  • Boffetta et al. (1999) published the latest update to the European studies of MMMFs among 3,685 rock-slag wool (RSW) and 2,611 glass wool (GW) production workers employed for 21 years in factories in Denmark, Finland, Norway or Sweden, and the standardized incidence ratios (SIRs) were calculated on the basis of national incidence rates. For the entire cohort (male and female, RSW and GW), the calculated SIR and 95% CI for leukemia were 0.92 and (95% CI: 0.53–1.50), respectively.

  • Adegoke et al. (2003) reported a population-based case–control study of 486 leukemia subjects and 502 healthy controls residing in Shanghai from 1987 to 1989. Adjusted odds ratios (OR) were calculated for the self-reported association between occupational factors and leukemia risk. Among the various chemicals included in the study was a substance described as “synthetic fiber dust” (otherwise undefined). The calculated odds ratio (OR) and 95% confidence interval for leukemia (all forms) among those exposed to “synthetic fiber dust” were 2.0 and ((95% CI: 1.2–3.5), respectively. The relevance of this study is unclear because no definition or characterization of “synthetic fiber dust” is given.

• Asbestos: Asbestos (at least certain forms) has been proven to cause (among others) various malignant and non-malignant lung diseases. A few studies have been published that provide evidence regarding leukemia.

  • Selikoff (1990) provided data on causes of death among 17,800 asbestos insulation workers in the US and Canada, from 1 January 1967 to 31 December 1986 – observed deaths from all causes totaled 4951 based on best evidence. The SMR and 95% confidence interval based on 33 observed deaths (best evidence) for leukemia were 1.148 and (Fisher exact test 95% CI; 0.79–1.61), respectively, which Selikoff included in a table labeled “cancers not found with increased incidence”.

  • Kishimoto et al. (1988) & Chinushi et al. (1990) published case reports on a total of three persons admitted to Kure Kyosai Hospital, Kure, Japan with leukemia had evidence of asbestos exposure. In a later publication, Kishimoto (1992) noted that of 10 cases of leukemia, five showed evidence of asbestos exposure.

  • Goodman et al. (1999) performed a meta-analysis of eight studies covering asbestos exposure and leukemia. The calculated meta-SMR and 95% confidence interval were 0.95 and (0.80, 1.13), respectively.

  • Seidler et al. (2010) reported results of a large multicenter case–control study in Germany and Italy that examined the relationship between asbestos exposure and various diseases. Among various diseases, there were a total of 149 cases of chronic lymphocytic leukemia (CLL). Adjusted odds ratios (ORs) and confidence intervals were calculated as a function of fiber-years of asbestos exposure. All ORs (in each cumulative exposure category) were close to 1, there was no dose–response, and all confidence intervals included 1.0. The authors concluded: “We observed no statistically significant association between cumulative asbestos exposure and the risk of any lymphoma subtype”.

LeMasters et al. (2017) commented on the leukemia results in the UC study as follows:

The elevated leukemia SMR in the total cohort, but not in the high exposed group, was a new and unexpected finding. These eight cases had job tasks that included machine operator (4), millwright (2), welder (1) and maintenance (1). Exposures associated with leukemia and, in particular, acute myeloid leukemia (50% of cases in the current study) include ionizing radiation and benzene (Polychronakis et al., 2013; Tsai et al., 2014).

On a weight of evidence basis, we conclude that these studies fail to implicate exposure to any of several types of fibers as a cause or contributing factor for leukemia. Because of this and the absence of a dose–response [one of the Hill (1965) criteria], it is likely that the observed leukemia deaths are caused by some factor other than exposure to RCF or any of these other fibers, leaving occupational exposure to other materials or lifestyle factors as the likely explanation for the findings. Nonetheless, leukemia will continue to be included in the ongoing mortality study.

Mesothelioma

As noted above there was one reported, but unconfirmed, death from mesothelioma in the RCF-exposed cohort.

Although the calculated SMR was not significant, it is appropriate to examine this case further. The worker in question had self-reported occupational asbestos exposure working as a vehicle mechanic for 6.5 years. Numerous studies have shown that vehicle mechanics are exposed to asbestos-containing materials, which can result in adverse health effects, including lung cancer and mesothelioma (Castleman et al., 1975; Egilman & Billings, 2005; Egilman & Longo, 2012; Finkelstein, 2008; Freeman & Kohles, 2012; Hansen, 1989; Huncharek, 1990, 1992; Imbernon et al., 2005; Kakooei et al., 2011; Lemen, 2004; Michaels & Monforton, 2007; Roggli et al., 2002; Welch, 2007). For example, in the analysis of 1445 cases of mesothelioma studied by Roggli et al. (2002), the automotive sector ranked eighth in terms of the number of mesothelioma cases among 12 industrial sectors evaluated. Epidemiology studies of occupationally exposed cohorts are less easy to interpret, with some studies or analyzes concluding that automobile mechanics have an elevated risk. Nonetheless, other studies and meta-analyzes indicate that mesothelioma risks are not significantly elevated (Aguilar-Madrid et al., 2010; Butnor et al., 2003; Dotson, 2006; Finley et al., 2012; Garabrant et al., 2016; Goodman et al., 2004; Hessel et al., 2004; Laden et al., 2004; Paustenbach & White, 2012; Peto et al., 2009; Rake et al., 2009; Richter et al., 2009; Teschke et al., 1997; Wong 2001, 2006). This certainly does not mean that the incremental risks are zero. As noted by Lemen (2004):

The results of the exposure studies, experimental studies, case reports, and findings from the equivocal epidemiological studies by no means exonerate the brake mechanic from being susceptible to a causal relationship between asbestos exposure and mesothelioma.

Several articles have been published that address the relationship between mesothelioma and low levels of asbestos exposure (Iwatsubo et al., 1998; Rödelsperger et al., 2001). Moreover, the results of Roggli et al. (2002) clearly show that vehicle mechanics have developed mesothelioma.

Of greater probable relevance, in our judgment, is the history of other jobs held by this worker. LeMasters et al. (2017) report:

Other prior jobs this individual reported that have historically been associated with potential asbestos exposure included machinist apprentice overhauling railroad steam engines (Schenker et al., 1986; Roggli et al., 2002) in the early 1950s (only exposure he reported was cutting oil), aviation electrician from 1952 to 1956 in the US Navy (reported exposure was to aviation fuel) and working as a technician in fuel systems (reported exposures were fuel and cleaning solvents) for South Bend Bendix Aviation from the mid-1950s to early 1970s. Bendix Corporation manufactured asbestos containing friction brake products.

Shown below are additional materials that address possible asbestos exposure in these jobs.

• Asbestos exposure and railroads: Numerous epidemiological studies have been published of workers in the US and various countries in Europe and Asia showing that those workers employed performing various jobs in the railroad industry were exposed to asbestos and experienced a statistically significant excess of various asbestos-related diseases, including mesothelioma (Battista et al., 1999; Garshick et al., 1987; Gasparrini et al., 2008; Gerosa et al., 2000; Hosoda et al., 2008; Hjortsberg et al., 1988; Huncharek, 1987; Malker et al., 1985; Maltoni et al., 1995; Mancuso, 1983, 1988, 1991; McDonald & McDonald, 1989; Ohlson et al., 1984; Oliver et al., 1985; Plato et al., 2016; Roelofs et al., 2013; Roggli et al., 2002; Rolland et al., 2010; Schenker et al., 1986; Tessari et al., 2004). According to Roggli et al. (2002) Table 1 of this paper, railroad workers ranked seventh in the top 12 industry types based on their large (1445 cases) sample of mesothelioma deaths.

• Asbestos exposure and US Navy: Until efforts to use substitute materials for asbestos on US Navy ships (and ships from other nations) and enhanced asbestos control measures accelerated in the 1970s (Anonymous, 1979; Franke & Paustenbach, 2011; Harries, 1968; Mangold et al., 1970; Rushworth, 2005; Strand et al., 2010; Twight 1991; Winer & Holtgren, 1976), both amosite and chrysotile asbestos was used extensively on US Navy ships. Nearly all Navy personnel aboard ships had some asbestos exposure, even in berthing quarters and mess halls, particularly prior to 1980. Numerous studies have evaluated the health risks to seamen and those employed in shipyards (Bianchi et al., 2001; Greenberg, 1991; Kurumatani et al., 1999; Roggli et al., 2002; Selikoff & Hammond, 1978; Selikoff et al., 1990). With respect to mesothelioma specifically Roggli et al. (2002) noted that the numbers of mesothelioma cases were greatest in the shipbuilding and US. Navy sectors among his sample of 1445 mesothelioma cases [see illustration from Table 1 of Roggli et al. (2002)]. Similar results were reported in the Trieste-Monfalcone area, Italy (Bianchi & Bianchi, 2009; Bianchi et al., 2001) and the United Kingdom (Peto et al., 2009).

• Bendix Aviation: This plant made both automobile and aircraft brake shoes and is listed on several websites as a location where asbestos exposure occurred.

One of the difficulties of epidemiological studies of fibers is that some members of the cohort may have also had prior asbestos exposure, as was the case with studies of other SVFs including RSW (Marsh et al., 2001b; Boffetta et al., 1997, 2014) and glass wool.

Pulmonary function studies

LeMasters et al. (2017) also conducted pulmonary function studies on RCF-exposed workers. Among those with localized pleural thickening (LPT), percent predicted FVC and FEV₁ differed from those without LPT by <3%, a value judged clinically insignificant.

Zhu et al. (2015b) compared various measures of pulmonary function (FVC, FEV₁ and FEV₁/FVC) for 265 manufacturing and processing workers exposed to RCF with a group of 273 workers in a Chinese facility exposed to noise only. The exposed group was subdivided into subgroups based on gravimetric measurements of total dust and fibers. This study reported, inter alia, that the exposed group had statistically significantly lower mean values of FVC, FEV₁ and FEV₁/FVC (clinical significance unstated). The study reported that pulmonary effects were positively correlated with the fiber concentration (to a degree greater than total dust). This study did not consider the effects of initial weight or weight gain among the subjects. Unlike McKay et al. (2011), these investigators did not report any longitudinal analysis. McKay et al. (2011) offered the following comments on their longitudinal analysis of the US cohort:

In conclusion, no consistent longitudinal decline in FVC or FEV₁ with increasing RCF exposure category was observed, although cross-sectional changes were observed for subjects in the highest exposure category. Critical to this analysis was the recognition that lung function declines with age are non-linear and accelerate in older age groups who also have the longest duration of exposure. To our knowledge, this specific analysis strategy has not been published for evaluating longitudinal change in lung function among adults, although a similar methodology has been used in children.

It is possible that Zhu and colleagues would have reached similar conclusions had they conducted a longitudinal analysis.

Pleural plaques

As noted above, the X-ray studies conducted by the UC researchers have shown a significant relationship between RCF exposure and the development of pleural plaques. The overall rate of pleural changes reported by LeMasters et al. (2017) in their most recent publication was 6.1%, which increased across exposure categories reaching, in the highest CFE category, 21.4% (adjusted odds ratio (aOR) = 6.9, 95% CI 3.6–13.4) and 13.0% (OR= 9.1, 95% CI 2.5–33.6) for all subjects and for those with no potential asbestos exposure, respectively. The small increase in pleural plaques is not surprising as the presence of plaques is likely to be related to increasing latency. Prevalence among recent hires (>1985) was similar to the background. Interstitial changes were not elevated. And, as noted above, localized pleural thickening was found to be associated with small decreases in spirometry.

The finding that pleural plaques are related to RCF exposure is of potential concern because pleural plaques are widely considered to be a marker of exposure to fibers – particularly, but not exclusively, asbestos [see Clarke et al. [2006] for a list of other reported cases of pleural plaques]. Because occupational asbestos exposure has been shown to lead to a variety of adverse health outcomes, including asbestosis, lung cancer and mesothelioma in exposed cohorts, it is plausible to believe that there would be a correlation between the prevalence of pleural plaques and these asbestos-related diseases. Useful perspectives on this possibility are provided by Utell & Maxim (2010).

Three more recent papers have been published on the relevance of pleural plaques:

• Moolgavkar et al. (2014) published a detailed review and critique of U.S. EPA’s risk assessments for asbestos. EPA regarded pleural plaques an “adverse condition” and developed a reference concentration (RfC) based on this endpoint. They concluded:

Taken together, the totality of evidence suggests strongly that pleural plaques are markers of asbestos exposure with little or no clinical significance. Thus, pleural plaques do not appear to satisfy EPA’s own definition of an adverse condition.

• Kerper et al. (2015) published a systematic review of the relation between pleural plaques and lung function and concluded that the weight of evidence indicates that pleural plaques do not impact lung function and that the observed associations are most likely due to unidentified abnormalities or other factors. This result is also consistent with UC findings on the RCF-exposed cohort.

• Maxim et al. (2015) reviewed the extensive literature relating the linkage between pleural plaques and lung impairments/diseases and concluded that the available evidence supports the contention that, absent any other pleural disease, the presence of pleural plaques does not result in respiratory symptoms or clinically significant impacts on lung function. Pleural plaques are not premalignant, that is, they do not progress to malignant tumors (lung cancer or mesothelioma). For certain types of asbestos, the development of pleural plaques is statistically correlated with malignant disease, but the evidence is consistent with the hypothesis that pleural plaques (without other pleural diseases) are a marker of exposure, rather than an independent risk factor (see also IIAC, 2008).

Dermal studies

Zhu et al. (2015c) also examined the effects of exposure to RCF (fibers) and dust on workers’ skin by comparing effects on 281 RCF-exposed manufacturing and processing workers with a control group of 274 workers in a Chinese facility. The study found that skin itching symptoms and contact dermatitis were significantly correlated with total gravimetric dust measurements, but not with fiber concentrations. This finding is consistent with other studies of skin irritation related to exposure to SVFs. Some (but not all) persons exposed to various SVFs, including glass fibers (ATSDR, 2004; Jolanki et al., 2002; Possick et al., 1970; Sertoli et al., 1992; Tarvainen et al., 1994), mineral wool (Petersen & Sabroe, 1991), rockwool (Kieć-Świerczyńska & Szymczk, 1995) and RCF (Kieć-Świerczyńska & Wojtczak, 2000) as well as PCWs develop adverse skin reactions (sometimes termed “fiberglass itch” or more properly irritant contact dermatitis [ICD]) including folliculitis (a common skin condition in which hair follicles become inflamed), irritant symptoms including itching without rash on arms, face or neck, and burning of eyes. With most SVFs and PCWs, this is believed to be a physical (mechanical rather than chemical) phenomenon, although some binders or coatings are believed to be sensitizing agents that also cause dermatitis. Though perhaps uncomfortable, this disease is not life-threatening and most irritation is described as “mild”. Unlike most respiratory illnesses resulting from exposure to respirable fibers (which may have a latency – the time from first exposure until the disease manifests itself – which can be 15–50 years), dermatitis arises in some subjects exposed for a short time (Sertoli et al., 1992). Thus, although dermatitis is typically a less severe illness than many respiratory illnesses, it is “obvious” and appears promptly, so it is likely to be recognized.

Numerous authors have studied the effects of dermal exposure to various SVFs and dermatitis. Table A3 provides a summary of some of the relevant literature including review articles, focus groups, patch or rubbing tests, case reports and epidemiological studies.

Overall, these and other studies conclude that irritant contact dermatitis is associated with exposure to various SVFs/PCWs with diameters that are larger (∼5 μm or larger) than those of respirable fibers and typically becomes less pronounced with continued exposure (ATSDR, 2004; Possick et al., 1970; Sertoli et al., 1992). As noted by Sertoli et al. (1992):

The pathogenic effect of fiberglass on the skin is directly proportional to the diameter and inversely proportional to the length. Fiberglass is harmful only if its diameter is greater than 4.5 µm or, according to other authors, 5 µm.

There is very little evidence of irritant contact dermatitis being caused by or associated with exposure to SVFs with diameters in the respirable range. But, because fibers with larger diameters weigh proportionally more than thinner fibers, it is reasonable that a gravimetric measure would be superior to fiber number concentrations as an indicator of the potential for ICD as reported by Zhu et al. (2015c).

Other analyses

Several other potentially relevant works (shown below in chronological order) have been published since 2010.

The Scientific Committee on Occupational Exposure Limits (SCOEL, 2011) published a review of RCF toxicology and epidemiology and developed a no observed adverse effect level (for possible impacts on pulmonary function) of 0.3 f/ml. The SCOEL report acknowledged the lack of evidence of carcinogenicity from epidemiology studies, but based on the results of the animal studies concluded:

From the available information it is concluded that the genotoxic effects observed in the different studies are secondary so that RCF are classified as SCOEL Carcinogen group C carcinogens: Genotoxic carcinogens for which a practical threshold is supported

Some German scientists concluded based on IP injection study results that RCF was as potent as amphibole asbestos in causing lung diseases. Walker et al. (2012a,b) tested the hypothesis that RCF was as potent as amphibole asbestos in causing lung cancer or mesothelioma. These investigators found that a cohort occupationally exposed to asbestos at identical levels to the RCF exposed cohort would have experienced significantly greater mortality than actually observed. Otherwise, there is no new risk analyses published since the Utell & Maxim (2010) review article. Earlier risk estimates based on extrapolation from animal studies span a very wide range (NIOSH, 2006; Maxim et al., 2003).

Costa & Orriols (2012) published a review article dealing with MMVF (including RCF) and the respiratory tract. Among other topics, this review commented on the finding that there was no parenchymal lung disease reported in the UC and Cowie et al., (2001) RCF studies as follows:

In spite of this, in most of the cohort studies in MMMF factory workers, exposure levels were estimated to be low; therefore, it is considered that the epidemiological studies may not have detected cases of pulmonary fibrosis for this reason.

Whether or not this conjecture is correct, it underscores the prudence of continuing efforts to maintain or reduce occupational exposures, a major objective of the industry PSP.

As noted above, the industry PSP also includes a product research component, focused on the development of possible substitutes for present high-temperature insulation materials with less potential for toxic effects. This effort led to the development of a new class of materials, termed alkaline earth silicate (AES) wools. AES wools are less biopersistent fibers capable of substituting for RCF in some (but not all) applications. Brown & Harrison (2012) published an article describing these materials and the history of their development.

Greim et al. (2014) explored analogies (e.g. fiber dimensions, breakage mechanism and measured biopersistence in animal inhalation studies) between RCF and conventional mineral wool and concluded that the risks associated with occupational exposure are likely to be comparable for these two fibers. This is of interest because large and robust epidemiological studies of occupational exposure to mineral wool found that risks of lung cancer and mesothelioma are not elevated. The evidence was sufficiently compelling that IARC downgraded the carcinogen classification for glass and mineral wool from 2B to 3.

Boffetta et al. (2014) (see above) completed a systematic review of occupational exposure to SVFs and mesothelioma. This comprehensive review paper examined the epidemiological (case–control and cohort) and toxicological evidence for a linkage between occupational exposure to SVFs (including RCF) and mesothelioma. These investigators concluded that the combined evidence from epidemiology and toxicology “provide little evidence that exposure to SVF increases the risk of mesothelioma”.

The HTIW Coalition and ECFIA continue to publish outreach materials in English and several other languages (as part of the product stewardship program) designed to inform workers about good working practices for handling RCF and other high temperature insulation wools (see e.g. http://www.ecfia.eu/files/ecfia-cartoon-redesign-english-v1_0-2014-04.pdf and http://guidance.ecfia.eu/index.htm) as do other agencies (HSE, 2008; NIOSH, 2006).

Matsuzaki et al. (2015) published a review article on biological effects of RCF exposure. Among their concluding remarks they wrote:

Thus, given the biological effects of RCF previously reported in the literature, it is necessary to consider further monitoring in addition to the development of measures to prevent adverse health effects caused by exposure to RFCs.

Harrison et al. (2015) wrote a recent review of regulatory risk assessment approaches for synthetic mineral fibers (including RCF). They pointed out that occupational exposure limits (OELs) for RCF developed by regulatory and advisory bodies in various countries varied by more than an order of magnitude and argued that:

The resulting differences in established OELs prevent consistent and appropriate risk management of SMF worldwide, and that development of a transparent and harmonised approach to fibre risk assessment and limit-setting is required.

Andujar et al. (2016) published a 5-year update on the relationships between malignant pleural mesotheliomas and exposure to asbestos and other elongated mineral particles. The article reviewed earlier studies published by some of the same authors, which (as noted above) reported an apparently synergistic relation between exposure to asbestos and certain mineral fibers, including mineral wool and RCF. This article recapitulated the findings and some of the limitations of these earlier studies and (in a more cautious vein) noted:

While the issue of the simultaneous effect of asbestos and other mineral particles needs to be further explored in reality, the hypothesis of a synergistic joint effect needs to be considered.

Drummond et al. (2016) published a review article that examined the relationship between the results of intra-pleural and intraperitoneal studies with those from inhalation and intratracheal tests for the assessment of pulmonary responses to inhalable dust and fibers. They concluded:

For some of the fibrous material reviewed, there is conformity between the results of intraperitoneal and inhalation tests such that they are either consistently positive or consistently negative. For the remaining fibrous materials reviewed, intraperitoneal and inhalation tests give different results, with positive results in the intraperitoneal test not being reflected by positive inhalation results. It is suggested that the intraperitoneal test can be used to exonerate a dust or fiber (because if negative in the intraperitoneal test it is extremely unlikely to be positive in either inhalation or intratracheal tests) but should not be used to positively determine that a dust or fiber is carcinogenic by inhalation. We would argue against the use of intraperitoneal tests for human health risk assessment except perhaps for the purpose of exoneration of a material from classification as a carcinogen.

This article considered the relationship between IP and inhalation results for several fibers, including RCF. For RCF, the authors noted that the RCC animal inhalation studies that resulted in fibrosis and tumors might have been compromised by the presence of non-representative amounts of particulate material, a point made in several earlier articles (Brown et al., 2005).

Concluding comments

Several useful and informative publications have appeared since the Utell & Maxim (2010) review. Based on these and the earlier studies, we conclude:

• Correctly interpreting the animal bioassay data is difficult because of uncertainties in correcting for or otherwise accounting for the possible effects of lung overload. Published risk estimates based on extrapolation of animal data span a wide range of unknown accuracy.

• The results of epidemiology studies (particularly the UC study) continue to support the conclusion that present RCF occupational exposures are unlikely to result in material decrements in lung function, interstitial fibrosis, incremental lung cancer or mesothelioma in the exposed population. The latest UC results confirm an elevated urinary cancer SMR in the occupationally exposed cohort, which UC investigators thought might be accounted for by smoking or other occupational exposures. The finding of an elevated leukemia SMR (without evidence of an exposure–response relation) is probably unrelated to RCF exposure and more likely related to other occupational exposures or lifestyle factors. The finding of an unconfirmed death from mesothelioma is probably the result of prior self-reported asbestos exposure and a work history of jobs for which occupational asbestos exposure is likely. Nonetheless, continued follow-up of the RCF-exposed cohort is important to learn more about possible linkages between RCF exposure and kidney and/or bladder disease, leukemia, and maintaining vigilance for mesothelioma given its long latency and relative infrequency in the population.

• Product stewardship efforts have been successful in substantially reducing occupational exposures to RCF (and other fibers) and will be continued at both production and end-user facilities. Workers who joined the cohort in recent years have substantially lower exposures compared to those who were initially exposed during the 1980s or earlier.

• The medical surveillance component of the stewardship program may provide indications of morbidity in the cohort not captured in the earlier UC morbidity studies or the ongoing UC mortality study.

• The ongoing mortality study provides useful data and, as the cohort ages and the time since first exposure of the worker’s increases should yield yet more powerful data on long-latency outcomes.

• Finally, even though epidemiological findings indicate that present RCF occupational exposures are unlikely to result in adverse health outcomes, it is prudent to continue efforts to reduce RCF exposures and to develop efficient high temperature insulating wools with yet lower biopersistence and greater diameters to reduce the respirable fraction.

Acknowledgements

We would like to acknowledge the helpful contributions of Mr Ronald Niebo, Everest Consulting Associates and useful comments by referees and Prof. Dr Med. Helmut Greim, Director of the Institute of Toxicology and Environmental Hygiene, Technische Universität München.

Disclosure statement

The authors performed this work as independent consultants. Both authors serve as consultants on a scientific review board for Unifrax, a major producer of HTIWs and have performed studies for the HTIW Coalition. Neither author has appeared in any legal or regulatory proceeding relative to RCF. The findings and conclusions are those of the authors alone and do not necessarily represent the views of the sponsor.

This research was sponsored by the HTIW Coalition (see http://www.htiwcoalition.org/for a list of members and associate members), an organization that focuses on health and safety matters for producers of RCF and other high-temperature insulating wools (HTIWs) in the US.

Appendix

Table A1. Known risk factors for kidney cancer.

Site	Risk factor	Comments	Sources
Kidney cancer	Cigarette smoking	Strong evidence from cohort, case–control and meta-analysis studies in several countries indicates tobacco (particularly cigarette) smoking is a major risk factor.	Brown et al., 2012; Chow & Devesa, 2008; Hunt et al., 2005; Janout & Janoutová, 2004; Karami et al., 2012; Lipworth et al., 2009; Ljungberg et al., 2011; McLaughlin et al., 2006; Moyad 2001; Orth, 1997; Pascual & Borque, 2008; Qayyum et al., 2012; Rubagotti et al., 2006; Weikert & Ljungberg 2010; Zeegers et al., 2000.
	Obesity	Strong evidence from several studies that elevated body mass index (BMI) is a risk factor for kidney cancer.	Anderson et al., 2015; Brown et al., 2012; Chow et al., 2000, 2010; Chow & Devesa, 2008; Janout & Janoutová, 2004; Karami et al., 2012; Lipworth et al., 2009; Ljungberg et al., 2011; Mariusdottir et al., 2016; McLaughlin et al., 2006; Moyad, 2001; Qayyum et al., 2012; Rubagotti et al., 2006; Song et al., 2014; Vucenik & Stains, 2012; Weikert & Ljungberg 2010.
	Drugs	Mixed evidence relating to certain analgesics and diuretics.	Chow et al., 2010; Ljungberg et al., 2011; Rubagotti et al., 2006.
	Medical conditions and treatments	Hypertension is known risk factor for kidney cancer. Certain other diseases implicated (e.g. end stage, chronic kidney disease and long term dialysis). There are others including genetic factors and a family history of kidney cancer. There is a possible link to history of diabetes mellitus.	Chow et al., 2000, 2010; Chow & Devesa, 2008; Janout & Janoutová, 2004; Karami et al., 2012; Lipworth et al., 2009; Ljungberg et al., 2011; Mariusdottir et al., 2016; McLaughlin et al., 2006; Moyad 2001; Pascual & Borque, 2008; Qayyum et al., 2012; Rubagotti et al., 2006; Russo, 2012; Weikert & Ljungberg 2010.
	Occupational	“Renal cell cancer generally is not considered an occupational disease” (Chow et al., 2010), but occupational exposure to several chemicals (e.g. benzene, benzidine, coal tar, soot, pitch, gasoline, trichloroethylene, tetrachloroethylene, various metals (lead, cadmium), poly-aromatic hydrocarbons and solvents) implicated as risk factors. Employment in several sectors (e.g. agriculture, coke and coal oven workers, computer manufacturing, drycleaners, painters, mechanics, roofers, shipbuilders and textile workers), but evidence is mixed.	Chiu et al., 2013; Chow et al., 2010; Heck et al., 2010; Hu et al., 2002; Karami et al., 2011; Kim et al., 2014; Ljungberg et al., 2011; Mariusdottir et al., 2016; Moore et al., 2010; Partanen et al., 1991; Pascual & Borque, 2008; Pesch et al., 2000; Rubagotti et al., 2006; USEPA, 2009, 2012.

Table A2. Known risk factors for bladder cancer.

Site	Risk factor	Comments	Sources
Bladder cancer	Cigarette smoking	Tobacco smoking is the best established risk factor for bladder cancer. Numerous review articles, epidemiological studies (e.g. cohort and case–control) and meta-analyzes indicate that there are statistically significantly elevated odds ratios and high population attributable risks associated with smoking.	Baris et al., 2009; Brown et al., 2012; Brownson et al., 1987; Burger et al., 2013; Cassidy et al., 2009; Freedman et al., 2011; Ghadimi et al., 2015; Golka et al., 2007; Hemelt et al., 2009; IARC, 2004; Olfert et al., 2006; Orth, 1997; Silverman et al., 2006; Zeegers et al., 2000
	Obesity	Strong evidence from meta-analyzes that obesity is also a major risk factor for bladder as well as kidney cancer.	Koebnick et al., 2008; Qin et al., 2013; Song et al., 2014; Sun et al., 2015
	Medical conditions and treatments	Chronic bladder infections and irritations, personal or family history of bladder cancer, Some medications and dietary supplements – pioglitazone (Actos), aristolochic acid (mainly from plants in the Aristolochia family) and cyclophosphamide therapy. Schistosomiasis.	Burger et al., 2013, Lewis et al., 2011; Mostafa et al., 1999; Travis et al., 1995; http://www.medicalnewstoday.com/articles/167077.php.
	Occupational	Cohort and case–control studies have shown that occupational exposure to several chemicals (e.g. arsenic, paint components, dry cleaning fluids, polycyclic aromatic hydrocarbons, aromatic amines, diesel exhausts, lubricating oils or greases, petroleum product or additives, tetrachloroethylene and aromatic amines) linked to bladder cancer – strength of evidence varies. Employment is certain sectors (e.g. agricultural workers, bartenders, blacksmiths, bus drivers, dyers, painters, hairdressers, leather workers, maintenance workers, mechanics, medical workers, metal workers, miners, rubber industry, textile workers, transportation equipment, truck and bus drivers and waiters) also linked to bladder cancer, but strength of the evidence varies.	Brown et al., 2012; Brownson et al., 1987; Burger et al., 2013; Cassidy et al., 2009; Clapp et al., 2008; Ghadimi et al., 2015; Golka et al., 2004, 2007; González et al., 1989; Harling et al., 2010; Khoubi et al., 2013; Kogevinas et al., 2003; Lynge et al., 2006; McLaughlin et al., 2006; Olfert et al., 2006; Reulen et al., 2008; Richardson et al., 2007; Scarselli et al., 2011; Serra et al., 2008; USEPA, 2012; Wu et al., 2007; Zeegers et al., 2001.

Table A3. Studies on irritant contact dermatitis and fiber exposure.

Type of article	Typical results/statement	Source(s)
Review articles	Summarize other research findings that indicate fibers with diameters greater than those of respirable size are more likely to cause skin irritation.	ATSDR (2004) Björnberg (1985) INSERM (1999) http://www.ipubli.inserm.fr/bitstream/handle/10608/192/?sequence =10. Lachapelle (1986, 2006) Possick et al. (1970) Sertoli et al. (1992) Skotnicki-Grant (2008)
Focus groups	Interviews with workers exposed to insulation materials that contain some mention of the role of larger diameter fibers.	Lundgren et al. (2014)
Patch or rubbing test results	Patches containing fibers applied to skin of test subjects indicating larger diameters are associated with greater skin response.	Eun et al. (1991) Stam-Westerveld et al. (1994)
Miscellaneous other studies	Coarse fibers account for irritation	Heisel & Hunt (1968) Minamoto et al. (2002) Patiwael et al. (2005)
Case reports	One or several cases of contact irritant dermatitis caused by fibers with diameters greater than those of respirable size.	Chang et al. (1996) Koh et al. (1992) Lee & Lam (1992) Sim & Echt (1996) Wang et al. (1993)
Epidemiological studies	Studies of groups of occupationally exposed workers showing large diameter fibers associated with skin irritation.	Hsieh et al. (2001) Kieć-Świerczyńska & Wojtczak (2000)
Medical texts	Glass fibers with diameters greater than ∼5 µm are more likely to cause skin irritation than smaller diameter fibers	Adams (1990) Rom & Markowitz (2004) Kanerva et al. (2013) Konzen (1987)

Table A4. Causes, contributing factors and risk factors for adult leukemia.

Category	Examples	References
Occupational	Exposure to benzene and certain other chemicals (e.g. ethylene oxide (b), formaldehyde (a), pesticides, herbicides, insecticides, embalming chemicals, toluene and xylene).	Adegoke et al., 2003: Brown et al., 1990; Costantini et al., 2008; Deschler & Lübbert, 2006; Glass et al., 2003; IARC, 2012; Rinsky, 1989; Rodriguez-Abreu et al., 2007; Schwilk et al., 2010; Smith & Zhang, 1998; Zeeb & Blettner, 1998; Zhang et al., 2009
	Electromagnetic fields	Floderus et al., 1993; Karakosta et al., 2016; Rodriguez-Abreu et al., 2007
	Radiation	Band et al., 1996; Deschler & Lübbert, 2006; Greaves, 1997; Karakosta et al., 2016; Leuraud et al., 2015; Richardson et al., 2015; Rodriguez-Abreu et al., 2007; Smith & Zhang, 1998; Zeeb & Blettner, 1998
Lifestyle-related	Smoking	Brownson et al., 1993; Danaei et al., 2005; Fernberg et al., 2007; Fircanis et al., 2014; Kane et al., 1999; Karakosta et al., 2016; Smith & Zhang, 1998; Wang et al., 2015
	Obesity	Calle et al., 2003; Castillo et al., 2012; Larsson & Wolk, 2008; Strom et al., 2009
	Diet	McDonald et al., 2001; Ross et al., 2002; Smith & Zhang, 1998
Environmental	Radon exposures in the home.	Henshaw et al., 1990
Medical procedures	Chemotherapy (certain drugs) and therapeutic radiation.	Aidan et al., 2013; Curtis et al., 1992; Deschler & Lübbert, 2006; Zeeb & Blettner, 1998
Genetic disorders	Down syndrome, Klinefelter syndrome, Patau syndrome, Ataxia telangiectasia, Shwachman syndrome, Kostman syndrome, Neurofibromatosis, Fanconi anemia and Li-Fraumeni syndrome.	Deschler & Lübbert, 2006; Zeeb & Blettner, 1998
Certain viral infections	Infection with the human T-cell lymphoma/leukemia virus-1 (HTLV-1) can cause a rare type of T-cell acute lymphocytic leukemia. Most cases occur in Japan and the Caribbean area. In Africa, the Epstein-Barr virus (EBV) has been linked to Burkitt lymphoma, as well as to a form of acute lymphocytic leukemia. In the US, EBV most often causes infectious mononucleosis (“mono”).	Matsuoka & Jeang, 2007; De Roos et al., 2013; Rodriguez-Abreu et al., 2007
Family history	Family history of leukemia or any cancer.	Karakosta et al., 2016; Rauscher et al., 2002

(a) Some reported associations are controversial, such as the relation between occupational exposure to formaldehyde and leukemia (Collins & Lineker, 2004; Heck and Casanova, 2004).

(b) IARC (2012) concluded that there is limited human evidence for the carcinogenicity of ethylene oxide.