Primary prevention: exposure reduction, skin exposure and respiratory protection

Exposure response studies

Numerous studies, mostly cross-sectional in nature, have examined relationships between exposure to allergens and the occurrence of sensitisation or work-related asthma. Exposure response studies support the concept that exposure reduction is likely to be followed by a reduction in disease burden. A positive dose–response relationship between exposure and sensitisation has been found in both experimental animal studies [7] and studies of workers exposed to allergens of high molecular weight (HMW) and low molecular weight, including wheat flour, fungal α-amylase, laboratory animal allergens, organic acid anhydrides, isocyanates and platinum salts [8–20]. Some of these studies use variables known or likely to be associated with exposure level, such as duration of exposure or number of hours exposed per week. Others make use of more elaborate exposure assessment strategies, in which the exposure has been monitored by personal or area sampling equipment, followed by analysis of the allergen content of the dust sample. The latter approach facilitates the description of a quantitative exposure response relationship between measured exposure level and occurrence of sensitisation or asthma. Exposure response relationships indicate that implementation of primary preventive measures in the workplace that result in a reduction of exposure should also lead to a reduction in sensitisation rate.

Exposure reduction studies

What observations indicate that certain preventive measures lead to a reduction of exposure? The effect of few exposure reduction measures has been studied in practice. Thus, little is known about the effectiveness and efficacy of many possible exposure reduction measures. Studies have explored the effect on exposure of work tasks, cleaning and protective procedures, quality of ventilation systems and work routines in a range of different settings, such as bakeries [21–23], wood industries [24–27] and hairdressers [28]. However, these studies are usually cross-sectional and more exploratory in nature.

Natural rubber latex

Stronger evidence is shown in table 2, stratified by specific allergen. The most convincing example of the beneficial effects of an intervention is exposure to latex allergens. For latex, a meta-analysis is available that includes the separate studies described in table 2 [29]. Several studies explored differences in exposure levels between healthcare workers using powdered and non-powdered gloves. The most powerful study investigating the use of non-powdered gloves, which was associated with lower exposure, was a longitudinal case crossover intervention. In this study, introduction of powder-free, protein-poor natural rubber latex (NRL) gloves led to 10-fold lower aeroallergen exposure levels [31]. The effect of this single preventive measure on the prevalence or incidence of sensitisation and occupational asthma has been studied for NRL as well. A review of the literature in 2006 indicated that eight primary prevention intervention studies had been published on NRL exposure since 1990 [29], including the exposure study described previously [31]. All the studies in this review that explored disease as the outcome were observational studies that showed a decrease in sensitisation rates, either in a cross-sectional analysis or in a longitudinal design (both prospective and retrospective) [32, 34–36, 39]. These studies on latex form the largest evidence base of primary prevention studies for any occupational asthma. This study concluded that substitution of powdered latex gloves with low-protein, powder-free NRL gloves or latex-free gloves greatly reduces NRL aeroallergens, NRL sensitisation and NRL asthma in healthcare workers. None of the individual studies fulfilled strict criteria for good-quality intervention studies, i.e. they were observational studies without a randomised design. However, taken together, these studies support assertions that substitution of NRL greatly reduces NRL sensitisation and asthma. The studies evaluated as evidence in support of this statement were ranked Scottish Intercollegiate Guidelines Network (SIGN) level 2+, meaning they were well-conducted, case–control or cohort studies with a low risk of confounding, bias or chance, and a moderate probability that the relationship is causal.

Other asthma-inducing agents

Fewer studies are available for asthma-inducing agents other than NRL. One example of a longitudinal exposure study is the study by Meijster et al. [40], which explored the effect of control measures on dust and allergen exposure in a nonrandomised design. The authors found that changes in exposure over time varied substantially between sectors and jobs. For bakeries a modest downward annual trend in exposure of -2% was found for flour dust and -8% for fungal amylase. For flour mills the annual trend for flour dust was -12%, while no significant trend was observed for amylase. For ingredient producers, results were generally nonsignificant but indicated a reduction in flour dust exposure and increase in fungal α-amylase exposure. A modest increase in use of control measures and proper work practices was reported in most sectors, especially the use of local exhaust ventilation and decreased use of compressed air. Few longitudinal studies like this one have been performed and most studies have not used experimental designs.

In other environments, studies have been undertaken with interventions comprising combinations of different preventive dust control measures, as well as education and PPE. During a 10-yr follow-up, Smith [41] found a decrease in the annual incidence rates of symptomatic sensitisation to flour and fungal amylase in bakers from 2,085 per million to 405 per million employees per year (table 3). The intervention focused on information and training, installation of local exhaust ventilation, and wearing of respirators during handling of powdered bread improvers. No exposure data was included. Dissemination of information about exposure limits of diisocyanates to public (health) authorities in Ontario, Canada, together with a primary preventive programme and health surveillance, probably resulted in lower exposure levels and a decrease in accepted claims over time. Tarlo et al. [43] retrospectively assessed workers compensation data from 1980 to 1993 and found an initial increase in compensation claims, which were attributed to increased case findings due to the medical surveillance programme. The subsequent 50% decrease in accepted claims from 1991 to 1992–1993 was attributed to a combination of primary and secondary prevention measures. When measured levels of diisocyanate were compared among companies who had compensated claims for occupational asthma with companies without accepted claims, the former were more likely to have had measured levels of diisocyanates >0.005 ppm [43].

In the detergent industry, the introduction of work practices and a medical surveillance programme decreased sensitisation rates to enzymes among workers within almost 20 yrs [45]. Significant reductions in the prevalence of occupational asthma have been reported after introducing granulated proteases [44, 48]. In the study of Cathcart et al. [44], during the observation period, atmospheric enzyme concentrations and the reported incidence of enzyme asthma fell considerably. However, the number of cases dropped, but the denominator, consisting of the number of individuals at risk, was not established. So, it is unclear if the risk for an individual declined. It cannot be excluded that the number of workers exposed declined over the years because of mechanisation and automation of production processes. Cullinan et al. [49] reported an outbreak of asthma in a detergent factory which exclusively used encapsulated enzymes, while sensitisation rate was related to exposure level. A recent study showed a similar outbreak but in an enzyme factory using liquid enzyme formulations [50].

In laboratory animal workers allergy, a preventative programme including education, engineering and administrative controls, the use of respirators and medical surveillance showed a decrease in the incidence rate of asthma from 10% to 0% during a 5-yr follow-up [47]. However, this study was not designed as a cohort study, there was considerable loss to follow-up and forms of selection bias such as the healthy worker effect cannot be excluded. In addition, the effectiveness of the intervention to reduce allergen exposures was not evaluated. In a retrospectively assembled cohort of new employees working with laboratory animals, an education programme may have contributed to the decrease in annual incidence rate of laboratory animal allergy from 42% to 15% over 4 yrs [46, 47]. Comparison of the symptom prevalence in each entry year for each new cohort entering the workforce indicates a lower prevalence in cohorts that entered after the start of the intervention. However, trends over time cannot be interpreted because the occurrence of laboratory animal allergy was not explored by considering the proportion exposed and not expressed as a rate with person-time of follow-up in the denominator. Loss to follow-up was considerable, and the risk of developing laboratory animal allergy from year to year is likely to have been underestimated as a result. It is unclear if the apparent reduction in laboratory animal allergy occurrence was accompanied by a reduction in allergen levels since no allergen exposure data was obtained.

Assessment of skin exposure

To assess whether human skin exposure to allergens increases asthma risk requires methods to sample and quantify skin exposure. Such methods are not as well developed and not as widely available as airborne exposure methods. Skin exposure assessment is further complicated by factors such as the frequently sporadic nature of skin exposure, uncertainty about skin uptake, unknown effectiveness of protective clothing, mixed exposures, and the challenge of separating the risks of skin versus inhalational exposures. Despite these challenges, investigators have recently quantified isocyanate skin exposures in exposed workers using novel sampling and analytical approaches, including skin surface wipe sampling, skin tape stripping, and sampling of inner gloves and pads under PPE (table 4) [56, 58, 60–63]. Analysis of consecutive skin tape strips has documented dermal penetration of isocyanate, and correlations between isocyanate skin exposure and urinary metabolites support skin uptake [60–62]. These studies have also demonstrated frequent isocyanate skin exposure among workers in several work settings despite the use of standard PPE, such as gloves [56, 60, 63]. They have also demonstrated that while in some work settings skin and respiratory exposures are highly correlated, in others settings they are not, potentially enabling the differentiation of skin and respiratory health effects. Incorporation of skin exposure metrics into epidemiological studies of exposed workers should enable investigators to better define the risks of skin exposure and also the effectiveness of industrial hygiene controls, including protective clothing, to reduce such exposures.

Isocyanate skin exposure and asthma

To date, the evidence that human skin exposure to allergens can increase the risk of asthma comes primarily from case reports of isocyanate asthma or sensitisation in settings where isocyanate skin contact has been reported or suspected, and where airborne isocyanate levels are very low (table 5). Most of these cases have involved workplace exposure to methylene diphenyl diisocyanate (MDI), which is much less volatile than the other commonly used isocyanates, and is frequently handled as a liquid, creating greater opportunity for exposure through skin contamination than through inhalation. To date, the primary epidemiological study that addressed the risk of asthma related to occupational skin exposure was a cross-sectional and 1-yr follow-up study of 214 newly employed workers in a wood manufacturing plant that used MDI resins [64]. Skin exposure was assessed by a questionnaire regarding skin staining, MDI on clothes and type of work. 27% of workers in areas with high potential for liquid MDI exposure reported new-onset asthma-like symptoms versus 0% in low-potential areas. Skin staining and MDI on clothes, and working around and cleaning up MDI was associated with new asthma-like symptoms. Air monitoring data (six personal breathing zone samples) showed no detectable MDI and a single glove wipe sample that was taken had 0.078 mg of MDI. The authors concluded that skin might be a site for potential immunological sensitisation and subsequent risk for development of respiratory symptoms. In other studies, an investigation of approximately 500 coal miners who injected MDI for rock consolidation identified about 15 workers with a diagnosis of occupational asthma or sensitisation (positive MDI-immunoglobulin (Ig)E) [65]. Air sampling for MDI was reported to show very low levels (<1 ppb) and MDI skin exposure was reported to occur commonly among these workers. The authors concluded that isocyanate skin exposure probably contributed to MDI sensitisation and asthma [65]. Surveillance of 243 workers exposed to MDI in a polyurethane mould plant with MDI air levels consistently <0.005 ppm identified three cases of MDI asthma and one case of MDI-induced cutaneous anaphylaxis [66]. In one case the onset of asthma symptoms occurred after an MDI spill. All four workers were reported to work in areas with potential for skin contact with uncured MDI.

Studies among other groups of workers are also very limited. A cross-sectional study of 641 tannery workers found an asthma prevalence of 10.8% [67]. Multiple regression analysis showed the strongest risk factor for asthma was not using gloves (OR 3.28, 95% CI 1.72–6.26), with educational status, ethnicity, smoking, perceived allergy and duration of work also being significant risk factors (table 5]).

Several studies have provided data on the effectiveness of currently recommended PPE in preventing skin exposure to isocyanates. Although typically lower amounts are noted than on unprotected skin, isocyanate has been detected underneath latex and nitrile gloves, cartridge respirators and protective clothing [56, 60, 63].

In summary, skin exposure to certain occupational asthma-inducing agents probably increases the risk of occupational asthma, despite limited epidemiological studies to date. The contribution of skin exposure to asthma risk probably varies greatly with different allergenic exposures, work processes and settings, as well as other factors than can alter skin barrier function. Dose–response relationships with allergens frequently are nonlinear, and there are insufficient data to identify safe skin exposure levels for sensitisers. There are data indicating that currently recommended PPE may not be effective in limiting skin exposure to isocyanate chemicals in some settings. Improved skin exposure methodologies should facilitate the incorporation of skin exposure assessment into epidemiology studies to better define exposure risk factors and also help evaluate the effectiveness of preventive interventions. In the meantime, it would be prudent to increase awareness of the potential risks of allergen skin exposure and to limit such exposures.

PPE and the hierarchy of controls

In the hierarchy of controls for occupational health hazards, eliminating or minimising exposures at the source or in the environment is considered more effective than the worker using PPE [71]. The success of respiratory personal protection requires an ongoing commitment by employers and employees to a programme that includes selection, cleaning, maintenance and storage of equipment, as well as training, fit testing and medical monitoring of users. Respirators are best used as an interim measure while efforts to control exposures at the source or in the environment are being implemented, or when controls at these other levels are not possible. Perhaps, since respirators are not considered an optimal way to control exposures, they have often been used in conjunction with other control activities at the source and/or environmental level. Such comprehensive programmes that include the use of respirators have been implemented for workers exposed to laboratory animals [47, 72–74], dusts and fumes in aluminium production [75], diisocyanates [76] and disinfectants [76, 77]. While many of these programmes have reported success at prevention, it is not possible to determine the contribution made by respirators alone.

Previous statements from professional organisations

Two recent statements from professional organisations address use of respirators for primary prevention of work-related asthma. An expert panel convened by the American College of Chest Physicians (ACCP) produced a publication on the diagnosis and management of work-related asthma [78]. This document advises primary prevention by controlling exposures to known workplace sensitisers and irritants, briefly citing a variety of methods, including respirators. The examples of using respirators to control exposures involved exposure to hexahydrophthalic anhydride (HHPA) [79] and isocyanates [80]. The British Occupational Health Research Foundation (BOHRF) also developed guidelines for occupational asthma [81]. Similar to the ACCP document, the BOHRF guidelines emphasise reducing airborne exposures to occupational asthma agents. The advice specific to respiratory protective equipment (RPE) was: “The use of RPE reduces the incidence of, but does not completely prevent, occupational asthma” [81]. The evidence cited included the same article used in the ACCP document for HHPA [79] and two references for control of exposure to isocyanates [64, 82] not cited by the ACCP.

Indirect evidence for effectiveness of PPE in preventing occupational asthma

An updated review of the medical literature revealed indirect evidence that use of respiratory protective devices might prevent asthma onset, by demonstrating that respirators can reduce exposures to agents that can cause occupational asthma. These studies investigated: air purifying respirators [83] and half-face respirators with particulate/organic vapour/formaldehyde filters [84] used by firefighters; air purifying respirators [85], half-mask respirators with frequent cartridge changes [86], and half-face air purifying or full-face air-supplied respirators [87] for workers exposed to styrene; hood style supplied air respirators used to reduce exposure to chromium and other materials during sanding in aircraft manufacturing [88]; P2 facemasks and fresh-air helmets to reduce levels of rodent allergens among laboratory animal handlers [89]; and certified two-tie protective masks that reduced total particle concentrations by 97% in swine confinement buildings [90].

This indirect evidence takes on somewhat more significance for agents that have a positive dose–response relationship with occupational asthma, since a reduction in exposure should decrease the number of cases. Such a relationship has been reported for wheat allergen [91], and investigators compared exposure levels measured inside a P2 particle filter facemask to measurements taken outside the facemask [92]. Exposure levels were reduced by 93–96% using the facemasks, and the investigators concluded that these respirators might help to prevent baker's asthma.

Several studies have examined the effectiveness of respiratory protective devices intended to limit isocyanate exposure in paint operations. A study of 22 spray painters working in automobile body shops measured isocyanates both inside and outside negative pressure, air-purifying half-face piece respirators with organic vapour cartridges and paint pre-filters [80]. The authors concluded that these respirators provided reasonably effective protection if the workers were trained and fit tested. In a study conducted in a test chamber, air purifying respirators with organic vapour cartridges were, on average, 99.4% efficient based on comparisons of isocyanate exposures inside and outside the respirators [93]. In another study of spray painters, researchers concluded that air-fed visors provided good protection if they were well maintained and the airflow was sufficiently high [94].

Direct evidence for effectiveness of PPE in preventing occupational asthma

Despite the encouraging findings that respirators can substantially reduce exposures to asthma agents, these studies did not directly test whether respirator use is associated with a decline in the onset of occupational asthma. The two studies for isocyanates and respirators in the BOHRF guidelines at least suggest such a benefit. In one study, automobile body shop employees who applied paints containing isocyanates were approximately one-third as likely to have occupational asthma symptoms if they used a positive pressure respirator [82]. However, a relatively small number of participants used this respirator and the finding was not statistically significant [82]. A second study provided evidence that inconsistent use of respiratory protection might have negative consequences. Specifically, isocyanate-exposed workers at a wood products plant were at greater risk for new-onset asthma-like symptoms if they removed their respirators even briefly (p<0.05) [64].

A more direct investigation of the value of respiratory protection for primary prevention was conducted among workers who were manufacturing an epoxy resin that required HHPA (table 6) [79]. This is the same study cited in both the ACCP and BOHRF documents. Study participants were offered a choice of three different respirators: a disposable dust and mist respirator, a half-face organic vapour respirator, or a full-face organic vapour respirator. The highest annual incidence for asthma over the 7 yrs of follow-up was 2%, compared to approximately 10% that was observed in employees before the introduction of respirators. There was no statistically significant difference between respirators, but none of the workers who wore the full-face respirators developed occupational asthma, even those who worked in high-exposure jobs.