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health surveillance data
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference Type:
Report Date:

Materials and methods

Study type:
health record from industry
Endpoint addressed:
repeated dose toxicity: inhalation
Test guideline
no guideline available
Principles of method if other than guideline:
Multiple linear and logistic regression models and Monte Carlo multimodel analyses of two exposure scenarios were used to evaluate the effect of cumulative exposure to inhalable SAS dust on symptoms, spirometry, and chest films in 462 male workers from five German SAS producing plants.
GLP compliance:
not specified

Test material

Test material form:
solid: nanoform, surface-treated
Specific details on test material used for the study:


Type of population:
Ethical approval:
confirmed, but no further information available

Results and discussion

Any other information on results incl. tables

More than four of five workers were active smokers or former smokers (Table 1). About 11% of the workers reported chronic bronchitis. About two-third had a negative skin prick test and were negative by specific IgE. Three percent of the subjects reported anti-asthmatic medication. Only a minority was previously exposed to fibrogenic dust (17%) or substances causing

obstruction (27%). Almost 80% showed normal spirometry, and obstructive and restrictive patterns were observed in 17% and 4% of the subjects, respectively. Only two workers (0.4%) showed a profusion category 1/0 or 1/1.

There were significant effects of age, height, smoking, and medication on FEV1, the most comprehensive and robust spirometric parameter, with both exposure assessment procedures (Table 2). The effect of cumulative SAS exposure on FEV1 was not significant, and almost identical for both exposure assessments [P1 scenario: -4.9; 95% confidence interval (95% CI) -14.1 to

4.4; P2m scenario: -6.3; 95% CI -14.6 to 2.1]. Interestingly, there was a plant effect, showing lower FEV1 for plants 3 and 4 with both procedures. At these plants, a Masterlab was used as lung function device. Atopy and prior exposure to hazardous substances had no effect with any procedure.

Results of the multivariable linear regression models on FVC or the FEV1/FVC ratio gave overall similar results, but FVC

decreased with increasing cumulative SAS exposure for both exposure assessments. This was statistically significant for P2m, but not for P1. The effects of smoking and medication were less pronounced or absent, but the plant effects were significant in both scenarios (Table 3). For the FEV1/FVC ratio, the effect of cumulative exposure was nearly zero (Table 4) with an effect estimate of -0.04 (95% CI -0.16 to 0.07) for P1 and 0.04 (95% CI -0.06 to 0.14) for P2m. Further effects were similar as for FEV1, with the exception that plant effects were almost absent.

The results of the multinomial logistic regression on obstructive and restrictive patterns compared with normal spirometry are

presented in Table 5. The obstruction ORs were similar for both exposure assessments. No effect of cumulative SAS exposure was seen for P1 (OR 1.01; 95% CI 0.96 to 1.07) and the P2m scenario (OR 0.98, 95% CI 0.93 to 1.03). Antiobstructive medication showed an association with airways obstruction (OR 5.87; 95% CI 1.71 to 20.13) and restriction (OR 3.48; 95% CI 0.34 to 35.89).

Excluding study subjects with antiobstructive medication resulted in 361 study subjects with normal spirometry and 72 with

an obstructive pattern. This changed the ORs of the cumulative SAS exposure only slightly to 1.02 (95% CI 0.97 to 1.08) for P1 and to 1.00 (95% CI 0.95 to 1.05) for the P2m scenario (data not shown). For scenario P1, an increase of the OR until 100 mg/m³-years was observed but there was a decrease afterward (Fig. 1A), whereas for the P2m scenario, a decrease of the risk was shown throughout (Fig. A2).

For scenario P1, a 9% statistically significant increase of the restriction OR of the cumulative SAS exposure was observed (OR

1.09; 95% CI 1.01–1.18), but the 6% increase of the P2m scenario was not statistically significant (OR 1.06; 95% CI 0.99–1.13). The ORs for other covariables were similar for both exposure scenarios (P1, P2m). Antiobstructive medication showed nonsignificantly elevated ORs of 3.48 (95% CI 0.34 to 35.9) for P1 and 2.78 (95% CI 0.27 to 29.0) for the P2m scenario.

The exclusion of study subjects with antiobstructive medication had no influence on the ORs of the cumulative SAS exposure

of both exposure assessments (data not shown). A dose–response relationship between cumulative exposure and restrictive pattern was observed for both exposure assessment procedures P1 (Fig. B1) and P2m (Fig. B2).

For chronic bronchitis, a statistically significant increase of the OR was only observed for the highest exposure group (>100 mg/

m³-years) for scenario P1 (Table 6) with an OR of 3.68 (95% CI 1.29 to 10.5). Current smoking and antiobstructive medication increased the risk significantly. For the P2m exposure scenario, a decrease of the risk with increasing exposure was observed. Smoking and antiobstructive medication increased the risk as with P1. A dose–response relationship between cumulative exposure and chronic bronchitis was only observed for exposure assessment scenario P1 (Fig. C1), whereas a slight decrease was observed for the P2m scenario (Fig. C2).

All spline curves were accompanied by wide 95% CIs.

A Monte Carlo logistic regression analysis of the P2 exposure scenarios revealed a small downward trend of chronic bronchitis

with increasing cumulative exposure (data not shown).

Table 7 summarizes the results of MC regression models on lung function parameters (FEV1, FVC, FEV1/FVC) evaluating all

15 P2 exposure scenarios simultaneously. The effect of cumulative SAS dust exposure on FVC was the only significant finding. The estimated effect on FVC was smaller than the point estimate from the initial model based on the P2m scenario (-6 vs -11mL

per 10 mg/m³ -years, cp. Table 3), and the MC regression resulted in a P value of 0.04.

Applicant's summary and conclusion

Exposure to SAS was associated with a reduction in forced vital capacity (FVC) in one of the two exposure scenarios but had no effect on forced expiratory volume in 1 second (FEV1) or FEV1/FVC in either exposure scenario. Monte Carlo analysis indicated a decline in FVC of -11mL per 10 mg/m³-years exposure (-6 to -0.4). Chest films showed no evidence of pneumoconiosis.
Conclusion: This study provides limited evidence of minor dose-related effects of chronic exposure to SAS on lung function.
Executive summary:

The aim of this study was to assess the health impact of chronic exposure to synthetic amorphous silica (SAS) on nonmalignant respiratory morbidity.