Table 1. Description of included studies.
| Study | Gause 2011 [16] | Lee 2012 [17] | Liou 2012 [18] | Liao 2014a [19] | Liao 2014b [20] | Lee 2014 [21] | Pelclova 2015 [22,23] |
|---|---|---|---|---|---|---|---|
| Design type, e.g. descriptive, cross-sectional, longitudinal, exposure case control study | Descriptive Program | Descriptive Program Case Study | Cross-sectional; Exp case control study | Longitudinal (Six-month follow-up) study | Cross-sectional; Exp case control study | Cross-sectional; Exp case control study | Exp case control study (pre- & post-shift exposure) |
| Country | USA | South Korea | Taiwan | Taiwan | Taiwan | South Korea | Czech Republic |
| Participants | |||||||
| Occupation or Industry | Commercial research laboratory | Commercial, synthesis | Commercial, 14 plants handling ENMs | Commercial, 14 plants handling ENMs | Commercial, 14 factories handling ENMs | Commercial, manufactures MWCNTs | Commercial TiO2 pigment production plant |
| Participants’ N | N = 200, of which ± 20% exposed | N = 2, both exposed | N = 227 exp; N = 137 unexp | N = 124 expN = 77 unexp | N = 258 expo N = 200 unexp | N = 9 exp N = 4 unexp | N = 36 exp N = 45 unexp |
| Participants’ age (years) | NS | 37 and 42 | Exp < 40:173; Exp ≥ 40:54; Unexp < 40:89; Unexp ≥ 40:48 (p = 0.03) | Exp < 40:87Exp ≥ 40:37Unexp < 40:46Unexp ≥ 40:31(p = 0.26) | Exp < 40:194 Exp ≥ 40:64 Unexp < 40:135 Unexp ≥ 40:65 (p = 0.12) | Exp: 33.8 ± 4.9 Unexp: 28.3 ± 4.4 | 33.5 to 35.0 |
| Participants’ gender (%) | NS | Male exp: 100% | Male exp: 78% Male unexp: 54% | Male exp: 70.8–78% Male unexp: 46.8% | Male exp: 74.8–78.2% Male unexp: 60% | Male exp: 100% Male unexp: 75% | Male exp: 100% |
| Medical Surveillance | |||||||
| ENM Exposure material type | Carbon-based; Trimetaspheres ENMs; Variety of other ENMs | Metal (nano-Ag) | Metal (nano-Ag, nano-Au); Metal-oxide (TiO2, SiO2,Al2O3); Carbon-based (CNT); Nanoresins; Nanoclay; Mixed materials | Metal (nano-Ag);Metal-oxide (TiO2, SiO2); Carbon-based (CNT) | Metal (nano-Ag, nano-Au);Metal-oxide (Fe2O3, TiO2, SiO2, Al2O3); Carbon-based (CNT); Nanoresins; Nanoclay | Carbon-based (MWCNTs) | Metal-oxide (TiO2) |
| Exposure duration and frequency | NS | 7 years | Duration: 2.87 ± 2.34 years; Frequency: 2.43 times/week, 2.69 h/time; Exposure time: 7.91 h; Total cumulative exposure: 2,260 h | At baseline: Duration: 3.22 years; Frequency:2.43 times/week, 2.69 h/time; Exposure time: 8 h. After 6 months of NM exposure: Frequency: 2.78 times/week, 2.79 h/time; Exposure time: 9.38 h | Duration: 0.1 to 7 h/time; Frequency: 0.33 to 12 times/week | 3.9 ± 3.9 years, with 8 h shifts | 3.8 to 9.7 years, with 2.5 to 5.5 h per shift |
| Exposure route, e.g. inhalation / ingestion / dermal contact / in vivo administration | NS | Inhalation | Potential inhalation and/or dermal contact | Potential inhalation and/or dermal contact | Inhalation for powders; Dermal contact for gel & liquid solutions | Inhalation | Inhalation |
| Monitoring of exposure quantity, e.g. personal, internal or environmental | Environmental (amount not specified) | Personal (0.35 and 1.35 μg/m3 nano-Ag per 0.158 and 0.109 mg/m3 of TSP, respectively) | Self-administered exposure questionnaire identified potential inhalation and/or dermal contact | Environmental (amount used/manufacturing), with ranges between 2.1 to 4,000,000 mg/time | Environmental (amount used/manufacturing), with ranges between 2.1 to 4,000,000 mg/time | Personal and environmental, where elemental carbon was 6.2–9.3 μg/m3 in personal sampling and 5.5–7.3 μg/m3 in area sampling | Internal (EBC), where total mass of TiO2 concentrations were between 0.40 and 0.65 mg/m3 |
| Type of study, e.g. Biomarker–based / Clinical | Clinical | Biomarkers / Clinical | Biomarkers / Clinical | Biomarkers / clinical | Clinical | Biomarkers/Clinical | Biomarkers /Clinical: |
| Target | General Health | Blood and urine nano-Ag concentrations; Blood chemistry and FBC | Lung inflammation; Oxidative damage; Antioxidant enzymes; Cardiovascular markers; Genotoxicity; Lung function; Neurobehavioral function | Antioxidant enzymes; Lung inflammation; Cardiovascular markers; Genotoxicity; Lung function; Neurobehavioral function | Cardiovascular and respiratory symptoms/diseases; Sneezing; Skin diseases; Neurological symptoms | Health effects, e.g.: Pulmonary function test and lung response for inflammatory, oxidative stress and lipid peroxidation; Blood metal concentration; Blood chemistry and FBC | Lung Function; Pulmonary oxidative stress markers |
| Indicators& Biomarkers | “Periodic health status”; Lung function; Chest X-Ray | Nano-Ag concentration in blood and urine; Blood chemistry and FBC | Blood, urine and EBC used for antioxidant enzymes (MPO,GPX-1, SOD); Lung inflammation and oxidative damage markers (CC16, HSP 70, NO, NF-ΚB, 8-oxodG, m7G, 8-iso-PGF2α); Cardiovascular biomarkers (fibrinogen, VCAM, ICAM-1, IL-6, IL-6sR, arylesterase, paraoxonase, CRP); heart rate variability; Genotoxicity biomarkers (comet assay, MN); Lung function (FVC, FEV1, PEFR,MMF,FEF25%, FEF50%,FEF75%); Neurobehavioral tests (reaction time, memory tests). | Blood, urine and EBC used for antioxidant enzymes (SOD, GPX-1);Lung inflammation and oxidative damage markers (CC16, NO, NF-ΚB, 8-oxodG, m7G, 8-iso-PGF2α); Cardiovascular biomarkers (fibrinogen, VCAM, ICAM-1, IL-6,IL-6sR,arylesterase, paraoxonase, CRP, MPO);Heart rate variability; Genotoxicity biomarkers (comet assay, MN); Lung function (FVC, FEV1, PEFR, MMF, FEF25%, FEF50%, FEF75%); Neurobehavioral tests (reaction time, memory tests) | Self-administered symptom questionnaire, for “Work-relatedness of symptoms”, including sneezing and nose obstructions, difficulty breathing, chest pain, sweating, nausea/vomiting, dizziness, Hyperlipidemia, skin irritations and other potential diseases (atopic dermatitis, allergic dermatitis, skin cancer, Arrhythmia, Ischemic heart disease, Angina Valve heart disease) | The PFT as a percentage of FEV1, FVC; EBC oxidative stress biomarkers (MDA, H2O2, 4-HHE, n-hexanal); Blood content of catalyst metals may act as surrogate markers for MWCNT exposure, i.e. concentration of Co and Mo | Ti concentration in EBC; Markers of oxidation of nucleic acids (8-OHdG, 8-OHG, 5-OHMeU) and proteins (o-Tyr, 3-Cl-Tyr, 3-NOTyr) in EBC. |
| Program Outcomes | |||||||
| Summarized result | N/A | Nano-Ag in blood and urine not elevated (Blood nano-Ag concentration: 0.034 and 0.030 μg/dl; Urine nano-Ag concentration: 0.043 μg/dl and not detected) | No significant difference in lung inflammation, oxidative damage, genotoxicity or pulmonary function; Antioxidant enzymes decreased (SOD & GPX-1); Increased cardiovascular markers (fibrinogen, ICAM, IL-6) | Cardiovascular injury(increase in VCAM and decrease in paraoxonase); Pulmonary injury, i.e. a decrease in CC16 and lung function, i.e. not observed in previous study [18]; No significant change in heart rate, nor increase in oxidative stress or lipid peroxidation markers, only adecrease of SOD and GPX-1 was observed. | The study was limited to self-reported evaluations to heterogenous ENMs, which were compared to control banding tools that require validation. | Pulmonary stress increased, where MDA, 4-HHE and n-hexanal levels were higher; Significant difference in Co or Mo. | All oxidative markers were statistically significantly elevated in the exposed vs. the unexposed group |
| Early signs | N/A | Routine blood chemistry and FBC not deviant | 1 out of 3 neuro-tests impaired; Lung function showed no impairment | Lung impairment based on FVC, FEV1, FEF50%, FEF75% | N/A | Routine blood chemistry and FBC not deviant; Increased FEV1 in exposed workers, normal ratios | Lung function showed no impairment |
| Clinical signs | N/A | N/A | N/A | N/A | Increased prevalence of allergic dermatitis and ‘sneezing’ | N/A | N/A |
| Interpretation of outcomes and proposed recommendations | Nano-specific surveillance not deemed necessary | Surveillance measures did not detect any abnormalities | Although some biomarkers were elevated, these markers are not specific for ENM exposure | Although some biomarkers were elevated, these markers are not specific for ENM exposure | Allergic dermatitis has multiple causes, not specific for ENM exposure, where “Sneezing” is a non-specific symptom. | Oxidative stress markers increased, but the study had a small sample size and non-specific markers. MDA, 4-HHE and blood Mo content are proposed as useful biomarkers for MWCNTs. | Oxidative stress markers in EBC were significantly elevated in exposed group; Lung function tests were normal |
| Costs & Coverage | |||||||
| Monetary / Resource use | NS | NS | NS | NS | NS | NS | NS |
| Coverage | NS | 2 out of 5 workers participated | 97% of workers participated | Follow-up rate of 67.2% | NS | NS | NS |
3-Cl-Tyr = 3-chlorotyrosine; 3-NOTyr = 3-nitrotyrosine; 4-HHE = 4-hydroxy-2-hexenal; 5-OHMeU = 5-hydroxymethyl uracil; 8-iso-PGF2α = 8-iso-prostaglandin F2α; 8-OHdG = 8-hydroxy-2-deoxyguanosine; 8-OHG = 8-hydroxyguanosine; 8-oxodG = 8-Hydroxydeoxyguanosine; Ag = Silver; Al2O3 = Aluminium oxide; Au = Gold; CC16 = Clara cell protein; CNT = Carbon nanotubes; Co = Cobalt; CRP = C-reactive protein; EBC = Exhaled breath condensate; ENM = Engineered nanomaterial; Exp = Exposed; FBC = Full Blood Count; Fe2O3 = Iron oxide; FEF25% = Forced expiratory flow at 25%; FEF50% = Forced expiratory flow at 50%; FEF75% = Forced expiratory flow at 75%; FEV1 = Forced expiratory volume in 1 second; FVC = Forced vital capacity; GPX-1 = Glutathione peroxidase 1; H2O2 = Hydrogen peroxide; HSP 70 = Heat shock protein 70; ICAM-1 = Intercellular adhesion molecule 1; IL = Interleukin; IL-6 = Interleukin-6; IL-6sR = Interleukin-6soluble receptor; m7G = 7-Methylguanosine; MDA = Malondialdehyde; MMF = Maximal midexpiratory flow; MN = Micronucleus;Mo = Molybdenum; MPO = Myeloperoxidase; MWCNT = Multi-walled carbonnanotubes; N/A = Not applicable; NF-ΚB = Nuclear factor-κB; NO = Nitric oxide; NS = Not stated; o-Tyr = o-tyrosine; PEFR = Peak expiratory flow rate; PFT = Pulmonary function test; PG = Prostaglandin; SiO2 = Silicon dioxide; SOD = Superoxide dismutase; Ti = Titanium; TSP = Total suspended particulate;Unexpo = Unexposed; VCAM = Vascular cell adhesion molecule.