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Serum levels of soluble Fas ligand in patients with silicosis.

Certain patients with silicosis have been reported to exhibit immunological abnormalities such as the appearance of antinuclear antibodies and the occurrence of autoimmune diseases. Fas ligand (FasL) is a type II membrane protein which induces apoptosis by binding to its membrane receptor, Fas. FasL is converted to a soluble form by a metalloproteinase-like enzyme. We have already found serum soluble Fas (sFas) levels in silicosis patients as well as in patients with systemic lupus erythematosus (SLE) to be significantly higher than those in healthy volunteers. To examine further the role of the Fas/FasL system in silica-induced immunological abnormalities, we investigated serum soluble FasL (sFasL) levels in silicosis patients with no clinical symptoms of autoimmune diseases, using ELISA for sFasL. Although the serum sFasL levels in patients with SLE were significantly higher than those in healthy volunteers and showed a slight positive correlation with serum sFas levels, those in silicosis patients exhibited no significant difference from those in healthy volunteers, and there was no correlation with serum sFas levels. However, sFasL levels were elevated in silicosis patients with slight dyspnoea or normal PCO2 among various clinical parameters of silicosis. It may be speculated that the immunological disturbances presented by the abnormalities of apoptosis-related molecules in silicosis patients do not occur with a similar degree of respiratory involvement. Further studies are required to clarify which kinds of factors are involved in silicosis patients who exhibit immunological abnormalities.

Adult↗

Over-expression of the decoy receptor 3 (DcR3) gene in peripheral blood mononuclear cells (PBMC) derived from silicosis patients.

Dysregulation of apoptosis, particularly in the Fas/Fas ligand (FasL) pathway, is considered to be involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Recently, a soluble decoy receptor, termed decoy receptor 3 (DcR3), that binds FasL and inhibits FasL-induced apoptosis, has been identified. Silicosis is clinically characterized not only by respiratory disorders but by immunological abnormalities. We have found that serum soluble Fas (sFas) levels are elevated in silicosis patients and that sFas message is dominantly expressed in PBMC derived from these patients. This study examined DcR3 gene expression in PBMC derived from patients with silicosis, SLE, or progressive systemic sclerosis (PSS), and compared it with that in healthy volunteers (HV). The relative expression level of the DcR3 gene was examined in PBMC derived from 37 patients with silicosis without clinical symptoms of autoimmune disease, nine patients with SLE, 12 patients with PSS, and 28 HV using the semiquantitative multiplex-reverse transcriptase-polymerase chain reaction (MP-RT-PCR). The correlation between the relative expression level of the DcR3 gene and multiple clinical parameters for respiratory disorders and immunological abnormalities in individuals with silicosis was analysed. The DcR3 gene was significantly over-expressed in cases of silicosis or SLE when compared with HV. In addition, the DcR3 relative expression level was positively correlated with the serum sFas level in silicosis patients. It is unclear, however, whether over-expression of the DcR3 gene in silicosis is caused by chronic silica exposure, merely accompanies the alteration in Fas-related molecules, or precedes the clinical onset of autoimmune abnormalities. It will be necessary to study these patients further, establish an in vitro model of human T cells exposed recurrently to silica compounds, and resolve whether the increase in DcR3 mRNA expression is a cause or consequence of disease.

Adult↗

Exposure-response analysis and risk assessment for silica and silicosis mortality in a pooled analysis of six cohorts.

AIMS: To study the relation between exposure to crystalline silica and silicosis mortality. Although mortality is an important endpoint for regulators, there have been no exposure-response studies for silicosis mortality, because of the relative rareness of silicosis as an underlying cause of death, and the limited availability of quantitative exposure estimates. METHODS: Data from six occupational cohorts were pooled with good retrospective exposure data in which 170 deaths from silicosis were reported. Standard life table analyses, nested case-control analyses, and risk assessment were performed. RESULTS: The rate of silicosis mortality in the combined data was 28/100 000 py, increasing in nearly monotonic fashion from 4.7/100 000 for exposure of 0-0.99 mg/m(3)-years to 233/100 000 for exposure of >28.1 mg/m(3)-years. The estimated risk of death up to age 65 from silicosis after 45 years of exposure at 0.1 mg/m(3) silica (the current standard in many countries) was 13 per 1000, while the estimated risk at an exposure of 0.05 mg/m(3) was 6 per 1000. Both of these risks are above the risk of 1 per 1000 typically deemed acceptable by the US OSHA. CONCLUSION: The findings from this pooled analysis add further support to the need to control silica exposure and to lower the occupational standards. Our estimates of lifetime silicosis mortality risk are probably underestimates as, in addition to exposure misclassification, our study might have suffered from outcome misclassification in that silicosis deaths might have been coded to other related causes, such as tuberculosis or chronic obstructive pulmonary disease.

Adult↗

Kidney disease and silicosis.

AIM: To determine the prevalence of kidney disease in a cohort of individuals with silicosis. METHODS: Review of medical records and questionnaires from patients reported to a state surveillance system for silicosis. Reporting of individuals with silicosis is required by state law. All individuals with silicosis reported as required by law to the State of Michigan. Individuals included in this article were reported from 1987 to 1995. Cases were reported by hospitals, physicians, the state workers' compensation bureau, or from death certificates. Only individuals who met the criteria for silicosis developed by the National Institute for Occupational Safety and Health (NIOSH) were included. RESULTS: Medical records were reviewed of 583 individuals with confirmed silicosis. This was mainly a population of elderly men. Ten percent of the 583 silicotics were found to have some mention of chronic kidney disease, and 33% of the 283 silicotics who we had laboratory tests on had a serum creatinine level >1.5 mg/dl. An association between kidney disease and age and between kidney disease and race was found among this cohort of 583 silicotics. Individuals with silicosis were more likely to have a serum creatinine level >1.5 mg/dl than age- and race-matched controls. However, no relationship between duration of exposure to silica or profusion of scarring on chest X-ray and prevalence of kidney disease or elevated creatinine levels was found. CONCLUSIONS: This study confirms previous case reports and epidemiologic studies of end-stage renal disease that found an association between kidney disease and exposure to silica. The epidemiologic data are conflicting on the mechanism by which silica causes kidney disease and are compatible with silica being able to cause kidney disease by both an autoimmune and direct nephrotoxic effect. Chronic kidney disease should be considered as a complication of silicosis.

Aged↗

Rales in silicosis. A correlative study with physiological and radiological abnormalities.

Pulmonary auscultation, pulmonary function tests and radiological examination were done in 127 hospitalized patients with silicosis. Fine crackle (FC) was heard in 21.3% of patients, coarse crackle (CC) in 28.5%, rhonchi or wheeze (RorW) in 25.2% and friction rub (FR) in 5.5%. In complicated silicosis the incidence of rales was paradoxically lower than in simple silicosis (54.6 vs. 83.3%, respectively, p less than 0.05). In simple silicosis, patients with CC and/or RorW had lower %VC and FEV1/FVC%, but in complicated silicosis, the relation between the presence of rales and pulmonary functional status was not so apparent. These results suggest that in relatively advanced silicosis, all kinds of rales are heard, and in simple silicosis, rales are useful indicators of physiological impairment, but in complicated silicosis, they do not seem to be so useful.

Aged↗

CT in silicosis: correlation with plain films and pulmonary function tests.

To investigate the usefulness of computed tomography (CT) in the qualitative and quantitative assessment of silicosis, CT scans, chest radiographs, and pulmonary function tests were obtained in 17 patients with silicosis and six controls. CT scans were graded for extent of silicosis visually and using mean attenuation values. The extent of associated emphysema was also determined. Extent of silicosis as assessed by CT was compared with extent estimated from the chest radiographs using the ILO 1980 classification and pulmonary function tests. Significant correlation was found between both the mean attenuation values (r greater than 0.62, p less than 0.001) and the visual CT scores (r greater than 0.84, p less than 0.001) compared with the ILO category of profusion. There was good inter- and intraobserver correlation for the visual CT grades of silicosis (r greater than 0.93, p less than 0.001). There was poor correlation between the pulmonary function tests and the nodular profusion on the chest radiograph and CT (r less than 0.50). Correlation was significant, however, between the CT emphysema score and both the FEV1% predicted (r greater than 0.66, p less than 0.001) and the diffusing capacity (r greater than 0.71, p less than 0.001). Using chest film assessment of the extent of silicosis, visual CT quantitation of silicosis is accurate and reproducible. Attenuation values were less reliable and their use is not recommended as an independent assessment of disease severity. The reduced levels of lung function in these patients correlated with superimposed emphysema rather than the nodular profusion. Emphysema associated with silicosis was easily detected on CT but not on the radiograph.

Adult↗

Symptoms and clinical findings in patients with silicosis.

Respiratory symptoms, radiographic findings, and lung function were analyzed in 144 Finnish patients with silicosis. The prevalence of persistent phlegm production in these patients was 46% and that of dyspnea 87%. Impairment of the vital capacity (VC) and the diffusion capacity (DLCO) (less than 80% of predicted values) were found in 46 and 47% of the patients with simple silicosis, respectively. The mean DLCO was lower in patients with advanced simple silicosis (category 3) than in those with slight simple silicosis (categories 1 and 2). In category 3 the DLCO was impaired in 9 out of 12 patients, the impairment being below 65% of the predicted values in six of the nine. All patients with large opacities showed impairment in their lung function tests. Twenty-eight of the silicosis patients had referents matched for exposure to silica dust, age, and gender. The referents had no radiographic signs of silicosis. The patients experienced dyspnea more often than their referents, whereas no difference was found in the prevalence of persistent phlegm production. The mean values of VC, forced expiratory volume in 1 s (FEV1.0), and DLCO were lower in the patients than in the referents. The results indicate a high prevalence of dyspnea, restrictive impairment of lung function, and impaired diffusion capacity in the patients with simple or complicated (ie, large radiographic opacities) silicosis. The DLCO proved to be a rather sensitive lung function parameter for advanced simple silicosis.

Adult↗

Relationship between silicosis and smoking.

An evaluation of the relationship between silicosis and smoking is important in exploring the etiology of silicosis, and the relationship could have an impact on studies dealing with silicosis and lung cancer. Data addressing this relationship were found in studies designed explicitly to evaluate this association and studies that explored other questions. Studies based on compensation registers were excluded. Smoking data and methods varied across the studies considered. Of the 13 studies, 3 supported the hypothesis that smoking was positively associated with silicosis, 8 provided limited support (most included subpopulations showing positive associations), and 1 did not support the hypothesis. The only autopsy study suggested an inverse association. It is unclear whether the generally positive results indicate that smoking predisposes to silicosis or that nonspecific radiographic appearances from smoking were interpreted as silicosis in some studies. A positive association between radiographic silicosis and smoking would bias studies of silicosis and lung cancer, especially those lacking smoking data.

Cross-Sectional Studies↗

[Potential effect of tumor necrosis factor-alpha and tumor necrosis factor receptor II gene polymorphisms on the pathogenesis of silicosis].

OBJECTIVE: To approach the role of tumor necrosis factor-alpha (TNF-alpha) and tumor necrosis factor receptor II (TNFR II) gene polymorphisms in genetic susceptibility to silicosis and their interaction with silica-dust exposure. METHODS: Two hundred and fifty-nine cases of silicosis and three hundred and forty-one silica-dust exposure workers (control) were selected, and the cases of silicosis were divided into three subgroups based on the various stages of I, II and III. Exposure history, pneumoconiosis history and past history of each subject were obtained by questionnaire. 3 ml peripheral venous blood was drawn from each subject. Using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) techniques, TNF-alpha and TNFRII gene polymorphisms were analyzed. RESULTS: In both group matching and 1:1 paired matching, there was no significant difference between cases of silicosis and workers in control in distribution frequencies of G/A + A/A (TNF-alpha-308) and T/G + G/G (TNFRII 196) genotypes. The risk of silicosis in those with G/A + A/A genotype was 6.74-fold higher than G/G genotype (OR = 6.74, 95% CI: 1.01 approximately 44.99) in subjects whose exposure time was less than 15 years. CONCLUSION: TNF-alpha and TNFR II gene polymorphisms did not play an important role in susceptibility to silicosis of Han race. There was interaction between polymorphism of TNF-alpha gene promoter and exposure time in the occurrence of silicosis. The risk of silicosis in those with G/A + A/A genotype was significantly higher than G/G genotype in low accumulative exposure.

Adult↗

Silicosis mortality, prevention, and control--United States, 1968-2002.

Silicosis is a preventable occupational lung disease caused by inhaling dust containing crystalline silica; no effective treatment for silicosis is available. Deaths from inhalation of silica-containing dust can occur after a few months' exposure (1). Crystalline silica exposure and silicosis have been associated with work in mining, quarrying, tunneling, sandblasting, masonry, foundry work, glass manufacture, ceramic and pottery production, cement and concrete production, and work with certain materials in dental laboratories. To describe patterns of silicosis mortality in the United States, CDC analyzed data from the National Institute for Occupational Safety and Health (NIOSH) National Occupational Respiratory Mortality System (NORMS) for 1968-2002. This report summarizes the results of that analysis, which indicated a decline in silicosis mortality during 1968-2002 and suggested that progress has been made in reducing the incidence of silicosis in the United States. However, silicosis deaths and new cases still occur, even in young workers. Because no effective treatment for silicosis is available, effective control of exposure to crystalline silica in the workplace is crucial.

Humans↗

[On the association of tumor necrosis factor-alpha gene polymorphisms with the susceptibility to silicosis].

OBJECTIVE: To find out whether -308 and -238 locus (G --> A) mutation within the tumor necrosis factor-alpha gene (TNF-alpha) promoter region are associated with susceptibility to silicosis in the Han population of southwest China. METHODS: Governed by the principles of voluntatiness and cooperation, 75 patients with silicosis and 137 control with silica-exposure but without silicosis were recruited, and additionally, 140 elderly patients with silicosis and 135 healthy elderly (retired) controls were recruited in this case-control study. 5 ml peripheral vein blood was drawn from each subject. By means of polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) and sequencing techniques, TNF-alpha gene polymorphisms of all subjects were analyzed. RESULTS: The frequencies of TNF-alpha -308A and -238A in the 75 patients with silicosis were higher than those in the 137 controls (P < 0.01). After being adjusted for confounding factors, the -308A and the -238A were still associated with the presence of silicosis (P < 0.01). But the frequency of TNF-alpha -308A in the 140 elderly patients was significantly lower than that in the controls (P < 0.001). CONCLUSIONS: TNF-alpha gene -308 and -238 locus (G --> A) mutation might be related to the occurrence of silicosis and the severity of pulmonary fibrosis in silicosis among the Han population of southwest China, and TNF2 (-308A) allele might increase the risk of the disease.

Adult↗

[Radiological and functional progression in silicosis].

BACKGROUND: The incidence of silicosis has decreased today because of a clear improvement of working conditions. According to recent data from Italian National Compensation Agency (INAIL) silicosis represents more than 5% of occupational diseases claimed for annually. Since silicosis is an evolving chronic disease, it has serious consequences on patient health, modifying the quality of life and increasing public costs. Some studies show a relationship between occupational exposure to silica and radiological and functional deterioration, but the results are not satisfactory because of the variety of clinical patterns and the interference of many risk factors. OBJECTIVES: The aim of our investigation was to evaluate silicosis evolution in relation to living habits and to different occupational exposures. METHODS: All admissions from 1980 to 2000 in the Occupational Medicine Unit of the Maugeri Foundation in Cassano Murge (Bari), Southern Italy, with final diagnosis of silicosis were examined. From 586 medical records gathered, subjects with double admissions were selected and their chest radiographs and FVC, FEV1 from lung function test were detected. No industrial hygiene data were available and individual exposure was estimated through calculation of a global exposure index. RESULTS: On the basis of data quality control, 106 consecutive male patients were recruited (age at first admission 51.7 +/- 8.3 years, occupational exposure at second admission 23.8 +/- 9.1 years). More than 50% of the subjects had an estimated high risk exposure at work. The first diagnosis of silicosis was made at first admission in 40% of the cases, 33% of the patients had been suffering from silicosis for 10 years while 27% for more than 10 years. Chest radiographs showed mostly p, q nodular pattern, and over a 4. 7 +/- 3.3 year follow-up period they appeared largely unchanged, although 8 radiographs showed confluent areas, 18 subjects showed pleural thickening, 10 calcified opacities, 17 COPD (Chronic Obstructive Pulmonary Disease) with emphysema, 2 tubercolosis lesions, 4 radiographic abnormalities attributable to cancer (3 lung, 1 oesophageal). CONCLUSIONS: The mainly stationary results of chest radiographs and the slight loss of respiratory function we observed confirm the slow evolution over time of silicosis. Multiple logistic regression analysis of main risk factors showed that subjects with radiographic opacities having a diameter greater than 10 mm or conglomerate shadows at the time of diagnosis seem to have a lower risk of progression of the disease after a relatively short period of follow up, even in mining related exposure.

Cohort Studies↗

Fasting urinary hydroxyproline: creatinine ratios in silicosis.

Fasting urinary hydroxyproline: creatinine (HOP:C) ratios were measured in 74 patients with suspected (borderline) silicosis (10), simple silicosis (46) and complicated silicosis (9 silicotuberculosis, 4 massive fibrosis, and 5 combined silicotuberculosis and massive fibrosis) and in 18 healthy subjects (controls). There was no statistically significant difference in urinary HOP:C ratios between control subjects (mean 13.8, SD 3.6) and suspected silicotics (mean 18.0, SD 7.6); however, urinary HOP:C ratios were significantly higher in both simple silicosis (mean 25.0, SD 9.9, p less than 0.001) and complicated silicosis (silicotuberculosis and progressive massive fibrosis) (mean 28.6, SD 11.3; p less than 0.001). Urinary HOP:C ratios appeared to show a graduated increase to their highest levels in category 2 silicosis and thereafter remained constant or declined slightly in category 3 silicosis and massive fibrosis. The results support the suggestion that urinary hydroxyproline might be useful as an indicator of disease progression in established silicosis. However, further longitudinal studies are needed to confirm its predictive value.

Adult↗

Risk of silicosis in a Colorado mining community.

We investigated exposure-response relations for silicosis among 134 men over age 40 who had been identified in a previous community-based random sample study in a mining town. Thirty-two percent of the 100 dust-exposed subjects had radiologic profusions of small opacities of I/O or greater at a mean time since first silica exposure of 36.1 years. Of miners with cumulative silica exposures of 2 mg/m3-years or less, 20% had silicosis; of miners accumulating > 2 mg/m3 years, 63% had silicosis. Average silica exposure was also strongly associated with silicosis prevalence rates, with 13% silicotics among those with average exposure of 0.025-0.05 mg/m3, 34% among those with exposures of > 0.05-0.1 mg/m3, and 75% among those with average exposures > 0.1 mg/m3. Logistic regression models demonstrated that time since last silica exposure and either cumulative silica exposure or a combination of average silica exposure and duration of exposure predicted silicosis risk. Exposure-response relations were substantially higher using measured silica exposures than using estimated silica exposures based on measured dust exposures assuming a constant silica proportion of dust, consistent with less exposure misclassification. The risk of silicosis found in this study is higher than has been found in workforce studies having no follow-up of those leaving the mining industry and in studies without job title-specific silica measurements, but comparable to several recent studies of dust exposure-response relationships which suggest that a permissible exposure limit of 0.1 mg/m3 for silica does not protect against radiologic silicosis.

Adult↗

Mixed dust fibrosis and tuberculosis in comparison with silicosis and macular pneumoconiosis.

BACKGROUND: To assess the relationship between mixed dust fibrosis (MDF) and tuberculosis. METHODS: We performed a comparative analysis with MDF, silicosis, and macular pneumoconiosis (Mac), using autopsy records from 1975 to 1994. RESULTS: Prevalences of having tuberculosis among MDF, silicosis, and Mac were not significantly different, albeit a tendency of higher prevalence in silicosis. Cure rates of tuberculosis were, in order, silicosis < MDF < Mac (P=0. 085). Death rates associated with tuberculosis were, in order, silicosis > MDF=Mac (P=0.911). With respect to the two types of association with tuberculosis, i.e., combined type (tuberculopneumoconiosis) and complicated one (pneumoconiosis with tuberculosis); the former was significantly dominant in silicosis, the latter was significantly dominant in Mac, and intermediate in MDF. As a whole, the complicated type had a tendency of a higher cure rate than the combined type (P=0.071). Although the differences of profiles between the combined and complicated types were not statistically significant, the combined type had a tendency to have longer duration of exposure to dusts, earlier registration for treatment, higher profusion score, and earlier death compared with the complicated type. CONCLUSIONS: From our findings, MDF takes an intermediate position between silicosis and Mac regarding the relationship with tuberculosis. The type of association with tuberculosis rather than the kind of background pneumoconiosis seemed to be more important in light of responsiveness to the treatment.

Autopsy↗

Case-control study of silicosis, silica exposure, and lung cancer in white South African gold miners.

A case-control study was undertaken to assess the association between lung cancer and silicosis or silica dust exposure in white South African gold miners. Cases and controls were identified from deaths reported to the Gold Miners Provident Fund for the period January, 1979-October, 1983. Two controls were matched to each case by year of birth (+/- 2 years) and by smoking (+/- 5 cigarettes or equivalents per day) assessed 10 years (+/- 2 years) prior to death. One hundred thirty-three matched triplets were identified. The results showed no overall association between lung cancer and radiological silicosis (OR = 1.08, p = 0.92). Autopsy data indicated no overall associations between lung cancer and silicosis of the lung parenchyma (OR = 1.49, p = 0.11), the pleura (OR = 0.72, p = 0.30), or the hilar glands (OR = 0.85, p = 0.72). A trend toward increased severity of silicosis of the parenchyma was evident; however, this was not statistically significant (p = 0.08). Odds ratios for lung cancer and silicosis were higher at lower levels of cumulative silica dust exposure (ORs = 2.43, 1.72, 1.35 and 0.62 for lung cancer and autopsy silicosis of the parenchyma for the lowest, second, third, and highest quartiles of dust exposure, respectively; all p greater than 0.05). Cases did not differ from controls for total silica dust exposure, length of exposure, weighted average intensity of exposure, or number of shifts at high dust (all p greater than 0.20). The data do not support the hypothesis of a carcinogenic role for silica dust and no statistically significant associations were found between lung cancer and silicosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Gold↗

Risk of silicosis in a cohort of white South African gold miners.

The risk of silicosis was investigated in a cohort of 2,235 white South African gold miners who had, on average, 24 years of net service from 1940 to the early 1970s and who were followed up to 1991 for radiological signs of onset of silicosis (ILO category 1/1 or more). There were 313 (14%) miners who developed signs of silicosis at an average age of 55.9 years. The latency period was largely independent of the cumulative dust exposure. In 57% of the silicosis, the radiological signs developed, on average, 7.4 years after mining exposure ceased. The risk of silicosis increased exponentially with the cumulative dust dose, the accelerated increase being after 7 mg/m3-years. At the highest exposure level of 15 mg/m3-years, which represents approximately 37 years of gold mining at an average respirable dust concentration of 0.4 mg/m3, the cumulative risk for silicosis reached 77%. In conclusion, the risk of silicosis was strongly dose dependent; however, the latency period was largely independent of the dose.

Age of Onset↗

Exploring the joint effects of silicosis and smoking on lung cancer risks.

Cigarette smoking and silicosis are potential causes of lung cancer among workers exposed to silica dust, but their joint effects are unclear. We explored the possible interactions between silicosis and smoking on lung cancer risks by summarizing data from the published literature. The standardized mortality ratio or standardized incidence ratio reported in each published report was first adjusted using "smoking adjustment factors" to correct for the biased estimation of the expected numbers of lung cancer among smokers and nonsmokers when using general population rates in the indirect standardization process. The ratio of the effect of silicosis on lung cancer risk among smokers to that among nonsmoker was calculated and named the "relative silicosis effect (RSE)". The synergy index was estimated to assess the additive interaction. Metaanalyses were used to obtain the weighed means of the RSE and synergy index. Ten cohort studies were reviewed and combined to yield a weighed RSE of 0.29 (95% CI: 0.20, 0.42), indicating negative risk-ratio multiplication between smoking and silicosis on the lung cancer risk. The combined weighed synergy index was 1.00 (95% CI: 0.79, 1.26), suggesting no departure from additivity. Sensitivity analyses showed that both estimates were quite robust. The independent risk-ratio effect of silicosis on lung cancer in smokers was about 30% of that in nonsmokers, and the joint effects of smoking and silicosis on the risk of lung cancer did not deviate from additivity and hence did not support biological synergism/antagonism.

Case-Control Studies↗