Prognostic impact of carotid plaque imaging using total plaque area added to SCORE2 in middle-aged subjects: the ARteris Cardiovascular Outcome (ARCO) cohort study.

AIMS: Many cardiovascular events occur in seemingly healthy individuals.We set out to assess the predictive value of atherosclerosis imaging in combination with cardiovascular risk calculators in subjects aged 40-65 years. METHODS: We compared PROCAM (PROspective CArdiovascular Münster study), SCORE (Systematic COronary Risk Evaluation) and SCORE2 with carotid ultrasound (total plaque area, TPA) in subjects without cardiovascular disease. In this prospective cohort study, follow-up was obtained by phone or mail from patients; or from clinical records, if needed. RESULTS: In 2842 subjects (mean age 50±8 years; 38% women), cardiovascular events occurred in 154 (5.4%) of them over an mean follow-up period of 5.9 (range 1-12) years, specifically: 41 cases of AMI (myocardial infarction), 16 strokes, 21 CABG (coronary artery bypass grafting), 41 PTCA (percutaneous transluminal coronary angioplasty) and 35 CAD (coronary artery disease). Mean PROCAM risk was 5±6%, mean SCORE risk was 1.3±1.6% and mean SCORE2 risk was 5±3%. Both for the primary outcome (major adverse cardiovascular events, MACEs, i.e. AMI + strokes) and the secondary outcome (atherosclerotic cardiovascular disease, ASCVD, i.e. MACEs + CABG + CAD + PTCA), hazards increased significantly for TPA tertiles and SCORE2 post-test risk between 6.7 to 12.8 after adjustment for risk factors (age, smoke, sex, systolic blood pressure, lipids, medication) and after adjustment for results from PROCAM, SCORE and SCORE2. Model performance was statistically improved regarding model fit in all models using TPA. Net reclassification improvement for SCORE2 with TPA post-test risk increased significantly by 24% for MACEs (p = 0.01) and 39% for ASCVD (p <0.0001). CONCLUSIONS: Integration of TPA post-test risk into SCORE2 adds prognostic information, supporting the use of carotid ultrasound when assessing ASCVD risk in subjects aged 40-65 years.

[Ultrasound examination of the carotid artery for improved prediction of cardiovascular events and the effect of statin treatment in advanced atherosclerosis : An observational study]. / Ultraschalluntersuchung der A. carotis zur verbesserten Vorhersage kardiovaskulärer Ereignisse und der Wirkung einer Statinbehandlung bei fortgeschrittener Atherosklerose : Eine Beobachtungsstudie.

BACKGROUND: Advanced atherosclerosis of the carotid artery is associated with a high risk of cardiovascular diseases. It was investigated whether ultrasound provides a better prediction of cardiovascular events compared to the prospective cardiovascular Münster study (PROCAM) score and whether treatment of subjects with advanced atherosclerosis with statins improves the prognosis. METHOD: Between 2009 and 2016 a total of 4482 subjects (41% women) aged 35-65 years with no signs of cardiovascular disease underwent carotid artery ultrasound examination. Total plaque area (TPA) and maximum plaque thickness were measured. The PROCAM score was used to determine the cardiovascular risk. RESULTS: The median follow-up time was 77 months (6.4 years) for the men and 74 months (6.2 years) for the women. Events, such as myocardial infarction, ischemic stroke, coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA), occurred in 131 (3.4%) of the 3833 subjects with complete follow-up data. The prediction of cardiovascular events was better with ultrasound than with the PROCAM score. Ultrasound predicted 79.4% of 131 events and the PROCAM score predicted 22.9%. Treatment of subjects with advanced atherosclerosis (types III, IV b) with a statin significantly improved the prognosis. The event rate was 12.6% in men and women in the treated group vs. 31.5% (p < 0.0001) in the untreated group. Mortality (from any cause) was significantly lower in men treated with statins (p = 0.0148). CONCLUSION: The prediction of cardiovascular events was better with plaque burden measurements than with the PROCAM score. Treatment with statins in subjects with advanced carotid atherosclerosis (types III-IV b findings on ultrasound) significantly improved the prognosis in a nonrandomized observational study.

PROCAM based myocardial infarction risk in relation to global vascular disease risk: observations from the ARCO cohort study.

BACKGROUND: In Switzerland, risk for acute myocardial infarction (AMI) has been considered as equivalent to risk for atherosclerotic cardiovascular disease (ASCVD). This may lead to an underestimation of ASCVD risk and prevent adequate preventive measures. METHODS: We calculated correction factors for AMI risk to obtain ASCVD risk, tested predicting abilities of PROCAM/AGLA, SCORE, HerzCheck® and carotid plaque imaging (TPA) for ASCVD events in this cohort study and calculated survival curves, calibration and discrimination for ASCVD outcomes derived from PROCAM/AGLA, SCORE and TPA. RESULTS: In 2842 subjects (age 50 ± 8, 38% women), 154 (5.4%) cardiovascular events occurred (ASCVD: 41 myocardial infarctions, 16 strokes or TIAs, 21 CABG, 41 PTCA, 35 coronary artery disease [CAD]defined by invasive angiography) during a mean follow-up time of 5.9 (1-12) years. AGLA-AMI risk was well calibrated for AMI (15% underreported risk for the risk of AMI), but was poorly calibrated for ASCVD (stroke, CABG, PTCA or CAD, which contributed to the secondary outcome variables) with underreported risk resulting in a correction factor of 3.45. Discrimination was comparable for all risk calculators, but TPA outperformed risk calculators for survival using Cox proportional survival functions. Net reclassification improvement for PROCAM and SCORE using TPA tertiles groups increased significantly between 30% to 48%. CONCLUSIONS: PROCAM-derived risk calculators are well calibrated for the risk of AMI. PROCAM-AMI should be multiplied by a factor of 4 to obtain ASCVD. PROCAM-AMI does not represent global cardiovascular risk. Corresponding adjustments in the AGLA communication of risk appear necessary.

Effect of Statin Treatment in Patients With Advanced Carotid Atherosclerosis: An Observational Outcome Study.

BACKGROUND: Advanced atherosclerosis of the carotid artery is associated with a high risk of cardiovascular disease. The aim of the study was to investigate whether treatment with statins improved the prognosis. METHODS: Sum of all plaque areas (total plaque area (TPA)) and the maximum plaque thickness were determined in healthy subjects using ultrasound. We compared the outcome in subjects with advanced atherosclerosis of the carotid artery (type III-IV b finding) with and without statin treatment. The follow-up was recorded during follow-up examinations as part of preventive occupational health examinations or by personal communication. RESULTS: In 7,106 subjects aged 35 - 65 years (50 ± 8 years, 43% women), we found 669 subjects with advanced atherosclerosis of the carotid artery (type III-IV b finding). A follow-up was available for 640 (95.4%) subjects. In these subjects (54 ± 8 years, 20.4% women), 94 (88 men) had cardiovascular events (35 myocardial infarctions, 13 bypass operations, 32 stent implantations, and 14 strokes) with a mean follow-up time of 3.9 (1 - 12) years. Two hundred sixty subjects were treated with a statin, while 339 received no statin. Fourteen cardiovascular events occurred in the treated group (eight stent implantations, two heart attacks, two bypass operations, and two strokes). In the untreated group, 80 cardiovascular events occurred (12 strokes, 11 bypass operations, 33 heart attacks, and 24 stent implantations). The event rate was 5.4% for the subjects treated with a statin and 23.6% for the untreated subjects. Both groups were well matched for the baseline presence of cardiovascular risk factors. CONCLUSION: Statin treatment in subjects with advanced atherosclerosis of the carotid artery (type III-IV b finding on ultrasound) significantly improves the prognosis in a non-randomized observational cohort study.

Cost-effectiveness analysis of statins in primary care: results from the Arteris cohort study.

BACKGROUND: The Swiss Federal Office of Public Health performed a health technology assessment regarding statins in primary care. The chosen models may lead to a situation where a clinically indicated statin therapy is estimated not to be cost effective. METHODS: We performed a cohort study regarding cardiovascular events, comparing SCORE and AGLA risk categories with tertiles of carotid plaque burden and used two models for cost-effectiveness analysis of high-potency statins. RESULTS: Subjects (n = 2842) were followed up for 5.9 ± 2.9 years with the occurrence of 154 cardiovascular events (extrapolated 10-year risk was 9.2%). Carotid plaque imaging (total plaque area, TPA) significantly improved cardiovascular risk prediction compared with AGLA and SCORE for event-free survival prediction, test accuracy (discrimination) and calibration. Discrimination was significantly improved by about 4% with the inclusion of TPA. Cost-effectiveness analysis using quality-adjusted life years (QALYs) and sensitivity analyses (based on 16 models) ranged between CHF 144,496 and −128,328 per QALY. Cost-effectiveness analysis using direct and indirect costs showed that a treat-them-all strategy in the Swiss population would be cost effective with a return-on-investment per patient in 10 years of between CHF 4442 and 19,059, and the use of carotid imaging was also cost effective (incremental cost-efficiency ratio −2.97 to −7.86). CONCLUSIONS: Carotid ultrasound significantly improved cardiovascular risk stratification and is cost effective. The Swiss Medical Board QALY model presents several drawbacks, which are shown in our sensitivity analysis, where results vary considerably and are not useful for clinical decision making. A “treat them all” strategy with statins in the Swiss population aged 30–65 years may be cost effective, when indirect costs of avoidable cardiovascular events are included, even at an unacceptably low value of a statistical life year.

Prediction of cardiovascular events with traditional risk equations and total plaque area of carotid atherosclerosis: The Arteris Cardiovascular Outcome (ARCO) cohort study.

A large number of cardiovascular events occur in seemingly healthy individuals. Atherosclerosis imaging can improve the outcome and treatment regime of such subjects. We aim to assess the predictive value of atherosclerosis imaging beyond traditional risk calculators in subjects aged 40-65 years. We compared PROCAM, SCORE and FRAM with carotid ultrasound (total plaque area, TPA) and arterial age (AA) was calculated in subjects without known cardiovascular diseases. Follow-up was obtained by phone or mail. In 2842 subjects (age 50 ± 8, 38% women) 154 (5.4%) cardiovascular events occurred (ASCVD: 41 myocardial infarctions, 16 strokes or TIA, 21 CABG, 41 PTCA, 35 coronary artery disease defined by invasive angiography) during a mean follow-up time of 5.9 (1-12) years. PROCAM risk was 5 ± 6%, SCORE risk 1.3 ± 1.6% and FRAM 10 ± 6%. Both for the primary outcome (AMI, STROKE/TIA, CABG) and the secondary outcome (adding CAD and PTCA) hazards increased significantly for TPA tertiles and AA groups between 1.4 (0.1-16.1) and 21.4 (2.8-163.6) after adjustment for risk factors (age, smoke, sex, systolic BP, lipids, BMI, medication in Model 1) and after adjustment for results from PROCAM, SCORE and FRAM (Model 2). Model performance was statistically improved regarding model fit in all models using TPA and AA. Net reclassification improvement (NRI) for PROCAM and SCORE using TPA tertiles or AA age groups increased significantly between 30% to 48%. TPA and AA added prognostic information to conventional risk equations, supporting the assessment of ASCVD risk with carotid ultrasound in subjects aged 40-65 years.

The Determination of the Plaque Burden on the Carotid Artery With Ultrasound Significantly Improves the Risk Prediction in Middle-Aged Subjects Compared to PROCAM: An Outcome Study.

BACKGROUND: There are only few data about the predictive value of atherosclerosis imaging beyond traditional risk calculators in younger subjects. METHODS: We assessed cardiovascular risk prediction with the PROCAM (the Prospective Cardiovascular Munster Study) risk equation and with carotid plaque imaging (determination of total plaque area (TPA) and the maximum plaque thickness with ultrasound) in subjects without known cardiovascular diseases. The follow-up was generated during follow-up examinations as part of preventive medical examinations or by telephone calls. RESULTS: In 2,508 subjects aged 35 - 64 years (50 ± 8 years, 34% women), 132 (5.3%) cardiovascular events occurred (42 myocardial infarction, 17 bypass surgery, 31 stent implantation, 42 coronary artery disease defined by invasive angiography) during a mean follow-up period of 5.4 (1 - 12) years. TPA in combination with the maximum plaque thickness (type III - IV b plaques ) tended to be superior compared to TPA, and both plaque imaging methods were superior to PROCAM: area under the curve (AUC) 0.9 (95% confidence interval (CI): 0.91 - 0.89) vs. 0.89 (95% CI: 0.90 - 0.88), P = 0.2 vs. 0.82 (95% CI: 0.84 - 0.81), P = 0.001; positive predictive value (PPV) 27% (95% CI: 0.31 - 0.22) vs. 19% (95% CI: 0.22 - 0.16) vs.19% (95% CI: 0.27 - 0.13). CONCLUSIONS: Amount of carotid plaque assessed by carotid plaque imaging significantly improves cardiovascular risk prediction beyond the PROCAM risk equation.

Sonographic assessment of carotid atherosclerosis: preferred risk indicator for future cardiovascular events?

Carotid ultrasound allows rapid and reliable quantification of atherosclerosis in humans. Although the definition of carotid plaque is not uniform, intimal thickening of at least 1.5 mm is currently defined as plaque. Plaque can be easily quantified by tracing the plaque area, a software-independent low-cost technique. More sophisticated quantifications involve 3D volume acquisitions, which is software-dependent and not widely available. Carotid plaque has a higher prognostic impact than intimal thickening, and carotid plaque volume showed comparable prognostic power to coronary calcifications. According to the latest European Joint ESC guidelines, carotid artery scanning should be considered for adjusting the level of risk especially in intermediate-risk subjects. There are various methods to incorporate results from imaging into clinical decision making, such as using arterial age instead of chronological age in risk equations or post-test risk calculations using the sensitivity and the specificity of the results from a given carotid plaque burden. In subjects with low or intermediate cardiovascular risk, the search for atherosclerosis may be appropriate and ultrasound of the carotid or the femoral arteries could be the primary method applied (depending on local expertise). Assessment of carotid total plaque presence, progression, stability and regression over time may be a valuable clinical tool for optimising the intensity of preventive therapies.

Advanced carotid atherosclerosis in middle-aged subjects: comparison with PROCAM and SCORE risk categories, the potential for reclassification and cost-efficiency of carotid ultrasound in the setting of primary care.

OBJECTIVE: About 50% of acute coronary syndromes occur in patients classified as being at low coronary risk. We aimed to assess the potential preventive benefit of carotid plaque imaging with ultrasound. METHODS: We assessed the prevalence of “old” arteries (vascular age ≥70 years; VA70) in 3248 healthy subjects aged 40–65 years from the Swiss region of Olten and the German region of Koblenz. We compared sensitivity, specificity and discriminatory performance of SCORE, PROCAM and AGLA coronary risk calculators to detect VA70 for various decision thresholds and performed reclassification and cost-efficiency analysis. RESULTS: VA70 was found in one out of eight subjects. Sensitivity for VA70 was 6% at the 10% AGLA threshold in women and 30% in men in the Olten area, which was confirmed for the Koblenz area with PROCAM (sensitivity 8% in women, 56% in men). Results were similar for SCORE. The discriminatory performance ranged between 0.69 and 0.82. Reclassification from low risk to a higher risk category occurred in 17–35% of patients. Analysis showed that carotid imaging for CHF 100 per person was highly cost efficient. CONCLUSIONS: In subjects aged 40–65 years, the prevalence of old arteries is one out of eight and the detection rate of AGLA and SCORE is lower in women (6% for PROCAM) than for men (30%) at the 10% threshold. Carotid imaging may be used to reclassify subjects from low to intermediate or high cardiovascular risk. Our method is highly cost efficient at a price of CHF 100 per examination.

Early Diagnosis and Treatment of Coronary Heart Disease in Asymptomatic Subjects With Advanced Vascular Atherosclerosis of the Carotid Artery (Type III and IV b Findings Using Ultrasound) and Risk Factors.

BACKGROUND: A study was conducted as to whether the early diagnosis of coronary heart disease in asymptomatic subjects with advanced atherosclerosis of the carotid artery which additionally shows at least one risk factor is successful using ultrasound technology. METHODS: Within the scope of an occupational screening program using subjects from diverse employment sectors, people were given the opportunity to determine their risk of heart attack. During the study the total plaque area (TPA), the maximum plaque thickness in the carotid artery and the PROCAM-Scores of 3,748 healthy men and 2,260 healthy women between the ages of 20 and 64 years were determined. During the subsequent follow-up study 94 subjects sickened. An ultrasound examination of the carotid artery of 79 patients revealed a type III or IV b finding. In a pilot study 33 asymptomatic subjects with a type III or IV b finding in the ultrasound examination were assessed using a computed tomography (CT) coronary angiogram. Additional 10 asymptomatic subjects were examined independently to undergo further cardiac examinations. RESULTS: In the final analysis only five patients had entirely smooth coronary arteries, six had coronary sclerosis, eight had a 30% stenosis, one had a 30-50% stenosis and 23 patients had a stenosis ≥ 50%; and in extreme case, a left main coronary artery stenosis with three-vessel disease. CONCLUSIONS: Asymptomatic subjects with advanced atherosclerosis of the carotid artery (type III and type IV b findings) had a high risk for coronary heart disease (CHD). Early treatment of the disease improves the patient's prognosis. A screening consisting in the combination of TPA measurement and determining the maximum plaque thickness is recommended.

Early Diagnosis and Treatment of Coronary Heart Disease in Symptomatic Subjects With Advanced Vascular Atherosclerosis of the Carotid Artery (Type III and IV b Findings Using Ultrasound).

BACKGROUND: A study was conducted as to whether the early diagnosis of coronary heart disease (CHD) in symptomatic patients with advanced atherosclerosis of the carotid artery was more successful using ultrasound technology than exercise electrocardiography (ECG). METHODS: Within the scope of an occupational screening program using subjects from diverse employment sectors, people were given the opportunity to determine their risk of heart attack. During the study, the total plaque area (TPA), the maximum plaque thickness in the carotid artery and the PROCAM scores of 3,513 healthy men and 2,088 healthy women between the ages of 20 and 65 were determined. During the subsequent follow-up study, 36 subjects developed symptoms such as exertional dyspnea, atypical angina pectoris (AP) or typical AP. Four patients displayed no symptoms. The initial cardiac diagnostic testing was conducted on 31 patients using an exercise ECG, four patients were assessed using a coronary angiogram, and five further patients were assessed using a computed tomography (CT) coronary angiogram. An ultrasound examination of the carotid artery of 39 patients revealed a type IV b finding and in one patient, the examination revealed a type III finding. RESULTS: In 17 patients, the PROCAM score was < 10%, 13 patients had a score of 10-20% and 10 patients had a score of > 20%. In the final analysis, only two patients had entirely smooth coronary arteries, seven had coronary sclerosis, seven had a 30% stenosis, one had a 30-40% stenosis, one had a 40% stenosis, and 22 patients had a stenosis ≥ 50%, and in extreme cases, a left main coronary artery stenosis with three-vessel disease was shown. The exercise ECG only achieved a true positive result in four patients, and in 21 patients, the result was false negative. CONCLUSIONS: Symptomatic patients with advanced atherosclerosis of the carotid artery (type III and type IV b findings) had a high risk for CHD. The diagnosis of CHD is better achieved by using carotid duplex than with an exercise ECG. Early treatment of the disease improves the patient's prognosis.

Extensive carotid atherosclerosis and the diagnostic accuracy of coronary risk calculators.

Preventive therapy in primary care is guided by risk thresholds for future cardiovascular events. We aimed to assess whether the sensitivity of various risk calculators for the detection of subclinical carotid atherosclerosis (TPA80) could be improved by lowering risk thresholds in younger age groups. We compared sensitivity, specificity, and discriminatory performance of SCORE, SCORE-HDL, PROCAM, AGLA, FRAM and PCE coronary risk calculators to detect total plaque area > 80 mm2 (TPA80), a coronary risk equivalent, in age groups 40-55, 56-65, 66-75 from Germany (DE, N = 2942) and Switzerland (CH, N = 2202) during the years 2002 to 2016. All calculators showed good to moderate discriminatory performance to detect TPA80 with AUC ranging from 0.74 (CH-AGLA) to 0.87 (DE- SCORE), but the sensitivity of high risk risk thresholds varied widely from 39% for DE-FRAM-CVD to 5% for CH-AGLA. Lowering of the risk threshold increased sensitivity substantially at the expense of minor losses in specificity, but the sensitivity generally remained < 45% at the 90% specificity threshold. Current risk thresholds of American and European coronary risk calculators have a low sensitivity to detect TPA80 in younger individuals.

[Prediction of coronary artery stenosis by measurement of total plaque area and thickness versus intima media thickness of the carotid artery]. / Vorhersage einer stenosierenden KHK durch Bestimmung von Plaque-Fläche und -Dicke vs. IMT an der A. carotis.

Total plaque area (TPA), maximum plaque thickness and intima media thickness (IMT) in the carotid arteries of 431 patients aged 27-88 years were measured 1 day before a planned coronary artery angiography without any clinical knowledge about the patient. Age-related cut-off values of the TPA for the presence of coronary stenosis were evaluated. Using ultrasound four types of carotid artery atherosclerosis were identified. The accuracy of detection of cardiovascular coronary stenosis was 87% for types III and IVb. No type I patient had coronary stenosis. The IMT was significantly less predictive: the area under the curve (AUC) for TPA by age and plaque thickness was 0.82 (95% CI: 0.78-0.85) versus IMT 0.59 (95% CI: 0.54-0.64, p = 0.001). Prediction with TPA measurement by age and plaque thickness was better than TPA alone: AUC 0.82 (95% CI: 0.78-0.85) versus 0.77 (95% CI: 0.73-0.81, p = 0.0028), respectively. In a second cohort of 2566 healthy men and 1216 healthy women aged between 20 and 64 years who were examined in an occupational screening program, 11.2% of the men and 3.4% of the women showed a type III or IVb result. In the mean follow-up of period of 23.4 ± 14.4 months, 14 heart attacks, 7 bypass operations and 3 stent implantations occurred and 6 subjects showed coronary stenosis between 50% and 95% in coronary angiography. In the baseline examination 26 out of 30 patients showed a type III or IVb result. In the case of men and women with types III and IVb diagnosis by ultrasound, pharmaceutical treatment could be indicated in order to reduce the risk of cardiovascular events. Type I patients do not need preventive medication or coronary catheterization.

Occupational exposure to polycyclic aromatic hydrocarbons and DNA damage by industry: a nationwide study in Germany.

Exposure to polycyclic aromatic hydrocarbons (PAH) and DNA damage were analyzed in coke oven (n = 37), refractory (n = 96), graphite electrode (n = 26), and converter workers (n = 12), whereas construction workers (n = 48) served as referents. PAH exposure was assessed by personal air sampling during shift and biological monitoring in urine post shift (1-hydroxypyrene, 1-OHP and 1-, 2 + 9-, 3-, 4-hydroxyphenanthrenes, SigmaOHPHE). DNA damage was measured by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and DNA strand breaks in blood post shift. Median 1-OHP and SigmaOHPHE were highest in converter workers (13.5 and 37.2 microg/g crea). The industrial setting contributed to the metabolite concentrations rather than the air-borne concentration alone. Other routes of uptake, probably dermal, influenced associations between air-borne concentrations and levels of PAH metabolites in urine making biomonitoring results preferred parameters to assess exposure to PAH. DNA damage in terms of 8-oxo-dGuo and DNA strand breaks was higher in exposed workers compared to referents ranking highest for graphite-electrode production. The type of industry contributed to genotoxic DNA damage and DNA damage was not unequivocally associated to PAH on the individual level most likely due to potential contributions of co-exposures.

Dose-response modeling of occupational exposure to polycyclic aromatic hydrocarbons with biomarkers of exposure and effect.

In regulatory toxicology, the dose-response relationship between occupational exposure and biomarkers is of importance in setting threshold values. We analyzed the relationships between occupational exposure to polycyclic aromatic hydrocarbons (PAH) and various biomarkers of internal exposure and DNA damage with data from 284 highly exposed male workers. Personal exposure to phenanthrene and other PAHs was measured during shift and correlated with the sum of 1-, 2+9-, 3-, and 4-hydroxyphenanthrenes in post-shift urine. PAHs and hydroxyphenanthrenes were associated with DNA damage assessed in WBC as 8-oxo-7,8-dihydro-2'-deoxyguanosine/10(6) dGuo and strand breaks by Comet assay as Olive tail moment. Hydroxyphenanthrenes correlated with phenanthrene (Spearman r(s) = 0.70; P < 0.0001). No correlations could be found between strand breaks and exposure (r(s) = 0.01, P < 0.0001 for PAHs; r(s) = -0.03, P = 0.68 for hydroxyphenanthrenes). Correlations with 8-oxo-7,8-dihydro-2'-deoxyguanosine/10(6) dGuo were weakly negative (r(s) = -0.22, P = 0.004 for PAHs) or flat (r(s) = -0.08, P = 0.31 for hydroxyphenanthrenes). Linear splines were applied to assess the relationships between the log-transformed variables. All regression models were adjusted for smoking and type of industry. For hydroxyphenanthrenes, 51.7% of the variance could be explained by phenanthrene and other predictors. Up to 0.77 microg/m(3) phenanthrene, no association could be found with hydroxyphenanthrenes. Above that point, hydroxyphenanthrenes increased by a factor of 1.47 under a doubling of phenanthrene exposure (slope, 0.56; 95% confidence interval, 0.47-0.64). Hydroxyphenanthrenes may be recommended as biomarker of occupational PAH exposure, whereas biomarkers of DNA damage in blood did not show a dose-response relation to PAH exposure.

Occupational exposure to polycyclic aromatic hydrocarbons in German industries: association between exogenous exposure and urinary metabolites and its modulation by enzyme polymorphisms.

A cross-sectional study was conducted in 170 German workers exposed to polycyclic aromatic hydrocarbons (PAH) to investigate the role of 11 polymorphisms of CYP1A1, CYP1A2, CYP1B1, CYP3A4, EPHX1, GSTM1, GSTT1, and GSTP1 in the association between occupational exposure to PAH and urinary PAH metabolites. Polymorphisms were genotyped with real-time PCR. Exposure to 16 PAH was measured by personal air sampling. Urinary concentrations of 1-hydroxypyrene (1-OHP) and the sum of 1-, 2+9-, 3-, and 4-hydroxyphenanthrenes (OHPhe) were determined post-shift. Urinary 1-OHP and OHPhe correlated significantly with exogenous pyrene (Spearman r=0.52, p<0.0001) and phenanthrene (Spearman r=0.72, p<0.0001), respectively. ANCOVA was applied to investigate potential predictors of the metabolite levels. Current smoking and type of industry turned out to be predictors of 1-OHP but not of OHPhe. CYP1A1 3801TC carriers showed 1.6-fold higher OHPhe levels than 3801TT carriers (p=0.03). EPHX1 113HH was associated with higher and 139RR with lower metabolite levels when compared with the corresponding reference genotypes (113YY; 139HH). In comparison to GSTP1 114AA, carriers of the V allele had 1.5-fold higher 1-OHP (p=0.03) and 2-fold higher OHPhe concentrations (p=0.001). OHPhe turned out to be also a suitable biomarker of occupational PAH exposure. The association with ambient PAH exposure and the influence of polymorphisms was more pronounced for OHPhe.