G De Palma

Environmental risk factors for parkinson's disease and parkinsonism : the geoparkinson study

Objective: To investigate the associations between Parkinson’s disease and other degenerative parkinsonian syndromes and environmental factors in five European countries. Methods: A case–control study of 959 prevalent cases of parkinsonism (767 with Parkinson’s disease) and 1989 controls in Scotland, Italy, Sweden, Romania and Malta was carried out. Cases were defined using the United Kingdom Parkinson’s Disease Society Brain Bank criteria, and those with drug-induced or vascular parkinsonism or dementia were excluded. Subjects completed an interviewer-administered questionnaire about lifetime occupational and hobby exposure to solvents, pesticides, iron, copper and manganese. Lifetime and average annual exposures were estimated blind to disease status using a job-exposure matrix modified by subjective exposure modelling. Results were analysed using multiple logistic regression, adjusting for age, sex, country, tobacco use, ever knocked unconscious and family history of Parkinson’s disease. Results: Adjusted logistic regression analyses showed significantly increased odds ratios for Parkinson’s disease/parkinsonism with an exposure–response relationship for pesticides (low vs no exposure, odds ratio (OR) = 1.13, 95% CI 0.82 to 1.57, high vs no exposure, OR = 1.41, 95% CI 1.06 to 1.88) and ever knocked unconscious (once vs never, OR = 1.35, 95% CI 1.09 to 1.68, more than once vs never, OR = 2.53, 95% CI 1.78 to 3.59). Hypnotic, anxiolytic or antidepressant drug use for more than 1 year and a family history of Parkinson’s disease showed significantly increased odds ratios. Tobacco use was protective (OR = 0.50, 95% CI 0.42 to 0.60). Analyses confined to subjects with Parkinson’s disease gave similar results. Conclusions: The association of pesticide exposure with Parkinson’s disease suggests a causative role. Repeated traumatic loss of consciousness is associated with increased risk.

Gene‐environment interactions in parkinsonism and Parkinson's disease: the Geoparkinson study

Objectives: To investigate associations of Parkinson’s disease (PD) and parkinsonian syndromes with polymorphic genes that influence metabolism of either foreign chemical substances or dopamine and to seek evidence of gene-environment interaction effects that modify risk. Methods: A case-control study of 959 prevalent cases of parkinsonism (767 with PD) and 1989 controls across five European centres. Occupational hygienists estimated the average annual intensity of exposure to solvents, pesticides and metals, (iron, copper, manganese), blind to disease status. CYP2D6, PON1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, CYP1B1, MAO-A, MAO-B, SOD 2, EPHX, DAT1, DRD2 and NAT2 were genotyped. Results were analysed using multiple logistic regression adjusting for key confounders. Results: There was a modest but significant association between MAO-A polymorphism in males and disease risk (G vs T, OR 1.30, 95% CI 1.02 to 1.66, adjusted). The majority of gene-environment analyses did not show significant interaction effects. There were possible interaction effects between GSTM1 null genotype and solvent exposure (which were stronger when limited to PD cases only). Conclusions: Many small studies have reported associations between genetic polymorphisms and PD. Fewer have examined gene-environment interactions. This large study was sufficiently powered to examine these aspects. GSTM1 null subjects heavily exposed to solvents appear to be at increased risk of PD. There was insufficient evidence that the other gene-environment combinations investigated modified disease risk, suggesting they contribute little to the burden of PD.

Glutathione S-transferases M1-1 and T1-1 as risk modifiers for renal cell cancer associated with occupational exposure to chemicals.

Aims: To investigate the possible interaction between occupational risk factors and genotype for glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) in renal cell cancer (RCC). Methods: One hundred patients with RCC and 200 outpatient controls were enrolled at Parma University Hospital. The polymorphisms of glutathione S-transferase M1-1 (GSTM1) and T1-1 (GSTT1) were investigated by PCR; occupational history was collected by a structured questionnaire. Results: Subjects with GSTM1 present genotype showed higher risks for RCC, compared to GSTM1 null subjects, if exposed to metals (OR 2.73; 95% CI 0.91 to 8.22 v 1.14; 95% CI 0.46 to 2.82) or pesticides (OR 3.46; 95% CI 1.12 to 10.74 v 1.59; 95% CI 0.48 to 5.34). The GSTT1 present genotype also enhanced the risk (about twofold) of RCC among subjects exposed to solvents and pesticides, compared with those GSTT1 null. Conclusions: Results support the hypothesis that GSTM1 and GSTT1 polymorphisms can interact with several occupational exposures to significantly modify the risk of RCC among exposed subjects.

Assessing variability and comparing short-term biomarkers of styrene exposure using a repeated measurements approach

The aim of this work is to compare several short-term biomarkers of styrene exposure, namely urinary styrene (StyU), mercapturic acids (M1+M2), mandelic acid (MA), phenylglyoxylic acid (PGA), phenylglycine (PHG), and 4-vinylphenol conjugates (VP), for use as biomarkers of exposure in epidemiologic studies. A repeated measurements protocol (typically 4 measurements per worker over 6 weeks) was applied to measure airborne styrene (StyA) and urinary biomarkers in 10 varnish and 8 fiberglass reinforced plastic workers. Estimated geometric mean personal exposures to StyA were 2.96mg/m(3) in varnish workers and 15.7mg/m(3) in plastic workers. The corresponding levels of StyU, M1+M2, MA, PGA, MA+PGA, PHG and VP were 5.13microg/L, 0.111, 38.2, 22.7, 62.6, 0.978, and 3.97mg/g creatinine in varnish workers and 8.38microg/L, 0.303, 146, 83.4, 232, 2.85 and 3.97mg/g creatinine in plastic workers. Within-worker (sigma(wY)(2)) and between-worker (sigma(bY)(2)) variance components were estimated from the log-transformed data as were the corresponding fold ranges containing 95% of the respective lognormal distributions of daily levels ((w)R(0.95)) and subject-specific mean levels ((b)R(0.95)). Estimates of (w)R(0.95) (range: 4-26) were generally smaller than those of (b)R(0.95) (range: 5-790) for both environmental and biological markers; this indicates that exposures varied much more between workers than within workers in these groups. Since attenuation bias in an estimated exposure-response relationship increases with the variance ratio lambda=sigma(wY)(2)/sigma(bY)(2), we estimated values of lambda for all exposure measures in our study. Values of lambda were typically much less than one (median=0.220) and ranged from 0.089 for M1+M2 in plastic workers to 1.38 for PHG in varnish workers. Since values of lambda were 0.147 and 0.271 for StyA in varnish workers and plastic workers, respectively, compared to 0.178 and 0.210 for MA in the same groups, our results suggest that either air measurements or conventional biomarker measurements (urinary MA) would be comparable surrogates for individual exposures in epidemiologic studies.

An integrated approach to biomonitoring exposure to styrene and styrene-(7,8)-oxide using a repeated measurements sampling design

Abstract The aim of this work was to investigate urinary analytes and haemoglobin and albumin adducts as biomarkers of exposure to airborne styrene (Sty) and styrene-(7,8)-oxide (StyOX) and to evaluate the influence of smoking habit and genetic polymorphism of metabolic enzymes GSTM1 and GSTT1 on these biomarkers. We obtained three or four air and urine samples from each exposed worker (eight reinforced plastics workers and 13 varnish workers), one air and urine samples from 22 control workers (automobile mechanics) and one blood sample from all subjects. Median levels of exposure to Sty and StyOX, respectively, were 18.2 mg m−3 and 133 µg m−3 for reinforced plastics workers, 3.4 mg m−3 and 12 µg m−3 for varnish workers, and <0.3 mg m−3 and <5 µg m−3 for controls. Urinary levels of styrene, mandelic acid, phenylglyoxylic acid, phenylglycine (PHG), 4-vinylphenol (VP) and mercapturic acids (M1+M2), as well as cysteinyl adducts of serum albumin (but not those of haemoglobin) were significantly associated with exposure status (controls<exposed workers). Also, levels of VP and M1+M2 were significantly affected by smoking, and levels of M1+M2 were significantly affected by GSTM1 polymorphisms. Multiple linear regression analyses of the subject-specific (logged) metabolite levels across exposed workers showed that Sty was a significant predictor for all urinary analytes while StyOX was a significant predictor of PHG only. Interestingly, the log scale regression coefficients for Sty in these models were significantly less than one for all metabolites except M1+M2. This suggests that the natural scale relationships between levels of all Sty metabolites, except M1+M2, displayed downward concavity with increasing Sty exposure, suggestive of saturable metabolism. Levels of the protein adducts were not associated with exposure to either Sty or StyOX among exposed subjects.