Passive environmental residential exposure to agricultural pesticides and hematological malignancies in the general population: a systematic review.

Incidence rates of hematological malignancies have been constantly increasing over the past 40 years. In parallel, an expanding use of agricultural pesticides has been observed. Only a limited number of studies investigated the link between hematological malignancies risk and passive environmental residential exposure to agricultural pesticides in the general population. The purpose of our review was to summarize the current state of knowledge on that question. A systematic literature search was conducted using PubMed and Scopus databases. We built a scoring scale to appraise relevance of each selected articles. We included 23 publications: 13 ecological studies, 9 case-control studies and a cohort study. Positive associations were reported between hematological malignancies and individual pesticides, pesticide groups, all pesticides without distinction, or some crop types. Relevance score was highly various across studies regardless of their design. Children studies were the majority and had overall higher relevance scores. The effect of passive environmental residential exposure to agricultural pesticides on hematological malignancies risk is suggested by the literature. The main limitation of the literature available is the high heterogeneity across studies, especially in terms of exposure assessment approach. Further studies with high methodological relevance should be conducted.

Occupational exposure to pesticides and central nervous system tumors: results from the CERENAT case-control study.

BACKGROUND: The etiology of the central nervous system (CNS) tumors remains largely unknown. The role of pesticide exposure has been suggested by several epidemiological studies, but with no definitive conclusion. OBJECTIVE: To analyze associations between occupational pesticide exposure and primary CNS tumors in adults in the CERENAT study. METHODS: CERENAT is a multicenter case-control study conducted in France in 2004-2006. Data about occupational pesticide uses-in and outside agriculture-were collected during detailed face-to-face interviews and reviewed by experts for consistency and exposure assignment. Odds ratios (ORs) and 95% confidence intervals (95% CI) were estimated with conditional logistic regression. RESULTS: A total of 596 cases (273 gliomas, 218 meningiomas, 105 others) and 1 192 age- and sex-matched controls selected in the general population were analyzed. Direct and indirect exposures to pesticides in agriculture were respectively assigned to 125 (7.0%) and 629 (35.2%) individuals and exposure outside agriculture to 146 (8.2%) individuals. For overall agricultural exposure, we observed no increase in risk for all brain tumors (OR 1.04, 0.69-1.57) and a slight increase for gliomas (OR 1.37, 0.79-2.39). Risks for gliomas were higher when considering agricultural exposure for more than 10 years (OR 2.22, 0.94-5.24) and significantly trebled in open field agriculture (OR 3.58, 1.20-10.70). Increases in risk were also observed in non-agricultural exposures, especially in green space workers who were directly exposed (OR 1.89, 0.82-4.39), and these were statistically significant for those exposed for over 10 years (OR 2.84, 1.15-6.99). DISCUSSION: These data support some previous findings regarding the potential role of occupational exposures to pesticides in CNS tumors, both inside and outside agriculture.

Residential proximity to power lines and risk of brain tumor in the general population.

The effect of ELF-MF on human health is still controversial, particularly as regards long-term health effects like cancer. The literature does suggest, however, that they could be involved in the occurrence of brain tumors, although results concerning residential exposure are scarce. Our objective was to investigate the association between residential proximity to power lines and brain tumors among adults in France by using a geographical information system.CERENAT is a population-based case-control study carried out in France in 2004-2006. We used geographical data sources on power line location to create exposure scores based on distance between residence and power lines, and on the number of lines near residences. Conditional logistic regression for matched sets was used to estimate Odds Ratios (ORs) and 95% confidence intervals (95%CI).We found significant associations between cumulated duration living at <50 m to high voltage lines and: i) all brain tumors (OR 2.94; 95%CI 1.28-6.75); ii) glioma (OR 4.96; 95%CI 1.56-15.77). Further investigations are needed, particularly to improve the quality and availability of geographical and technical data on power lines.

Maternal cumulative exposure to extremely low frequency electromagnetic fields, prematurity and small for gestational age: a pooled analysis of two birth cohorts.

BACKGROUND: Data on the effects of extremely low frequency electromagnetic fields (ELF-EMF) on pregnancy outcomes are inconclusive. OBJECTIVE: To study the relation between maternal cumulative exposure to ELF-EMF during pregnancy and the risk of prematurity or small for gestational age (SGA) in a pooled analysis of two French birth cohorts. METHODS: Elfe and Epipage2 are both population-based birth cohorts initiated in 2011 and included 18 329 and 8400 births, respectively. Health data and household, mother and child characteristics were obtained from medical records and questionnaires at maternity and during follow-up. A job exposure matrix was used to assess cumulative exposure to ELF-EMF during three periods: (1) until 15 weeks of gestation, (2) until 28 weeks of gestation and (3) until 32 weeks of gestation. Analyses were restricted to single live births in mainland France and to mothers with documented jobs (N=19 894). Adjusted logistic regression models were used. RESULTS: According to the period studied, 3.2%-4% of mothers were classified as highly exposed. Results were heterogeneous. Increased risks of prematurity were found among low exposed mothers for the three periods, and no association was observed among the most exposed (OR1=0.92 (95% CI 0.74 to 1.15); OR2=0.98 (95% CI 0.80 to 1.21); OR3=1.14 (95% CI 0.92 to 1.41)). For SGA, no association was observed with the exception of increased risk among the low exposed mothers in period 2 and the most exposed in period 3 (OR=1.25 (95% CI 1.02 to 1.53)). CONCLUSION: Some heterogeneous associations between ELF-EMF exposure and prematurity and SGA were observed. However, due to heterogeneity (ie, their independence regarding the level of exposure), associations cannot be definitely explained by ELF-EMF exposure.

Development of a Job-Exposure Matrix for Assessment of Occupational Exposure to High-Frequency Electromagnetic Fields (3 kHz-300 GHz).

OBJECTIVES: The aim of this work was to build a job-exposure matrix (JEM) using an international coding system and covering the non-thermal intermediate frequency (IF) (3-100 kHz, named IFELF), thermal IF (100 kHz-10 MHz, named IFRF), and radiofrequency (RF) (>10 MHz) bands. METHODS: Detailed occupational data were collected in a large population-based case-control study, INTEROCC, with occupations coded into the International Standard Classification of Occupations system 1988 (ISCO88). The subjects' occupational source-based ancillary information was combined with an existing source-exposure matrix and the reference levels of the International Commission on Non-Ionizing Radiation Protection (ICNIRP) for occupational exposure to calculate estimates of level (L) of exposure to electric (E) and magnetic (H) fields by ISCO88 code and frequency band as ICNIRP ratios (IFELF) or squared ratios (IFRF and RF). Estimates of exposure probability (P) were obtained by dividing the number of exposed subjects by the total number of subjects available per job title. RESULTS: With 36 011 job histories collected, 468 ISCO88 (four-digit) codes were included in the JEM, of which 62.4% are exposed to RF, IFRF, and/or IFELF. As a reference, P values for RF E-fields ranged from 0.3 to 65.0% with a median of 5.1%. L values for RF E-fields (ICNIRP squared ratio) ranged from 6.94 × 10-11 to 33.97 with a median of 0.61. CONCLUSIONS: The methodology used allowed the development of a JEM for high-frequency electromagnetic fields containing exposure estimates for the largest number of occupations to date. Although the validity of this JEM is limited by the small number of available observations for some codes, this JEM may be useful for epidemiological studies and occupational health management programs assessing high-frequency electromagnetic field exposure in occupational settings.

Residential sources of pesticide exposure during pregnancy and the risks of hypospadias and cryptorchidism: the French ELFE birth cohort.

OBJECTIVES: Prenatal occupational exposure to pesticides has been associated with male reproductive tract abnormalities. Little is known about the possible impact of non-occupational pesticide exposure on fetal and child development in the general population. Using data from a nationwide birth cohort, we aimed to assess the association between residential sources of prenatal pesticide exposure and the risks of hypospadias and cryptorchidism. METHODS: Of the 9281 boys in ELFE (French Longitudinal Study of Children), the national French birth cohort, 53 were diagnosed with hypospadias and 137 with cryptorchidism. We assessed residential exposure sources from self-reported domestic use of eight types of pesticide products and French spatial land use data with acreage within a 1000 m radius around each family's home for 21 crop types. We used logistic regression modelling, adjusted for possible confounders that included estimated dietary pesticide intake. Multiple imputations were used to handle missing data. RESULTS: An increased risk of hypospadias was associated with domestic pesticide use against fleas and ticks (OR=2.28, 95% CI 1.09 to 4.75); no associations were found between cryptorchidism and any domestic pesticide use. Slightly increased risks of cryptorchidism were observed in association with all crop acreages near homes during pregnancy, especially for orchards, and no association was observed for hypospadias. CONCLUSIONS: Our results suggest a possible increased risk of hypospadias associated with prenatal use of some domestic pesticide products, likely to contain insecticides, and of cryptorchidism with nearby orchard acreage (crops repeatedly sprayed with pesticides). This work is limited by its modest number of cases.

Occupational exposure to pesticides: development of a job-exposure matrix for use in population-based studies (PESTIPOP).

Occupational exposure to pesticides concerns a wide population of workers not only in agriculture. The reliability of self-reported information on pesticide use is questionable because of the diversity of use. The PESTIPOP job-exposure matrix has been designed to assess pesticide occupational exposure in the general population. The matrix is composed of two axes: the first axis corresponding to jobs (combinations of occupations and industries) and the second one to pesticide exposure. The estimated exposure metric is the probability of exposure coupled with a reliability assessment (low, medium or high). These metrics were defined by combining different sources: (1) an a priori expert assessment (Agricultural industry experts); (2) data from a multicenter case-control study on brain tumors in the general population (occupational history, specific questionnaires); and (3) an a posteriori expert assessment based on the data of a case-control study. So far, 2559 jobs have been identified and 209 (8%) were found to be exposed to pesticides. Jobs with agricultural exposure had a higher exposure probability than jobs with non-agricultural exposure (wood preservation, park maintenance, pest control). Indirect exposure was more frequent than direct exposure. The PESTIPOP matrix will be transcoded into international classifications for use in epidemiological studies.

Residential proximity to agricultural land and risk of brain tumor in the general population.

The effect of pesticides on human health is still controversial, particularly as regards long-term health effects like cancer. The literature does suggest, however, that they could be involved in the occurrence of brain tumors, although the results concerning residential exposure are scarce. Our objective was to investigate the association between residential proximity to agricultural pesticides and brain tumors among adults in France by using a geographical information system. CERENAT is a population-based case-control study carried out in France in 2004-2006. We used two geographical data sources on agricultural land use to create exposure scores based on crop surface areas near the residence, for open field crops, vineyards and orchards. Conditional logistic regression for matched sets was used to estimate Odds Ratios (ORs) and 95% confidence intervals (95%CI). We found a significant association between meningioma and proximity to open field crops above the 75th percentile (OR 2.30 95%CI 1.04-5.10). Non-significant associations were also found with proximity of vineyards above the 95th percentile (OR 1.90 95%CI 0.41-8.69) and orchards above the 95th percentile (OR 5.50, 95%CI 0.49-61.94). No significant association was found between glioma and proximity to agricultural land. Further investigations are needed, particularly to improve the quality and availability of geographical data on agricultural land use.

A French crop-exposure matrix for use in epidemiological studies on pesticides: PESTIMAT.

Pesticide exposure assessment is a key methodological issue for epidemiological studies. The history of pesticide has proven difficult to obtain from individuals' report because of the wide range of active ingredients (AIs). We developed a crop-exposure matrix, which intends to reconstitute parameters of pesticide exposure in France since 1950. PESTIMAT is composed of tables crossing crops and AIs by year and providing the following metrics: (1) probability (proportion of farmers having used the AIs); (2) frequency (number of treatment days); and (3) intensity (application rate of the AIs in kg/ha). Metrics were obtained by the combination of six sources: (i) registration information from the Agriculture Ministry; (ii) information from agricultural bodies on products marketed; (iii) agricultural recommendations by the Plant Health Protection body; (iv) treatment calendars provided by farmers; (v) data from associations of farmers; and (vi) data from the industry. To date, 529 AIs usable between 1950 and 2010 are included in PESTIMAT: 160 fungicides; 160 herbicides; and 209 insecticides. When combined with duration and determinants of intensity, the metrics in PESTIMAT will make it possible to calculate exposure scores and to search for dose-effect relationships, an important criterion for causality judgment in epidemiology.

Use of job-exposure matrices to estimate occupational exposure to pesticides: A review.

The health effects of pesticides have been extensively studied in epidemiology, mainly in agricultural populations. However, pesticide exposure assessment remains a key methodological issue for epidemiological studies. Besides self-reported information, expert assessment or metrology, job-exposure matrices still appear to be an interesting tool. We reviewed all existing matrices assessing occupational exposure to pesticides in epidemiological studies and described the exposure parameters they included. We identified two types of matrices, (i) generic ones that are generally used in case-control studies and document broad categories of pesticides in a large range of jobs, and (ii) specific matrices, developed for use in agricultural cohorts, that generally provide exposure metrics at the active ingredient level. The various applications of these matrices in epidemiological studies have proven that they are valuable tools to assess pesticide exposure. Specific matrices are particularly promising for use in agricultural cohorts. However, results obtained with matrices have rarely been compared with those obtained with other tools. In addition, the external validity of the given estimates has not been adequately discussed. Yet, matrices would help in reducing misclassification and in quantifying cumulated exposures, to improve knowledge about the chronic health effects of pesticides.

Increase in the Risk of Respiratory Disorders in Adults and Children Related to Crop-Growing in Niger.

Background and Objective. Environmental factors are an increasing concern for respiratory health in developing countries. The objective of this study was to investigate whether Nigerien people living in cultivated areas have more respiratory symptoms than those living in pastoral areas. Method. A cross-sectional study was conducted in 2013 in two populations during the rainy season when land is cultivated. Environmental factors including pesticide use and respiratory symptoms were collected in adults and children during face-to-face interviews. Multivariate analysis between exposures and symptoms was performed in children and in adults separately. Results. The study included 471 adults and 229 children. Overall, none of the households reported the use of pesticides for agricultural purposes. However, 87.2% reported the use of insecticides at home. Multivariate analysis showed that people living in agricultural areas compared to those in pastoral areas had an increased risk of respiratory symptoms in adults (wheezing, dyspnea, sudden shortness of breath, and cough without fever) and in children (cough without fever). The use of insecticides showed no effect on respiratory symptoms after adjustment. Conclusion. This first epidemiological study on the environment and respiratory health conducted in Niger demonstrates a significant relationship between respiratory manifestations and the agricultural characteristics of the living area. However only the effect of insecticides in the home on respiratory health was observed.

Environmental exposure to pesticides and respiratory health.

Respiratory effects of environmental exposure to pesticides are debated. Here we aimed to review epidemiological studies published up until 2013, using the PubMed database. 20 studies dealing with respiratory health and non-occupational pesticide exposure were identified, 14 carried out on children and six on adults. In four out of nine studies in children with biological measurements, mothers' dichlorodiphenyldichloroethylene (DDE) blood levels during pregnancy were associated with asthma and wheezing in young children. An association was also found between permethrin in indoor air during pregnancy and wheezing in children. A significant association between asthma and DDE measured in children's blood (aged 7-10 years) was observed in one study. However, in three studies, no association was found between asthma or respiratory infections in children and pesticide levels in breast milk and/or infant blood. Lastly, in three out of four studies where post-natal pesticide exposure of children was assessed by parental questionnaire an association with respiratory symptoms was found. Results of the fewer studies on pesticide environmental exposure and respiratory health of adults were much less conclusive: indeed, the associations observed were weak and often not significant. In conclusion, further studies are needed to confirm whether there is a respiratory risk associated with environmental exposure to pesticides.

Occupational exposure to pesticides and respiratory health.

This article aims to review the available literature regarding the link between occupational exposure to pesticides and respiratory symptoms or diseases. Identification of epidemiological studies was performed using PubMed. 41 articles were included, 36 regarding agricultural workers and five regarding industry workers. Among the 15 cross-sectional studies focusing on respiratory symptoms and agricultural pesticide exposure, 12 found significant associations with chronic cough, wheeze, dyspnoea, breathlessness or chest tightness. All four studies on asthma found a relationship with occupational exposure, as did all three studies on chronic bronchitis. The four studies that performed spirometry reported impaired respiratory function linked to pesticide exposure, suggestive of either obstructive or restrictive syndrome according to the chemical class of pesticide. 12 papers reported results from cohort studies. Three out of nine found a significant relationship with increased risk of wheeze, five out of nine with asthma and three out of three with chronic bronchitis. In workers employed in pesticide production, elevated risks of chronic obstructive pulmonary disease (two studies out of three) and impaired respiratory function suggestive of an obstructive syndrome (two studies out of two) were reported. In conclusion, this article suggests that occupational exposure to pesticides is associated with an increased risk of respiratory symptoms, asthma and chronic bronchitis, but the causal relationship is still under debate.

Mobile phone use and brain tumours in the CERENAT case-control study.

UNLABELLED: The carcinogenic effect of radiofrequency electromagnetic fields in humans remains controversial. However, it has been suggested that they could be involved in the aetiology of some types of brain tumours. OBJECTIVES: The objective was to analyse the association between mobile phone exposure and primary central nervous system tumours (gliomas and meningiomas) in adults. METHODS: CERENAT is a multicenter case-control study carried out in four areas in France in 2004-2006. Data about mobile phone use were collected through a detailed questionnaire delivered in a face-to-face manner. Conditional logistic regression for matched sets was used to estimate adjusted ORs and 95% CIs. RESULTS: A total of 253 gliomas, 194 meningiomas and 892 matched controls selected from the local electoral rolls were analysed. No association with brain tumours was observed when comparing regular mobile phone users with non-users (OR=1.24; 95% CI 0.86 to 1.77 for gliomas, OR=0.90; 95% CI 0.61 to 1.34 for meningiomas). However, the positive association was statistically significant in the heaviest users when considering life-long cumulative duration (≥896 h, OR=2.89; 95% CI 1.41 to 5.93 for gliomas; OR=2.57; 95% CI 1.02 to 6.44 for meningiomas) and number of calls for gliomas (≥18,360 calls, OR=2.10, 95% CI 1.03 to 4.31). Risks were higher for gliomas, temporal tumours, occupational and urban mobile phone use. CONCLUSIONS: These additional data support previous findings concerning a possible association between heavy mobile phone use and brain tumours.

Agricultural exposure and asthma risk in the AGRICAN French cohort.

Epidemiological studies have reported an increased risk of respiratory diseases in agricultural population, but a protective "farm-effect" has also been reported for asthma. In the AGRICAN cohort, self-reported doctor-diagnosed asthma was analyzed according to allergy, in relation with history of life-time exposure to 13 crops and 5 livestock, pesticide exposure and early life on a farm, taking into account sex, age, education and body mass index. Among the 1246 asthmatics (8.0%), 505 were allergic (3.3%) and 719 non-allergic (4.6%). In multivariate analysis, a significant excess was observed, only for allergic asthma, in vine-growing (OR=1.43, p=0.002), fruit-growing (OR=1.58, p=0.001), greenhouses (OR=1.66, p=0.02), grasslands (OR=1.35, p=0.009), beets (OR=1.52, p=0.003) and horses (OR=1.35, p=0.04). Pesticide use and history of pesticide poisoning were significantly associated with allergic asthma in grassland, vineyards and fruit-growing and with non-allergic asthma in beets. Living on a farm in the first year of life tended to be protective for childhood allergic asthma in farms with livestock (OR=0.72, p=0.07) but deleterious in farms with vineyards, fruit or vegetables (OR=1.44, p=0.07). In AGRICAN, an increased risk of allergic asthma was observed with crop exposure, pesticide use and early life on a farm, especially in vine-growing, grassland, beets, fruit and vegetable-growing.

Cognitive disorders and occupational exposure to organophosphates: results from the PHYTONER study.

The involvement of organophosphate insecticides in cognitive disorders is supported by epidemiologic and biological evidence, but the effects of long-term exposure remain debated. We studied the association between organophosphate exposure and cognitive performance in vine workers from the PHYTONER study cohort in the Bordeaux area of France. Results from interviews of 614 subjects conducted at the 4-year follow-up between 2001 and 2003 were analyzed. Exposure to pesticides since 1950 was assessed with cumulative exposure scores for 34 organophosphates combining an historical crop-exposure pesticide matrix and field exposure studies, taking into account the characteristics of treatment (mixing, spraying, equipment cleaning) and reentry tasks. For the 11 organophosphates retained in the analysis, exposure (ever vs. never) was associated with low cognitive performance. No dose-effect relationship was found, but an increased risk was observed with a 50-mg increase in the cumulative score, which was greater with mevinphos (Benton Visual Retention Test: odds ratio = 3.26, 95% confidence interval: 1.54, 6.88; Trail Making Test, part A: odds ratio = 3.03, 95% confidence interval: 1.39, 6.62). Our results support the hypothesis that cognitive disorders observed in vine workers may be associated with exposure to specific organophosphates.

Levels and determinants of pesticide exposure in operators involved in treatment of vineyards: results of the PESTEXPO Study.

Exposure assessment is a critical point for epidemiological studies on pesticide health effects. PESTEXPO study provides data on levels of exposure and their determinants in real conditions of pesticide use. We described levels of exposure in vineyards during treatment tasks (mixing, spraying and cleaning) and we analysed their determinants. Sixty-seven operators using dithiocarbamates or folpet were observed. Detailed information on the tasks (general conditions, operator, farm and equipment characteristics) were collected and dermal contamination was measured, using patches placed onto the skin on eleven body parts, and washing the hands at the end of each phase. The spraying phase represented roughly half of the contamination, whereas mixing and equipment cleaning accounted for 30% and 20% of the contamination, respectively. The main determinants of exposure were the number of phases, the characteristics of the equipment, the educational level of the operator and his status (farm -worker or -owner) and the general characteristics of the vines. Algorithms were built to estimate daily external contamination, according to these characteristics during mixing, spraying or equipment cleaning. With additional information of frequency and duration of use, they will enable to develop exposure indices usable in epidemiological studies on farmers' health.

Brain tumors and hormonal factors: review of the epidemiological literature.

BACKGROUND: To date, the etiology of primary tumors of the central nervous system (mainly gliomas and meningiomas) is poorly understood. The role of sex hormones has been suggested, based on clinical, experimental, biological, and epidemiological data. OBJECTIVE: To review the epidemiological studies on the relation between hormonal factors and the occurrence of glioma and meningioma, in order to identify new research developments. METHODS: Articles published until September 2010 were selected by considering exogenous and endogenous exposures and specific brain tumors. Standardized information was collected from 20 articles: 15 concerning gliomas and 13 meningiomas. RESULTS: An increased glioma risk was observed with later menarche and menopause, while a reduced glioma risk was observed with hormone replacement therapy (HRT) and oral contraceptive use, despite duration of use had no effect on risk. Meningioma risk increased after menopause and with HRT use. No clear association was found with pregnancy and breastfeeding. CONCLUSION: Results are globally concordant with the biologic hypothesis assuming that female sex hormones are protective against glioma and may increase the risk of meningioma. However, new epidemiological studies should be conducted in order to confirm these associations and to refine the role of hormonal factors in brain etiology.

Environmental and biological monitoring of exposure to organophosphorus pesticides: application to occupationally and non-occupationally exposed adult populations.

The purpose of the study was to assess non-dietary exposure of workers and the general population in the Paris area to some organophosphorus (OP) pesticides. In total, 21 workers from different occupational places (two greenhouses, three florist shops and three veterinary departments) and 20 subjects assumed to be non-occupationally exposed were recruited. Indoor air, hand wipes, and three first morning urine samples were collected. Seven OPs were measured by GC/ECD and GC/TSD, and six urinary dialkylphosphate metabolites by GC/PFPD. All indoor air samples from the workplaces and only one-third of the samples from the residences contained at least one of the seven OPs. However, almost all participants were dermally exposed to OPs. Total OP indoor air and cutaneous levels were significantly higher for workers than for the general population (air median = 185 pmol/m3 versus nondetectable, P < 0.0001; hands median = 1250 pmol/hands versus 475 pmol/hands, P = 0.03). From the air, gardeners and florists were mainly exposed to methyl-OPs and veterinary staff to ethyl-OPs (mainly diazinon). From their hands, all subjects were exposed to methyl-OPs, with gardeners and florists exposed to somewhat but not significantly higher levels. Ethyl-OPs were more found frequently and at higher levels on the hands of veterinary workers. Total OP levels in indoor air and from hand wipes were significantly correlated (Spearman R = 0.34, P = 0.03). DAP detection frequencies and levels were not different between workers and the general population (workers median=168 nmol/g creat and general population median = 241 nmol/g creat, P = 0.31), and did not correlate with air or hand levels. Subjects not occupationally exposed showed significant residential exposure to OPs, more frequently from their hands than from the air. Different occupations were associated with different exposure profiles and levels. The lack of differences in DAP levels between the different groups of exposure suggests that dietary exposure to OP residues and exposure to other OPs are involved.