Lidwien A.M. Smit

Pesticide poisoning in the developing world—a minimum pesticides list

In parts of the developing world, pesticide poisoning causes more deaths than infectious diseases. Use of pesticides is poorly regulated and often dangerous; their easy availability also makes them a popular method of self-harm. In 1985, the UN Food and Agriculture Organisation (FAO) produced a voluntary code of conduct for the pesticide industry in an attempt to limit the harmful effects of pesticides. Unfortunately, a lack of adequate government resources in the developing world makes this code ineffective, and thousands of deaths continue today. WHO has recommended that access to highly toxic pesticides be restricted--where this has been done, suicide rates have fallen. Since an Essential Drugs List was established in 1977, use of a few essential drugs has rationalised drug use in many regions. An analogous Minimum Pesticides List would identify a restricted number of less dangerous pesticides to do specific tasks within an integrated pest management system. Use of safer pesticides should result in fewer deaths, just as the change from barbiturates to benzodiazepines has reduced the number of deaths from pharmaceutical self-poisoning.

CD14 and Toll-like Receptor Gene Polymorphisms, Country Living, and Asthma in Adults

RATIONALE It has been shown that country living protects against asthma, which may be explained by microbial exposures. OBJECTIVES To study whether single nucleotide polymorphisms (SNPs) in CD14 and Toll-like receptor (TLR) 2, TLR4 and TLR9 genes are associated with asthma in adults, and whether these SNPs modify associations between country living and asthma. METHODS Twenty-five SNPs in CD14, TLR2, TLR4, and TLR9 genes were genotyped in adult subjects from the French Epidemiological study on the Genetics and Environment of Asthma, Bronchial Hyperresponsiveness, and Atopy (EGEA). We conducted a case-control analysis on unrelated subjects (239 with asthma and 596 without asthma), and a family-based association test (FBAT) in 192 families ascertained through probands with asthma. MEASUREMENTS AND MAIN RESULTS The TLR2/+596 C allele was associated with an increased risk for asthma in both case-control and family-based analyses (under a dominant model, odds ratio [OR] 1.91 and 95% confidence interval [CI] 1.34-2.72, P = 0.0003; Z statistics from FBAT = 2.48, P = 0.01). In skin prick test (SPT) positive subjects, the CD14/-260 C allele was negatively associated with asthma (additive model, OR 0.66; CI 0.48-0.91). Significant gene-environment interactions between variation in CD14 and TLR genes and country living during childhood were found for ten SNPs. In SPT positive subjects carrying CD14/-260 CC, country living protected against asthma (OR, 0.32; 95% CI, 0.12-0.85), whereas country living was not associated with asthma in subjects who were atopic and carrying CD14/-260 T (OR, 1.11; 95% CI, 0.65-1.90) (gene-environment interaction, P < 0.05). CONCLUSIONS TLR2 and CD14 SNPs were associated with asthma and atopic asthma respectively. In addition, CD14, TLR2, TLR4, and TLR9 SNPs modified associations between country living and asthma.

Exposure-response analysis of allergy and respiratory symptoms in endotoxin-exposed adults

The objective of the present study was to investigate exposure–response relationships between current endotoxin exposure and allergic and respiratory symptoms in adults, taking into account farming exposures during childhood. A cross-sectional study was conducted among 877 Dutch farmers and agricultural industry workers in 2006. Based on 249 full-shift personal airborne endotoxin samples, a job-exposure matrix was constructed to assign endotoxin exposure levels to all participants. Associations between endotoxin exposure and questionnaire data on symptoms were studied by multiple logistic regression. Adjusted odds ratios (OR) for an interquartile range increase in endotoxin level were elevated for respiratory symptoms such as wheezing (OR 1.41 (95% confidence interval 1.16–1.72)), wheezing with shortness of breath (1.50 (1.18–1.90)) and daily cough (1.29 (1.03–1.62)). In contrast, endotoxin was strongly associated with a decreased prevalence of hay fever (0.62 (0.49–0.78)). Workers who had grown up on a farm had a lower prevalence of hay fever, but no evidence was found of effect modification by farm childhood. In conclusion, occupational endotoxin exposure in adulthood is associated with an increased risk of asthma-like symptoms but a reduced prevalence of hay fever.

Loss of Function of Transient Receptor Potential Vanilloid 1 (TRPV1) Genetic Variant Is Associated with Lower Risk of Active Childhood Asthma

Transient receptor potential cation channels of the vanilloid subfamily (TRPV) participate in the generation of Ca2+ signals at different locations of the respiratory system, thereby controlling its correct functioning. TRPV1 expression and activity appear to be altered under pathophysiological conditions such as chronic cough and airway hypersensitivity, whereas TRPV4 single nucleotide polymorphisms (SNP) are associated with chronic obstructive pulmonary disease. However, to date, there is no information about the genetic impact of either TRPV1 or TRPV4 on asthma pathophysiology. We now report on the association of two functional SNPs, TRPV1-I585V and TRPV4-P19S, with childhood asthma. Both SNPs were genotyped in a population of 470 controls without respiratory symptoms and 301 asthmatics. Although none of the SNPs modified the risk of suffering from asthma, carriers of the TRPV1-I585V genetic variant showed a lower risk of current wheezing (odds ratio = 0.51; p = 0.01), a characteristic of active asthma, or cough (odds ratio = 0.57; p = 0.02). Functional analysis of TRPV1-I585V, using the Ca2+-sensitive dye fura-2 to measure intracellular [Ca2+] concentrations, revealed a decreased channel activity in response to two typical TRPV1 stimuli, heat and capsaicin. On the other hand, TRPV4-P19S, despite its loss-of-channel function, showed no significant association with asthma or the presence of wheezing. Our data suggest that genetically determined level of TRPV1 activity is relevant for asthma pathophysiology.

17q21 variants modify the association between early respiratory infections and asthma

Single nucleotide polymorphisms (SNPs) at chromosome 17q21 confer an increased risk of early-onset asthma. The objective was to study whether 17q21 SNPs modify associations between early respiratory infections and asthma. Association analysis was conducted in 499 children (268 with asthma, median age 11 yrs) from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). The 12-yr follow-up data were used to assess persistent or remittent asthma in young adulthood. Respiratory infection before 2 yrs of age was assessed retrospectively. For the 12 17q21 SNPs studied, the odds ratios (OR) for association between infection and early-onset asthma (age at onset ≤4 yrs) were higher in carriers of risk genotypes (OR 3.42–6.36) than in noncarriers (OR 1.84–2.44; p-value for interaction 0.02–0.04 for five SNPs). Risk genotypes also increased the association between infection and childhood asthma that remits in adulthood (OR 4.84–7.16 in carriers and 1.74–2.25 in noncarriers; p-value for interaction 0.008–0.05 for 10 SNPs). In children with 17q21 risk genotypes and early-life environmental tobacco smoke (ETS) exposure, associations between infection and asthma were further enhanced. 17q21 genetic variants and early ETS exposure enhance the association between early respiratory infections and early-onset asthma and childhood asthma that remits in adulthood.

Transient receptor potential genes, smoking, occupational exposures and cough in adults

BackgroundTransient receptor potential (TRP) vanilloid and ankyrin cation channels are activated by various noxious chemicals and may play an important role in the pathogenesis of cough. The aim was to study the influence of single nucleotide polymorphisms (SNPs) in TRP genes and irritant exposures on cough.MethodsNocturnal, usual, and chronic cough, smoking, and job history were obtained by questionnaire in 844 asthmatic and 2046 non-asthmatic adults from the Epidemiological study on the Genetics and Environment of Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Occupational exposures to vapors, gases, dusts, and/or fumes were assessed by a job-exposure matrix. Fifty-eight tagging SNPs in TRPV1, TRPV4, and TRPA1 were tested under an additive model.ResultsStatistically significant associations of 6 TRPV1 SNPs with cough symptoms were found in non-asthmatics after correction for multiple comparisons. Results were consistent across the eight countries examined. Haplotype-based association analysis confirmed the single SNP analyses for nocturnal cough (7-SNP haplotype: p-global = 4.8 × 10-6) and usual cough (9-SNP haplotype: p-global = 4.5 × 10-6). Cough symptoms were associated with exposure to irritants such as cigarette smoke and occupational exposures (p < 0.05). Four polymorphisms in TRPV1 further increased the risk of cough symptoms from irritant exposures in asthmatics and non-asthmatics (interaction p < 0.05).ConclusionsTRPV1 SNPs were associated with cough among subjects without asthma from two independent studies in eight European countries. TRPV1 SNPs may enhance susceptibility to cough in current smokers and in subjects with a history of workplace exposures.

Occupational Endotoxin Exposure Reduces the Risk of Atopic Sensitization but Increases the Risk of Bronchial Hyperresponsiveness

Background: Microbial exposures in both childhood and adult life are protective against atopy, allergic rhinitis and atopic asthma. In adults, this protective effect is paralleled by an increased prevalence of non-atopic asthma. This study was undertaken to investigate associations between occupational endotoxin exposure and atopic sensitization and bronchial hyperresponsiveness to methacholine (BHR) in agricultural workers. In addition, the role of atopy in endotoxin-related respiratory effects was studied. Methods: Data were available for 427 farmers and agricultural industry workers, for whom airborne endotoxin exposure levels were estimated by 249 personal exposure measurements. Atopy was assessed as specific serum IgE to common inhalant allergens, and respiratory symptoms and personal characteristics by standardized questionnaires. BHR was determined in a subset of 113 subjects. Associations were adjusted for age, sex, smoking and living on a farm during childhood. Results: Endotoxin exposure was positively associated with BHR and wheeze (p < 0.05). In contrast, endotoxin exposure was inversely associated with atopy and IgE to grass pollen (p < 0.001). The proportions of wheeze and BHR that were attributable to atopy were only 16.6 and 32.8%, respectively. Conclusions: High endotoxin exposure is a risk factor for BHR and wheeze, which were characterized by a predominantly non-atopic phenotype. At the same time, endotoxin exposure is related to a reduced risk of atopy and IgE to grass pollen in adults. It is unlikely that this is entirely a result of healthy worker selection, as significant inverse associations between endotoxin and IgE to grass pollen were found regardless of reported allergic symptoms.

Q Fever and Pneumonia in an Area with a High Livestock Density: A Large Population-Based Study

Concerns about public health risks of intensive animal production in the Netherlands continue to rise, in particular related to outbreaks of infectious diseases. The aim was to investigate associations between the presence of farm animals around the home address and Q fever and pneumonia. Electronic medical record data for the year 2009 of all patients of 27 general practitioners (GPs) in a region with a high density of animal farms were used. Density of farm animals around the home address was calculated using a Geographic Information System. During the study period, a large Q fever outbreak occurred in this region. Associations between farm exposure variables and pneumonia or ‘other infectious disease’, the diagnosis code used by GPs for registration of Q fever, were analyzed in 22,406 children (0–17 y) and 70,142 adults (18–70 y), and adjusted for age and sex. In adults, clear exposure-response relationships between the number of goats within 5 km of the home address and pneumonia and ‘other infectious disease’ were observed. The association with ‘other infectious disease’ was particularly strong, with an OR [95%CI] of 12.03 [8.79–16.46] for the fourth quartile (>17,190 goats) compared with the first quartile (<2,251 goats). The presence of poultry within 1 km was associated with an increased incidence of pneumonia among adults (OR [95%CI] 1.25 [1.06–1.47]). A high density of goats in a densely populated region was associated with human Q fever. The use of GP records combined with individual exposure estimates using a Geographic Information System is a powerful approach to assess environmental health risks.

Sensitisation to common allergens and respiratory symptoms in endotoxin exposed workers: a pooled analysis

Objective To test the hypotheses that current endotoxin exposure is inversely associated with allergic sensitisation and positively associated with non-allergic respiratory diseases in four occupationally exposed populations using a standardised analytical approach. Methods Data were pooled from four epidemiological studies including 3883 Dutch and Danish employees in veterinary medicine, agriculture and power plants using biofuel. Endotoxin exposure was estimated by quantitative job-exposure matrices specific for the study populations. Dose–response relationships between exposure, IgE-mediated sensitisation to common allergens and self-reported health symptoms were assessed using logistic regression and generalised additive modelling. Adjustments were made for study, age, sex, atopic predisposition, smoking habit and farm childhood. Heterogeneity was assessed by analysis stratified by study. Results Current endotoxin exposure was dose-dependently associated with a reduced prevalence of allergic sensitisation (ORs of 0.92, 0.81 and 0.66 for low mediate, high mediate and high exposure) and hay fever (ORs of 1.16, 0.81 and 0.58). Endotoxin exposure was a risk factor for organic dust toxic syndrome, and levels above 100 EU/m3 significantly increased the risk of chronic bronchitis (p<0.0001). Stratification by farm childhood showed no effect modification except for allergic sensitisation. Only among workers without a farm childhood, endotoxin exposure was inversely associated with allergic sensitisation. Heterogeneity was primarily present for biofuel workers. Conclusions Occupational endotoxin exposure has a protective effect on allergic sensitisation and hay fever but increases the risk for organic dust toxic syndrome and chronic bronchitis. Endotoxins protective effects are most clearly observed among agricultural workers.

Agricultural seed dust as a potential cause of organic dust toxic syndrome.

Aims: Episodes of serious work related health problems resembling organic dust toxic syndrome (ODTS) in workers of a grass seed quality inspection laboratory prompted the authors to study personal endotoxin exposure levels in this facility and in the agricultural seed processing industry. In addition, microbial and inflammatory characteristics of agricultural seeds were studied. Methods: The authors assessed inhalable dust and endotoxin levels in 101 samples from 57 workers in grass, cereal, and vegetable seed plants who were handling mainly grass seeds as bulk product, and horticulture seeds in smaller quantities. Additionally, real-time dust exposure was measured using a DataRAM monitor in 12 grass seed workers to obtain more information on exposure patterns during specific tasks. Endotoxin concentrations in seed extracts were determined by LAL assay and seed samples were analysed by scanning electron microscopy. Release of inflammatory cytokines was measured in supernatants of whole blood samples stimulated with lipopolysaccharide (LPS) or agricultural seed extracts in a human whole blood assay (WBA). Results: Endotoxin concentrations in personal samples were high (geometric mean 1800 EU/m3), particularly in the grass seed quality inspection lab where endotoxin levels up to 274 000 EU/m3 were measured. The recommended health based endotoxin exposure limit of 50 EU/m3 was amply exceeded in almost all personal samples. Job tasks dumping and mixing were associated with highest dust and endotoxin exposures, which was confirmed by real-time measurements. Microbial infestation was found in almost all seed samples. WBA results showed that most seed extracts were capable of inducing a pronounced dose dependent cytokine release. Conclusions: Workers handling grass, cereal, or vegetable seeds are at risk of exposure to high levels of endotoxin containing seed dust. Occupational exposure to inhalable agricultural seed dust can induce inflammatory responses, and is a potential cause of ODTS.