Personal exposure assessment of pesticides in residents: The association between hand wipes and urinary biomarkers.

BACKGROUND: Residential exposure to pesticides may occur via inhalation of airborne pesticides, direct skin contacts with pesticide-contaminated surfaces, and consumption of food containing pesticide residues. The aim was to study the association of dermal exposure to pesticides between the use and non-use periods, between farmer and non-farmer families and between dermal exposure and the excretion of metabolites from urine in residents living close to treated agricultural fields. METHODS: In total, 112 hand wipes and 206 spot urine samples were collected from 16 farmer and 38 non-farmer participants living within 50 m from an agricultural field in the Netherlands. The study took place from May 2016 to December 2017 during the use as well as the non-use periods of pesticides. Hand wipes were analysed for the parent compound and urines samples for the corresponding urinary metabolite of five applied pesticides: asulam, carbendazim (applied as thiophanate-methyl), chlorpropham, prochloraz and tebuconazole. Questionnaire data was used to study potential determinants of occurrence and levels of pesticides in hand wipes according to univariate and multivariate analysis. RESULTS: Carbendazim and tebuconazole concentrations in hand wipes were statistically significantly higher in the pesticide-use period compared to the non-use period. In addition, especially during the use periods, concentrations were statistically significantly higher in farmer families compared to non-farmer families. For asulam, chlorpropham and prochloraz, the frequency of non-detects was too high (57-85%) to be included in this analysis. The carbendazim contents in urine samples and hand wipes were correlated on the first and second day after taking the hand wipe, whereas chlorpropham was only observed to be related on the second day following the spray event. CONCLUSIONS: Concentrations in hand wipes were overall higher in pesticide use periods compared to non-use periods and higher in farmer families compared to non-farmer families. Only for carbendazim a strong correlation between concentrations in hand wipes and its main metabolite in urine was observed, indicating dermal exposure via contaminated indoor surfaces. We expect this to be related to the lower vapour pressure and longer environmental lifetime of carbendazim compared to the other pesticides studies.

Clinical relevance of Scedosporium spp. and Exophiala dermatitidis in patients with cystic fibrosis: A nationwide study.

An increased prevalence of various filamentous fungi in sputum samples of patients with cystic fibrosis (CF) has been reported. The clinical significance, however, is mostly unclear. The aim of this study was to investigate the clinical relevance of Scedosporium spp. and Exophiala dermatitidis from sputum samples of patients with CF in the Netherlands. In this cross-sectional study, all CF patients of the Dutch national CF registry who were treated at five of the seven recognized CF centers during a 3-year period were included. We linked clinical data of the national CF registry with the national Dutch filamentous fungal database. We investigated the association between clinical characteristics and a positive sputum sample for Scedosporium spp. and E. dermatitidis, using logistic regression. Positive cultures for fungi were obtained from 3787 sputum samples from 699 of the 1312 patients with CF. Scedosporium spp. was associated with severe genotype, CF-related diabetes, several microorganisms, and inhaled antibiotics. E. dermatitidis was associated with older age, female sex, and Aspergillus spp. CF patients with and without Scedosporium spp. or E. dermatitidis seemed comparable in body mass index and lung function. This study suggests that Scedosporium spp. and E. dermatitidis are probably no major pathogens in CF patients in the Netherlands. Greater understanding of epidemiologic trends, risk factors, and pathogenicity of filamentous fungi in the respiratory tracts of patients with CF is needed.

Toxicokinetics of a urinary metabolite of tebuconazole following controlled oral and dermal administration in human volunteers.

Tebuconazole (TEB) is a widely used triazole fungicide, but the toxicokinetics of its human metabolites are not fully described. For proper interpretation of biological monitoring data, knowledge on the metabolism and elimination of the compound is required. A human volunteer study was performed with the aim to describe the time courses of urinary excretion after controlled oral and dermal administration of TEB. Six healthy volunteers (three males and three females) received on separate occasions a single oral dose of 1.5 mg of TEB and a single dermal dose of 2.5 mg during 1 h. In addition to a pre-exposure urine sample, complete urine voids were collected over 48 h post-administration. The main metabolite hydroxy-tebuconazole (TEB-OH) was quantified in each urine sample. Peak excretion rates after oral and dermal administration were reached after 1.4 and 21 h, mean elimination half-lives were 7.8 and 16 h, and recoveries within 48 h were 38% and 1%, respectively. The time courses of excretion were compared to simulations with an established physiologically based toxicokinetic model for TEB that was extended with a parallel model for TEB-OH. Overall, TEB-OH was rapidly excreted into urine after oral exposure, and renal elimination was considerably slower after dermal exposure. Urinary time courses between individuals were similar. The model predictions were in good agreement with the observed time courses of excretion.

Knowledge and awareness of health effects related to the use of mercury in artisanal and small-scale gold mining in Suriname.

BACKGROUND: The use of mercury in artisanal and small-scale gold mining has negative effects on human health and the environment. In Suriname, the current gold rush resulted in estimated mercury emissions up to 63t per year. To reduce the use of mercury and the subsequent health impact to gold miners and local inhabitants, knowledge and awareness in the community should be increased. METHODS: This study evaluated the effects of a health education programme (HEP) on the levels of knowledge and awareness among local inhabitants and small-scale gold miners in active gold mining areas in the interior of Suriname, South-America. Baseline knowledge levels were assessed with a survey prior to the implementation of the HEP. Thereafter, the exact same questions were asked to evaluate the effects. A total of 959 local inhabitants and 140 gold miners completed the survey including five topics: general knowledge on mercury, potential routes of exposure, health risks for children versus adults, mercury related health effects, and reproductive risks. Additionally, participants were asked in a separate survey (n = 107) about potential exposure reduction techniques and their willingness to be involved in a future human biomonitoring programme. RESULTS: The HEP influenced knowledge on exposure routes of mercury (increase from 64% to 78% of respondents who could name the relevant exposure routes) and on health effects attributed to mercury (increase from 48% to 70% of respondents who were able to list the correct health effects). After the HEP, 70% of the respondents affirmed the higher sensitivity of children, while knowledge on reproductive health effects increased from 39% to 63%. Self-estimated levels of knowledge also increased, indicating lower anxiety regarding potential risks of mercury. Gold miners reported to be willing to improve their work procedures (e.g. burning amalgam with a retort), although suitable tools were not always available. Consistent results were found for individuals included in both surveys, before and after the health education programme. Almost all respondents in the separate survey reported to be willing to give consent for participation in a future human biomonitoring programme, for themselves and their children. CONCLUSION: The implementation of a health education programme within an existing local healthcare structure proved effective and levels of knowledge and awareness improved. Most improved was the knowledge on health effects attributable to mercury, more specifically reproductive health effects.

Gonadal function in adult male patients with congenital adrenal hyperplasia.

CONTEXT: Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly limited to single-center/country studies enrolling small patient numbers. Overall data indicate that gonadal function can be compromised in men with CAH. OBJECTIVE: To determine gonadal function in men with CAH within the European 'dsd-LIFE' cohort. DESIGN: Cross-sectional clinical outcome study, including retrospective data from medical records. METHODS: Fourteen academic hospitals included 121 men with CAH aged 16-68 years. Main outcome measures were serum hormone concentrations, semen parameters and imaging data of the testes. RESULTS: At the time of assessment, 14/69 patients had a serum testosterone concentration below the reference range; 7 of those were hypogonadotropic, 6 normogonadotropic and 1 hypergonadotropic. In contrast, among the patients with normal serum testosterone (55/69), 4 were hypogonadotropic, 44 normogonadotropic and 7 hypergonadotropic. The association of decreased testosterone with reduced gonadotropin concentrations (odds ratio (OR) = 12.8 (2.9-57.3)) was weaker than the association between serum androstenedione/testosterone ratio ≥1 and reduced gonadotropin concentrations (OR = 39.3 (2.1-732.4)). Evaluation of sperm quality revealed decreased sperm concentrations (15/39), motility (13/37) and abnormal morphology (4/28). Testicular adrenal rest tumor (TART)s were present in 39/80 patients, with a higher prevalence in patients with the most severe genotype (14/18) and in patients with increased current 17-hydroxyprogesterone 20/35) or androstenedione (12/18) serum concentrations. Forty-three children were fathered by 26/113 patients. CONCLUSIONS: Men with CAH have a high risk of developing hypothalamic-pituitary-gonadal disturbances and spermatogenic abnormalities. Regular assessment of endocrine gonadal function and imaging for TART development are recommended, in addition to measures for fertility protection.

REducing STEroids in Relapsing Nephrotic syndrome: the RESTERN study- protocol of a national, double-blind, randomised, placebo-controlled, non-inferiority intervention study.

INTRODUCTION: Oral corticosteroids are the first-line treatment for idiopathic childhood nephrotic syndrome. Most children experience several relapses, needing repeated courses of corticosteroid therapy. This exposes them to side effects and long-term complications. For most patients, long-term prognosis is for complete resolution of the disease over time and maintenance of normal kidney function. Therefore, it is vital to focus on minimising adverse events of the disease and its therapy. Unfortunately, no randomised controlled trials are available to determine the optimal corticosteroid treatment of an infrequent relapse of nephrotic syndrome. Recent studies show that treatment schedules for the first episode can safely be shortened to 2 months. The hypothesis of the REducing STEroids in Relapsing Nephrotic syndrome (RESTERN) study is that a 4-week reduction of alternate-day steroids after inducing remission is effective and safe, reduces steroid exposure by 35% on average and is therefore preferable. METHODS AND ANALYSIS: The RESTERN study is a nationwide, double-blind, randomised, placebo-controlled, non-inferiority intervention study. Children aged 1-18 years with a relapse of steroid-sensitive nephrotic syndrome are eligible for this study. Study subjects (n=144) will be randomly assigned to either current standard therapy in the Netherlands or a reduced prednisolone schedule. The primary outcome of the RESTERN study is the time to first relapse after the final prednisolone dose. The secondary outcomes are the number or relapses, progression to frequent relapsing or steroid dependent nephrotic syndrome and the cumulative dosage of prednisolone during the study period. ETHICS AND DISSEMINATION: This non-inferiority trial will be performed in accordance with the Declaration of Helsinki and has been approved by the medical ethical committee of Arnhem-Nijmegen and the Dutch Competent Authority (Central Committee on Research Involving Human Subjects, CCMO). After completion of this study, results will be published in national and international peer-reviewed scientific journals. Papers will be published according to CCMO guidelines. The final report will be made available to trial participants. TRIAL REGISTRATION NUMBER: NTR5670, EudraCT no 2016-002430-76.

Eculizumab Dosing Regimen in Atypical HUS: Possibilities for Individualized Treatment.

Recent studies indicate that eculizumab is often given in excess to atypical hemolytic uremic syndrome (aHUS) patients. Individualization of treatment is thus highly requested; however, data on the pharmacokinetics and pharmacodynamics of eculizumab remain limited. We analyzed 11 patients during induction (weekly), maintenance (2-weekly), and tapering (every 3-8 weeks) phases of treatment. The trough eculizumab levels increased with each additional dose during the induction phase (depending on body weight). During maintenance, high eculizumab concentrations of up to 772 µg/mL were observed. The levels decreased with each following dose during tapering (3- and 4-week intervals); however, three patients maintained target eculizumab levels over long time periods (30-48 weeks). At intervals of 6-8 weeks, target eculizumab levels were no longer attained. Serum samples with eculizumab concentrations ≥50 µg/mL showed adequate complement blockade. Our data provide essential insight for optimization of eculizumab dosing schemes and lessening of therapy burden for the patients and cost of the treatment.

Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline.

Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers of such a mutation have an increased risk of breast cancer. Other health risks for carriers are suspected but have never been studied systematically. Consequently, evidence-based guidelines for carriers are not available yet. We systematically analyzed all literature and found that ATM mutation carriers have a reduced life expectancy because of mortality from cancer and ischemic heart diseases (RR 1.7, 95% CI 1.2-2.4) and an increased risk of developing cancer (RR 1.5, 95% CI 0.9-2.4), in particular breast cancer (RRwomen 3.0, 95% CI 2.1-4.5), and cancers of the digestive tract. Associations between ATM heterozygosity and other health risks have been suggested, but clear evidence is lacking. Based on these results, we propose that all female carriers of 40-50 years of age and female ATM c.7271T>G mutation carriers from 25 years of age onwards be offered intensified surveillance programs for breast cancer. Furthermore, all carriers should be made aware of lifestyle factors that contribute to the development of cardiovascular diseases and diabetes.

Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection.

BACKGROUND: Respiratory viral infections follow an unpredictable clinical course in young children ranging from a common cold to respiratory failure. The transition from mild to severe disease occurs rapidly and is difficult to predict. The pathophysiology underlying disease severity has remained elusive. There is an urgent need to better understand the immune response in this disease to come up with biomarkers that may aid clinical decision making. METHODS: In a prospective study, flow cytometric and genome-wide gene expression analyses were performed on blood samples of 26 children with a diagnosis of severe, moderate or mild Respiratory Syncytial Virus (RSV) infection. Differentially expressed genes were validated using Q-PCR in a second cohort of 80 children during three consecutive winter seasons. FACS analyses were also performed in the second cohort and on recovery samples of severe cases in the first cohort. RESULTS: Severe RSV infection was associated with a transient but marked decrease in CD4+ T, CD8+ T, and NK cells in peripheral blood. Gene expression analyses in both cohorts identified Olfactomedin4 (OLFM4) as a fully discriminative marker between children with mild and severe RSV infection, giving a PAM cross-validation error of 0%. Patients with an OLFM4 gene expression level above -7.5 were 6 times more likely to develop severe disease, after correction for age at hospitalization and gestational age. CONCLUSION: By combining genome-wide expression profiling of blood cell subsets with clinically well-annotated samples, OLFM4 was identified as a biomarker for severity of pediatric RSV infection.

Maternal hypertensive disorders, antihypertensive medication use, and the risk of birth defects: a case-control study.

OBJECTIVE: To study previously identified associations between specific maternal hypertensive disorders and/or prenatal exposure to antihypertensive medication and birth defects. DESIGN: Case-control study. SETTING: Slone Birth Defects Study, 1998-2010. POPULATION: A total of 5568 cases with birth defects and 7253 liveborn infants without malformations as controls. METHODS: Adjusted odds ratios (aORs) for birth defects associated with prenatal exposure to maternal hypertensive disorders and/or antihypertensive medication were calculated using multivariable logistic regression analyses. MAIN OUTCOME MEASURES: Specific birth defects previously linked to maternal hypertension or antihypertensive medication use during pregnancy. RESULTS: Non-pharmacologically managed chronic hypertension was associated with a three-fold risk of oesophageal atresia (95% CI 1.2-8.3), and pre-eclampsia superimposed on non-pharmacologically managed chronic hypertension was associated with ventricular septal defects (aOR 3.9, 95% CI 1.3-11.7) and atrial septal defects (aOR 6.5, 95% CI 1.8-23.7). For chronic hypertension that was pharmacologically treated early in pregnancy, increased risks were observed for first-degree hypospadias (aOR 2.9, 95% CI 1.1-7.4). Non-pharmacologically managed pre-eclampsia was related to second-/third-degree hypospadias and ventricular septal defects. Pharmacological treatment for gestational hypertension was associated with a number of congenital heart defects. CONCLUSIONS: Our results confirm some, but not all, previously identified associations between pharmacologically treated and non-pharmacologically managed hypertensive disorders and specific birth defects. They support the hypothesis that physiological changes early in pregnancy that manifest in gestational hypertension and pre-eclampsia may play a role in the aetiology of major birth defects, including congenital heart defects and hypospadias.

Anorectal malformations and pregnancy-related disorders: a registry-based case-control study in 17 European regions.

OBJECTIVE: To identify pregnancy-related risk factors for different manifestations of congenital anorectal malformations (ARMs). DESIGN: A population-based case-control study. SETTING: Seventeen EUROCAT (European Surveillance of Congenital Anomalies) registries, 1980-2008. POPULATION: The study population consisted of 1417 cases with ARM, including 648 cases of isolated ARM, 601 cases of ARM with additional congenital anomalies, and 168 cases of ARM-VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects), along with 13 371 controls with recognised syndromes or chromosomal abnormalities. METHODS: Multiple logistic regression analyses were used to calculate adjusted odds ratios (ORs) for potential risk factors for ARM, such as fertility treatment, multiple pregnancy, primiparity, maternal illnesses during pregnancy, and pregnancy-related complications. MAIN OUTCOME MEASURES: Adjusted ORs for pregnancy-related risk factors for ARM. RESULTS: The ARM cases were more likely to be firstborn than the controls (OR 1.6, 95% CI 1.4-1.8). Fertility treatment and being one of twins or triplets seemed to increase the risk of ARM in cases with additional congenital anomalies or VACTERL (ORs ranging from 1.6 to 2.5). Maternal fever during pregnancy and pre-eclampsia were only associated with ARM when additional congenital anomalies were present (OR 3.9, 95% CI 1.3-11.6; OR 3.4, 95% CI 1.6-7.1, respectively), whereas maternal epilepsy during pregnancy resulted in a five-fold elevated risk of all manifestations of ARM (OR 5.1, 95% CI 1.7-15.6). CONCLUSIONS: This large European study identified maternal epilepsy, fertility treatment, multiple pregnancy, primiparity, pre-eclampsia, and maternal fever during pregnancy as potential risk factors primarily for complex manifestations of ARM with additional congenital anomalies and VACTERL.

Aetiology of hypospadias: a systematic review of genes and environment.

BACKGROUND: Hypospadias is a common congenital malformation of the male external genitalia. Most cases have an unknown aetiology, which is probably a mix of monogenic and multifactorial forms, implicating both genes and environmental factors. This review summarizes current knowledge about the aetiology of hypospadias. METHODS: Pubmed was used to identify studies on hypospadias aetiology published between January 1995 and February 2011. Reference lists of the selected manuscripts were also searched to identify additional studies, including those published before 1995. RESULTS: The search provided 922 articles and 169 articles were selected for this review. Studies screening groups of patients with hypospadias for single gene defects found mutations in WT1, SF1, BMP4, BMP7, HOXA4, HOXB6, FGF8, FGFR2, AR, HSD3B2, SRD5A2, ATF3, MAMLD1, MID1 and BNC2. However, most investigators are convinced that single mutations do not cause the majority of isolated hypospadias cases. Indeed, associations were found with polymorphisms in FGF8, FGFR2, AR, HSD17B3, SRD5A2, ESR1, ESR2, ATF3, MAMLD1, DGKK, MID1, CYP1A1, GSTM1 and GSTT1. In addition, gene expression studies indentified CTGF, CYR61 and EGF as candidate genes. Environmental factors consistently implicated in hypospadias are low birthweight, maternal hypertension and pre-eclampsia, suggesting that placental insufficiency may play an important role in hypospadias aetiology. Exogenous endocrine-disrupting chemicals have the potential to induce hypospadias but it is unclear whether human exposure is high enough to exert this effect. Other environmental factors have also been associated with hypospadias but, for most, the results are inconsistent. CONCLUSIONS: Although a number of contributors to the aetiology of hypospadias have been identified, the majority of risk factors remain unknown.

Early infantile electroencephalography in patients with spina bifida*.

OBJECTIVE: The aim of this prospective study was to assess the prognostic value of electroencephalography in infants born with spina bifida.31 infants with spina bifida born between 2002 and 2007 at the Radboud Nijmegen University Medical Centre were evaluated and followed for 2½ years. Electroencephalography (EEG) was performed during the first 8 weeks after birth. RESULTS: EEG recordings were all within normal limits and showed no abnormalities. 3 of the 31 children showed mild mental disability and major physical disabilities at the age of 30 months. CONCLUSION: Single Infantile EEG recordings are of limited prognostic value for infants born with spina bifida. Serial EEG recordings in combination with other clinical or neurophysiological investigations might ameliorate the contributing predictive value of neonatal EEG.

Occupational exposure to potential endocrine disruptors: further development of a job exposure matrix.

OBJECTIVES: The aim was to develop a new up-to-date and comprehensive job exposure matrix (JEM) for estimating exposure to potential endocrine disruptors in epidemiological research. METHODS: Chemicals with endocrine disrupting properties were identified from the literature and classified into 10 chemical groups: polycyclic aromatic hydrocarbons (PAHs), polychlorinated organic compounds, pesticides, phthalates, organic solvents, bisphenol A, alkylphenolic compounds, brominated flame retardants, metals and a miscellaneous group. Most chemical groups were divided into three to six subgroups. Focusing on the years 1996-2006, three experts scored the probability of exposure to each chemical group and subgroup for 353 job titles as "unlikely" (0), "possible" (1) or "probable" (2). Job titles with positive exposure probability scores were provided with exposure scenarios that described the reasoning behind the scores. RESULTS: Exposure to any chemical group was unlikely for 238 job titles (67%), whereas 102 (29%) job titles were classified as possibly (17%) or probably (12%) exposed to one or several endocrine disruptors. The remaining 13 job titles provided too little information to classify exposure. PAHs, pesticides, phthalates, organic solvents, alkylphenolic compounds and metals were often linked to a job title in the JEM. The remaining chemical groups were found to involve very few occupations. CONCLUSIONS: Despite some important limitations, this JEM could be a valuable tool for exposure assessment in studies on the health risks of endocrine disruptors, especially when task specific information is incorporated. The documented exposure scenarios are meant to facilitate further adjustments to the JEM to allow more widespread use.

Time-to-pregnancy among male greenhouse workers.

OBJECTIVES: Fertility problems are an increasing public health issue in industrialised countries. Exposure to exogenous agents with endocrine disrupting properties, such as some pesticides, are potential risk factors for subfertility. The aim of this study was to determine whether time-to-pregnancy (TTP) is prolonged in male greenhouse workers exposed to pesticides in comparison with a non-exposed reference group. METHODS: Data were collected through self-administrated questionnaires with detailed questions on TTP, as well as on lifestyle (for example, smoking habits, coffee and alcohol consumption), work tasks, and occupational exposures of the men and their partners in the six months before conception of the most recent pregnancy. TTP was compared between male greenhouse workers (n = 694) and a non-exposed reference group (n = 613) by means of discrete proportional hazards regression analysis. RESULTS: The crude analyses did not show a decreased overall fecundability among greenhouse workers compared to the non-exposed reference group. However, when fecundability was assessed for primigravidous couples, duogravidous couples, and multigravidous couples separately, greenhouse workers were found to be less fecund when trying to conceive their first pregnancy (FR = 0.65; 95% CI 0.46 to 0.92), which is also the most valid analysis in which pregnancy planning issues were avoided. Among couples who already experienced one or more pregnancies, no association was seen between pesticide exposure and TTP after adjustment for confounders. CONCLUSION: A prolonged time-to-pregnancy was observed in male greenhouse workers exposed to pesticides before conception of their first pregnancy.

Month of birth related to fecundity and childlessness among contemporary women.

To determine the associations of fecundity and childlessness with month of conception and to find a causal mechanism for these associations, we reanalyzed some of our previous data according to the predictions of the seasonal optimal ripening oocyte (SOptRO) and seasonal preovulatory over-ripeness ovopathy (SPrOO) hypotheses. Prime and minor SOptRO months as well as high-risk, no-risk, and very high risk SPrOO months were defined on the basis of a priori knowledge of the existence of ovulatory and anovulatory seasons in mammals and of the general birth distribution in Europe. The month of birth was assessed among 899 mothers with three or more children and 388 childless women extracted from a 1% sample of the Austrian population. The women with three or more children were born in excess during the prime and less often during the minor SOptRO months (chi2 = 2.81; p = 0.045; relative risk = 1.16; 95% CI = 1.01-1.33). This is in line with the SOptRO predictions. The childless women were more frequently born during the high-risk SPrOO months compared to the no-risk months but less often during the very high risk months. The linear trend (chi2 = 8.43; p = 0.009) is in line with the SPrOO predictions. We suggest that fecundity and childlessness are dependent on the gradient of oocyte maturation reflected by mother's month of birth, which may modulate future constitution.

[Improvement of public health in London in the nineteenth century and the probably limited role of the new sewage system]. / Verbetering van de volksgezondheid in Londen in de negentiende eeuw en de waarschijnlijk beperkte rol van het nieuwe rioolstelsel daarin.

--London was one of the most rapidly expanding cities in the world in the nineteenth century, but the water supply and sanitary conditions were extremely poor. --In the nineteenth century, there were many theories regarding the causes and spread of epidemic diseases. The miasma theory, which postulated that disease was the result of bad air and odours, was the most popular. --In 1858, as a result of the foul smells from the Thames, the decision was made to improve the sewage system. The new system was first used in 1865, but its actual effect on public health is not clear. --The life expectancy of Londoners did not change in the period 1826-1871, but increased substantially thereafter. In view of this time window, this may have been a result of improvements in the sewage system. --However, it is likely that several other factors, such as improvements in the food and water supply, vaccination programmes, and natural circumstances, were responsible for a large part of this increase.

Adverse reproductive outcomes among male painters with occupational exposure to organic solvents.

OBJECTIVES: To assess the risks of reproductive disorders and birth defects in offspring of male painters with exposure to organic solvents, and to determine the shape of the dose-response relationship. METHODS: Random samples of painters and carpenters were drawn from workers affiliated with the Dutch Trade Union for Construction Workers, the Netherlands, 2001. Information on reproductive outcomes, occupational exposures, and lifestyle habits was retrospectively obtained through self-administered questionnaires filled in by 398 painters exposed to organic solvents in paints, thinners, and cleansers in the period of three months before the last pregnancy, and 302 carpenters with little or no exposure to solvents. A statistical model was used to estimate quantitative exposure measures. RESULTS: Workers employed as painters at three months before pregnancy had an increased risk (odds ratio 6.2, 95% CI 1.4 to 27.9) of congenital malformations in offspring compared to carpenters. There was a positive exposure-response trend with increasing exposure to organic solvents based on quantitative model predicted exposure estimates using toluene as a marker. There was some indication of an increased risk of functional developmental disorders in offspring among painters with intermediate and high model predicted exposure. The risk of low birth weight children seemed to be slightly increased among painters as well. Results for other reproductive outcomes (time to pregnancy, spontaneous abortion, and preterm birth) did not show increased risks. CONCLUSION: This study showed a positive association between paternal occupational exposure to organic solvents and congenital malformations in offspring. However, the small numbers of cases, especially when examining different exposure levels, as well as the self-reported nature of exposure and outcome variables, may hamper interpretation of the results.

Hypospadias: a transgenerational effect of diethylstilbestrol?

BACKGROUND: In 2002, an increased risk of hypospadias was reported for sons of women exposed to diethylstilbestrol (DES) in utero, suggesting transgenerational effects of DES. The aim of this study was to further assess the association between parental DES exposure and hypospadias in a case-referent study. METHODS: Cases with hypospadias were retrieved from the hospital information system. Referents were recruited via the parents of cases. Both parents completed postal questionnaires. Associations were estimated by odds ratios (OR) with 95% confidence intervals (CI). Additionally, conditional logistic regression analyses were performed for a matched subset of parents. RESULTS: The final database included 583 cases and 251 referents. In the initial analyses, an indication was found for an increased risk of hypospadias when mothers were exposed to DES in utero: OR=2.3 (95% CI 0.7-7.9). Conditional logistic regression resulted in a stronger risk estimate: OR=4.9 (95% CI 1.1-22.3). Paternal exposure to DES did not increase the risk. CONCLUSIONS: The results confirm an increased risk of hypospadias when mothers were exposed to DES in utero. However, the excess risk appears to be of much smaller magnitude than in the 2002 study. Further research on the potential health risks for the third generation is of great importance.

Time To Pregnancy and occupational lead exposure.

BACKGROUND: Lead exposure is known to be harmful to the male reproductive system, including impairment of fertility. However, it is unclear whether currently existing low levels of exposure have this effect. AIMS: To study retrospectively current workers in lead using industries (battery manufacture, smelting, etc), and in non-lead using control industries, in four European countries, with Time To Pregnancy as the outcome variable, as part of the EU funded Asclepios Project. METHODS: Exposure assessment was mainly by blood lead values, which were available from the late 1970s, supplemented by imputed values where necessary. Three exposure models were studied: (1) short term (recent) exposure; (2) total duration of work in a lead using industry; and (3) cumulative exposure. A Cox proportional hazards model with discrete ties was used for the statistical analysis, with covariates for both partners. RESULTS: A total of 1104 subjects took part, of whom 638 were occupationally exposed to lead at the relevant time. Blood lead levels were mainly less than 50 microg/dl. No consistent association of Time To Pregnancy with lead exposure was found in any of the exposure models, although reduced fertility was observed in one category each in models (2) and (3). CONCLUSIONS: This basically negative result is unlikely to be due to the misclassification of key variables, to insufficient statistical power, or to bias, for example, response bias. If any impairment of male reproductive function exists at the levels of occupational lead exposure now current, it does not appear to reduce biological fertility.