Endocrine Disruptors in the Workplace, Hair Spray, Folate Supplementation, and Risk of Hypospadias: Case-Control Study

Gillian Ormond; Mark J. Nieuwenhuijsen; Paul Nelson; Mireille B. Toledano; Nina Iszatt; Sara Geneletti; Paul Elliott


Environ Health Perspect. 2009;117(2):303-307. 

In This Article

Data and Methods

The study region included the health regions of North Thames, South Thames, and the Anglian part of Anglia and Oxford (Figure 1), comprising 120 London boroughs and local authority districts. Surgical centers in the study region and major surgical centers within 50 miles were visited. Hypospadias cases born in the study region over a 21-month period (1 January 1997-30 September 1998) were eligible if there was an abnormally positioned urethral orifice requiring surgery, with no major accompanying anomaly suggesting that it was part of a syndrome. Forty of 41 surgeons operating on hypospadias in the study region participated; 731 cases were identified from surgeons' records and case notes. After initial contact by letter, up to two further invitations were sent. Of the 731 mothers, 610 replied, of whom 471 (77%; 64% of total eligible cases) agreed to participate.

Figure 1.

The study area and major National Health Service (NHS) hospitals operating on hypospadias in the southeast of England.

Controls born in the study region during the same period as the cases were randomly selected from the birth registry by the Office for National Statistics (ONS; London, UK). Ethical approval was given by the West Midlands Multi-centre Research Ethics Committee, Birmingham, United Kingdom. Following guidelines from the ethics committee, ONS asked the health authorities (now primary care trusts) to contact the general practitioners (GPs) of the control children. The GPs were then asked to pass on the invitation to the mother of the control child; in turn, the mothers were asked to contact the study team. In total, 1,568 control mothers were selected, but letters were not sent out to 81 mothers. From the possible 1,487 invitees, there were 758 replies, of whom 490 (65%; 33% of total eligible controls) agreed to take part. We attempted to contact a sample (n = 200) of the 729 mothers who had not replied and found that 144 (72%) had not received an invitation, mainly because the GP had not passed on the information (73%); the family had moved without a forwarding address (9·5%); or for other reasons. The cases and control mothers who agreed to participate were interviewed by telephone between September 2000 and March 2003.

Case and control mothers were interviewed by telephone using a standard set of questions, with answers directly entered into a computer. The questionnaire included information on parental age, ethnicity, education, household income; family history of disease; pregnancy history; and maternal occupation, vegetarianism, folate supplements, smoking, alcohol use during pregnancy, and other questions related to diet history, vitamin use, demographics, and domestic and environmental exposures to chemicals.

Approval for the study was obtained from the Multi-centre Research Ethics Committee and local research ethics committees in the study area, and participating mothers gave written consent before taking part in the study.

Occupational Exposure to EDCs

To assess their occupational exposure to EDCs during the first 3 months of pregnancy, mothers were asked about their job title, department, company, their five main tasks, possible exposure to a list of 26 occupational substances (including hair spray, plastic fumes, cleaning agents such as disinfectants, solvents, paints and paint removers, printing ink, glue, heavy metal, welding and soldering fumes, anesthetics, cytostatics and antibiotics, and pesticides), and the hours per week that they were in contact with these exposures while at work.

We used a job exposure matrix that included 348 possible job titles (Van Tongeren et al. 2002) to classify job title, department, company, and main tasks into seven exposure categories assessed by a panel of occupational hygienists as to the likelihood of exposure to EDCs (Van Tongeren et al. 2002). We then dichotomized exposure into either exposed--including possible and probable exposure--or unexposed, blind to case or control status. The classes of EDCs were pesticides, polychlorinated organic compounds, phthalates, alkylphenolic compounds, biphenolic compounds, heavy metals, and other (Baskin et al. 2001; Vrijheid et al. 2003).

Statistical Methods

We assessed correlations between variables using Spearman's and kappa statistics. Exposure prevalence for cases and controls and unadjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Chi-square tests were used to test for statistical significance.

We performed multiple logistic regression in the statistical package R (version 2.2.0; R Development Core Team 2005). Variables were included in the multiple regression if they were statistically significant (p < 0.05) in the univariate model and improved fit of the multiple logistic regression model using Akaike Information Criteria (Akaike 1974). Positive family history of hypospadias and previous stillbirth were excluded from the multiple logistic regression models because among the control participants there were only one and two with the specific risk factor respectively. p-Values are uncorrected for multiple comparisons. Because of multicolinearity (kappa = 0.82), maternal occupational exposure to hair spray and phthalates were not entered together in the multiple logistic regression models. Income or level of education used to control for potential confounding by social class yielded similar findings; only models that included income are shown here. We also examined multiple logistic regression models that included maternal age.


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