New research published in the BMJ’s Occupational and Environmental Medicine suggests the use of insect repellent during the first three months of pregnancy may be linked to an increase in the risk of a specific male birth defect, called hypospadias. Hypospadias decribes a range of conditions where the urethra (the tube that carries urine from the bladder) is shortened and does not extend to the tip of the penis. The condition is thought to affect around one to two male births in every 500. Despite its prevalence, relatively little is known about the environmental risk factors for hypospadias, although it has been variously associated with low birthweight, a history of stillbirth, older mothers, poor fertility and smoking, among other things.
The researchers quizzed mothers of 471 babies with hypospadias and another 490 randomly selected babies about their lifestyles and certain environmental factors, including the use of insect repellents and biocides, such as pesticides or weedkillers.
The authors found that use of insect repellents during the first three months of pregnancy was associated with an 81% increased risk of hypospadias. The authors caution that their study did not look specifically at the type, content, and frequency of use of insect repellents, and this should be investigated further before firm conclusions can be drawn.
Our colleagues at the UK and Australian SMCs wrapped up comment from scientists on the paper.
The original paper can be found here.
A/Professor Irina Pollard, Associate Professor of Biological Sciences at Macquarie University in Sydney, said:
“Gonadotrophin-dependent testosterone synthesis regulates the growth and differentiation of the external genitalia and descent of the testes.
Hypospadias is the medical term that describes the continuum from small anomalies in penis morphology of no functional concern, to severe cases of ambiguous genitalia. Since the 1970s, increased incidences of testicular abnormalities including hypospadias have been reported. There is the strong suspicion these observations may result from, among other things, exposure to low concentrations of a range of toxins. Thousands of potential toxins are continually released into the environment, the great majority of which have never been studied for their effect on mammalian reproduction. Some scientists link rising estrogen levels in the environment with the male reproductive anomalies such as hypospadias. Many pollutants such as PCBs, organochloride insecticides and detergents exhibit estrogenic activity and may affect normal differentiation of male fetuses.
Perhaps a related phenomenon is the mounting evidence suggesting that the age at which girls reach puberty is decreasing; that is, the incidence of precocious puberty in girls is increasing. Puberty is a complex period in an individuals’ life during which adolescents reach sexual maturity and become capable of reproduction. In girls, the pubertal process is driven, among other physiological variables, by rising circulating estrogen levels. Studies such as described in this important paper, raise serious problems in that toxicologists are falling further and further behind in their ability to analyze and identify the contaminants and contaminant mixtures increasingly encountered in the environment. This is due, in part, to a lack of resource investment and the sheer magnitude of the problem. More information is available from the newly released book ‘Bioscience Ethics’ by Irina Pollard. Cambridge University Press, 2009.”
Prof Richard Sharpe, Medical Research Council Human Reproductive Sciences Unit based at University of Edinburgh, said:
“This study concurs with several previous studies which have shown that residence in an agricultural area with high pesticide usage can increase the risk of hypospadias by 2- to 3-fold, although these earlier studies like the present one, did not directly measure exposure to the chemicals in question but inferred it from questionnaire data. Where direct measurements have been undertaken, only rarely has an association between pesticide exposure and hypospadias been shown. Current thinking, based on animal experimental studies, is that it is exposure to mixtures of chemicals, which may include some insect repellents and agricultural pesticides, that is most likely to pose a reproductive development risk to the developing foetus, but this is extremely difficult to prove in humans. This uncertainty may be worrying to some women who are planning a pregnancy. To minimise their anxiety, they can modify their lifestyle so as to minimise their exposure to avoidable suspect chemicals, such as insect repellents and pesticides and to chemicals in cosmetics/body creams/personal care products, especially during the first 3 months of pregnancy. Although we do not have convincing evidence that such chemicals can harm the developing foetus, this course of action represents a positive step by the mother and cannot do any harm to her baby.”
Prof Alan Boobis, Director of the Department of Health Toxicology Unit at Imperial College London, said:
“This study provides some evidence of an association between exposure to insect repellents and the risk of hypospadias. As the authors themselves point out, there are a number of caveats that need to be borne in mind. Because of the number of comparisons performed, the result could be down to chance. The nature of the exposure (repellent used) is not defined. The major repellent is DEET, which in general has proven safe in use in millions of subjects. The toxicology of DEET has been studied quite extensively, and it does not provide any indication that such an effect would be anticipated at human exposure levels. Overall, it would be premature to draw conclusions from this study other than that we need more information.”
Prof Anthony Dayan, Former Director of Department of Toxicology, St Bartholomew’s Hospital Medical College, said:
“As the authors themselves note, their finding is only tentative and preliminary, and, as is common in such surveys at a distance, the participation rate of patients was low and some of the essential controls were missing. This means that there is a considerable risk of using unrepresentative data as so many potential subjects had to be omitted.
“There is no information about the nature and severity of the hypospadias except that the cases were identified through referral for surgery. If there were a link between exposure and disorder, one would expect a link between the severity of the disorder and the extent of exposure – which is not mentioned here.
“There is no information about the timing of exposure and the subsequent diagnosis of hypospadias except that the former was in the ‘first trimester’. But the process of formation of the penis and urethral folding, the latter being disorganised in hypospadias, is only active in the last 6-8 weeks of that period, the final form of the penis being produced towards the end even of that period. Exposures in the first few weeks will not affect the final state of that organ except in the way of major disorganisation, which is not suggested.
“Another aspect of hypospadias is epispadias. It is not mentioned and yet a factor causing hypospadias should also cause epispadias.
“From the references cited it is apparent that hypospadias has not previously been associated with this factor although many other possible maternal exposures have been linked to its occurrence. Why has it not been seen before? Is it possible that other factors have not been sufficiently excluded this time, e.g. people using insect repellents are also likely to use anti-insect bite applications, insecticides, quite possibly other skin applications for hygiene or for aesthetic reasons, etc?
“This publication is typical of an early epidemiological study that has revealed a possible weak association. Apply the Bradford Hill criteria and you get the answers not only that much more human information is needed but that the animal experimental results do not in any way support the claim.
“Note that many of the authors’ references to ‘toxic’ effects of DEET refer to organs and sites remote from the penis both embryologically and anatomically. How do we know the subjects used DEET? Citronella and the proprietary Autan are widely available and used for the same purpose. All have been extensively tested and have been widely employed by humans for years with no indication previously of such a link.
“There is also no information about the time of year of birth, or, better, of potential exposures, and recall confusion about exposure could be important. If the mothers of affected subjects had had their babies in the late autumn and early winter is it likely that they will have used repellents 7-8 months previously?”
Professor Chris Winder, Professor of toxicology and occupational health at the University of New South Wales, said:
“This is not so new news. This particular defect (of the male urethra) is quite common, has been increasing in recent years, and has been linked to environmental sources (as well as genetic problems). The ‘association’ found does not mean causality. While this paper suggests only an association with a type of congenital effect and pesticide exposure, here is more evidence that pregnant mothers or mothers planning pregnancy should limit their exposure to chemicals such as insect repellents.”
Associate Professor Peter Dingle, environmental and nutritional toxicologist at Murdoch University, said:
“This research is very relevant to Australia and highlights the increased sensitivity of the developing fetus to environmental toxins. It really raises the need to make pregnant woman aware of the use of insect repellents and potentially other toxic substances.”