Endocrine disrupters: we need research, biomonitoring and action

The majority of chemicals so far identified as having endocrine-disrupting (ED) abilities are organic compounds. Paradoxically, up to about 200 years ago organic compounds were only produced by living organisms. Examples are our own hormones and plant phytoestrogens, which together with many other naturally occurring organic compounds have been in our milieu for millions of years. However, with the evolvement of synthetic organic chemistry during the latter half of the 19th century, ignited by the petrochemical industry and the recognition of oil and gas as a vast and cheap source of organic raw material, the synthesis and development of new organic compounds literarily exploded. At the turn of the millennium, an estimated 30,000 new organic chemicals were on the market, with some 1000 new compounds being added annually (Barney, 1980). Thus, people today are likely to be exposed to thousands of organic chemicals that did not exist less than four generations ago. We need to acknowledge that the development of the petrochemical industry was a crucial prerequisite for the industrial revolution, and thus for the subsequent prosperity and development of the Western world. It has enabled the development of new medicines that have improved and saved lives. Today's modern living is filled with products and utensils consisting of such new materials, which make our everyday lives easier and safer. However, these obvious benefits must not make us blind to the fact that among all these new chemicals, some have turned out to be harmful to endocrine systems. Few of them, including pesticides, were designed to exert endocrine activities. But for many EDCs, their endocrine activity was not intended or foreseen and was only detected later as a result of animal testing or after exposure to wildlife and humans had occurred. It is important to keep in mind that the research field on endocrine disruption from the start was spurred by observations of increasing trends in the incidence of hormone related diseases and conditions in wildlife and human populations (Toppari et al., 1996; Gee, 2012). Some trends seen in wildlife have improved significantly following better cleansing of wastewater. Although trends in some reproductive problems seen in human populations have slowed down in some countries, they do not seem to have reversed (for review, see Skakkebaek et al., 2016). The fact remains that endocrine disruption is occurring in human populations; perhaps best documented by the increase in incidence rates of cancer in some endocrine organs, including breast, testicular, pancreas and thyroid cancer. [(Kilfoy et al., 2009; Znaor et al., 2015), see also Fig. 1, which contains data from the National Danish Cancer Registry; the first national cancer registry in the world (Wagner, 1991)]. It is also well documented that poor semen quality is very common among young men in industrialised countries (Jorgensen et al., 2012; Hart et al., 2015). Environmental factors are undoubtedly involved and endocrine-disrupting chemicals (EDCs) are among the suspects (WHO & UNEP Report 2013). Our governments and regulatory bodies are well aware that EDCs are potentially harmful. This has been proven by experimental laboratory studies for a large number of chemicals; some of which subsequently have been banned. From such carefully conducted experimental laboratory studies carried out over the last decades, we have learned some important facts about the effects of EDCs: Human biomonitoring studies have documented widespread human exposure to a large range of known and suspected EDCs (Frederiksen et al., 2014; CDC Report 2015; Den Hond et al., 2015). The realistic general human exposure scenario in most developed countries is therefore characterised by a mixed and simultaneous exposure to multiple EDCs; albeit human exposure levels for individual compounds are generally at much lower levels than those observed to cause adverse effects in experimental animal studies. A key question is: if human exposure to EDCs plays a significant role for the adverse trends in reproductive and other endocrine-related disease patterns observed in human populations, how do we identify the important culprits among the thousands of chemicals we are exposed to? For the chemicals, which are already recognised or suspected as having ED effects, decisions about the risks of individual chemicals often boils down to whether current human exposure levels pose a risk to human health and therefore require regulatory action, or whether the level of exposure can be considered safe. Traditionally, risk assessment is performed by comparing human exposure levels to a tolerable daily intake (TDI) level or to a reference level based on no (or lowest) observed adverse effect levels (NOAEL) or to benchmark doses derived from experimental animal studies. In this respect, a relevant point is that established guidelines for toxicological animal testing have been relatively insensitive with respect to detecting ED effects. Effects of EDCs are generally not acutely toxic and might not show up as reprotoxic, teratogenic or genotoxic. However, new test guidelines designed for detecting ED effects are currently being developed and implemented (see for example: www.oecd.org/env/ehs/testing/oecdworkrelatedtoendocrinedisrupters.htm). Inclusion of more ED-sensitive endpoints in animal testing has also lead to significantly lowering of some TDI, as recently seen for bisphenol A (EFSA 2016). As shown in papers from the 8th Copenhagen Workshop on Endocrine Disrupters (COW2015) included in this issue of Andrology, careful examination of endocrine-sensitive endpoints in experimental animal studies do indeed reveal the effects at levels lower than previously considered to be safe (Hass et al., 2016; Mandrup et al., 2016). Another point is that mixed exposures are still often not addressed when risk of individual compounds are discussed. Knowing that exposures to multiple EDCs are likely to lead to the dose-additive effects, we need to start taking this into account in risk assessment. We can, however, not just focus on the known EDCs. Thousands of chemicals, never properly evaluated for ED properties, are on the market currently representing a big unknown of the full human endocrine-disrupting milieu. Programmes using high-throughput in vitro screening such as the US EPA's programme ToxChem (Filer et al., 2014) are important when it comes to focussing efforts for further testing into the chemicals emerging as suspected EDCs. Programmes for human biomonitoring (HBM) geared to take on measurements of emerging EDCs are equally important for fast generation of valid human exposure data. This involves identification of the appropriate exposure biomarkers to be measured as well as generation of knowledge on human uptake, metabolism and excretion of new emerging chemicals while taking possible age and sex differences into account. While some countries have ongoing HBM programmes (e.g. US, Canada, Germany), most have not. In Europe, the European Commission is enhancing this area by supporting a European HBM initiative with €50 mill over the next 5 years [anticipated start ultimo 2016, (topic 3050-sc1-pm-05-2016.html, ec.europa.eu)]. This initiative is expected to promote the generation of current HBM data throughout Europe as well as the development of new biomarkers of exposure for emerging chemicals. This will most likely also facilitate faster generation of new European HBM data on chemicals emerging as potential endocrine disrupters and faster risk assessment. HBM is also an important tool for tracking the effectiveness of regulatory actions. Whenever possible HBM projects should be linked to health and epidemiological research studies for the added value of linking exposure data to health outcomes including relevant endocrine endpoints. As mentioned above, current debates on the human risk related to specific EDCs revolve on whether sufficient evidence is available supporting that human exposure levels pose a risk to human health. Valid questions to ask are: when is evidence sufficient to make a scientifically sound judgment? What type of evidence is needed? How do we obtain the required evidence in the fastest and most cost-efficient way? With current toxicological testing and risk assessment being better geared for dealing with ED effects as outlined above, we already have the tools available to reduce human exposure to EDCs. Human studies usually cannot prove causality and regulation should definitively not wait for human effects to be observed. Studies on ED effects in humans are, however, still important as there is much we can learn from the human epidemiological and case–control studies on exposure–outcome associations. Humans are genetically diverse, and significant gene–exposure interactions might exist, although not easily detected in experimental laboratory studies. Yet, regulation should also protect genetically vulnerable subpopulations. In a mother–child study of pregnant mothers working in greenhouses, significant associations between exposure to pesticides during early pregnancy and metabolic and cardiovascular markers in the offspring were only observed in the children who had a genetic variant of the HDL-associated enzyme paraoxonase 1 (Andersen et al., 2012; Jorgensen et al., 2015). Several birth cohort studies, and mother–child cohort studies, with a focus on early life exposure to EDCs and their endocrine effects have been initiated worldwide over recent years. These studies can be challenged because of the potentially long lag time between exposure events during foetal development and the manifestation of adverse effects in childhood or adulthood. One way to circumvent the need to wait up to 20 years or more to monitor adult life effects of early exposures is the use of validated early markers of ED effects that are linked to later adverse effects. The anogenital distance (AGD), a validated marker of androgen action during the foetal masculinisation window in rodents, is also a promising biomarker of foetal exposure to anti-androgenic effects in humans and is now being used in both cohorts of newborn and adults (Mendiola et al., 2016; Thankamony et al., 2016). Identification and validation of biomarkers of other early ED effects for use in human studies are highly desirable; in this context, we should call on the expertise of endocrinologist regarding which pathways are likely to be affected, and which intermediate effects could be expected, as well as draw on the opportunity of using proteomics or epigenomics technology to identify new biomarkers. Finally, linking animal and human studies has proven fruitful in the past (with the adaption of AGD to human studies as an example) and is likely to be so in the future as well. Human studies might provide important data on associations to known and new endocrine-related endpoints and might give hints on yet unrecognised ED modes of action that subsequently can be incorporated in both in vivo and in vitro testing and vice versa. In conclusion, the production of industrial chemicals used in consumer products has drastically increased during the 20th century. Unfortunately, many of these compounds have unintended endocrine disruption abilities. The bad news is that we are all exposed resulting in some endocrine health problems which have more than doubled over the past 70 years, including breast, testicular, pancreas and thyroid cancer. In addition, reproductive health problems are concerning. The good news is that exposure trends can be reversed by regulatory interventions. Thus, human breast milk samples now contain much less of the persistent organic chemicals than breast milk samples from the last part of the 20th Century (Fang et al., 2013, 2015). Although modern life is comfortable and we do not wish us back to the times of our grand-grandparents, we should not be content with the current incidence of endocrine-related problems. The fact that 10% of women suffer from breast cancer and more than 20% of young men have poor semen quality should not be considered acceptable, ‘normal’ and unavoidable. We gratefully acknowledge economic support of Kirsten and Freddy Johansens' Foundation for EDMaRC's research and educational activities.

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