Global Assessment of the State-of-the-Science of Endocrine Disruptors WHO 2002

Recently, the World Health Organization (WHO) released a comprehensive report, "Global Assessment of the State-of-the-Science of Endocrine Disruptors", examining the current state of the science of endocrine modulation. The WHO report provides a comprehensive and informative overview of endocrinology and endocrine toxicology as these fields relate to the concepts of endocrine modulation. Key case studies of examples of endocrine modulation in both wildlife and humans are interpreted, with careful examination of the evidence for a role for endocrine active compounds (EAC).

Exposure assessments were identified as a primary area of concern for the evaluation of the literature on endocrine modulation. Exposure to EACs during sensitive periods of development (embryo/fetal development, childhood and adolescence) during which 'programming' of the endocrine system occurs may result in a permanent change of function or sensitivity to stimulatory/inhibitory signals. Alternatively, exposure during adulthood may be compensated by normal homeostatic mechanisms and might not result in an adverse effect. Unfortunately, exposure data during these periods of development is often not available, thereby making it difficult to draw conclusions about adverse effects resulting from EAC exposure.

EAC dose is another area of concern identified by this report. EACs act by mimicking or antagonizing the actions of endogenous hormones (i.e. estrogens and androgens) which are far more potent than exogenous or synthetic hormones. This raises an important question regarding the relevance of exposure to EACs if adverse effects are only observed at very high concentrations, due to the very low potency of these chemicals. It is also possible that certain developmental stages are differentially sensitive to different doses of EACs. Further studies are required to investigate the actions of key EACs at environmentally-relevant concentrations during sensitive periods of development and following long-term exposure.

There are many methods to quantify EAC exposure including measurements of serum EAC, adipose tissue concentrations and pharmacokinetic modeling which provides an estimation of exposure. Unfortunately, exposure data is lacking in many studies or is improperly standardized, making comparisons of similar studies difficult. Exposure data is essential to conclude that exposure to EAC negatively impacts human health. Other general methodological concerns include very small sample sizes, criteria for diagnosis of disease, confounding factors and use of inclusion statistics for study analysis.

Wildlife studies act as sentinels of human exposure to EACs, however, these studies should be interpreted with caution as only a few species have been studied which are often biologically very different from humans. As with human studies, many of the cases of clear causation following EAC exposure have occurred in areas where contamination is high, indicating high EAC dose. Generally, evidence in most cases is weak and further knowledge is required into the basic physiology of these animals.

The WHO report identifies several areas of human health which may be adversely affected by EACs and include the reproductive system (sperm quality/testis function, fecundity and fertility, spontaneous abortion, sex ratio, male reproductive tract abnormalities, endometriosis, precocious puberty, polycystic ovary disease and abnormal function of the prostate gland), nervous system, immune system and hormonally-dependent cancers (breast, endometrial, testicular and thyroid cancer). Generally, the human data fails to show clear causation, but does raise general concerns. Because of numerous methodological discrepancies (data collected at different time periods, different experimental designs, different or missing exposure assessments, lack of exposure assessments during critical periods of development, exposure dose) it is difficult to compare studies for the purposes of establishing causation.

Reproductive System
The impact of EACs on reproductive health outcomes is a major area of concern. The WHO report concludes that the available human studies are generally inadequate to support the conclusion that reproductive health has been adversely affected by EAC exposure. For some health concerns (global declines in semen quality and fecundity and fertility) there may be geographical differences and temporal trends (e.g. seasonal changes) that confound the issue. Reproductive disorders including semen quality, male reproductive tract abnormalities and testicular cancer may represent a constellation of effects stemming from a single causative factor. How these adverse outcomes are related requires further study. Data on female reproductive health and EACs is comparatively sparse. Endometriosis and time to pregnancy (fecundity) are two areas that should be more thoroughly investigated.

Cancer
Incidence of hormonally-induced cancers appears to be increasing, however, whether this is due to improved screening methods (e.g. mammograms, prostate serum antigen (PSA) test) or increased EAC exposure is not clear in many cases. Though it is biologically plausible that EAC exposure may cause hormonally-induced cancer, the evidence does not yet show a clear link. For many cancers (e.g. testicular, prostate), studies have not yet examined the link with EAC exposure. Many studies have examined the association between breast cancer and EAC exposure however, the overall strength of the association is weak. Further study is required examining cancer incidence following EAC exposure during critical developmental periods (i.e. in utero, childhood, adolescence).

Neurobehaviour
Another area of concern is the impact of EACs on neurobehaviour. A variety of adverse health effects have been observed ranging from motor impairment and memory loss to subtle behavioural changes. Of particular concern are the potential effects of exposures on the developing nervous system. Changes in neurobehaviour may be mediated via endocrine modulation of thyroid hormone levels as impaired thyroid function in neonates has been associated with the long-term cognitive deficits. However, this hypothesis has yet to be rigorously tested. Many processes related to neural plasticity including development, regeneration after injury and aging have been shown to be regulated by steroid hormones, suggesting that the nervous system may be susceptible to endocrine modulation.

Immune System
The immune system may be another target of EACs. Only a few compounds have been identified that may cause immunotoxicity via an endocrine disruption. Diethylstilbestrol (DES) has been associated with weak immunological changes following in utero exposure. As immunotoxicity of DES occurs at pharmacological levels, it is questionable whether immunotoxic effects would occur at low exposure levels to weak estrogens. Further investigation is required.

Beyond addressing the evidence of EAC exposure on human health outcomes, the WHO report also establishes a proposed framework of 'causal criteria for assessing endocrine disruptors'. The framework includes a defined hypothesis, evaluation of scientific evidence (temporality, strength of association, consistency, biological plausibility, evidence for recovery) and overall strength of the evidence. This structured framework uses the principles of qualitative meta-analyses to help reconcile different results from different studies.

The general conclusions of the WHO report are as follows:

1. Developing countries should be better represented in epidemiological studies to improve knowledge of global disease trends.
2. There is weak evidence to suggest that human health has been adversely affected by exposure to endocrine active chemicals, however, sufficient evidence is available to conclude that adverse, endocrine-mediated effects have occurred in some wildlife populations.
3. Many examples of adverse human health effects have been observed at high exposure levels. Further study is required to determine effects of low dose exposure and exposure during critical developmental periods (in utero, childhood, adolescence).

Finally, the WHO report outlines some general research needs including the expansion of basic knowledge of endocrine systems in wildlife and humans, methodology (dose-response relationships), monitoring, identification of endocrine disruptors and database development to better monitor global disease trends.

The WHO report provides a comprehensive evaluation of the state of the science of endocrine modulation. The report includes a thorough overview of endocrinology and endocrine toxicology that is a valuable companion to the summaries of the evidence for endocrine modulation in wildlife and in humans. The report concludes that although there is only weak evidence to link exposure to endocrine active chemicals to adverse human health effects, this should foster further investigations into these areas. The recommendations to increase the number of epidemiological studies in developing countries due to the paucity of data available from these regions are particularly important given the global reach of the WHO. The recommendations regarding environmentally relevant dose and critical periods of exposure are similar to those proposed by The National Institute of Environmental Health Sciences, U.S. Environmental Protection Agency (EPA), U.S Food and Drug Administration/National Center for Toxicological Research and the Chemical Manufacturers Association in their workshop "Characterizing the effects of endocrine disruptors on human health at environmental exposure levels" (Raleigh, North Carolina, May 1998). While these recommendations endorsed by the WHO strengthen the call for improved studies in the area of low dose and critical periods of exposure, there are no specific guidelines to help address these concerns. Overall the WHO report on endocrine disruption is a critical review of potential mechanisms of endocrine disruption accompanied by notable case studies of endocrine disruption in both humans and wildlife that together serve to both inform and illuminate the public on the state of the science of endocrine disruption.