Perhaps the strongest evidence for adverse effects of EDCs is from studies of wildlife populations living in contaminated ecosystems such as the Great Lakes and the Baltic Sea, as well in areas of point source contamination such as Lake Apopka, Florida and sewage outfalls in the United Kingdom. Effects have been observed at all levels of biological organization, from elevated biomarkers of exposure to behavioral disturbances, overt malformations, and ultimately, population declines. Such effects have been observed in a variety of phyla and classes, including invertebrates, fish, reptiles, birds and mammals. Due to environmental regulations, wildlife populations in some areas such as the Great Lakes have improved dramatically over the past two decades as contaminant loads have decreased.

Experiments with laboratory animals are available for a number of chemicals with specific modes of action such as steroid receptor agonists and antagonists, inhibitors of steroid synthesis, and increased metabolic clearance of hormones. Following developmental exposure to estrogens (e.g., DES, methoxychlor) reproductive tract anomalies, accelerated puberty and reproductive senescence, reduced fertility, and in some instances, tumorgenic responses have been observed. Female offspring appear to be more sensitive than males. A number of chemicals have been shown either to bind to the estrogen receptor, induce estrogen-responsive genes in transcription assays, and/or are uterotrophic in animal tests (e.g., some phthalates and alkylphenols), but evidence for estrogen-receptor mediated developmental toxicity are generally lacking. Attention has also become focused on chemicals which act via anti-androgenic mechanisms. Principal manifestations of developmental exposure to anti-androgens (e.g. vinclozolin) are generally restricted to males, and include hypospadias, retained nipples, reduced testes and accessory sex gland weights, and decreased sperm production. Some phthalates have recently been shown to induce similar phenotypes in exposed offspring, but the mechanism of action has not been identified. Finally, alterations in thyroid gland physiology during development (e.g., by PCBs) have been linked to altered neurologic function.

Observational studies in humans include the reproductive tract malformations and tumors in female offspring from the use of the synthetic estrogen DES as a treatment for potential miscarriage in the 1950s, the adverse developmental effects of the rice oil contamination by PCBs and PCDFs in Japan and Taiwan in the 1960s and 70s, and several epidemiological studies of populations with lower exposure levels to PCBs that have found altered cognitive function in children. In addition, a number of effects, including decreasing human semen quality, altered sex ratios at birth, and increasing rates of cancers of the breast, testes and prostate, have been reported to be changing over the last several decades in at least some geographical areas. While not linked to particular exposures, the observations of these trends has further raised the over all level of concern about the impact of endocrine disruptors on human health.

Collectively existing studies clearly confirm that developing organisms are particularly susceptible to endocrine disruption due to the critical role of hormones in directing differentiation in many tissues. However, there is yet to be scientific consensus on the potential risk of exposure to EDCs in the ambient environment. Before firm conclusions can be drawn, several overarching questions or uncertainties must be addressed, including: (1) What is the universe of chemicals with the potential to interact with the endocrine system of the intact animal; (2) What is the relative contribution of synthetic chemicals versus naturally occurring dietary constituents in any health effects; (3) What is the shape of the dose-response curve for EDCs at environmental exposure levels; (4) What constitutes an adverse effect from perturbations of the endocrine system; (5) How well do our current regulatory test methods perform in characterizing the action of endocrine disruptors; (6) What are the effects of combined exposure to EDCs, especially those acting by diverse modes of action; and (7) What are the key risk factors behind the rise in a number of human health outcomes that have an endocrine basis. There are nearly 700 ongoing research identified in the Global Endocrine Disruptor Research Inventory (GEDRI) that should collectively reduce the uncertainties on this issue over the next few years.