The "low dose" hypothesis: validity and implications for human risk

In the late 1990s, a "low dose" hypothesis was proposed based on studies that purported to show that hormonally active environmental agents were causing a variety of effects, mainly reproductive and developmental, at "low doses." The supporters of this hypothesis claim that traditional "high-dose" toxicity studies are not adequate to assess adverse effects from these hormonally active agents in that they do not detect effects that are occurring at "low doses." In addition, it is claimed that these "low dose" effects are occurring at levels comparable to those to which humans are being exposed. These claims have been controversial and expert panels evaluated the evidence behind them in the early 2000s. Although these panels generally concluded that such "low dose" effects were not conclusively established, proponents of the "low dose" hypothesis assert that a large number of more recent studies now provide clear support for their hypothesis. This review carefully examines both recent and older studies that have been cited to support the "low dose" hypothesis, including their relevance for the human population. These include in vivo and in vitro laboratory studies as well as a very limited number of epidemiological investigations. Based on the evidence, it is concluded that these "low dose" effects have yet to be established, that the studies purported to support these cannot be validly extrapolated to humans, and the doses at which the studies have been performed are significantly higher than the levels to which humans are exposed.