Update, 14 May 2001

Low-dose effects confirmed by a scientific peer review conducted by the US National Toxicology Program. The primary purpose of the review was to address whether doses of chemicals in the dose range below doses typically tested for effects could produce effects.

Why are low dose effects important? Because virtually all of the science that has guided regulatory standards has assumed they don't happen. If they are verified, then many exposure standards will have to be strengthened, some by factors of 10,000x or more. More...

The NTP's scientific peer review, by confirming low-dose effects as real and no longer "controversial," is a key step in the developing science of endocrine disruption. Some critics, most notably from industry, had argued that because key low dose studies could not be replicated, that the results were controversial at best and false at worst. In either case, they were insufficiently reliable on which to base regulatory standards. NTP's conclusion means that low-dose considerations must be integrated into regulatory science. As noted above, in some cases it will result in dramatic changes in exposure standards.

Another important result of the NTP assessment is that it has confirmed the reality of non-monotonic dose response curves. What it means is that there are circumstances when a low dose may produce a greater response than a high dose. Some industry representatives have claimed that non-monotonic dose response curves violate scientific logic. The NTP's conclusion contradicts this assertion directly.

This is extremely significant from a regulatory/health perspective. Virtually all regulatory science is based on the assumption that the basic form of the dose-reponse curve is monotonic... "the dose makes the poison." Non-monotonicity means that a basic assumption key to thousands of regulatory tests used to establish safety is invalid. Meaning that the standards based on those tests may be invalid, also. Industry has fought this because it invalidates safety standards that have been established using traditional testing, as it is likely raises the possibility of biologically important responses well beneath the levels of exposure that are normally tested

Background. At the invitation of the US Environmental Protection Agency, the NTP and the National Institute of Environmental Health Sciences organized and conducted a scientific peer-review of data currently available on low dose effects of endocrine disrupting contaminants.

The review had two phases: scientists with relevant data were asked to submit their studies to the panel (composed of scientific experts in this field) for statistical assessment. They were then invited to make brief presentations to the panel at a public meeting held in October 2000 in Research Triangle Park, North Carolina, near the NIEHS headquarters.

What they reported. After the meeting, NTP issued a preliminary report summarizing the peer review's conclusions. When a final report is released, we will summarize it here and provide appropriate links. In the meantime, the preliminary report made the following points:

Low-dose effects have been demonstrated for estradiol (a natural form of estrogen) and some estrogenic compounds, for example the industrial chemical nonylphenol and the plant estrogen genestein. They acknowledged that contradictory results have been obtained in studies of another industrial compound, bisphenol A, with some labs consistently finding impacts and other labs failing to find them.

The preliminary report concludes that the laboratory and analytical procedures used studying bisphenol A with both positive and negative results have been appropriate: "credible and sound within the context of the experimental design." The report identifies a number of factors that might account for the conflicting results, including study design differences (e.g., species/strain, animal husbandry, diet, chemical purity, dosing regime, endpoints evaluated, genetic factors, etc.).

At least in the preliminary report, the panel fails to observe that the positive results have been obtained independently by scientists at academic institutions, whereas the negative results have been carried out in industry labs and/or funded by industry. This pattern is reminiscent of the state of the scientific research on neurocognitive impacts on lead in the mid-1970s, and generations of studies of tobacco health impacts. Independent scientists found impacts. Industry-funded scientists found no effects. Those debates have now been fully resolved: there are effects.

Commenting on another class of compounds, the anti-androgens, the report observes that none of the studies were designed explicitly for low-dose effects.

On non-monotonic dose response curves, the panel "concluded that the shape of the dose-response curve for endocrine disrupting agents would depend on numerous factors including the endpoint being evaluated, the chemical being studied, the dosing regime, and the biological characteristics of the target tissue." Non-monotonic dose response curves are well established in "receptor-mediated" response systems, so finding these curves with endocrine disruptors is consistent with these other findings.

What does this mean? Non-monotonicity means that a basic assumption key to thousands of regulatory tests used to establish safety is invalid. Meaning that the standards based on those tests may be invalid, also. More...

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