Endocrine-disrupting chemicals are among the most complex environmental health threats known today. By mimicking natural hormones such as estrogen and testosterone, these chemicals can interact with the body's endocrine system and exert toxic effects that may lead to reproductive and developmental abnormalities or cancer. In October 2000, the National Toxicology Program (NTP) and the NIEHS convened an independent panel of experts from academia, government, and industry to evaluate the evidence for low-dose effects and dose-response relationships for endocrine disruptors. "This was a highly experienced panel," says NIEHS toxicologist Ron Melnick, chair of the panel organizing committee. "Members had broad experience in areas including molecular biology, reproductive and developmental toxicology, and statistical and mathematical modeling. Many of them were professors and department chairs from some of the leading biomedical research institutes in the country." The panel's conclusions were released 14 May 2001 in the National Toxicology Program's Report of the Endocrine Disruptors Low-Dose Peer Review.
Low-Level Exposures and Public Health
The peer review panel was assembled at the request of the U.S. Environmental Protection Agency (EPA), which is now validating test methods to screen 87,000 chemicals for hormonal effects [see EHP 107:A458-A460 (1999)]. In assessing public health risks from endocrine disruptors, the EPA faces some difficult challenges. Unlike traditional toxicology, in which the dose always starts out from zero, exposure to endocrine disruptors adds incrementally to what's already present in the body as naturally occurring hormone. In some instances, the natural hormone is associated with a certain degree of risk. Estrogen, for example, is known to cause breast cancer in humans. "The question is, what happens to the risk when exposure to endocrine disruptors drives hormone levels higher than what they normally would be?" explains George Lucier, chair of the peer review panel.
For this specific review, the EPA's main concern was to resolve questions concerning the effects of low-dose exposures. Humans are usually exposed to these chemicals at extremely low levels. Yet the standard tests used by the EPA to evaluate reproductive and developmental toxicity (contained in the agency's August 1998 document Health Effects Test Guidelines OPPTS 870.3800: Reproduction and Fertility Effects) often fail to consider the impact of doses lower than those producing no evidence of overt adverse effects, described as the no-observed-effect level, or NOEL. For this review, the panel evaluated evidence of biologic changes due to exposure to endocrine disruptors at doses below the NOEL. Melnick says biologic changes were emphasized over adverse effects because in many cases the long-term consequences of altered endocrine function have yet to be fully characterized.
The organizing committee identified 59 studies for review. These studies investigated chemicals with a wide range of hormonal properties, including bisphenol A, diethylstilbestrol (DES), ethinyl estradiol, nonylphenol, octylphenol, genistein, methoxydor, 17[beta]-estradiol, and vinclozolin. Melnick says the main criterion for study inclusion was an "evaluation of multiple doses extending reasonably far into the low-dose region." The raw data from 39 of the studies underwent statistical reanalysis by a subgroup of experienced, impartial statisticians.
"This was an incredibly stringent review," says Lynn Goldman, professor at The Johns Hopkins University in Baltimore, Maryland, and former assistant administrator at the EPA. "In some cases, we found the initial statistics were not properly conducted. Overall, the review process was much more intensive than anything I've seen for publication in a journal," she says. "There was complete transparency at every step of the way for all the investigators and the public. Comment from industry and environmental groups was always welcome. …