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The low down on low-dose endocrine disruptors. (NIEH News).

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 endocrine system (ĕn`dəkrĭn), body control system composed of a group of glands that maintain a stable internal environment by producing chemical regulatory substances called hormones.  and exert toxic effects that may lead to reproductive and developmental abnormalities or cancer. In October 2000, the National Toxicology Program National Toxicology Program Environment A program that conducts toxicologic tests on substances frequently found at the EPA's National Priorities List sites, which have the greatest potential for human exposure  (NTP (Network Time Protocol) A TCP/IP protocol used to synchronize the real time clock in computers, network devices and other electronic equipment that is time sensitive. It is also used to maintain the correct time in NTP-based wall and desk clocks. ) and the NIEHS NIEHS National Institute of Environmental Health Sciences (NIH, DHHS)  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 molecular biology, scientific study of the molecular basis of life processes, including cellular respiration, excretion, and reproduction. The term molecular biology was coined in 1938 by Warren Weaver, then director of the natural sciences program at the Rockefeller , reproductive and developmental toxicology, and statistical and mathematical modeling. Many of them were professors and department chairs from some of the leading biomedical research Biomedical research (or experimental medicine), in general simply known as medical research, is the basic research or applied research conducted to aid the body of knowledge in the field of medicine.  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 Environmental Protection Agency (EPA), independent agency of the U.S. government, with headquarters in Washington, D.C. It was established in 1970 to reduce and control air and water pollution, noise pollution, and radiation and to ensure the safe handling and  (EPA EPA eicosapentaenoic acid.

eicosapentaenoic acid

EPA, See acid, eicosapentaenoic.

), which is now validating test methods to screen 87,000 chemicals for hormonal effects [see EHP EHP
1. effective horsepower

2. electric horsepower
 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 OPPTS Office of Prevention, Pesticides & Toxic Substances (US Environmental Protection Agency)  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 Bisphenol A is a chemical compound containing two phenol functional groups. It belongs to the phenol class of aromatic organic compounds. It is widely prepared and sold and various important polymers/plastics are made from it. , diethylstilbestrol diethylstilbestrol: see DES.  (DES), ethinyl estradiol eth·i·nyl estradiol
A synthetic estrogen derivative commonly used in oral contraceptives.

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 Statisticians or people who made notable contributions to the theories of statistics, or related aspects of probability, or machine learning: A to E
  • Odd Olai Aalen (1947–)
  • Gottfried Achenwall (1719–1772)
  • Abraham Manie Adelstein (1916–1992)

"This was an incredibly stringent review," says Lynn Goldman, professor at The Johns Hopkins University Johns Hopkins University, mainly at Baltimore, Md. Johns Hopkins in 1867 had a group of his associates incorporated as the trustees of a university and a hospital, endowing each with $3.5 million. Daniel C.  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."

Nonmonotonic Dose Response

A key outcome of the review was verification that some endocrine disruptors exhibit dose-response relationships described as nonmonotonic, meaning that within a certain dose range, a chemical's effects on a given end point actually become greater as the dose is reduced. The dose-response curves can be shaped like a U, with a high response at both low and high levels of exposure, or like an inverted inverted

reverse in position, direction or order.

inverted L block
a pattern of local filtration anesthesia commonly used in laparotomy in the ox.
 U, with the greatest response at intermediate dose levels. According to Frederick vom Saal, a professor in the Division of Biological Sciences at the University of Missouri in Columbia, nonmonotonic curves challenge the EPA's standard assumption of linear or threshold dose responses, which holds that toxic effects always lessen as the dose is reduced toward zero.

One chemical found to exhibit nonmonotonic relationships is bisphenol A, an estrogenic plastic used in products including baby bottles and water cooler jugs. Due in part to its high visibility in the marketplace, bisphenol A was the subject of its own separate subpanel review. Studies conducted by Vom Saal showed that low-dose exposure to bisphenol A in mice produces prostate enlargement with an inverted U-shaped dose-response curve. These findings have helped fuel the concern of environmentalists that exposures to the chemical might enhance the risk of prostate cancer prostate cancer, cancer originating in the prostate gland. Prostate cancer is the leading malignancy in men in the United States and is second only to lung cancer as a cause of cancer death in men. , in addition to other illnesses.

Vom Saal wasn't overly surprised by his results. "Any endocrinologist will tell you that hormone receptors are up-regulated [stimulated] at low doses and down-regulated at high doses," he says. "In fact, in clinical therapy you can shut down a hormonal system simply by treating with high levels of hormone."

Although Vom Saal's results were shown to be credible under the panel's statistical reanalysis, they were found not to be reproduced in other, equally credible studies. Interstudy differences in animal strain, diet, dosing regimens, and even housing conditions were all offered as possible explanations for the discrepancy.

Based on the inconsistency of the data, the panelists were not persuaded that a low-dose effect of bisphenol A has been conclusively established as a general or reproducible finding, an admission seized on by the plastics industry, which insists low-dose exposure to the chemical is safe.

"I believe Dr. Vom Saal is convinced of his findings, but he has not convinced his scientific peers," says Paul Foster, program director of endocrine, reproductive, and developmental toxicology at the CIIT CIIT Chemical Industry Institute of Toxicology
CIIT COMSATS Institute of Information Technology (Pakistan)
CIIT Chemical Industry Institute of Technology
CIIT Combat Institute of Information Technology
 Centers for Health Research in Research Triangle Park Research Triangle Park, research, business, medical, and educational complex situated in central North Carolina. It has an area of 6,900 acres (2,795 hectares) and is 8 × 2 mi (13 × 3 km) in size. Named for the triangle formed by Duke Univ. , North Carolina North Carolina, state in the SE United States. It is bordered by the Atlantic Ocean (E), South Carolina and Georgia (S), Tennessee (W), and Virginia (N). Facts and Figures

Area, 52,586 sq mi (136,198 sq km). Pop.
, a research organization sponsored by industry. "The inability to reproduce the findings of an increase in prostate weight [or any pathological responses associated with this weight change] in mice [of different strains] and rats indicates that this change is not robust, nor a universal phenomenon likely to have implications for human health risk assessment."

But Lucier cautions that the panel's statement on bisphenol A shouldn't be taken out of context. Vom Saal's data are of high quality, he says, and the evidence for a low-dose effect can't be discounted. Taken as a whole, the data for bisphenol A and other chemicals reviewed by the panel indicate nonmonotonic, linear, and even threshold responses are all possible outcomes of low-dose endocrine disruptor exposure. The fact that biologic effects were noted in the low-dose region below the NOEL for some data sets, he says, suggests that the EPA should review its current testing protocols to see if changes are required.

Multigenerational mul·ti·gen·er·a·tion·al  
Of or relating to several generations: multigenerational family traditions. 
 Studies at Issue

Another of the panel's most important conclusions concerns the ability of EPA testing protocols to accurately evaluate reproductive and developmental effects. Experts suggest that endocrine disruptors pose the greatest risk during fetal development, which is regulated by hormones at specific levels. Hormonal alterations due to maternal exposure in pregnancy could lead to effects such as reduced cognitive function cognitive function Neurology Any mental process that involves symbolic operations–eg, perception, memory, creation of imagery, and thinking; CFs encompasses awareness and capacity for judgment  or cancer that might not be evident for months, even years. The EPA's current method for evaluating these effects is the multigenerational reproduction study, in which animals are exposed at critical periods of sexual differentiation sexual differentiation See Hermaphroditism, hirsutism, Müllerian ducts, Precocious puberty, Pseudoprecocious puberty, Tanner staging, Testis-determining factor, Virilization, Wolffian ducts, XXX, XXY, XXXY, XYY syndromes, Y Chromosome.  and their second-generation offspring evaluated at 21 days after birth.

One of the panel's main concerns is that the 21-day period of evaluation is too short. The risk of missing developmental effects if studies are terminated too soon is exemplified by the research of Retha Newbold, a biologist with the NIEHS Laboratory of Toxicology who has studied DES, an estrogenic hormone once used to prevent miscarriages that wound up causing cancer in the adult daughters of treated women. Newbold has performed studies in which mice were exposed at 1-5 days of age to DES and then allowed to grow for 18 months. In her studies, Newbold found significant increases in uterine uterine /uter·ine/ (u´ter-in) pertaining to the uterus.

Of, relating to, or in the region of the uterus.
 tumors among the treated mice, which she says wouldn't have been detected with the standard multigenerational assay. Uterine tumors were also observed in similar studies with genistein, which is an estrogenic component of soybeans.

Echoing the opinion of the panel on this issue, Goldman says, "I think we're going to have to revisit the standard multigenerational test to ensure that the end points, the animal models, and the ages of evaluation are appropriate for assessing development effects from endocrine disruptor exposure."

Although evidence of low-dose biologic effects was confirmed by the review, panel members were careful to note that the toxicologic significance of these findings is unknown. "Take the issue of prostate enlargement with bisphenol A exposure," says Goldman. "I don't think we understand the significance of that finding. Where do we go with this? How is it going to impact the way in which we regulate bisphenol A? This is a new area, and we don't have many precedents to rely on. We just don't have years of decision making based on this type of data."

The panel's conclusions raise serious questions about the extent to which current EPA testing protocols are able to accurately evaluate endocrine-disrupting effects. The panel notes that extended dose ranges are not typically used, and end points such as cancer and neurodevelopmental effects are rarely considered in multigenerational assays. No specific recommendations as to how the process might be improved were made. But the panel's report clearly states that the EPA will need to revisit current test methods for evaluating reproductive and developmental toxicity to determine if changes are needed for endocrine-disrupting agents.
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Author:Schmidt, Charles W.
Publication:Environmental Health Perspectives
Date:Sep 1, 2001
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