Hormonally Active Agents in the Environment (1999) / Chapter Skim
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1 Introduction
1 Introduction
Pages 10-26
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From page 10... ...
. Some of the environmental chemicals associated with adverse reproductive and developmental effects in animals mimic the actions of the female sex hormone estradiol and it has been hypothesized that human exposure to these compounds, generically referred to as xenoestrogens, may produce similar adverse effects on reproduction and development and be involved in the increasing incidence of breast cancer in human populations (Davis et al.
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From page 11... ...
, and are the subject of continued, intensive investigation. In addition to alterations of the female genital tract caused by DES, the fertility and reproductive performance of DES daughters have been impaired, and the risks of prematurity, spontaneous abortion, and ectopic pregnancy have increased, particularly in DES daughters, with genital tract changes, that were exposed in early pregnancy (Herbst and Bern 1981; Stillman 1982; Mittendorf 1995~.
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From page 12... ...
. It must be recognized, however, that DES, which is a potent synthetic estrogen, was given to pregnant women and experimental animals in very high doses relative to physiologic estrogenic activity and that great care must be taken in extrapolating the DES experience to other estrogenic substances and dosing regimens.i Additionally, laboratory studies indicate that nonestrogenic agents, such as antiestrogens, androgens, and progestins (Bern 1992a,b)
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From page 13... ...
had difficulty deciding on the proper descriptors and definitions of its subject. Historically, the conceptual construct underlying the charge to the committee centered on the finding that the compounds under consideration have estrogenic activity and the hypothesis that this activity disrupts normal developmental and reproductive processes by interacting with estrogen receptors, the so-called "estrogen hypothesis." When the committee began its work, however, it was clearly recognized that the compounds to be evaluated also had antiestrogenic and antiandrogenic properties as well as some other hormonal activities, such as effects on thyroid function, and that not all of their actions are mediated by known hormone receptors.
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From page 14... ...
The NRC does not discourage its study committees from addressing risk management questions when the charge calls for it, but recognizes that its proper role is to inform public-policy choices to the extent practicable by describing and interpreting relevant scientific facts and uncertainties for the benefit of citizens and their representatives who must make the policy judgments. NRC committees must carefully separate their proper role of informing policy choices from the different role of recommending policy.
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From page 15... ...
evaluation of the scientific literature on the effects caused by those chemicals in laboratory animals, humans, and wildlife; and (3) consideration of whether observed effects can be attributed to the hormonal properties of the chemicals and to observed environmental exposures.
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From page 16... ...
how to extrapolate information on one species to others, including humans; and (9) the definition and quantification of environmentally relevant doses, concentrations, and exposures.
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From page 17... ...
The endocrine system can be disrupted in many ways that would lead almost every chemical with a disruptive effect on the organism to be classified as an endocrine disrupter; however most proponents of the hypothesis have a narrower definition in mind. Their formulation of the hypothesis suggests that some chemical inputs can act analogously to specific hormones, and the chemicals either overmodulate or undermodulate specific activities of hormones, producing specific effects that are hormonally mediated.
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From page 18... ...
TCDD, planar PCBs, and a variety of other compounds affect development through processes governing cell fate and organ development and function. Phenotypically, these effects in some species resemble effects resulting from excess or from deficient levels of retinoic acid (Birnbaum et al.
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From page 19... ...
Koch's postulates, for example, depend entirely on the ability of the investigator to isolate putative causal agents from alternatives. Many important hypotheses about causal mechanisms cannot be tested through critical experiments simply because the factors generating responses cannot be isolated from each other.
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Research cannot remove all uncertainties in describing the real world, and so some assumptions must be made in statistical analyses. Specifically, some committee members felt that the precautionary principle requires statistical analysts to assume as the default hypothesis that an environmental agent has adverse effects.
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From page 21... ...
Furthermore, because all the compounds initially considered by the committee possessed hormonelike activity in at least some test system, the committee adopted hormonally active agents (HAAs) as a more neutral mechanistic descriptor.
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From page 22... ...
If it is the former, then should all the biologic effects of such a compound be considered in this report, even if they are unrelated to hormonal pathways? Is it even theoretically possible to describe a biologic effect of an HAA, indeed of any chemical, as completely unrelated to hormonal pathways?
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From page 23... ...
Periods of Susceptibility The committee members agreed that there are important, critical periods during pro- and postnatal life during which an organism is particularly sensitive to exposure to various chemicals, but disagreed on how much emphasis should be placed on such critical periods in the absence of relevant data regarding HAAs. Despite growing information on the timing of events in differentiation in vertebrates, there is not much information that specifically links that timing to the actions of specific HAAs.
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From page 24... ...
High doses often are used in the laboratory, as, for example, the use of maximum tolerated dose in early phases of evaluating carcinogenicity of chemicals (Goldstein 1994~. However, our greatest concern in this report is whether the much lower doses of HAAs that result from environmental exposure cause adverse effects.
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From page 25... ...
The effect of environmental chemicals depends on their concentration and the degree and method of exposure to them that organisms undergo. Experiments that use such concentrations may produce exposures typical of those experienced by organisms in the real world, but to faithfully reproduce such exposures, all routes of exposure must be considered and integrated.
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From page 26... ...
. This is also often called the "internal dose." An "environmentally relevant dose" as used in this report means a dose administered in an experimental setting similar to that which would result from exposure to the same chemicals at concentrations that occur in the environment.
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