Authors
Nira Ben-Jonathan, Ralph L. Cooper, Paul Foster, Claude L. Hughes, Patricia B. Hoyer, Diane Klotz, Michael Kohn, Dolores J. Lamb, George M. Stancel.

Title
An approach to the development of quantitative models to assess the effects of exposure to environmentally relevant levels of endocrine disruptors on homeostasis in adults

Journal
Environmental Health Perspectives 107(Suppl 4):605-611. 1999.

The authors of this article were members of a working group that addressed the mechanisms by which disruption of endocrine homeostasis may lead to disease, with specific focus on environmental contaminants that effect estrogen, androgen, and thyroid hormone systems. Several potential effects of environmental contaminants were selected on the basis of perceived threat to the health of affected individuals and the likelihood of developing quantitative model(s) to be used in determining low-dose effects in the human population. The effects selected were endometrial cancer, the female-hypothalamic-pituitary-gonadal axis up to and including successful implantation, reproductive senescence in the female, mammary cancer, and adverse cardiovascular and skeletal actions.

Testicular function was selected as a prototypical end point for modeling purposes and the working group decided to focus on spermatogenesis, sperm characteristics, and steroidogenesis. Testicular function provides a model of a coordinated biologic system susceptible to endocrine disruption by many individual toxicants at a number of different sites and through various mechanisms. A number of animal models are available to study the effects of endocrine disruption on testicular function (i.e., baboons, rodents, domestic farm animals). Both animals and humans have almost identical enzyme structure and regulation involved in testicular steroidogenesis. In addition, the large number of animal models available provides the opportunity to study the varying sensitivities of humans to potential endocrine disrupting substances.

In terms of creating baseline models of spermatogenesis and daily sperm production rates, the working group decided to include specific measurements. These include: i) measures of sperm characteristics (i.e., sperm motility and morphology); ii) measures of hormone and steroid levels; iii) the rates of production and degradation of these hormones under various conditions; iv) the number of cells in major cell types within the testes; and v) studies of mitosis and meiosis. In creating a risk assessment model, the group incorporated a variety of biologic processes that would likely be altered by endocrine disruption. These include: i) testicular hormone synthesis; ii) hormone biotransformation; iii) hormone degradation; iv) hormone disposition (i.e., binding and distribution); and v) factors affecting cell proliferation and cell death in the testes. Numerous other factors, including age, disease, genetic variability, and lifestyle factors, were incorporated into the testicular function model of endocrine disruption.

From a quantitative perspective, the working group defined an adverse effect resulting from endocrine disruption as any change in a homeostatic parameter (i.e., hormone levels, steroid clearance) that falls outside the normal range for a species. This is an important point that has hitherto not been widely appreciated in the toxicology literature in general, and in regards to endocrine disrupting chemicals in particular. Specifically, the authors are saying that biological significance of an effect is the gold standard and statistical significance although important, is not enough. This is an interesting point but it must be appreciated that evidence of a toxicant-induced change has implications particularly to individuals in the populations that are either susceptible to adverse effects or in whom the hormone level is already close to the boundaries of what is considered normal.

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