• Current approaches toward chemical mixture studies at the National Institute of Environmental Health Sciences and the U.S. National Toxicology Program. (1998)
• Sexual differentiation and environmental endocrine disrupters. (1998)
• Health risk assessment of drinking water contaminants in Canada: the applicability of mixture risk assessment methods. (1997)
• Environmental estrogens and reproductive health: a discussion of the human and environmental data. (1997)
• The workshop on endocrine disrupter research needs: a report. (1997)
• Relevance of risk assessment to exposed communities. (1995)

TITLE: Sexual differentiation and environmental endocrine disrupters.
AUTHORS: Toppari J; Skakkebaek NE
SOURCE: Baillieres Clin Endocrinol Metab 1998 Apr;12(1):143-56
ABSTRACT: Male sexual differentiation is dependent on normal testicular function, including secretion of testosterone from the Leydig cells, and mullerian-inhibiting substance from the Sertoli cells. External factors, such as anti-androgens and oestrogens, that disturb endocrine balance cause demasculinizing and feminizing effects in the developing male fetus. Oestrogens also causes adverse effects in female fetuses, whereas anti-androgens have little influence. A growing number of chemicals have been found to possess either weak oestrogenic, anti- androgenic or other hormonal activities, and these are often referred to as endocrine disrupters. In animals in the wild, abnormal sexual development has been associated with exposure to mixtures of endocrine disrupters. The emerging adverse trends in human reproductive health, such as increased incidences of cryptorchidism, hypospadias and testicular cancer, and the ubiquitous presence of endocrine disrupters in the environment, support the hypothesis that disturbed sexual differentiation could in some cases be caused by increased exposure to environmental endocrine disrupters.

TITLE: Health risk assessment of drinking water contaminants in Canada: the applicability of mixture risk assessment methods.
AUTHORS: Krishnan K; Paterson J; Williams DT
SOURCE: Regul Toxicol Pharmacol 1997 Oct;26(2):179-87
ABSTRACT: The objectives of this article are: (i) to review the current approaches of Health Canada to the risk assessment of drinking water contaminants, and (ii) to examine the applicability of mixture risk assessment methods to drinking water contaminants. Health Canada's current approaches to drinking water risk assessment, like those of many regulatory agencies, focus almost solely on the effects of individual chemicals. As such, no formal method is currently used for developing mixtures guidelines or for modifying guidelines of individual chemicals to account for the possibility of the occurrence of interactions (supraadditive or infraadditive). Recent interest in the risk assessment of mixtures, at least in part, stems from concerns over the potential health risks of mixtures of very commonly occurring compounds in Canadian drinking water supplies, namely the disinfection by-products. Before any mixtures methods can be considered for incorporation into Health Canada's current approaches to the risk assessment of drinking water contaminants, it is essential to consider the limitations and data requirements of the various mixture risk assessment methods (i.e., whole mixture approach, similar mixture approach, components-based approaches, interactions-based assessment). Among the existing mixture risk assessment methods, the components- based and interactions-based approaches could be applicable to drinking water contaminants. Specifically, among the components-based approaches, dose-addition, response-addition, and the toxic equivalency factor approaches are the most applicable ones for drinking water contaminants. Until an interactions-based, mechanistic risk assessment approach (e.g., physiological model-based approach) becomes available for routine use, the components-based approaches remain the default methods for consideration. Progress in the development and validation of an interactions-based risk assessment methodology should facilitate a more realistic assessment of risk due to drinking water contaminants without increasing the levels of uncertainty in risk estimates above those associated with existing single-chemical methods. Copyright 1997 Academic Press.

TITLE: Environmental estrogens and reproductive health: a discussion of the human and environmental data.
AUTHORS: Daston GP; Gooch JW; Breslin WJ; Shuey DL; Nikiforov AI; Fico TA; Gorsuch JW
SOURCE: Reprod Toxicol 1997 Jul-Aug;11(4):465-81
ABSTRACT: Estrogenic activity of certain xenobiotics is an established mechanism of toxicity that can impair reproductive function in adults of either sex, lead to irreversible abnormalities when administered during development, or cause cancer. The concern has been raised that exposure to ambient levels of estrogenic xenobiotics may be having widespread adverse effects on reproductive health of humans and wildlife. The purpose of this review is to evaluate (a) the nature of the evidence supporting this concern, and (b) the adequacy of toxicity screening to detect, and risk assessment procedures to establish safe levels for, agents acting by this mechanism. Observations such as adverse developmental effects after maternal exposure to therapeutic levels of the potent estrogen diethylstilbestrol or male fertility problems after exposure to high levels of the weak estrogen chlordecone clearly demonstrate that estrogenicity is active as a toxic mechanism in humans. High level exposures to estrogenic compounds have also been shown to affect specific wildlife populations. However, there is little direct evidence to indicate that exposures to ambient levels of estrogenic xenobiotics are affecting reproductive health. Reports of historical trends showing decreasing reproductive capacity (e.g., decreased sperm production over the last 50 years) are either inconsistent with other data or have significant methodologic inadequacies that hinder interpretation. More reliable historical trend data show an increase in breast cancer rate, but the most comprehensive epidemiology study to data failed to show an association between exposure to persistent, estrogenic organochlorine compounds and breast cancer. Clearly, more work needs to be done to characterize historical trends in humans and background incidence of abnormalities in wildlife populations, and to test hypotheses about ambient exposure to environmental contaminants and toxic effects, before conclusions can be reached about the extent or possible causes of adverse effects. It is unlikely that current lab animal testing protocols are failing to detect agents with estrogenic activity, as a wide array of estrogen- responsive endpoints are measured in standard testing batteries. Routine testing for aquatic and wildlife toxicity is more limited in this respect, and work should be done to assess the validity of applying mammalian toxicology data for submammalian hazard identification. Current risk assessment methods appear to be valid for estrogenic agents, although the database for evaluating this is limited. In conclusion, estrogenicity is an important mechanism of reproductive and developmental toxicity; however, there is little evidence at this point that low level exposures constitute a human or ecologic health risk. Given the potential consequences of an undetected risk, more research is needed to investigate associations between exposures and effects, both in people and animals, and a number of research questions are identified herein. The lack of evidence demonstrating widespread xenobiotic-induced estrogenic risk suggests that far-reaching policy decisions can await these research findings.

TITLE: The workshop on endocrine disrupter research needs: a report.
AUTHORS: Tilson HA; Kavlock RJ
SOURCE: Neurotoxicology 1997;18(2):389-92
ABSTRACT: On April 10-13, 1995 the US EPA sponsored a workshop to develop research needs for endocrine disrupters. Participants were assigned to discussion groups for health effects issues and risk assessment methodologies. The neurotoxicology workgroup identified several chemicals including the PCBs and dioxins that affect nervous system function possibly by acting on the endocrine system during development. The study of endocrine disrupter is confounded by a number of uncertainties, including the presence of chemical mixtures in the environment unclear exposure parameters, poorly understood mechanisms of action, poor dose-response characterization, and uncertain animal-to- human extrapolation. The working group proposed a research strategy to address these uncertainties, which includes initial identification of effects of concern to human and/or wildlife populations and determining whether those effects can be associated with exposure to specific chemicals in the environment and neuroendocrine disruption. Once a problem chemical has been identified and the exposure conditions established, hypothesis-driven research to determine mechanism of action could proceed.

TITLE: Relevance of risk assessment to exposed communities.
AUTHORS: Brickey C
SOURCE: Environ Health Perspect 1995 Feb;103 Suppl 1:89-91
ABSTRACT: Current environmental policy tends to evaluate potential, theoretical exposure to health risks by evaluating one chemical or hazard at a time. Risk assessment techniques used by the U. S. Environmental Protection Agency (EPA) and other government agencies do not evaluate the cumulative impact of exposure to environmental contaminants. This problem is of particular significance to low-income and minority populations who tend to live in neighborhoods and work in locations that involve exposure to pollutants in air, water, and workplace activity. Certain areas within the border typify this lifestyle. The problem is further complicated by the fact that EPA operates separate programs for different "media." Exposure patterns in the border suggest the need for a cross-media pollution prevention approach. Minority recruitment into health research, a coordination of research approaches and dollars, and new resources for effective monitoring of minority communities could provide a basic assessment of the risks and their sources. Further research into the cumulative impacts of prevalent subsets of chemicals is also needed. Recent efforts in the Great Lakes may provide a model for this type of regional, cross-border effort.