Synergistic disruption of external male sex organ development by a mixture of four antiandrogens

Reproduced with permission from Environmental Health Perspectives.Background: By disrupting the action of androgens during gestation, certain chemicals present in food, consumer products, and the environment can induce irreversible demasculinization and malformations of sex organs among male offspring. However, the consequences of simultaneous exposure to such chemicals are not well described, especially when they exert their actions by differing molecular mechanisms. Objectives: To fill this gap, we investigated the effects of mixtures of a widely used plasticizer, di(2-ethylhexyl) phthalate (DEHP); two fungicides present in food, vinclozolin and prochloraz; and a pharmaceutical, finasteride, on landmarks of male sexual development in the rat, including changes in anogenital distance (AGD), retained nipples, sex organ weights, and malformations of genitalia. These chemicals were chosen because they disrupt androgen action with differing mechanisms of action. Results: Strikingly, the effect of combined exposure to the selected chemicals on malformations of external sex organs was synergistic, and the observed responses were greater than would be predicted from the toxicities of the individual chemicals. In relation to other hallmarks of disrupted male sexual development, including changes in AGD, retained nipples, and sex organ weights, the combined effects were dose additive. When the four chemicals were combined at doses equal to no observed adverse effect levels estimated for nipple retention, significant reductions in AGD were observed in male offspring. Conclusions: Because unhindered androgen action is essential for human male development in fetal life, these findings are highly relevant to human risk assessment. Evaluations that ignore the possibility of combination effects may lead to considerable underestimations of risks associated with exposures to chemicals that disrupt male sexual differentiation.European Union and the Danish Environmental Protection Agency

Microbial Risk Assessment Framework for Exposure to Amended Sludge Projects

BackgroundAlthough the U.S. Environmental Protection Agency has a long history of using risk-based approaches for regulatory purposes, pollutant limits for pathogens in biosolids are not currently based on quantitative risk assessments.ObjectivesWe developed and demonstrated a risk-based methodology for assessing the risk to human health from exposure to pathogens via biosolids.MaterialsFour models were developed, incorporating direct ingestion, groundwater, and aerosol exposure pathways. Three sources of environmental data were used to estimate risk: pathogen monitoring of sludge, efficacy of sludge treatment, and pathogen monitoring of biosolids.ResultsRisk estimates were obtainable even for Class A biosolids, where posttreatment monitoring data are below detectable levels, demonstrating that risk assessments for biosolids exposure are practical. Model analyses suggest that: a) a two-digester design decreases the probability of risks >10(-4) compared with one-digester designs, b) risks associated with exposures to groundwater and aerosol pathways were, in general, lower than exposures to the direct ingestion pathway, and c) secondary transmission can be an important factor in risk estimation.ConclusionsThe risk-based approach presented here provides a tool to a) help biosolids producers interpret the results of biosolids monitoring data in terms of its health implications, b) help treatment plant engineers evaluate the risk-based benefits of operational changes to existing or projected treatment processes, and c) help environmental managers evaluate potential capital improvements and/or land application site placement issues. Regulation of pathogens can now be based on human health risk in a manner parallel to other water-related risks

State-of-the-Science Workshop Report: Issues and Approaches in Low-Dose–Response Extrapolation for Environmental Health Risk Assessment

Low-dose extrapolation model selection for evaluating the health effects of environmental pollutants is a key component of the risk assessment process. At a workshop held in Baltimore, Maryland, on 23–24 April 2007, sponsored by U.S. Environmental Protection Agency and Johns Hopkins Risk Sciences and Public Policy Institute, a multidisciplinary group of experts reviewed the state of the science regarding low-dose extrapolation modeling and its application in environmental health risk assessments. Participants identified discussion topics based on a literature review, which included examples for which human responses to ambient exposures have been extensively characterized for cancer and/or noncancer outcomes. Topics included the need for formalized approaches and criteria to assess the evidence for mode of action (MOA), the use of human versus animal data, the use of MOA information in biologically based models, and the implications of interindividual variability, background disease processes, and background exposures in threshold versus nonthreshold model choice. Participants recommended approaches that differ from current practice for extrapolating high-dose animal data to low-dose human exposures, including categorical approaches for integrating information on MOA, statistical approaches such as model averaging, and inference-based models that explicitly consider uncertainty and interindividual variability

An evaluation of parsimony for microbial risk assessment models

Microbial risk assessment (MRA) is a process that evaluates the likelihood of adverse human health effects following exposure to a medium in which pathogens are present. Several different classes of models are available to quantitatively characterize risks to human health from exposure to pathogens. Herein, we consider the question of parsimony for specific realizations of representative static and dynamic MRA models and identify conditions under which the more complex dynamic model provides sufficient additional insight to justify the added modeling complexity. To address this question, a standard static individual-level risk model is compared to a deterministic dynamic population-level model that explicitly includes secondary transmission and immunity processes. Exposure parameters are based on a scenario defined by human exposure to pathogens in reclaimed water. A sensitivity analysis is implemented to identify conditions under which static and dynamic models yield substantially different results. Under low risk conditions, defined by a combination of exposure levels and infectivity of the pathogen, the simpler static model provides satisfactory risk estimates. The approach presented here provides a basis for model selection for a broad range of MRA applications. Copyright © 2007 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/57535/1/856_ftp.pd

The Forest for the Trees: A Systems Approach to Human Health Research

We explore the relationship between current research directions in human health and environmental and public health policy. Specifically, we suggest there is a link between the continuing emphasis in biomedical research on individualized, therapeutic solutions to human disease and the increased reliance on individual choice in response to environmental and/or public health threats. We suggest that continued research emphasis on these traditional approaches to the exclusion of other approaches will impede the discovery of important breakthroughs in human health research necessary to understand the emerging diseases of today. We recommend redirecting research programs to interdisciplinary and population-focused research that would support a systems approach to fully identifying the environmental factors that contribute to disease burden. Such an approach would be able to address the interactions between the social, ecological, and physical aspects of our environment and explicitly include these in the evaluation and management of health risks from environmental exposures