Low-Level Exposure to Multiple Chemicals: Reason for Human Health Concerns?

BACKGROUND: A key question in the risk assessment of exposures to multiple chemicals is whether mixture effects may occur when chemicals are combined at low doses which individually do not induce observable effects. However, a systematic evaluation of experimental studies addressing this issue is missing. OBJECTIVES: With this contribution, we wish to bridge this gap by providing a systematic assessment of published studies against well-defined quality criteria. RESULTS: On reviewing the low-dose mixture literature, we found good evidence demonstrating significant mixture effects with combinations of chemicals well below their individual no observable adverse effect levels (NOAELs), both with mixtures composed of similarly and dissimilarly acting agents. CONCLUSIONS: The widely held view that mixtures of dissimilarly acting chemicals are "safe" at levels below NOAELs is not supported by empirical evidence. We show that this view is also based on the erroneous assumption that NOAELs can be equated with zero-effect levels. Thus, on the basis of published evidence, it is difficult to rule out the possibility of mixture effects from lowdose multiple exposures

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

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

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 Implications of Using a Physiologically Based Pharmacokinetic (PBPK) Model for Pesticide Risk Assessment

Background: A physiologically based pharmacokinetic (PBPK) model would make it possible to simulate the dynamics of chemical absorption, distribution, metabolism, and elimination (ADME) from different routes of exposures and, in theory, could be used to evaluate associations between exposures and biomarker measurements in blood or urine. Objective: We used a PBPK model to predict urinary excretion of 3,5,6-trichloro-2-pyridinol (TCPY), the specific metabolite of chlorpyrifos (CPF), in young children.Methods We developed a child-specific PBPK model for CPF using PBPK models previously developed for rats and adult humans. Data used in the model simulation were collected from 13 children 3–6 years of age who participated in a cross-sectional pesticide exposure assessment study with repeated environmental and biological sampling. Results: The model-predicted urinary TCPY excretion estimates were consistent with measured levels for 2 children with two 24-hr duplicate food samples that contained 350 and 12 ng/g of CPF, respectively. However, we found that the majority of model outputs underpredicted the measured urinary TCPY excretion. Conclusions: We concluded that the potential measurement errors associated with the aggregate exposure measurements will probably limit the applicability of PBPK model estimates for interpreting urinary TCPY excretion and absorbed CPF dose from multiple sources of exposure. However, recent changes in organophosphorus (OP) use have shifted exposures from multipathways to dietary ingestion only. Thus, we concluded that the PBPK model is still a valuable tool for converting dietary pesticide exposures to absorbed dose estimates when the model input data are accurate estimates of dietary pesticide exposures

A Personal Perspective on the Initial Federal Health-Based Regulation to Remove Lead from Gasoline

Objective: This article describes the personal experience and perspective of the authors, who had primary responsibility for drafting the initial health-based regulation limiting lead content of gasoline during the early 1970s while employed by the U.S. Environmental Protection Agency (EPA). Data s o u r c e: Information used by the U.S. EPA in developing the initial health-based regulation limiting lead content of gasoline in December 1973 and studies documenting the impact of that and subsequent actions. Data extraction: Among the lessons learned from this experience is the importance of having input from independent scientists to the regulatory decision-making process. This also demonstrates the critical role of independent peer-reviewed research, such as that supported by the National Institutes of Health, as well as research conducted by scientists from the Centers for Disease Control and Prevention, in delineating the consequences of lead exposure in the population. Data synthesis: Removal of lead from gasoline in the United States has been described as one of the great public health achievements of the 20th century, but it almost did not happen. The experience of the authors in developing this regulation may be helpful to others involved in developing health-based regulatory policy in the future. Co n c l u s i o n: The initial U.S. EPA health-based regulation to remove lead from gasoline is clearly an example where science successfully affected public policy. The leadership of the U.S. EPA at that time deserves much credit for establishing an atmosphere in which this was possible