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Background: Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an 'adverse effect' in the context of hazard identification and risk assessment.Objectives: Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events) , and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available.Discussion: Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects.Conclusions: For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population. [ABSTRACT FROM AUTHOR]

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.

Background: Perchlorate is a common contaminant of drinking water and food. It competes with iodide for uptake into the thyroid, thus interfering with thyroid hormone production. The U.S. Environmental Protection Agency's Office of Solid Waste and Emergency Response (OSWER) set a groundwater preliminary remediation goal (PRG) of 24.5 microg/L to prevent exposure of pregnant women that would affect the fetus. This does not account for the greater exposure that is possible in nursing infants or for the relative source contribution (RSC), a factor normally used to lower the PRG due to nonwater exposures., Objectives: Our goal was to assess whether the OSWER PRG protects infants against exposures from breast-feeding, and to evaluate the perchlorate RSC., Methods: We used Monte Carlo analysis to simulate nursing infant exposures associated with the OSWER PRG when combined with background perchlorate., Results: The PRG can lead to a 7-fold increase in breast milk concentration, causing 90% of nursing infants to exceed the reference dose (RfD) (average exceedance, 2.8-fold). Drinking-water perchlorate must be < 6.9 microg/L to keep the median, and < 1.3 microg/L to keep the 90th-percentile nursing infant exposure below the RfD. This is 3.6- to 19-fold below the PRG. Analysis of biomonitoring data suggests an RSC of 0.7 for pregnant women and of 0.2 for nursing infants. Recent data from the Centers for Disease Control and Prevention (CDC) suggest that the RfD itself needs to be reevaluated because of hormonal effects in the general population., Conclusions: The OSWER PRG for perchlorate can be improved by considering infant exposures, by incorporating an RSC, and by being responsive to any changes in the RfD resulting from the new CDC data.

Risk assessment for airborne carcinogens is often limited by a lack of inhalation bioassay data. While extrapolation from oral-based cancer potency factors may be possible for some agents, this is not considered feasible for contact site carcinogens. The change in contact sites (oral: g.i. tract; inhalation: respiratory tract) when switching dose routes leads to possible differences in tissue sensitivity as well as chemical delivery. This research evaluates the feasibility to extrapolate across dose routes for a contact site carcinogen through a case study with epichlorohydrin (EPI). EPI cancer potency at contact sites is compared across three bioassays involving different dose routes (gavage, drinking water, inhalation) through the use of dosimetry models to adjust for EPI delivery to contact sites. Results indicate a large disparity (two orders of magnitude) in potency across the three routes of administration when expressed as the externally applied dose. However, when expressed as peak delivered dose, inhalation and oral potency estimates are similar and overall, the three potency estimates are within a factor of seven. The results suggest that contact site response to EPI is more dependent upon the rate than the route of delivery, with peak concentration the best way to extrapolate across dose routes. These results cannot be projected to other carcinogens without further study.

In the long run, molecular epidemiological techniques can provide important insights for understanding a wide variety of important issues in current risk assessment and are applicable across a broad spectrum of adverse effects in addition to carcinogenesis. Unfortunately, current risk assessment practices make very little use of the kind of detailed mechanistic information that molecular epidemiology can provide. Eventually, there is reason to hope that the availability of mechanistic insights provided in part by molecular epidemiology can produce some of the "essential tension" required to reform paradigms for the formulation of quantitative risk assessment models in general.