Academic journal article Environmental Health Perspectives

Meeting Report: Moving Upstream-Evaluating Adverse Upstream End Points for Improved Risk Assessment and Decision-Making

Academic journal article Environmental Health Perspectives

Meeting Report: Moving Upstream-Evaluating Adverse Upstream End Points for Improved Risk Assessment and Decision-Making

Article excerpt

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.

KEY WORDS: adverse health effects, androgen antagonists, hazard identification, immunotoxicants, risk assessment, science policy, thyroid hormone, toxicologic assessments. Environ Health Perspect 116:1568-1575 (2008). doi:10.1289/ehp.l1516 available via [Online 10 July 2008]

To evaluate the potential of environmental chemicals to cause harm, to estimate the risks: hat chemical exposures pose to the population, and to identify opportunities for prevention and intervention, the type and extent of adverse effects associated with exposure to a chemicai must be elucidated. To date, hazard and risk assessments have relied largely on data from traditional toxicologic studies, such as the 2 -year, chronic toxicology and carcinogenesis studies or the two-generation reproductive toxcity assay. A primary goal of these studies is to identify whether chemical exposures cause avert disease outcomes, such as birth defects and neoplasia. These studies also provide data on biological events that precede these overt disease outcomes, often referred to as precursor effects. Adverse effects identified in existing hazard and risk assessments have often been the more overt diseases or defects, rather than events that occur earlier in the disease process.

Increasingly, toxicology assays are providing more information on how chemicals can interfere with cellular signaling or metabolism, disrupt hormone homeostasis, alter gene expression, or otherwise play a role early in disease processes. As scientific understanding of the mechanisms through which chemical exposures advance pathologic processes resulting in disease increases, so too does the opportunity for effective and efficient hazard Identification and risk assessment. A necessary step in incorporating data on early biological perturbations is to consider how these early events relate to the concept of "adverse effects." The U.S. Environmental Protection Agency (EPA) defines an adverse effect as "a biochemical change, functional impairment, or pathologic lesion that affects the performance of the whole organism, or reduces an organism's ability to respond to an additional environmental challenge" (U. …

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