Meeting report: moving upstream-evaluating adverse upstream end points for improved risk assessment and decision-making

Abstract

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.

Keywords: adverse health effects; androgen antagonists; hazard identification; immunotoxicants; risk assessment; science policy; thyroid hormone; toxicologic assessments.

Figure 1

Distribution of 12 monthly measurements of total T₄ in 15 healthy men (white bars) and one individual (black bars). The distribution in one individual is about half the width of the distribution in the group. Frequency represents number of measurements. Adapted from Andersen et al. (2002) with permission.

Figure 2

Distribution of a typical physiological parameter within the population and how that may vary depending on the influence of chemical and biologic background.