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based on geographic proximity modeling. In such studies, dose-response relationships cannot be determined. The same is true of the studies of deployed personnel; in war situations (particularly combat, in which depleted-uranium exposure is most likely), environmental monitoring is not feasible.

Outcome Assessment

Biologic Plausibility

Biologic plausibility reflects knowledge of the biologic mechanism by which an agent can lead to a health outcome. That knowledge comes through mechanism-of-action or other studies in pharmacology, toxicology, microbiology, physiology, and other fields—typically in studies of animals. Biologic plausibility is often difficult to establish or may not be known when an association is first documented. The committee considered such factors as evidence from animal and human studies that exposure to an agent is associated with diseases known to have biologic mechanisms similar to that of the disease in question, evidence that some outcomes are commonly associated with occupational or environmental exposures, and knowledge of routes of exposure, storage in the body, and excretion that suggests that a disease is more likely to occur in some organs than in others. The extent to which the data are consistent with a biologically plausible mechanism influences the weight attached to the results of a study, as does an indication that the mechanism is similar in the animals under study and humans.

Biomarkers

A biomarker is a molecular or cellular indicator of exposure, effect, or susceptibility. More specifically, a biomarker of effect is defined as a “measurable biochemical, physiologic, behavioral, or other alteration in an organism that, depending on the magnitude, can be recognized as associated with an established or possible health impairment or disease” (NRC, 2006). Biomarkers of effect can include biochemical, cellular, and physiologic indicators of disease. Numerous studies evaluated by the committee incorporated biomarkers of effect to evaluate health outcomes related to uranium exposure, including biomarkers to evaluate cell toxicity and renal dysfunction.

Adequate Followup Period

To strengthen the evidence of a true cause-effect association (particularly for some health outcomes, such as most cancers), the followup period should allow sufficient time after exposure for the health outcome to occur in the population of concern. There are several time-related factors. Biologic latency of cancer is a factor in the delay between exposure to a putative carcinogen and the appearance of cancer. For



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