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CUMULATIVE RISK ANALYSIS FOR ORGANOPHOSPHORUS PESTICIDES
Citation:
Setzer, R W. CUMULATIVE RISK ANALYSIS FOR ORGANOPHOSPHORUS PESTICIDES. Presented at Society of Toxicology 42nd Annual Meeting, Salt Lake City, Utah, March 9-13, 2003.
Description:
Cumulative Risk Analysis for Organophosphorus Pesticides
R. Woodrow Setzer, Jr. NHEERL MD-74, USEPA, RTP, NC 27711
The US EPA has recently completed a risk assessment of the effects of exposure to 33 organophosphorous pesticides (OPs) through the diet, water, and residential exposures. Oral, dermal, and inhalation routes were considered, but the oral route has by far the richest data set, and is the route discussed in detail here. The risk assessment combined a relative potency factor (RPF) approach to dose-response assessment with a probabilistic exposure assessment to estimate distributions of margins of exposure in the US population. RPFs for the oral route of exposure were based on benchmark doses (BMDs) calculated as the expected daily dose that would result in a 10% inhibition of brain acetylcholinesterase (AChE) in rats. For almost all of the 33 OPs considered, multiple dose-response data sets were available. The data sets formed a nested hierarchy: major studies conducted by different laboratories or the same laboratory at different times, and observations from serial sacrifices within major studies. Dose-response models were fit to all the data for each OP using a hierarchical model to account for variation in both levels of the hierarchy. Two interesting aspects of the dose-response shape complicated the modeling. The dose-responses for about half of the chemicals had a "shoulder" at the low-dose end: the steepness of the response increased with increasing dose. At the other extreme of dose, for many OPs, as dose increased, AChE activity decreased asymptotically to a non-zero level that varied among OPs. The RPF approach applies strictly only when dose-additivity applies, and dose-additivity applies strictly only when dose-responses can be superimposed by rescaling dose. Thus, these observations question of the quality of the approximation to risk that the RPF approach provides for these data. Reliable pharmacokinetic and pharmacodynamic models of the distribution and metabolism of the OPs and of their effects on AChE would have facilitated the interpretation and use of the data base by providing an estimate of the precision of the RPF approach. [This is an abstract of a presentation and does not necessarily reflect EPA policy.]