Characterization of the dose decrement in regulatory rat pesticide toxicity feeding studies

Abstract

In typical rodent pesticide feeding studies of 4 up to 104weeks, animals are offered the pesticide at constant concentrations in the feed. Throughout the entire study duration of up to 104weeks, the daily feed consumption per animal remains nearly constant. This results in decreasing doses per kg bodyweight from the first day of treatment onwards as the bodyweight increases. Recently, we have identified this dose decrement as the major cause for lower No Observed Effect Levels (NOAEL, expressed as mg/kg bodyweight) in longer-term studies compared to shorter-term studies, rather than the exposure duration itself. In the current evaluation we investigated the nature of the dose decrement in more detail by using male and female bodyweight and feed consumption data from 118 feeding studies of three rat strains to calculate dose development over time. In male rats, after a steep initial dose decrement, the mean dose at week 7 of treatment is on average half of the initial dose and after 29weeks one third of the initial dose. In females, 50% of the initial dose is reached at week 18 and in 25% of the studies one third of the initial dose is reached at approximately 75weeks of treatment. Although bodyweights and feed intakes per animal were different between strains, doses and dose development curves over time are similar. The fact that ingested doses in rats continually decrease, especially in the first 13weeks, should be taken into account in dietary risk assessments.