Impact of study design and database parameters on NOAEL distributions used for toxicological concern (TTC) values.

TTC values for chemicals with unknown toxicity but known structure are derived from 5th percentiles of NOAEL distributions from compounds with known toxicity. The impact of chemical structures on TTC values was repeatedly investigated but not the impact of parameters such as study numbers per compound and differences in study design. Recently, study design parameters such as application route with related dose-decrements, dose-spacing and number of animals per group but not exposure duration were found to affect NOAEL distributions. Here, the impact of study design parameters on lowest NOAEL distributions and consequently on TTC values was analyzed in a database on 423 Cramer class III pesticides. Using NOAELs related to lowest LOAELs instead of lowest NOAELs, excluding studies with a dose spacing >8, and standardizing NOAELs to the initial dose animals received shifted the 5th percentile of NOAEL distributions from 0.22 to 0.5mg/kg body weight per day. In contrast, weighting of NOAELs for the study numbers per compound shifts 5th percentiles downwards to lower values by 10-20%. The results show that database and study design parameters influence NOAEL distributions to a minor degree and derived TTC values therefore can be considered reliable in that perspective.

Development of a risk management tool for prioritizing chemical hazard-food pairs and demonstration for selected mycotoxins.

We developed a simple tool for ranking chemical hazard-food pairs to assist policy makers and risk managers selecting the hazard-food pairs that deserve more attention and need to be monitored during food safety inspections. The tool is based on the derivation of a "Priority Index" (PI) that results from the ratio of the potency of the hazard and the consumer exposure. The potency corresponds to a toxicity reference value of the hazard, whereas the exposure results from the combination of the concentration of the hazard in the food, and the food consumption. Tool's assumptions and limitations are demonstrated and discussed by ranking a dataset of 13 mycotoxins in 26 food items routinely analyzed in Switzerland. The presented ranking of mycotoxin-food pairs has to be considered as relative due to scarce exposure data availability, and uncertainties in toxicity reference values. However, this representative example allows demonstrating the simplicity and the ability of the PI tool to prioritize chemical hazard-food pairs.

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

In typical rodent pesticide feeding studies of 4 up to 104 weeks, animals are offered the pesticide at constant concentrations in the feed. Throughout the entire study duration of up to 104 weeks, 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 29 weeks 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 75 weeks 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 13 weeks, should be taken into account in dietary risk assessments.

Study parameters influencing NOAEL and LOAEL in toxicity feeding studies for pesticides: exposure duration versus dose decrement, dose spacing, group size and chemical class.

The effect of exposure duration on no observed adverse effect levels (NOAEL) and lowest observed adverse effect levels (LOAEL) in rodent pesticide feeding studies was evaluated. Ratios of NOAEL (and LOAEL), expressed as pesticide concentrations in feed, were calculated from subacute to subchronic, subchronic to chronic and subacute to chronic studies. There was no statistical significant effect of exposure duration on ratio distributions. Whereas geometric means of ratios were in a narrow range of 1.1-2.5, the geometric standard deviations and 95th percentiles increased with dose spacing of the involved studies. With the exception of carbamates, the chemical class of pesticides had no influence on the ratio distributions. However, the number of animals in the shorter-term study of ratio couples being ≤ 1 was statistically significantly higher than in ratio couples being >1. Ratios ≤ 1 may be partly explained by the dose decrement over time observed in feeding studies applying the test substances in constant concentrations. The dose decrement possibly converts initially toxic doses to less toxic doses beyond the subacute phase. Ratios >1 seem to be caused predominantly by differences in study design parameters. In dietary risk assessment, the acceptable daily intake (ADI) is compared to pesticide intake estimates based on mean food consumption (i.e. the so called theoretical maximum daily intake, TMDI) being orders of magnitude lower than actual food consumption on eating occasions for certain food commodities. As subacute, subchronic and chronic NOAEL (and LOAEL), expressed as pesticide concentration in feed did not differ statistically significantly, the TMDI as benchmark for the ADI may underestimate the significance of the toxicity of subacute exposure.