title: Study parameters influencing NOAEL and LOAEL in toxicity feeding studies for pesticides: exposure duration versus dose decrement, dose spacing, group size and chemical class.
abstract: 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.
authors.affiliation: Federal Office of Public Health FOPH, Food Safety Division, Stauffacherstrasse 101, 8004 Zürich, Switzerland. juerg.zarn@bag.admin.ch
authors.forename: Jürg A
authors.initials: JA
authors.lastname: Zarn
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Engeli
authors.forename: Josef R
authors.initials: JR
authors.lastname: Schlatter
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D019055:No-Observed-Adverse-Effect Level; D010575:Pesticides / Q000633:toxicity*; D051381:Rats; D012107:Research Design; D018570:Risk Assessment / Q000379:methods; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D010575:Pesticides