A retrospective analysis of the two-generation study: what is the added value of the second generation?
Increasing pressure is exerted by some stakeholders to reduce the two-generation study to a one-generation study, a measure that would considerably reduce the number of animals and other costs involved in these lengthy studies. The present study retrospectively evaluates 176 multi-generation studies to assess potential differences between the first and the second generation, both in terms of the types of effects observed and in terms of the effective doses. All substances classified as reproductive toxicants by the Directive 92/32/EEC or considered as toxic to fertility by the California EPA for which we found a multi-generation study were included (n=58 studies). The second generation in the two-generation studies considered affected neither the overall NOAEL nor the critical effect. Therefore, it had no impact on the ensuing risk assessment, nor on classification and labeling. However, several substances did show an increased sensitivity of the F(1) adults in comparison to the P(0). These results support the proposal of replacing the current two-generation study by a one-generation study with a more extensive assessment of parameters at F(1) adulthood.
Janer
Gemma
G
National Institute of Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands. Gemma.Janer@RIVM.nl
Hakkert
Betty C
BC
Slob
Wout
W
Vermeire
Theo
T
Piersma
Aldert H
AH
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D010064:Embryo Implantation / Q000187:drug effects; D004785:Environmental Pollutants / Q000145:classification / Q000633:toxicity*; D004822:Epididymis / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D005854:Germ Cells / Q000187:drug effects*; D048788:Growth and Development / Q000187:drug effects; D008098:Litter Size / Q000187:drug effects; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D010575:Pesticides / Q000145:classification / Q000633:toxicity*; D011157:Population Dynamics; D012098:Reproduction / Q000187:drug effects*; D012189:Retrospective Studies; D018570:Risk Assessment; D013094:Spermatozoa / Q000187:drug effects; D013997:Time Factors; D036401:Toxicity Tests, Chronic / Q000379:methods*
D004785:Environmental Pollutants; D010575:Pesticides