Combined retrospective analysis of 498 rat multi-generation reproductive toxicity studies: on the impact of parameters related to F1 mating and F2 offspring.
The multi-generation reproductive toxicity study (OECD TG 416 and USEPA 870.3800) has been extensively used internationally to assess the adverse effects of substances on reproduction. Recently the necessity of producing a second generation to assess the potential for human health risks has been questioned. The present standardized retrospective analysis of the impact of the second generation on overall study outcome combines earlier analyses and includes 498 rat multi-generation studies representing 438 different tested substances. Detailed assessment of study reports revealed no critical differences in sensitivities between the generations on the basis of a consideration of all endpoints evaluated. This analysis indicates that the second generation mating and offspring will very rarely provide critical information. These findings are consistent with the conclusions of previous retrospective analyses conducted by RIVM, USEPA and PMRA and support adoption of the proposed OECD extended one-generation reproductive toxicity study protocol in regulatory risk assessment testing strategies.
Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. aldert.piersma@rivm.nl
A H
AH
Piersma
E
E
Rorije
M E W
ME
Beekhuijzen
R
R
Cooper
D J
DJ
Dix
B
B
Heinrich-Hirsch
M T
MT
Martin
E
E
Mendez
A
A
Muller
M
M
Paparella
D
D
Ramsingh
E
E
Reaves
P
P
Ridgway
E
E
Schenk
L
L
Stachiw
B
B
Ulbrich
B C
BC
Hakkert
D000375:Aging; D000818:Animals; D004305:Dose-Response Relationship, Drug; D047108:Embryonic Development / Q000187:drug effects; D023381:Endpoint Determination; D005260:Female; D005298:Fertility / Q000187:drug effects; D005865:Gestational Age; D007774:Lactation; D008098:Litter Size / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure; D018812:Paternal Exposure; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D012098:Reproduction / Q000187:drug effects; D055703:Reproductive Physiological Phenomena / Q000187:drug effects*; D012107:Research Design / Q000592:standards; D018570:Risk Assessment; D018675:Toxicity Tests / Q000592:standards