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Regul Toxicol Pharmacol. 2019 Oct;107:104410. doi: 10.1016/j.yrtph.2019.104410. Epub 2019 Jun 19.

Testing developmental toxicity in a second species: are the differences due to species or replication error?

Author information

1
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
2
Medicines Evaluation Board, Utrecht, the Netherlands.
3
Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
4
Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
5
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands; Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands. Electronic address: aldert.piersma@rivm.nl.

Abstract

Developmental toxicity studies for chemical and pharmaceutical safety are primarily performed in rats. Regulatory frameworks may require testing in a second, non-rodent species, for which the rabbit is usually chosen. This study shows that differences in NOAELs or LOAELs (N(L)OAELs) observed between rat and rabbit developmental toxicity studies performed according to OECD guidelines could just as well be caused by study replication errors, and not necessarily by differences in species sensitivity. This conclusion follows from an analysis of a database with rat and rabbit developmental toxicity studies for over 1000 industrial chemicals, pesticides, veterinary drugs and human pharmaceuticals, which included 143 compounds with multiple oral rat studies and 124 compounds with multiple oral rabbit studies. Our analysis confirms earlier findings that, on average over all compounds, rat and rabbit do not differ in sensitivity to developmental effects. There is substantial scatter in the correlation plots comparing rat and rabbit developmental N(L)OAELs, which is easily interpreted as species differences for individual compounds. However, for compounds tested twice in the same species, these N(L)OAELs may differ up to a factor of 25. Thus, potential interspecies differences in developmental N(L)OAEL will be overwhelmed by the reproducibility error, rendering the added value of a second species study questionable. As N(L)OAELs serve as point of departure (POD) for setting health-based guidance values in risk assessment, the large reproducibility error of N(L)OAELs should be taken into account by the introduction of an additional uncertainty factor. It is recommended to aim for reducing the reproducibility error by applying dose-response (BMD) analysis, optimize study designs and harmonize study protocols.

KEYWORDS:

Developmental toxicity; LOAEL; NOAEL; Replication error; Reproducibility error; Residual variance; Species differences

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