Reproductive toxicants have a threshold of adversity

Abstract

This paper surveys the scientific basis for the current threshold approach for reproductive hazard and risk assessment. In some regulatory areas it was recently suggested to consider reproductive toxicants under the stringent linear extrapolation risk assessment paradigm that was developed for genotoxic carcinogens. First, the current risk assessment paradigm for genotoxic carcinogens is addressed, followed by an overview of reproductive toxicology and its threshold dose approach for hazard and risk assessment, the testing procedures for assessing the reproductive toxicity of chemicals, and the derivation of conclusions on their risk assessment and Classification, Labelling and Packaging (CLP). Relevant details of testing methodologies are discussed, such as exposure time windows, parameters determined, and the coverage of the entire reproductive cycle. In addition, the dose-response relationship is considered, illustrated with several examples. It is concluded that the current risk assessment methodology for genotoxic carcinogens is a debatable worst-case scenario and that for risk assessment of reproductive toxicants the threshold dose approach remains valid.

Keywords::

• ADME
• ALARA
• benchmark dose
• classification and labeling
• dose-response
• genotoxic carcinogen
• homeostasis
• linear extrapolation
• Margin of Exposure (MoE)
• reproductive cycle
• reproductive toxicology
• risk assessment

Acknowledgments

The authors greatfully acknowledge the critical review of the manuscript by Drs. Wil ten Berge, Peter Bogaard, Liesbeth Heijink, Ada Knaap, Taeke Pal, Ine Waalkens-Berendsen, Ruud Woutersen, and Peter Weterings.

Declaration of interest

This work was sponsored by the Dutch Ministry of Social Affairs and Employment (SZW). The authors’ affiliations are as shown on the first page. The authors have sole responsibility for the writing and content of the paper.