[Developmental and reproductive toxicology: interest and interpretation]. / Toxicologie de la reproduction : intérêt et interprétation.

Developmental and reproduction toxicology studies (DART) are an essential part of the non-clinical dossier for a regulatory submission. They are performed according to internationally recognized and regulatory protocols. They allow a reasonable risk evaluation when a drug is given at any stage of the reproduction cycle. They study impact of the test compound on reproductive functions of both sexes, on pregnancy and embryo/fetal development, parturition and postnatal development of the progeny. The data interpretation and the establishment of safety margins lead to the edition of specific recommendations in the summary of product characteristics (SPC) and directly to the prescribers.

Conclusions of the French Food Safety Agency on the toxicity of bisphenol A.

Since more than 10 years, risk assessment of bisphenol A (BPA) is debated at the international level. In 2008, the U.S. National Toxicology Program (NTP) expressed some concern for adverse effects, at current level of exposure to BPA, on developmental toxicity. In this context, the French Food Safety Agency (AFSSA) decided to review the toxicity data on BPA with a special focus on this endpoint at doses below 5mg/kg bw/day (the no observed adverse effect level set by different regulatory bodies). This paper summarizes the conclusions of a collective assessment conducted by an expert Working Group from AFSSA. Studies were classified into 3 groups: (i) finding no toxicity, (ii) reporting results not considered to be of concern and (iii) indicating warning signals. The term "warning signal" means that no formal conclusion can be drawn regarding the establishment of a health based guidance value but the study raises some questions about the toxicity of BPA at low doses. It was concluded that studies are needed to ascertain the significance for human health of these warning signals and to be able to propose new methodologies for assessing the risks associated with low doses of BPA and more generally of endocrine disruptors.

Preclinical evaluation of juvenile toxicity.

A pediatric assessment is now a required component of every New Drug Application in North America or Marketing Authorization Application in Europe, unless a waiver has been granted previously. Nonclinical juvenile toxicity studies are usually required as part of this assessment. The protocols for juvenile toxicity studies are devised in consultation with the FDA or EMEA. It is important to approach the regulatory authority well in advance in order not to delay the marketing authorization of the drug and to confirm the need or not to perform a preclinical evaluation in juvenile animals. The choice of species and the design of juvenile studies are based on a series of complex considerations, including: the therapeutic use of the drug, the age at which children will be treated, the duration of treatment, and potential age- or species-specific differences in pharmacokinetics or toxicity.

PEGylated proteins: evaluation of their safety in the absence of definitive metabolism studies.

During the development of any PEGylated protein or peptide, toxicology in relevant species will be conducted prior to human exposure. Normally, comprehensive metabolism data accompany the toxicity studies for a small molecule. We have examined whether such studies would be relevant in the safety assessment of PEGylated material. Literature data indicate that the polyethylene glycol (PEG) associated with a biological molecule should provide no extra concern because the exposure-toxicity relationship of PEG in animals and humans has been thoroughly investigated and metabolism/excretion of PEG is well understood. Based on the comparisons of PEG exposure from PEGylated biological products and the exposure of PEG associated with toxicity in humans, the therapeutic index is large (approximately 600-fold or greater). Therefore, assuming that toxicological evaluation of a biological molecule of interest is complete and satisfactory therapeutic windows are achieved, the data contained in this review indicate that the PEG associated with a protein or other biological molecule does not represent an additional unquantified risk to humans.