Teratology testing under REACH.

REACH guidelines may require teratology testing for new and existing chemicals. This chapter discusses procedures to assess the need for teratology testing and the conduct and interpretation of teratology tests where required.

The teratology testing of food additives.

The developmental and reproductive toxicity testing (including teratogenicity) of new foods and food additives is performed worldwide according to the guidelines given in the FDA Redbook. These studies are not required for substances that are generally recognized as safe, according to the FDA inventory. The anticipated cumulated human exposure level above which developmental or reproduction studies are required depends on the structure-alert category. For food additives of concern, both developmental (prenatal) and reproduction (multigeneration) studies are required. The developmental studies are performed in two species, usually the rat and the rabbit. The reproduction study is generally performed in the rat. The two rat studies are preferably combined into a single experimental design, if possible. The test methods described in the FDA Redbook are similar to those specified by the OECD for the reproductive toxicity testing of chemicals.

Developmental toxicity testing of vaccines.

Preventative and therapeutic vaccines are increasingly used during pregnancy and present special considerations for developmental toxicity testing. The various components of the vaccine formulation (i.e., protein or polysaccharide antigen, adjuvants, and excipients) need to be assessed for direct effects on the developing conceptus. In addition, possible adverse influences of the induced antibodies on fetal and/or postnatal development need to be evaluated. A guidance document on the preclinical testing of preventative and therapeutic vaccines for developmental toxicity was issued by the FDA in 2006. Preclinical studies are designed to assess possible influences of vaccines on pre- and postnatal development. The choice of model animal for these experiments is influenced by species differences in the timing and extent of the transfer of the induced maternal antibodies to the fetus. The cross-placental transport of maternal immunoglobulins generally only occurs in late gestation and tends to be greater in humans and monkeys than in non-primate species. For many vaccines, the rabbit shows a greater rate of prenatal transfer of the induced antibodies than rodents. For biotechnology-derived vaccines that are not immunogenic in lower species, nonhuman primates may be the only appropriate models. It may be advisable to test new adjuvants using the ICH study designs for conventional pharmaceuticals in addition to the developmental toxicity study with the final vaccine formulation.

The teratology testing of cosmetics.

In Europe, the developmental toxicity testing (including teratogenicity) of new cosmetic ingredients is performed according to the Cosmetics Directive 76/768/EEC: only alternatives leading to full replacement of animal experiments should be used. This chapter presents the three scientifically validated animal alternative methods for the assessment of embryotoxicity: the embryonic stem cell test (EST), the micromass (MM) assay, and the whole embryo culture (WEC) assay.

Teratology studies in the rat.

The rat is the rodent species of choice for the regulatory safety testing of xenobiotics, such as medicinal products, food additives, and other chemicals. Many decades of experience and extensive data have accumulated for both general and developmental toxicology investigations in this species. The high fertility and large litter size of the rat are advantages for teratogenicity testing. The study designs are well defined in the regulatory guidelines and are relatively standardized between testing laboratories across the world. Teratology studies address maternal- and embryo-toxicity following exposure during the period of organogenesis. This chapter describes the design and conduct of a teratology study in the rat in compliance with the regulatory guidelines. The procedures for the handling and housing of the pregnant animals, the caesarean examinations and the sampling of fetuses for morphological examinations are described. The utility and design of preliminary studies and the inclusion of satellite animals in the main study for toxicokinetic sampling are discussed.

Frog embryo teratogenesis assay on Xenopus and predictivity compared with in vivo mammalian studies.

Frog embryo teratogenesis assay on Xenopus (FETAX) has been routinely used in our laboratory for the last 12 years as a routine developmental toxicity screening test for pharmaceutical candidate compounds. To date, out of more than 400 candidates tested in FETAX, around 60 have also been evaluated in mammalian embryotoxicity studies according to standard ICH protocols.Compound teratogenic potential in both FETAX and mammalian embryotoxicity studies is determined after analysis of the developmental toxicity characterized by embryotoxicity, growth delay, and/or potential to induce malformations. Based on this experience, the predictivity of FETAX is 81% with a minimal proportion of false positive results.

Reproductive toxicity risk assessment for pesticides.

Human health risk assessment for pesticides is based mainly on animal studies submitted by the applicant and aims to determine safe exposure levels for operators (farmers and agricultural workers) and consumers of all age groups. Critical effects, including those resulting from reproductive toxicity, are identified during hazard assessment from an evaluation of all studies in the toxicity package. Reproductive or developmental effects are considered critical if they are more severe or occur at lower doses than other toxicities. Reference values for human exposure are then derived from No Adverse Effect Levels for the relevant critical effects by applying safety factors. This paper describes methods and caveats applicable to the evaluation of prenatal toxicity and two-generation studies from the view of a regulator, stressing the importance of individual litter data and the relationship between different endpoints.

[ Legal aspects of advice provided by an institutional pharmacovigilance specialist to health-care professionals. Consequences in the field of teratology ]. / Aspects juridiques des conseils donnés par un pharmacovigilant institutionnel aux professionnels de santé. Conséquences dans le champ de la tératologie.

An institutional pharmacovigilance specialist gives advice only when consulted by a prescribing physician about a pregnant woman. The situation may involve a pregnant woman for whom a prescription may be considered or a pregnant woman for whom a prescription has been given. The aim is to evaluate the risk for the fetus, both before and after the fact. In view of recent decisions by the Cour de Cassation (*) which imposed penalties for preventing a woman exposed to a teratogenic risk from resorting to an abortion by providing her with inapropriate information, we are suggesting here the hypothesis that an institutional pharmacovigilance specialist acting as a consultant could be implicated. However, this hypothesis is purely academic. If action were taken to render a pharmacovigilance specialist liable, it is in fact the State that would have to answer.