Problems in testing and risk assessment of endocrine disrupting chemicals with regard to developmental toxicology.

Endocrine disrupting chemicals (EDCs) may affect mammalian development either indirectly (by impairing implantation, placental development, lactation, etc.) or directly, altering the maturation of target tissues. Current regulatory tests for reproductive/developmental toxicity should be carefully evaluated with regard to risk assessment of EDCs, considering hazard identification (are relevant endpoints being assessed?) and dose-response assessment (are sensitive NOEL/dose-response curves being provided?). Many in vitro and in vivo assays for sex steroid disruption are available; provided that the metabolic capacities of the assays are defined, they could be integrated in a sensitive battery for early detection of steroid-disrupting potentials. The screening battery should address further regulatory in vivo tests (e.g. what specific parameters have to be investigated). As regards dose-response, qualitative differences may be observed between lower and higher exposures, showing primary hormone-related effects and frank embryotoxicity, respectively. Other problems concern (a) the identification of critical developmental windows, according to hormone concentrations and/or receptor levels in the developing target tissues; (b) the potential for interactions between chemicals with common mechanism/target (e.g. xenoestrogens); (c) most important, besides sex steroids more attention should be given to other mechanisms of endocrine disruption, e.g., thyroid effects, which can be highly relevant to prenatal and postnatal development.

[Effects of chemical mixtures on embryonic development: examples of experimental models and problems in risk assessment]. / Effetti tossici di miscele chimiche sullo sviluppo prenatale: esempi di modelli sperimentali e problemi relativi alla valutazione del rischio.

Toxicological risk deriving from the exposure to mixtures of toxic substances, the study of possible interactions among them and their mechanisms of action are of special interest in prenatal toxicology. In fact, embryo is a dynamic complex system whose gradual development substantially modulates the extent and type of damages to which it may be sensitive, through specific, critical periods of sensitivity. In this paper, a number of types of interactions among toxic substances which show the same mechanisms of action and/or the same target site, are analysed. Besides, pharmacokinetic interactions among teratogenic agents and substances modulating their metabolism, need specific evaluations because of the wide variability of possible events. In conclusion, risk assessment in prenatal toxicology has to put greater attention to the various types of effect and pharmacokinetic interaction since they might result in an increasing risk at low doses.

The usefulness of a prenatal genetic questionnaire in genetic risk assessment.

OBJECTIVE: To evaluate a prenatal questionnaire as a genetic screen and as an aid in pre-amniocentesis genetic risk assessment. METHODS: In a retrospective cohort study, charts were reviewed for 158 consecutive women of advanced maternal age referred for genetic counseling. Genetic risks identified by use of a questionnaire completed by 79 consecutive patients were compared with those risks identified by the referring physician, those identified during subsequent three-generation pedigree analysis, and to genetic risks identified by pedigree evaluation of 79 consecutive individuals who underwent genetic counseling without the aid of a questionnaire (controls). RESULTS: Sixteen (20%) of the questionnaires revealed a previously unidentified genetic risk. The sensitivity and specificity of the questionnaire were determined to be 40.0 and 97.4%, respectively. Pedigree analysis alone (control group) identified significantly more at-risk pedigrees than did the questionnaire alone (34 versus 20%, P < .05), but identified significantly fewer at-risk pedigrees than obtained from the study group patients who completed a questionnaire and pedigree evaluation (34 versus 50.6%, P < .05). Of all 158 patients, 15.2% (n = 24) underwent additional testing on the basis of genetic risk assessment. There was no difference between the study and control groups in additional evaluations performed (P = 1.0). CONCLUSION: A three-generation pedigree is superior to a questionnaire in genetic risk assessment. The questionnaire was not sufficiently sensitive to serve independently as an adequate genetic screen or risk assessment tool and did not influence subsequent fetal evaluation. Assessment of the sensitivity and specificity of prenatal genetic questionnaires should be undertaken before their routine clinical use.