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toxicology ch 10
| Question | Answer |
|---|---|
| Thalidomide | sleep aid, alleviate N&V |
| Amelia | absence of limbs |
| Phocomelia | (reduction of long bones in limbs |
| Diethylstilbestrol (DES) | miscarriage prevention, Clear cell adenocarcinoma of the vagina Genital tract anomalies in offspring, Males - low/poor quality semen volume, Latent manifestations, susceptibility to abnormalities may be passed on to future offspring |
| Ethanol | Low birth weight: dose-related |
| Fetal Alcohol Spectrum Disorder (FASD) | Milder forms of neurologic & behavioral disorders |
| Fetal Alcohol Syndrome (FAS) | Craniofacial dysmorphism, Intrauterine & postnatal growth retardation, Retarded psychomotor & intellectual development |
| Tobacco Smoke | Spontaneous abortions, Perinatal effects - affect branching morphogenesis & maturation of lungs, risk of sudden infant death syndrome (SIDS), learning, behavioral, & attention disorders, ¯ birth weight |
| Nicotine | known neuroteratogen in experimental animals Premature births, stillbirths, abruptio placentae |
| Cocaine | local anesthetic w/ vasoconstrictor properties, Abruptio placentae, Premature birth, Microcephaly, Altered prosencephalic (cerebrum) development birth weight, SIDS |
| Neonatal neurologic syndrome | abnormal sleep, tremor, poor feeding, irritability, occasional seizures |
| Retinoids | synthetic vitamin A (retinol; Accutane: treats cystic acne) |
| Fetal Retinoid Syndrome | pattern of mental & physical birth defects; variable range/severity of abnormalities Spontaneous abortion Growth delay; malformations - face, limbs, heart, CNS, & skeleton deformities |
| Antiepileptic Drugs (AEDs) | considered human teratogens, Seizure control during pregnancy crucial but difficult,Most current AEDs (phenytoin [Dilantin], carbamazepine [Tegretol], valproic acid [Depakote]) carry risk of developmental toxicity (abortions, premature, ¯ birth weight) |
| Angiotensin Converting Enzyme (ACE) Inhibitors & Angiotensin Receptor Antagonists In 2nd half of pregnancy | •Oligohydramnios (¯ amniotic fluid), Fetal growth retardation Pulmonary hypoplasia (incomplete lung development), Joint contractures, Hypocalvaria (skull malformations), Neonatal renal failure, Hypotension, Death |
| CRITICAL PERIODS OF SUSCEPTIBILITY & END POINTS OF TOXICITY | Migration/proliferation of primordial germ cells, Zygote & early embryo |
| Preimplantation | toxicity causes either no/slight effect on growth or death |
| Maternal, placental, & embryonic compartments - independent but interacting | Amount & how toxic agent reaches embryo important determinants of developmental impacts |
| Abnormal development may occur through | 1.Direct effect on embryo/fetus 2.Indirectly through toxicity to mother &/or placenta Combination of direct & indirect effects |
| Endocrine disruptor | exogenous agent that interferes w/ production, release, transport, metabolism, binding, action, or elimination of natural hormones |
| Estrogenic or antiestrogenic | ♀ more sensitive - altered pubertal development, ¯ fertility, reproductive tract anomalies |
| antiandrogens | generally restricted to ♂ - hypospadias, retained nipples, ¯ testes & accessory sex gland weights, ¯ sperm production |
| low Thyroid hormones | growth retardation, cognitive defects, delayed eye-opening (animals), hyperactivity, auditory defects, urogenital differentiation |
| Three modes of action | 1.serving as ligands of steroid receptors 2.modifying steroid hormone metabolizing enzymes disturbing hypothalamic-pituitary release of trophic hormones |
| FDA REGULATORY GUIDELINES FOR IN VIVO TESTING Goals: | 1.Detection of any indication of toxicity to reproduction 2.Identify NOAEL that does not produce a significant in adverse effects in offspring |
| Chernoff/Kavlock in vivo test* | 1.Pregnant ♀ exposed during major organogenesis to limited number of doses, levels near but below those inducing maternal toxicity 2.Offspring evaluated over neonatal period for external malformations, growth, & viability |
| Epidemiologic Studies | Link exposures to adverse outcomes w/ rarity of defect & exposure Small population Short timespan |
| Challenges | 1.Elective abortions 2.Homogeneity 3.Recording 4.Confounding factors |
| MODERN SAFETY ASSESSMENT | 1.Assumptions 2.Extrapolation of animal data to humans: 2 directions a.Drugs (voluntary & dose) |
| Approaches | a.Benchmark-dose b.Biologically based dose-response modeling - integrates pharmacokinetic data w/ molecular, cellular/tissue response, & developmental toxicity |
Created by:
aceofspades08