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10-devtox-actual.ppt

– 50%-80% die before term– Most before implantation – Major malformations: 2% to 5%: 20 to 50 per 1000 live births • Genetic syndromes: 20% or ≤ 10 per 1000 live births• Environmental origins: – Maternal infections: 2%-3%: ≤ 1.5 per 1000 live births– Maternal metabolic imbalance 1%-2%: ≤ 1 per 1000 live births – Maternal infections 2%-3%: ≤ 1.5 per 1000 live births – Drugs and other chemicals: 4-6%: ≤ 3 per 1000 live births • The causes of 60%-70% of birth defects are unknown
• 2-5% of newborns have a major malformation – For 2/3 of major malformations, we don’t know why.
• We can prevent ~ 10% of major malformations Organogenesis
Pattern formation
Organ formation
Physical defects
• Adequate nutrition• Hormonal balance Fetal Period
Maturation and growth
Functional deficits
Test for developmental toxicity before chemicals are marketed.
Proven positive
SCORE CARD
Proven positive
Probably negative
Probably negative
Identifying Human Developmental Toxicants 1. The developmental toxicant must have access to the target
Physical agents must penetrate maternal tissues • Animal studies
Epidemiology
2a. Dose-response relationships differ from other forms of toxicity
2b. There is a threshold dose below which there is no fetal damage
Most developmental toxicants are not mutagens (But most mutagens are developmental toxicants.) • Alert clinicians
3. Genetics interacts with the fetal environment
Most developmental toxicants affect only some exposed fetuses ~ 30% of offspring of alcoholic mothers have fetal alcohol syndrome Thalidomide and possibly retinoic acid are exceptions to this rule Anencephaly and spina bifida (ASB) illustrate this rule Between strains or individuals within species 4. Time of exposure is very important in determining
– Type of malformation– Incidence of malformation– Most birth defects must occur before a tissue or organ is • Exception: cocaine• The most sensitive period for malformations is during – Well before the end of the 3rd month of pregnancy Timetable of Thalidomide-Induced Malformations in Humans Human Organogenesis: Post-ovulatory days ~ 20-56 (Timing is from the start of the last menstrual period) Malformations Induced by a Hypothetical Teratogen 5. Manifestations of developmental toxicity include
– Death– Malformation– Growth retardation– Functional deficit • A single chemical may cause several effects by different mechanisms Functional Deficits
Growth Retardation
• Often occur in an already formed organ• Are not readily apparent at birth• Chemicals causing neurological deficits – Diphenylhydantoin (DilantinTM)– All psychoactive drugs? – Continuous dosing from before mating of parents (F ) to • Highest dose must affect dam adversely• Additional studies to examine effects on – Fertility and mating– Organogenesis– Parturition and lactation

Source: http://www.life.illinois.edu/ib/485/10-DevTox.pdf

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