Developmental toxicology 18 nov-11-1

Developmental Developmental ToxicologyToxicology

Iyad ABOU RABIIBDS, OMS, MD, PhD

Why studying Developmental Why studying Developmental Toxicology and Pharmacology?Toxicology and Pharmacology?

At present, the etiology of congenital malformations can be divided into three categories: ◦Unknown , ◦genetic, and ◦environmental.

How Drugs Cross the PlacentaHow Drugs Cross the Placenta

•Some of the fetus's blood vessels are contained in tiny hairlike projections (villi) of the placenta that extend into the wall of the uterus. •The mother's blood passes through the space surrounding the villi (intervillous space).

How Drugs Cross the PlacentaHow Drugs Cross the Placenta

Only a thin membrane (placental membrane) separates the mother's blood in the intervillous space from the fetus's blood in the villi. Drugs in the mother's blood can cross this membrane into blood vessels in the villi and pass through the umbilical cord to the fetus.

Pharmacokinetics and metabolism ofPharmacokinetics and metabolism ofthe drug or chemicalthe drug or chemical

Background reproductive risks in pregnancy.


Etiology of human congenital malformations observed during the first year of life.


Considerations that affect the interpretation of dose-response relationships.


Pregnancy-related physiological alterations in the mother that affect the pharmacokinetics of drugs.


Pregnancy-related physiological alterations in the fetus that may affect the pharmacokinetics of drugs.

Which Toxics are Dangerous?Which Toxics are Dangerous?

illegal drugs, such as heroin and cocaine, pose dangers to a pregnant woman.

Legal substances, such as alcohol and tobacco, are also dangerous

Medical drugs, both prescription and over-the-counter, can be harmful.

Environmental pollutants

Drugs and the Stages of Drugs and the Stages of PregnancyPregnancy

Some drugs can be harmful when used at any time during pregnancy;

others, however, are particularly damaging at specific stages. ◦Stage of organ formation◦Stage of prenatal growth◦Stage of birth


The stage of organ formationMost of the body organs and systems of the baby-to-be are formed within the first ten weeks or so of pregnancyDuring this stage, some drugs and toxics cause malformations of such parts of the developing fetus, as the heart, the limbs, and the facial features.


The stage of prenatal growthAfter about the tenth week, the fetus should grow rapidly in weight and size. At this stage, certain drugs may damage organs that are still developing, such as the eyes, as well as the nervous system.


The stage of prenatal growthThe greatest danger drugs pose at this stage is their potential to interfere with normal growth. This will result in a low-birthweight baby—a baby born too early, too small, or both.Low-birthweight babies require special care and run a much higher risk of severe health problems or even death.


The stage of birth Some drugs can be especially harmful at the end of pregnancy. They may make delivery more difficult or dangerous, or they may create health problems for the newborn baby.

Drugs and Toxics affecting Drugs and Toxics affecting Development : NarcoticsDevelopment : Narcotics

Drugs affecting Development : Drugs affecting Development : NarcoticsNarcotics

Cocaine and methamphetamine are powerful stimulants of the central nervous system.

They suppress the mother’s appetite, the blood vessels to constrict, the heart to beat faster, and the blood pressure to soar.

Drugs affecting Development : Drugs affecting Development : NarcoticsNarcotics

Heavy narcotics use increases the danger of premature birth with such accompanying problems for the infant as low birth weight, breathing difficulties, low blood sugar (hypoglycemia), and bleeding within the head (intracranial hemorrhage).

intracranial hemorrhage

Drugs affecting Development : Drugs affecting Development : MedicationsMedications

Isotretinoin (Accutane) and etretinate (Tegison) are used to treat chronic acne and psoriasis. They may cause chronic malformations during the stage of organ development.


Anticonvulsants, such as phenytoin (Dilantin) and carbamezapine (Tegretol), are used to prevent epileptic seizures. They are associated with defects of the heart and face, as well as mental retardation.

defects of the face


Trimethadione (Anticonvulsant)TRIDIONE®

◦Increased risk of miscarriage in the woman

◦High (70%) risk of birth defects, including a cleft palate and defects of the heart, face, skull, hands, or abdominal organs

Cleft palate


Valproate (Anticonvulsant)DEPARENE®

High risk of birth defects, including a cleft palate and defects of the face, skull, or hands.risk of miscarriage .


Antimigraine drugs, such as ergotamine and methysergide, are used to head off migraine attacks but raise the risk of premature labor.


Anticoagulant drugs based on coumarin are used in the treatment of heart disease and stroke, to slow blood clotting. Taken during early pregnancy, they are associated with facial malformations and mental retardation. Later on they raise the risk of uncontrolled bleeding.


Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs (NSAIDs) interfere with blood clotting and increase the risk of uncontrolled bleeding for both mother and baby. Toward the end of pregnancy, they hinder production of the hormones that stimulate labor, so that labor may be dangerously delayed or extended.


Tetracycline (ACHROMYCIN® TETRACYN® SUMYCIN®)

Slowed bone growth, permanent yellowing of the teeth, and increased susceptibility to cavities in the babyOccasionally, liver failure in the pregnant woman

TetracyclineTetracycline


Angiotensin-converting enzyme (ACE) inhibitors (Antihypertensive)When the drugs are taken in pregnancy, kidney damage in the fetus, a reduction in the amount of fluid around the developing fetus (amniotic fluid), and defects of the face, limbs, and lungs

defects of the lungs


Busulfan (Chemotherapy) MYLERAN ® Birth defects such as underdevelopment of the lower jaw, cleft palate, abnormal development of the skull bones, spinal defects, and ear defects

Similar effects are found with Methotrexate (RHEUMATREX ®)

nderdevelopment of the lower jaw

Toxics affecting Development : Toxics affecting Development : Alcohol Alcohol

Alcohol is one of the most dangerous substances for pregnant women, especially in the early weeks.

In the mother’s body, alcohol breaks down chemically to a cell-damaging compound that is readily absorbed by the fetus.

Heavy drinking during early pregnancy greatly increases the risk of a cluster of birth defects known as fetal alcohol syndrome

Toxics affecting Development: Toxics affecting Development: Alcohol Alcohol

fetal alcohol syndromeThis syndrome includes a small skull (microcephaly), abnormal facial features, and heart defects, often accompanied by impeded growth and mental retardation. Heavy drinking in later pregnancy may also impede growth.

Toxics affecting Development : Toxics affecting Development : TobaccoTobacco

Nicotine depresses the appetite at a time when a woman should be gaining weight, and smoking reduces the ability of the lungs to absorb oxygen. The fetus, deprived of sufficient nourishment and oxygen, may not grow as fast or as much as it should.

Chemical Toxics affecting Chemical Toxics affecting DevelopmentDevelopment

Polychlorinated biphenyls : Poisoning has occurred from adulteration of food products (cola-colored babies, ◦CNS effects, ◦pigmentation of gums, nails, teeth and groin, ◦hypoplastic deformed nails, ◦intrauterine growth retardation, abnormal skull

calcification).

abnormal skull calcification


Toluene addiction : Facial dysmorphology, mental retardation

Gasoline addiction : Facial dysmorphology, mental retardation

Facial dysmorphology


Mercury : Causes Minamata disease consisting of cerebral palsy, microcephaly, mental retardation, blindness, and cerebellum hypoplasia.

cerebellum hypoplasiamicrocephaly

ConclusionConclusion

Concerns about environmental chemicals and physical agents are clearly justified because, in most cases, not enough information is available on the potentially differential effects on the fetus and child

it is not possible to determine whether a chemical or drug is safe or hazardous unless the magnitude of the exposure is known.

ConclusionConclusion

Such information, can only be obtained from high-quality human and animal toxicology and epidemiological studies which include toxicokinetic and toxicodynamic data.

Keep in mindKeep in mind

All chemicals and drugs have the potential for developmental toxicity if the exposure is high enough

So extensive program of monitoring, reducing, and ,eliminating the delivery of chemicals to the environment and the exposure of populations to chemicals is needed

Developmental toxicology 18 nov-11-1

Health & Medicine

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