Teratology• The science of teratology (a word coined in 1832 by

Geoffrey Saint-Hilares as literally ‘the study of monsters’) has a history predating that of medicine as we know it today. The contemporary definition of teratology is ‘the science dealing with the causes, mechanisms, and manifestations of a structural or functional nature of abnormal prenatal development’.

study of the etiology of abnormal development (the study of birth defects).

• Teratology can be considered a subdivision of

developmental biology (Embryology)

TeratogenTeratogens are xenobiotics and other factors

that cause malformations in the developing conceptus

Examples of teratogens may include pharmaceutic compounds, substances of abuse, hormones found in contraceptive agents, cigarette components, and heavy metals.

Also included in this category are viral agents, altered metabolic states induced by stress, and nutrient deficiencies (e.g., folic acid deficiency).

PRINCIPLES OF TERATOLOGY James Wilson (in 1959) proposed six principles of teratology. A

simplified version of these is as follows:1. Susceptibility to teratogenesis depends on the embryo’s

genotype that interacts with adverse environmental factors (G × E interaction).

2. The developmental stage of exposure to the conceptus determines the outcome.

3. Teratogenic agents have specific mechanisms through which they exert there pathogenic effects.

4. The nature of the teratogenic compound or factor determines its access to the developing conceptus/tissue.

5. The four major categories of manifestations of altered development are death, malformation, growth retardation, and functional deficits.

6. The manifestations of the altered development increase with increasing dose (i.e., no effect to lethality).

When describing teratogens, one may think of three basic characteristics of teratogens:

1. A given teratogen may be organ specific.2. It may be species specific.3. It can be dose specific.

CRITICAL PERIODS

HISTORICAL TERATOGENSThalidomideAccutane (Isotetrinoin)Diethylstilbestrol (DES)Alcohol‘‘Non Chemical’’ Teratogens

Reproductive Toxicity and Teratogenicity

(I) in adults, treatment during a pre-mating period and optionally continuation for the female through implantation or lactation;

(II) in pregnant animals treatment during the major period of organogenesis; and

(III) treatment of pregnant/lactating animals from the completion of organogenesis through lactation (peri- and postnatal study).

TESTING PROTOCOLSFDA Guidelines for Reproduction Studies

for Safety Evaluation of Drugs for Human UseMultigenerational Study.Single-Generation Studies.

Segment I: Evaluation of Fertility and Reproductive Performance

Segment II: Assessment of Developmental Toxicity. Segment III: Postnatal Evaluation.

The end points observed in these types of tests, depending on study design, are as follows:

1. Fertility index, the number of pregnancies relative to the number of matings.

2. The number of live births, relative to the number of total births.

3. Pre-implantation loss, or number of corpora lutea in the ovaries relative to the number of implantation sites.

4. Postimplantation loss, or the number of resorption sites in the uterus relative to the number of implantation sites.

5. Duration of gestation.6. Effects on male or female reproductive systems.7. Litter size and condition, gross morphology of pups at

birth, gender, and anogenital distance.8. Survival of pups.9. Weight gain and performance of adults and pups.10. Time of occurrence of developmental landmarks, such

as eye opening, tooth eruption, vaginal opening in females, preputial separation in males.

11. Morphological abnormalities in weanlings.

International Conference of Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)—US FDA, 1994

ICH 4.1.1: Fertility Assessment.ICH 4.1.2: Postnatal Evaluation and

Pregnancy State Susceptibility.ICH 4.1.3: Assessment of Developmental

Toxicity.

Alternative Test Methods

Behavioral Teratology

Behavioral teratology, or neurobehavioral teratology, is often referred to separately from behavioral toxicology. Behavioral teratology focuses on the behavioral impact of toxic exposures occurring prenatally or during early development. In some cases, these studies may only track the consequences of chemical exposures into early postnatal life, but in others effects may be studied well into the juvenile and even adult stages of the life cycle. Because the possibility has been raised that developmental exposures may accelerate the processes of aging, some studies are now beginning to follow subjects throughout the lifespan. Behavioral teratology studies typically include a series of tasks designed to evaluate multiple behavioral functions. Consequently, such experiments

may include assessment of the development of various reflexes and developmental landmarks (e.g., eye opening), performance on a functional battery (FOB), motor activity, sensory capabilities, learning, and even schedule-controlled operant behavior. In addition, some such experiments may include evaluation of behaviors deemed ‘species specific’ (i.e., behaviors that are innate and unique to that species), such as the ontogeny of aggression, play, or vocalization in rodents.