Biologic Markers in Reproductive Toxicology (1989) / Chapter Skim
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27. Methodologic Issues of Extrapolation from Animal Studies to Human Toxicant Exposure
27. Methodologic Issues of Extrapolation from Animal Studies to Human Toxicant Exposure
Pages 289-296
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From page 289... ...
INVESTIGATION OF UNDERLYING MECHANISMS One way of relating animal findings and human hazard is to evaluate underlying structural, biochemical, and physiologic correlates of overt functional changes seen in animals. The rationale is that the determination of the target and degree of toxicity produced by developmental exposure will yield information relevant to the human situation.
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From page 290... ...
· The startle reflex is mediated via simple neuronal circuits. TABLE 27-1 Sequelae of Developmental Exposure to Drugs in Humans and Animalsa REM~ Sleep Relevant Effects in Effects in Deprivation Transmitter Drug Humans Animals Effects System Clonidine Smaller head Hyperactivity, + + + Norepinephrine circumference, delayed motor questionable development necrologic status, increased myoclonic jerks during sleep Diazepam Low Apgar score, Hyperactivity, + Gamma-amino reluctance to decreased male isobutyric acid eat sexual behavior, decreased startle reflex Imipramine- Poor sucking, Hyperactivity, + + + Norepinephrine, lye agents irritability decreased male acetylcholine, sexual behavior, serotonin smaller brain Reserpine Anorexia, Smaller brain, + Norepinephrine, lethargy altered activity, dopami;ne, altered startle seroton~n reflex aData from Mirmiran et al., 1985.
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From page 291... ...
In the spinal cord and facial motor nucleus, serotonin and norepinephrine increase auditory startle and glycine tonically inhibits it; it appears that GABA can also inhibit the response at this level. Supraspinally, dopamine and perhaps GABA receptor stimulation increases startle, and serotonin activation depresses it.
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From page 292... ...
Both clinical and experimental studies designed to evaluate neurobehavioral outcomes after prenatal drug or chemical exposures provide primarily descriptive information. The methods permit a description of functional deficits after insult, but not of underlying physiologic or neurochemical mechanisms responsible for the observed behavioral alterations.
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From page 293... ...
The clinical relevance of experimental data on cognitive functions is more difficult to evaluate. Tests of human and animal cognitive abilities might evaluate very different functions; i.e., a rodent TABLE 27-2 Examples of Motor Dysfunction After Behavioral-Teratogen Exposuresa Agent Effects in Humans Effects in Rodents Lead Mercury PCBs Phenytoin Ethanol Methadone Delayed growth and motor development, motor incoordination, deficits in fine motor control Delayed growth and motor development, cerebral palsy, seizure disorders Depressed reflexes, delayed motor development Delayed growth and motor development Delayed growth and motor development Neonatal abstinence syndrome: tremors, sleep disturbances, hyporeflexia, irritability aData from Adams 1986.
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From page 294... ...
TABLE 27-3 Examples of Cognitive Dysfunction After Behavioral-Teratogen Exposuresa Agent Effects in Humans Effects in Rodents Lead Decreased general intelligence, decreased attention span, impaired verbal ability PCBs Phenytoin Ethanol Mercury Decreased general intelligence, decreased attention span Impaired visual recognition memory Decreased general intelligence Decreased general intelligence, decreased attention span, delayed reaction time Methadone None reported Impaired learning ability on passive avoidance and T-maze tasks Learning deficits on many tasks Impaired learning on avoidance tasks Impaired spatial learning on water-maze tasks Learning deficits on many tasks None reported aData from Adams, 1986.
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From page 295... ...
The literature of animal behavioral teratology has expanded greatly in recent years and suggests that a number of additional drugs and chemicals warrant clinical investigation. However, the potential value of animal data in predicting human hazard cannot be determined fully until clinical studies to look for behavioral dysfunctions identified in experimental animals are designed and conducted.
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From page 296... ...
Thus, whether developmental-toxicology studies are performed with inbred strains of mice or in the highly diverse human and whether one or both parents have been exposed to a toxicant are important considerations in evaluating and interpreting postnatal functional data. The postnatal environment can have an impact on developmental toxicity, maximizina or minimizing the expression of NEURODEVELOPMENTAL TOXICOLOGY enrichment might contribute to the mani festations of toxicity.
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