Reproductive Toxicology, Vol. 7, pp. 171-173, 1993 0890-6238/93 $6.00 + .00 Printed in the U.S.A. All rights reserved. Copyright © 1993 Pergamon Press Ltd.

PRINCIPLES OF N E U R O B E H A V I O R A L TERATOLOGY*

JANE ADAMS University of Massachusetts, Boston

I. Introduction A. Endpoints of abnormal development

Death Malformation Growth retardation Functional deficits

B. Neurobehavioral teratology Teratogenic agents can cause one or more of the 4 adverse outcomes. Neurobehavioral teratology is the study of abnormal develop- ment of the nervous system and the func- tional consequences of this structural abnor- mality. Abnormalities may be represented by gross malformation or by non-life-threaten- ing, but nevertheless, significant disruptions in brain morphology. Structural abnormali- ties may be anatomically detectable by im- aging techniques or inferred from develop- mental disorders. For this reason, growth retardation and functional deficits are pri- mary endpoints of interest to the neurobe- havioral teratologist. In order to associate dysfunction with prenatal insult, other poten- tial causative factors must be excluded.

II. Principles of Neurobehavioral Teratology (adapted from Wilson [1], Vorhees [2]) Neurobehavioral teratology is governed by many of the same principles as is the parent discipline, teratology. This discussion will focus on information more specific to the endpoints of growth retardation and functional deficits. A. Susceptibility to insult depends on the geno-

type of the conceptus and the manner in which this interacts with the environment. With respect to general mental abilities, both genetic endowment and postnatal environ- mental quality are prominent determinants. Two key predictive variables for children's mental abilities are parental educational level and socioeconomic status. Thus, it is critical

*This d e t a i l e d o u t l i n e w a s u s e d to s u p p l e m e n t a n o r a l p r e s e n - t a t i on . U s e d b y a r r a n g e m e n t w i t h D o c t o r A d a m s .

B.

C.

that these variables be examined in human studies. Susceptibility to insult varies with the devel- opmental stage at the time of exposure. As with other major malformations, major structural abnormalities in brain develop- ment are produced during the period of or- ganogenesis (days 14 to 60 in humans). Thus, the life-threatening or most severely handi- capping functional deficits are produced fol- lowing exposures during this interval. This does not mean, however, that exposures at later stages of pregnancy are "safe." During the remainder of pregnancy (as well as in the postnatal period), changes in brain develop- ment take place that are critical to higher level functioning. Thus, when endpoints such as growth retardation, sensory deficits, motor impairments, mental retardation, and learning disabilities are of interest, one must consider the entire pregnancy period as a period of risk. The final manifestations of abnormal devel- opment are death, malformations, growth re- tardation, and functional disorder. Unlike death and malformation, growth and function are represented by continuous vari- ables. Growth retardation and functional deficit are usually defined by degree of devia- tion from the normal "score," often as the lowest fifth or tenth percentile. In the case of general mental ability, "ability level" is defined by performance on a standardized test for which scores from representative samples of individuals of different ages have been normalized using Z statistics. This pro- duces a normal distribution of scores in which 100 is average and the standard devia- tion is 15. Widely accepted performance cat- egories are shown in Table I. Many studies that have examined adverse drug effects on cognitive ability have focused on the inci- dence rate of mental retardation only, an out- come that exists in only 2.1% of the general

171

172 Volume 7, Number 2, 1993 Reproductive Toxicology

Table 1. Performance categories

Score Description Prevalence

-<70 Mentally Retarded 2.1% 71-85 Borderline Intelligence 13.6% 86-115 Average Intelligence 68.2%

116-130 Superior 13.6% >> 130 Gifted 2.1%

D.

population. This approach is quite conserva- tive: it does not examine effects on the inci- dence of borderline intelligence or average, but learning-disabled (having at least one area of special weakness). Clearly, we are more interested in the full range of outcomes with respect to general mental abilities, and should examine outcome with greater resolu- tion and corresponding attention to degree of impairment (see discussion by Adams, Vor- hees, and Middaugh [3]). The probability of detection of adverse neu- robehavioral outcome varies with the method of measurement and the age at mea- surement. 1. Method of measurement of functional dis-

order. In both human and animal studies, it is important to examine multiple aspects of nervous system functioning (for exam- ple, human: sensory abilities, motor skill and coordination, s enso ry -moto r integra- tion, language-based abilities, accumu- lated knowledge, attention, reasoning ability, and other aspects of cognition.

2. Age at measurement of functional disor- der. Due to practical constraints, most hu- man studies within this field have mea- sured outcome during the neonatal or infancy period. Clearly, many aspects of neuropsychological functioning cannot be assessed at this time, and others can be assessed only in a minimal fashion. Re- search has repeatedly shown that the de- tection of adverse outcomes increases with the age at measurement. This has been elegantly demonstrated in longitudi- nal studies of children exposed to the ru- bella or cytomegalovirus during gestation (4,5).

Table 2. Neurobehaviora| teratogens

Ethanol Heroin Methadone Cocaine Retinoic acids Diphenylhydantoin

Valproic acid Rubella; CMV Lead Methylmercury PCBs X-irradiation

3. Early warning signs. Since detection of neurobehavioral impairment is difficult in infancy, it is important to pay attention to early warning indicators. Features known to place the infant at greater risk are low birthweight, maturational delay, presence of major malformation(s), presence of 3 or more minor anomalies, and presence of craniofacial defects.

E. The access of adverse environmental influ- ences to developing tissues depends on the nature of the agent. While the specific mechanisms underlying access to and influence on neural develop- ment are poorly understood, there are, nev- ertheless, classes of agents that should be scrutinized more carefully in light of the preg- nant patient (6). Among these are: 1) all agents known to cause CNS malforma-

tions 2) psychoact ive drugs and chemicals 3) adult neurotoxicants 4) hormonally active agents 5) peptides, amino acids Known human neurobehavioral teratogens include those listed in Table 2.

F. Agents of insult act upon developing cells through specific mechanisms that initiate pathologic development. Regardless of the specific mechanism in- volved, there is a finite set of final common pathways that appear to cause behavioral dysfunction, the ultimate final common path. Behavioral deficits have been associated with defects in cellular migration or elabora- tion such that the architecture and intercon- nectedness of neural systems are abnormal (see, for example, methylmercury [7]).

G. With increasing dosage level, the endpoints of abnormal development increase from the no-effect to the totally lethal level. 1. Nature of the dose - response effect. It is

now well-established that effects on growth and function can occur at dosage levels below those producing major mal- formations. For agents with neurobehavioral terato- genic activity, increasing doses of many agents have been associated with more extensive neuropathology and, thereby, more severe functional deficits (7).

2. Implied continuum of~'severi ty. ' ' Histor- ically, in teratology, this principle has im- plied an increase in the degree of severity of outcome, with severity defined as in-

Principles of neurobehavioral teratology • J. ADAMS 173

creasing from the milder end, marked by functional impairment, to the more severe end, marked by malformation and then death. These relationships are expressed by many compounds. One must consider, however, that many parents may rate mental retardation as far more severe and handicapping than certain major malfor- mations of other organs of the body.

REFERENCES

Wilson JG. Current status of teratology: general principles and mechanisms derived from animal studies. In: Wilson JG, Fraser FC, eds. Handbook of teratology, vol 1. New York: Plenum Press; 1977.

2. Vorhees CV. Principles of behavioral teratology. In: Riley EP, Voorhees CV, eds. Handbook of behavioral teratology. New York: Plenum Press; 1986:23-46.

3. Adams J, Vorhees CV, Middaugh LD. Developmental neuro- toxicity of anticonvulsants: human and animal evidence on phenytoin. Neurotoxicol Teratol. 1990;12:203-12.

4. Alford CA, Pass RF, Stagno S. Chronic congenital infections: common environmental causes for severe and subtle birth defects. White Plains, New York: March of Dimes Birth De- fects Foundation; Birth Defects: Original Article Series; 1983;19:87-96.

5. Adams J. Prenatal exposure to teratogenic agents and neurode- velopmental outcome. Res Infant Assess. 1989;25:63-72.

6. Rees DC, Francis EZ, Kimmel CA. Scientific and regulatory issues relevant to assessing risk for developmental neurotoxic- ity: an overview. Neurotoxicol Teratol. 1990;12:175-81.

7. BurbacherTM, Rodier PM, Weiss B. Methylmercury develop- mental neurotoxicity: a comparison of effects in humans and animals. Neurotoxicol Teratol. 1990;12:191-201.