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OCR for page 265
24
Introduction
This section of the report examines many
topics salient to the study of developmen-
tal markers in persons more than 24 hours
old. Rather than discuss in detail the
development of the many systems and proc-
esses of the human body, we focus the
review on the development of the central
nervous system. Then, using radiation
as a paradigm, we examine the effects of
timing and dose on central nervous system
teratogenesis. The consequences of abnor-
mal cell migration for host behavior are
also examined. The critical topic of meth-
odologic issues encountered in construct-
ing inferences abut human effects from
animal data is discussed next. Finally,
neurodevelopmental outcomes that might
be among the most sensitive markers of
neurotoxicant-engendered dysfunction
in humans are surveyed. Lead, the neuro-
toxicant with the largest neurotoxicolog-
ic data base, is used as a paradigm to ex-
amine some of the methodologic issues in-
evitably encountered in the pursuit of
a valid collection of markers.
Many discussions of biologic markers
and development focus on using markers
to ascertain effects of xenobiotic sub-
stances on development. However, the in-
fluence of growth and development on xeno-
biotic disposition and effect is equally
265
important. Biologic markers that might
be useful at one age might not be useful
at other ages.
Results of many assessments differ quan-
titatively and qualitatively from one age
group to another. That is particularly
true of concentrations of substances in
blood and pharmacokinetic (absorption,
distribution, metabolism, and elimina-
tion) characteristics in general. There-
fore, interpretation of biologic markers
of internal dose must take into account
the developmental status of the subject.
The pharmacodynamics (biochemical and
physiologic effects of drugs and their
mechanisms of action) of target-organ
response and short- and long-term conse-
quences of exposures also vary with age.
From birth until 2 or 3 years of age, major
developmental changes occur in the CNS
and major changes occur in the regulation
of the endocrine system during puberty.
Thus, the end-organ effects in these sys-
tems after exposure at different times
of life are likely to be different, and the
biologic markers used to assess the effects
might be different.
In neurodevelopment, the demonstration
of sensitive, specific markers that clear-
ly link exposure and outcome has been
rare; many variables intervene between
OCR for page 266
266
toxicant exposure and demonstration of
altered behavior. Demonstration of causal
relationships between low-dose exposure
and impairment has been particularly dif-
ficult. Establishing causal relation-
ships often depends on inferences drawn
from the combined results of animal experi-
ments and epidemiologic studies; neither
might be sufficient in isolation. Animal
studies raise the question of species dif-
ferences; some human teratogens or neuro-
toxicants might not cause measurable al-
terations in commonly used species, and
some animal teratogens have not been shown
to be human teratogens. It is hard for epi-
demiologic studies to establish causal
links, owing to the complex exposure hlS-
tories of the subjects to many compounds,
inability to control exposure levels of
the subjects, and the population-based
statistical procedures.
Relationships between phenotypic ef-
fects of pollutants and behavioral altera-
tions are increasingly apparent. The re-
cent recognition that agents that affect
physical development can be expressed at
an early age in alterations of nervous
system function—possibly as aberrant
behavior-has given rise to a new disci-
pline: behavioral teratology.
Before beginning the discussion of
neurodevelopmental markers themselves,
we digress briefly to consider issues of
developing and using biologic markers to
assess the status of children, using as
a paradigm the exposure to and effects of
halogenated aromatic hydrocarbons. Our
examples illustrate the need for careful
integration of chemical, pharmacodynamic
and pharmacokinetic, analytic, and cel-
lular methods in epidemiologically sound
studies to assess the multifaceted nature
of health effects.
BIOLOGIC MARKERS OF EXPOSURE:
PHARMACOKINETIC
CONSIDERATIONS
Therapeutic agents usually are adminis-
tered in known amounts for defined
periods, but accurate quantitative his-
tories of exposure to environmental chemi-
cals are rare. Because polychlorinated
biphenyls (PCBs) are found in most adipose
NEURODE~ELOPMENTAL TOXICOLOGY
tissue samples from randomly selected
persons (Mes et al., 1982; Kreiss, 1985),
it is difficult to design experiments to
decide what degree of contamination con-
stitutes significant risk. These consid-
erations emphasize the value of intensive
study of populations with massive expo-
sures, very high body burdens, or evidence
of chemically induced disease in the mother
during gestation. Infants exposed in utero
under such circumstances probably would
manifest more readily detectable physical
and biochemical findings and serve as mod-
els for phenomena to be examined in off-
spring of less-exposed populations.
Many pharmacokinetic considerations
are discussed in the previous part of the
report. Here these are briefly discussed
with regard to the specific situation of
PCB exposures. Interpretation of concen-
trations of a toxicant, or drug, depends
on knowledge of the amount and timing of
exposure relative to sampling of serum
and route of administration.
Highly sensitive and specific assays
have been developed for various halogen-
ated aromatic compounds (Albro et al.,
1986~. Isomer-specific detection and
quantification in the parts-per-trillion
range are possible. The ability to deter-
mine multiple compounds and their break-
down products is critical, because expo-
sures rarely involve pure substances;
the blood of people reportedly exposed
In Japan and Taiwan to PCB-contaminated
rice oil contained products of thermal
degradation, such as dibenzofurans (Chen
et al., 1981; Kashimoto et al., 1981~. PCB
isomers have different half-lives and
different biologic effects with respect
to enzyme induction (Safe et al., 1985),
so interpretation of biologic markers of
effects of these substances must account
for chronic exposure and the presence of
specific compounds at the time when the
markers are examined.
Although quantification of environmen-
tal pollutants in biologic samples, in-
c~uo~ng serum and tissues, is possible,
pharmacokinetic interpretation of data
remains difficult. Indeed, for such fat-
soluble, extremely long-lived compounds,
direct relationships among serum concen-
tration (internal dose), concentrations
,
OCR for page 267
INTRODUCTION
at receptor (biologically effective
dose), and biologic effect are difficult
to establish (Evans et al., 1986~. Furth-
ermore, the distribution of lipophilic
compounds can be altered by diet, disease
states, and other drug or chemical exposure
(Gibaldi and Perrier, 1982), as well as
by developmental differences in metabol-
ism, body size, and fat distribution from
fetal life through adulthood.
Continuous changes in composition and
amounts of fat stores and altered metabol-
ism in pregnant women and children would
be expected to have profound effects on
the availability of compounds like halo-
genated aromatics to interact with recep-
tors critical to their toxic effects
and, consequently, affect the behavioral
findings during childhood (Krauer et
al., 1984; MacLeod and Radde, 1985~. Preg-
nancy is associated with as much as a 25%
increase in subcutaneous fat. Other phar-
macokinetic changes during pregnancy
include decreased and erratic absorption
from the intestine, increased blood vol-
ume, increased total body water, decreased
protein binding due to a decrease in serum
albumin concentration and an increase in
endogenous displacing substances, in-
creased glomerular filtration rate, and
generally increased renal and hepatic
clearance of many xenobiotics. Basing
interpretation of body burden of a given
lipid-soluble, slowly cleared compound
on an isolated blood or serum concentration
is extremely difficult. Similarly, fat
stores in the developing fetus change mark-
edly with gestational age. Body fat in-
creases from less than 1% of body weight
at 28 weeks to 15% at term. Total body bur-
den in the newborn depends not only on the
total maternal exposure, but on when that
exposure took place and on the gestational
age at birth.
Mobilization of a compound from fat
stores might increase its clearance via
hepatic and renal mechanisms, but might
also make more of it available at toxico-
logically important sites. Sampling of
fat from biopsy samples could provide a
better index of total body stores, but this
still might not reflect toxicologically
relevant concentrations. Mobilization
might be particularly high during lacta-
267
lion, increasing the clearance of lipid-
soluble compounds from the mother, but
also increasing delivery to a nursing in-
fant. Complex pharmacokinetic mathemati-
cal models could be helpful in assessing
relevance of various tissues concentra-
tions to body burden, quantification of
exposure, and biologic effects. Such mod-
els will have to incorporate additional
complexity based on multifactorial deter-
mination of outcomes. Establishing dose-
response relationships in humans is
further complicated by individual dif-
ferences in biologic response to exposure
(pharmacogenetics).
BIOLOGIC MARKERS OF EFFECT:
PHARMACODYNAMIC
CONSIDERATIONS
Toxic exposures that might affect the
developing child can occur before or after
birth. In assessing the relationship be-
tween exposure and effects, one must
study the mother, the neonate, and the
child.
Markers in the Mother
Most studies of pharmacologic effects
of pregnancy focus on pharmacokinetics.
However, pharmacodynamics and suscepti-
bility to toxicity might also differ. For
example, susceptibility to tetracycline-
induced hepatic injury increases marked-
ly during gestation, owing to unknown
mechanisms.
Attempts to interpret data obtained
from offspring of mothers exposed to poly-
halogenated aromatics should include
histories, physical examinations, and
laboratory findings of the mothers. Again,
people with massive exposure, such as those
exposed to contaminated rice-cooking oil
in Japan and Taiwan (Yusho and Yuchen)
(Masuda et al., 1982; Lu and Wong, 1984~,
or histories of maternal illness, should
be studied. In humans, dermatologic find-
ings-especially chloracne—have been the
most consistent clinical feature among
people with massive exposure to polyhalo-
genated aromatics (Suskind, 1985~. His-
tologic features of chloracne are not path-
ognomonic of exposure, but the combination
OCR for page 268
268
of chloracne with measurement of exposure
and of PCB concentrations in adipose tissue
and plasma suggests chemical-induced
disease. Other histologic findings in
skin are not likely to be helpful in assess-
ing the existence or extent of chemically
mediated illness (Moses and Prioleau,
1985~. Other physical features and clin-
ical laboratory findings associated with
massive exposure include weight loss,
porphyria, hepatic dysfunction, and peri-
pheral neuropathies (Mocarelli et al.,
1986; Kimbrough, 1987~. None is diagnos-
tic of the PCB-induced disease.
Target organs and toxic manifestations
vary widely among species (Safe, 1986~.
Recently, immunologic changes have been
emphasized, particularly because thymic
involution occurs in most animals suscep-
tible to 2,3,7,8-tetrachlorodibenzo-
p-dioxin (TCDD) toxicity. Subclinical
changes in cell-mediated immunity have
been reported in humans with possible TCDD
exposure (Hoffman et al., 1986~; none of
the subjects examined had other manifesta-
tions of illness—including chloracne—
and body burden of TCDD was not documented.
Much work needs to be done in populations
with clearly massive exposures, to verify
whether any immunologic changes can serve
as useful markers. No human data are avail-
able about effects of TCDD exposure during
pregnancy.
Many effects of halogenated aromatics
are mediated via a specific cytosolic re-
ceptor (Roberts et al., 1985; Denison
et al., 1986~. Induction of specific drug-
metabolizing enzymes is the most widely
recognized outcome of interaction of the
compounds with receptors (Poland and Knut-
son, 1982; Denison and Wilkinson, 1985;
Denomme et al., 1986; Okey et al., 1986~.
The toxicity of various halogenated aro-
matics in different species is correlated
with the affinities of various analogues
for the receptor and with characteristics
of the receptor in specific species and
strains. Results of animal studies show
that genetically determined receptor
differences are correlated with induci-
bility of specific cytochrome P-450 and
with toxic outcomes of exposure to polycyc-
lic aromatic hydrocarbons, including
carcinogenesis and teratogenesis (Nebert
NEURODE^LOPMENT~ TOMCOL~Y
and Jensen, 1979~. Results of studies of
human peripheral blood lymphocytes sug-
gest that inducibility of arylhydrocarbon
hydroxylase (AHH) is correlated with sus-
ceptibility to lung cancer (Kellerman et
al., 1973a,b; Kouri et al., 1984), but the
mode of inheritance of inducibility in
humans remains uncertain.
The above considerations suggest that
a variety of markers might be used to assess
biologic effects of halogenated aromatic
exposure. If susceptibility to adverse
effects depends in part on the nature of
the aryl hydrocarbon receptor (possibly
under genetic control), biochemical and
molecular analyses of differences in
human receptors might be helpful in cor-
relat~ng outcomes with exposures and in
typing the population according to suscep-
tibility. Such analyses could use human
lymphocytes or skin cells. One strategy
would be to include direct assessment of
the presence and binding properties of
the receptor, as well as molecular ap-
proaches to the receptor gene and the whole
AHH gene complex (Whitlock, 1986~.
The major effect of most halogenated
aromatic compounds is to induce a pattern
of enzyme activity similar to that produced
by 3-methylcholanthrene. Some PCB and
polybrominated biphenyl (PBB) isomers,
however, also induce enzymes typically
induced by phenobarbital (Safe et al.,
1985~. Enzyme induction in humans can be
assessed with nontoxic, in vivo probes
(e.g., caffeine for AHH), with examination
of induction capacity in vitro in lympho-
cytes (Kellerman et al., 1973a,b; Kouri
et al., 1984), with direct measurement
of enzymes in tissues (liver or skin biop-
sies), and perhaps with molecular tech-
niques, including quantification of mRNAs
for specific forms of cytochrome P-450
(Jaiswal et al., 1985b). Enzyme activity
can be influenced not only by genetic dif-
ferences, but by a wide range of environ-
mental exposures-such as cigarette smoke,
diet (including consumption of charcoal-
broiled foods or cruciferous vegetables),
and medications (Okey et al., 1986~. Preg-
nancy also affects activity of drug-metab-
olizing enzymes (Krauer et al., 1984~.
Interpretation of data obtained in
the diverse human population requires
OCR for page 269
INTRODUCTION
careful attention to experimental design-
number of subjects and their clerical sta-
tus, documentation of exposure, defini-
tion of sensitivity and specificity of
methods, and selection of control popu-
lations. An ideal study would include a
population with defined exposures (in-
cluding large exposures), quantification
of exposure in family members (especially
fathers), determination of endogenous
(perhaps genetic) and environmental vari-
ables that might alter outcome, detailed
medical and biochemical analyses of family
members, and thorough study of pregnancy
outcomes. Drug-metabolizing enzymes
should be analyzed (particularly during
pregnancy); the metabolism of hormones
critical to pregnancy also would be of
interest, because steroid hormone metab-
olism might be altered by exposure to com-
pounds such as TCDD (Okey et al., 1986~.
Placental Markers
Placental markers were discussed in
the previous part of the report. Here,
the markers relevant to PCB exposure are
discussed in the context of the need to
study population longitudinally.
The placenta is obviously a critical
organ in determining pregnancy outcomes;
it is a potential target for environmental
chemical toxicity and influences fetal
exposure. No information is available
from exposed people about placental tissue
markers before delivery. Such techniques
as chorionic villus biopsy (discussed
previously) might prove useful in follow-
ing pregnancies prospectively. The pla-
centa early in gestation is different from
the placenta at term; therefore, extrapo-
lation of markers from different times
in pregnancy should be undertaken cau-
tiously. Similarly, vast differences
among species in placental derivation and
structure make cross-species extrapola-
tion questionable.
At-term placenta markers include quan-
tification of halogenated aromatic com-
pounds, determination of histopathologic
changes, determination of enzyme induc-
tion status, determination of presence
and characteristics of aryl hydrocarbon
receptor. Considerable data are available
269
on at-term placentas of women exposed to
contaminated rice oil in Taiwan; AHH ac-
tivity and 7-ethoxycoumarin-O-deethylase
(7-ECOD) activity were markedly increased
in placentas from such pregnancies (Won"
et al., 1985a), even though exposures oc-
curred 3-4 years before pregnancy. The
induction by other factors, such as cigar-
ette-smoking (Fujino et al., 1984), had
to be ruled out. In the rice-oil-exposed
population, the AHH induction was greater
than expected, as determined by the meta-
bolic profile of benzoapyrene in placen-
tal homogenates. Cotinine and thiocyanate
were used as markers to ensure that the
subjects were not smokers and were not
exposed to substantial passive smoking.
Some methodologic issues in studying pla-
cental tissue have been discussed (Won"
etal., 1985a).
In more recent studies, specific cyto-
chrome anti-P-450 isozyme 6 rabbit anti-
bodies were used to detect an increase
in one P-450 protein in microsomes from
the placentas of women exposed to contamin-
ated rice oil (T.K. Wong et al., 1986~.
Thus, direct measurement of P-450 activi-
ties, use of monoclonal antibodies, and
perhaps direct molecular probes are prom-
ising markers of effects of exposure to
enzyme inducers during late pregnancy.
Neither maternal blood PCB concentra-
tion nor clinical symptoms were correlated
with AHH or 7-ECOD induction in the study
(T.K. Wong et al., 1986~. The placenta
of one of the nine mothers with clear ex-
nosure and substantial clinical symptoms
showed no induction. That is interesting,
with respect to study of other environmen-
tal variables or individual differences
in susceptibility related to endogenous
and perhaps genetic mechanisms. Aryl hy-
drocarbon receptor has been measured in
human placentas (Manchester et al., 1987),
and correlations of induction with recep-
tor characteristics will be of interest.
Similarly, study of adducts of reactive
metabolites—particularly of products
of cigarette smoke-holds promise of quan-
tifying exposures that lead to toxicolog-
ically relevant tissue interactions.
Placental enzyme induction by compounds
that are metabolized to electrophilic
toxicants (such as some components of
OCR for page 270
270
cigarette smoke) might protect the fetus
from exposure (Manchester and Jacoby,
1984; Manchester et al., 1984~. High in-
duction and placental metabolism might
prevent compounds from crossing the pla-
centa. Umbilical vein endothelial cells
from placentas of women who smoke do not
show enzyme induction in situ, but retain
the capacity for in vitro induction (Man-
chester and Jacoby, 1984; Manchester et
al., 1984~. Similarly, decreased placen-
tal enzyme induction appears to be corre-
lated with an increased risk of birth de-
fects. However, it is uncertain whether
that is true for nonmetabolized inducers,
such as PCBs or TCDD, in which case induc-
tion of placental enzymes might not in-
crease first-pass clearance of the com-
pound. Studies have examined the roles
of genetics and environmental variables
on placental response to cigarette-smoke-
mediated enzyme induction (Gottlieb and
Manchester, 1986~. Studies of placentas
from pregnancies that produce identical
and fraternal twins show that heredity
has a role in determining outcome, and
position of the placentas in utero might
contribute greatly to the extent of induc-
tion.
Little information is available to as-
sess and predict interactions of markers
of placental exposure, receptors, enzyme
induction, function (including steroid
hormone metabolism), anatomy (including
pathologic changes), and pregnancy out-
comes. An ideal approach integrates as-
sessment of each of these factors; it is
unlikely that any marker will adequately
predict outcomes that are multifactorial.
Intensive study of placental tissue—
including potentially early -biopsies
and at-term perfusion models-could lead
to an integrated picture of critical
determinants of outcome and their
contributions.
Markers in the Newborn
The following discusses markers men-
tioned in the previous part of the report
specifically as they relate to assessing
effects of PCB exposure.
Newborns are unique pharmacokinetically
and pharmacodynamically. Their fat con-
NEURODEVELOPMENTAL TOXICOLOGY
tent, total body and extracellular water,
protein binding, and renal and hepatic
clearance of compounds vary widely with
gestational age and can be influenced
by many prenatal factors (e.g., nutrition,
disease, genetics, medication, and en-
vironmental exposures) (Boreus, 1973~.
Unique interaction of variables can lead
to unusual susceptibility to toxic ef-
fects that do not occur in other age groups,
such as kernicterus resulting from in-
creased red-cell turnover (Karp et al.,
1985), decreased protein binding of bili-
rubin (Karp et al., 1984), decreased
hepatic capacity to metabolize bilirubin
(Karp et al., 1984), and increased entry
of bilirubin into the CNS because of im-
maturity of the blood-brain barrier (Karp
et al., 1984~. Newborns differ markedly
from older subjects in organ sizes and
physiologic roles (e.g., the fetal adrenal
gland is a major drug-metabolizing organ).
These considerations suggest that new-
borns differ from children and adults in
responses to a variety of exposures and
require different interpretations of bio-
logic markers—or different markers—of
internal dose and effect. Many data are
available on kinetic differences, but more
work is needed on receptor maturation,
response to enzyme inducers, and pharmaco-
dynamic differences, including unique
CNS responses of the immature brain; e.g.,
phenobarbital and antihistamines produce
excessive excitation in infants and chil-
dren and sedation in adults at comparable
blood concentrations (MacLeod and Radde,
1985~.
Physical examination of newborns ex-
posed to halogenated aromatic compounds
should be comprehensive and quantitative
(including weight, height, head circum-
ference, and such other measurements as
internal and external canthal distances),
and should be performed by persons un-
aware of the nature of the exposure. Ap-
propriate control subjects should be ex-
amined simultaneously.
Several features are possible sequelae
of in utero exposure (Rogan, 1982), includ-
ing low birthweight, conJunct~v~t~s
with enlarged sebaceous glands in the eye-
lids, natal teeth, pigmentary changes
of gums and skin with deformed and pig-
OCR for page 271
INTRODUCTION
mented nails, peculiar skin coloration,
and chloracne. The findings of important
dermatologic effects are interesting,
given the similarity of sites of toxic
effects in adults. Later necrologic devel-
opment in children with these effects might
also be abnormal (Harada, 1976), but such
findings require further verification.
The possible effects on immune function
that appear in adults after TCDD exposure
and effects in animals suggest developmen-
tal immunologic abnormalities (Lubes et
al., 1984; Silkworth et al., 1984) and need
to be evaluated in newborns and children.
Other than physical findings, few mark-
ers of exposure have been documented.
Cord blood concentrations of environmen-
tal chemicals could be obtained and corre-
lated with maternal and placental concen-
trations. A great deal is known about
developmental patterns for a variety of
drug-metabolizing enzymes in humans and
the effects of inducing substances, such
as the effects of phenobarbital on glucuro-
nyl transferase (Catz and Yaffe, 1968~.
Probes, such as caffeine, would be worth
using to assess the status of AHH-like
cytochrome P-450 activity in infants
with possible exposure to halogenated
aromatics. Caffeine metabolism and clear-
ance in the newborn are extremely limited
and can be followed with a C-labeled probe
for breath testing (to estimate oxidative
demethylation) or with analysis of specif-
ic urinary metabolites that reflect prob-
able cytochrome P~-450 activity (Lambert
et al., 1986; Campbell et al., 1987~. De-
termination of aryl hydrocarbon receptor
and P~-450 induction by molecular tech-
niques in available cell types will add
to a comprehensive picture of the effects
of prenatal exposure on newborn drug-
metabolizing capacity. Appropriate psy-
chometric testing of newborns also should
be performed for later comparison with
results of followup studies.
Markers in Children
The extremely long half-lives of many
compounds of interest warrant careful,
long-term followup study of the conse-
quences of exposure. Content of environ-
mental chemicals in breast milk should
271
be documented if an infant is breast-fed.
Concentrations might vary during a given
breast-feeding and over an extended period
as the maternal stores of lipid-soluble
compounds are redistributed into breast
milk.
Accurate clinical descriptions of the
skin with photographic records and his-
topathologic examination are necessary.
Routine growth characteristics and ap-
propriate assessments of CNS development
should be documented. Given the current
focus on immunologic effects of halogen-
ated aromatic compounds, knowledge of
responses to routine childhood immuniza-
tions and documentation of histories of
infectious disease, allergy, and auto-
immune disease will be helpful. The roles
of environmental exposures and altered
immunologic status (Marshall, 1986) are
controversial, and verifiable markers
and clinically accurate descriptions of
outcomes are badly needed.
The ultimate goal of studies of the
long-term consequences of in utero expo-
sure to environmental toxicants is to as-
sess the effects of growth and development
on handling of and response to the toxi-
cants and the effects of the toxicants on
the very processes of ontogeny. Standard
estimates of half-lives of various halo-
genated aromatic compounds are typically
based on sparse data on adults. The devel-
oping child changes dramatically in body
composition, and the change likely has
major effects on distribution and clear-
ance of lipid-soluble compounds. Renal
and hepatic clearance rates of most com-
pounds generally are greater in children
(until puberty) than in adults (MacLeod
and Radde, 1985~.
Kinetics of environmental contaminants
depend on what compounds a subject is ex-
posed to over a long period. For example,
enzyme induction could result from persis-
tence of the inducing substance or from
an effect manifested long after exposure.
The latter situation is exemplified by
changes in steroid-hormone metabolism
at puberty in rats that received one dose
of phenobarbital during gestation (Gupta
and Yaffe, 1981~. It is uncertain whether
a similar phenomenon occurs in humans,
but long-term effects caused by short-
OCR for page 272
272
exposures are possible; any effects noted
in children who were exposed prenatally
to halogenated aromatic compounds will
have to be separated into effects of chron-
ic exposures to compounds with very long
half-lives and persistent effects of pre-
vious acute exposures.
A safe, noninvasive approach to assess-
ing in viva phenotype with respect to cyto-
chrome P' -450 induction would be extremely
useful as a tool for comparing development
in exposed and control populations. Oxida-
tive demethylation of caffeine is mediated
by cytochrome P~-450 and can be monitored
with breath tests that use carbon-13 and
measurements of urinary-metabolite ratios
(Lambert et al., 1986; Campbell et al.,
1987~. Such a procedure can be repeated
on the same subjects. For example, metab-
olism is high in children after the neo-
natal period and later declines to values
characteristic of adults; patterns of
metabolism at the time of puberty differ
between males and females (Lambert et al.,
1986~. The relatively rapid P-450-medi-
ated clearance of most compounds in prepu-
NEURODEVELOPMENTAL TOXICOLOGY
bertal children might make it more diffi-
cult to assess the effects of enzyme
inducers. Many children exhibit caffeine
clearance as great as that in adults in whom
it is maximal because it is induced by
cigarette-smoking (Campbell et al.,
1987~. Some of the most dramatic effects
of exposure to environmental inducers
might be noted at puberty, when drug-metab-
olism rates normally decline to adult
values.
The simultaneous observation of symp-
toms, monitoring of persistent specific
chemicals, assessment of inducibility
of AHH in lymphocytes, and continual moni-
toring of P~-450 metabolism status will
allow determination of the health implica-
tions of exposures and induction. Growing
understanding of individual differences
in inducibility, perhaps related to dif-
ferences in aryl hydrocarbon receptor
characteristics, might make it possible
to divide the population with respect to
these variables and health outcomes, in-
cluding long-range susceptibility to
cancer.
Representative terms from entire chapter:
enzyme induction
