Environmental Health Perspectives Volume
103, Supplement 6, September 1995
[Citation
in PubMed]
Behavioral Toxicology
Herbert L. Needleman
Departments of Psychiatry and Pediatrics, University of Pittsburgh, Pittsburgh,
Pennsylvania
Abstract
The new fields of behavioral toxicology and behavioral teratology investigate
the outcome of specific toxic exposures in humans and animals on learning,
memory, and behavioral characteristics. Three important classes of behavioral
neurotoxicants are metals, solvents, and pesticides. The clearest data on
the deleterious effects of prenatal exposure to toxicants comes from the
study of two metals, lead and mercury, and from epidemiological investigations
of the effects of alcohol taken during pregnancy. Less complete data are
available for two other groups of agents, solvents and pesticides. What
we do know about their effects on the fetal brain is convincing enough to
demand caution in their distribution. -- Environ Health Perspect
103(Suppl 6):77-79 (1995)
Key words: toxicants, lead poisoning, brain development, synapse,
neurotransmitter, neurons, astrocytes
This article was presented at the symposium on Preventing
Child Exposures to Environmental Hazards: Research and Policy Issues held
18-19 March 1993 in Washington DC.
Address correspondence to Dr. Herbert L. Needleman, Departments
of Psychiatry and Pediatrics, University of Pittsburgh, 305 Iroquois Bldg.
3600 Forbes Avenue, Pittsburgh, PA 15213-3411. Phone (412) 624-0877. Fax
(412) 624-1467.
Behavioral Toxicology
Behavioral toxicology, the study of chemical toxicants and their inþuence
on brain function, is a young field. The notion that a chemical can affect
the brain and that the earliest expression of toxicity could be found in
altered behavior, thinking, or mood is not new; it was voiced at least 2
thousand years ago by Dioscerides when he wrote, "Lead makes the mind
give way." Despite this early warning, the scientific community has
until recently paid little systematic attention to the impact of neurotoxicants
on behavior. The first textbook on this subject was published in 1975 (1).
Behavioral teratology, the effect on behavior of chemical exposure of
the fetus in utero, is an even newer discipline. Until recently,
the uterus had been visualized as a time capsule with a 9-month lease, sheltering
the developing fetus from most adverse inþuences such as drugs, toxicants,
or nutritional deprivation. The thalidomide and Minamata disasters quickly
disabused scientists and laymen alike of this false comfort. It is now clear
that many chemicals cross the placenta and impinge on the developing brain.
Behavioral deficits have been shown for some agents at doses well below
those that cause anatomical alterations.
Three important classes of neurotoxicants are metals, solvents, and pesticides.
The clearest data on the deleterious effects of prenatal exposure to toxicants
comes from the study of two metals, lead and mercury, and from epidemiologic
investigations of the effects of alcohol taken during pregnancy. Less complete
data are available for two other groups of agents, solvents and pesticides.
What we do know about their effects on the fetal brain is convincing enough
to demand caution in their distribution.
Lead
Lead has been known to affect workers for millennia, and its hazards
to the reproductive process have been available for at least a century.
British factory inspectors at the turn of the twentieth century noted that
women who were exposed to lead through working in the cottage ceramic industry
tended to be barren and that children who were born to these women were
often short lived (2). Childhood lead poisoning was first described
in Australia 100 years ago. For 50 years it was believed that if lead did
not kill the child, he or she was left with no stigma of the exposure. Careful
follow-up of children who had recovered from the disease showed that most
had school failure or behavioral problems. For the past 20 years, epidemiologists
and child development specialists have been investigating the effects of
lead exposure in children with no clinical symptoms. This controversial
issue has now been effectively settled. Almost all workers in the field
agree that lead at silent doses produces deficits in psychological function;
these include intelligence, perception, attention, language function, and
perhaps social adjustment. The recently published report of the National
Academy of Sciences provides a thorough summary of this issue (3).
In the late 1970s, attention began to shift to the question of intrauterine
exposure to lead. Scanlon (4) measured umbilical-cord blood lead
concentrations in newborns and showed that infants born to inner city mothers
tended to have higher blood lead levels than those born to suburban mothers.
The observation that lead crossed the placenta sparked studies of prenatal
exposure on infant development. The first study examined a large cohort
of births at the Boston Hospital for Women (5). Umbilical-cord bloods
were obtained from almost 12,000 births over a 2-year period. Lead was found
to be related to minor birth defects in a subsample of 5,000 of these infants.
A subsample of these subjects that was evenly divided among low exposure
(<3µg/dl), medium exposure (6-7µg/dl), and high exposure
(>10µg/dl) was followed. Subjects were seen at 6, 12, 24, 57, and
120 months of age. Significant deficits in infant IQ scores were found in
children in the high cord blood lead group as late as 24 months of age (6).
At 57 and 120 months of age, the effect of umbilical-cord blood was no longer
significant, but the effect of the 24-month blood lead level was statistically
significant (7). Similar data have subsequently been reported from
studies in Cincinnati (8) and Australia (9). It is clear that
lead exposure during pregnancy is a behavioral teratogen.
Mercury
Knowledge about the neurotoxicity of mercury dates from the 1950s. In
Minamata, Japan, a chemical plant used the waters of Minamata Bay to discharge
its wastes. One of the most important discharge products was mercury, mostly
in its inorganic form. Aquatic bacteria transformed it to the organic form
methylmercury. Because it enters the brain more readily, this form is much
more toxic. It was taken up by the local fish and, in the 1950s, residents
who ate fish from the bay were found to suffer severe organic brain damage.
Most severely stricken were infants exposed in utero.
Another epidemic of mercury poisoning occurred in 1960. The U.S. government
sent seed grain to Iraq as part of an international-aid effort, intending
for the grain to be planted and not eaten. The seed was treated with methylmercury
to prevent fungal infestation and dyed pink to indicate that it was unsuited
for baking. The largely illiterate Iraqi peasants baked bread with it, and
an outbreak of over 5,000 cases of poisoning occurred. Infants were about
10 times more sensitive than adults.
An unexpected outbreak of acute mercury intoxication occurred in 1981
when a family repainted a large part of their home with water soluble paint.
This product contained phenylmercury added as an antifungal agent. Paint
companies have voluntarily agreed to stop this practice, but no product
recall was made.
Alcohol
The toxic effects of alcohol on the fetal brain were first established
in France in 1968 (10) and in the United States in 1973 by David
Smith, a West Coast pediatrician (11). The unraveling of this relationship
has followed a traditional history--the problem was first brought to attention
when infants born to mothers with high alcohol intakes were noticed to have
characteristic features: impaired growth, þat face, long upper lip,
and mental retardation. This set of dysmorphic features was termed the fetal
alcohol syndrome. Investigators then began to examine the effects of lower
doses. This kind of question can only be addressed by sizable samples of
infants followed over long periods of time. The pioneer in this effort has
been Dr. Anne Streissguth, whose studies have unequivocally established
that small doses of alcohol taken during pregnancy are associated with cognitive
and attentional dysfunction in offspring in later life (12).
Solvents
Alcohol, because it is a fat soluble chemical, readily crosses the blood-brain
barrier and enters brain cells. Many other solvents share this property
and are found in the household in proximity to pregnant women and young
children. Among the more common solvents found in households are paint thinners,
degreasing and dry cleaning agents, and spot removers. Nearly all solvents
can cause acute and chronic injury to the central nervous system. Inhalation
of high doses of almost any solvent (including gasoline) can cause dizziness,
nausea, and hallucinations within a few moments. This can rapidly lead to
unconsciousness. The only studies of long-term solvent exposure have been
conducted in workers in which chronic exposure causes vertigo, clumsiness,
drowsiness, and often learning problems and memory and attentional deficits.
Although the literature on prenatal exposure to solvents is sparse, prudence
dictates that pregnant women should avoid contact with these agents. One
case of fetal solvent syndrome was reported in 1979 (13). The offspring
closely resembled that of a mother who had abused alcohol. In this case
the mother was addicted to sniffing toluene.
Pesticides
Most pesticides poison insects by interfering with the metabolism of
certain neurotransmitters. The human nervous system uses the same neurotransmitters
to conduct signals between brain cells. This is the source of both the agents'
benefits and their dangers to human health. Most pesticides poison the enzymes
that break down acetylcholine, one of the most important and widely distributed
neurotransmitters. As a result, the transmitter continues to stimulate the
nerve and, in extreme circumstances, this can lead to convulsions or even
death.
More than 1,500 different pesticides are currently in use in the United
States, These are blended to produce 50,000 commercial products of varying
toxicity. Two groups of pesticides, the organophosphates and the carbamates,
are extremely toxic to acetylcholine-destroying enzymes and can lead to
both acute and chronic symptoms. Organochlorine compounds such as DDT and
Heptachlor have less acute toxicity, but many have been shown to resemble
estrogen compounds; by binding to estrogen receptors in the body, they may
have a host of unwanted effects. Most recently, increased levels of DDT
were reported in the breast tissue of women with breast cancer.
The widespread use of pesticides has resulted in many opportunities for
toxic or subclinical exposures. These can occur through contamination of
drinking water, medical and veterinary applications, rodent control, mosquito
control, and through residues on fruits and vegetables.
The National Academy of Sciences has recently completed a thorough review
of the question of foodborne pesticides hazards to children (14).
It notes the particular sensitivity of the developing brain to these agents
and calls for newer, more stringent standards to reduce childhood exposure
to these agents.
Measuring the True Costs of Pollutants
Economists have recognized that the true costs of a product or activity
are rarely reþected in the price but are diverted to other objects.
The price of a barrel of fuel oil in 1990 did not reþect the cost
of the Persian Gulf War. That cost may have been as much as $80 billion,
or $23 per barrel of oil. Instead of being attached to fuel costs, this
was entered into the defense budget and passed on to the taxpayer. Economists
call this practice "externalizing the costs." When we do this
we often mislead ourselves about the real personal or societal costs of
a given activity. To a considerable extent, the degree to which a society
internalizes costs is a measure of its civility. There were, and are, societies
that externalized the costs of labor--they held slaves. Internalizing the
cost of workplace safety resulted in regulations and actions that have reduced
morbidity and mortality on the job.
Similarly, we have externalized to a considerable degree the costs for
producing commercial products. The cost of not making houses safe is externalized
to the health of children who are exposed to lead and other toxicants. The
Public Health Service estimated the cost of deleading the dangerous housing
stock in the United States at $28 billion (15). This is what it would
take to reduce the number of houses bearing large amounts of lead. The Public
Health Service took this one step further and calculated the money that
would be saved by taking this expensive action. To do this, they estimated
the societal lead costs that accrue from money spent on medical care for
lead-exposed children, the amount spent on remedial education, and the lost
tax revenues that ensue when IQ is lowered. The economists concluded that
deleading the houses would result in a monetized benefit of $60 billion,
a net return of $28 billion. We may ask, can we afford not to delead houses?
Similar analyses could be applied to any neurotoxicant. What is required
is a metric for lost cognitive and behavioral function. Only when we attach
all of the costs of production and consumption of commercial products will
we be in a position to make informed judgments about their use and control.
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3. National Academy of Sciences. Measuring Lead Exposure
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4. Scanlon J. Umbilical cord blood lead concentration.
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