Neurotoxicity and Developmental Disabilities - P. Davidson, et. al., (AP, 2006) WW.pdf - Bio Med 19 - hilakku

Neurodevelopmental Effects of Alcohol

THOMAS M. BURBACHER AND KIMBERLY S. GRANT

DEPARTMENT OF ENVIRONMENTAL AND OCCUPATIONAL HEALTH SCIENCES

SCHOOL OF PUBLIC HEALTH AND COMMUNITY MEDICINE

WASHINGTON NATIONAL PRIMATE RESEARCH CENTER AND

CENTER ON HUMAN DEVELOPMENT AND DISABILITY

UNIVERSITY OF WASHINGTON

SEATTLE, WASHINGTON

INTRODUCTION

The goal of this chapter is to provide an overview of the developmental

ects of prenatal exposure to alcohol in the forms of ethanol and methanol.

All alcohols have a similar chemical structure. The three most commonly

known alcohols are ethyl alcohol (ethanol), methyl alcohol (methanol), and

isopropyl alcohol (isopropanol). Isopropanol is better known as rubbing

alcohol, a common item in most American homes. Human exposures to

toxic levels of isopropanol are uncommon and have not been reported in

pregnant women. Health e

ects data from animal studies suggest that iso-

propanol has low acute and chronic toxicity and is not a teratogen or

developmental neurotoxicant ( Kapp et al., 1996 ). Most research on the fetal

ects of maternal alcohol exposure has focused on the compounds ethanol

and methanol. The physical chemical properties of these two agents are

displayed in Table I . Methanol (H 3 C–OH), a component of many products,

including alternative motor fuels, antifreeze, glass cleaner, paints, and

varnishes, is the simplest alcohol with a chain consisting of a carbon atom

with three hydrogen atoms attached. Ethanol (H 3 C–CH 2 –OH), the psycho-

active ingredient in alcoholic beverages that results in intoxication, has a

chain that is two times as long.

While similar exposure scenarios exist for these two compounds (occupa-

tional exposure, intentional ingestion), the primary routes of exposure that

are related to developmental e

erent. Ethanol is an ancient

drug that is widely accepted throughout the world, consumed in the form of

alcoholic beverages to achieve a pleasant state of euphoria or relaxation.

Although women working in professions such as nurses, assemblers, janitors,

ects are quite di

INTERNATIONAL REVIEW OF RESEARCH IN

MENTAL RETARDATION, Vol. 30

0074-7750/06 $35.00

DOI: 10.1016/S0074-7750(05)30001-2

Thomas M. Burbacher and Kimberly S. Grant

TABLE I

P HYSICAL C HEMICAL P ROPERTIES OF E THANOL

AND M ETHANOL a

Name

Methanol

Ethanol

Synonyms

Methyl alcohol, wood alcohol

Ethyl alcohol, alcohol

Structure

H 3 C–OH

H 3 CCH 2 OH

Formula

CH 4 O

C 2 H 6 O

CAS RN

‐

Molecular weight

32.04

46.07

98 C

114 C

Melting point

64.6 C

78.5 C

Boiling point

12 C

13 C

Flash point

Physical appearance

Clear, colorless, very mobile,

ﬂammable liquid with

pungent, slightly

alcoholic odor

Clear, colorless, very mobile,

ﬂammable liquid with pleasant

alcoholic odor and burning

taste

Miscibility

Miscible with water and most

other organic solvents

Miscible with water and most

other organic solvents

Principal uses

Industrial and laboratory solvent,

to denature ethanol, chemical

reagent, antifreeze octane booster

in gasoline, requisite for

hydrogen fuel cell technology

Alcoholic beverages

Industrial and laboratory

solvent

In pharmaceutical

preparations and perfumes

Antiseptic

Octane booster in gasoline

a From ‘‘The Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals’’ (2001).

Merck & Co., Inc, Whitehouse Station, New Jersey.

clinical lab technicians, and housekeepers can also be exposed to ethanol ( Seta

et al., 1988 ), a recent review found that low blood alcohol levels resulting from

occupational exposure do not represent a risk to pregnant women ( Irvine,

2003 ). In contrast, exposure to methanol occurs almost exclusively in indus-

trial and laboratory settings. Women working as assemblers, janitors, clinical

laboratory technicians, machine operators, and mechanics can be exposed to

methanol via dermal absorption and inhalation ( Seta et al., 1988 ). Since 1988,

methanol has received attention as a low

performance motor

fuel and the primary fuel source for vehicles powered by hydrogen

emission, high

‐

based fuel

cell technology ( Gold & Moulis, 1988; Fuller et al., 1997 ). If methanol

‐

based

fuels were used on a widespread basis in the future, there would be public

exposure on streets, refueling stations, and garages. This chapter draws from

both the human and animal literature to explore the consequences of prenatal

exposure to ethanol and methanol on the behavioral development of exposed

‐

NEURODEVELOPMENTAL EFFECTS OF ALCOHOL

spring . For ethanol , the weigh t of ev idence to determ ine the risk of adverse

e cts on developm en t from prenata l expo sure comes large ly from prospec-

tive , longit udinal studies of human maternal–i nfant pairs. While a large

volume of suppo rtive studi es using animal models does exist for ethanol , a

compreh ensive review of these studi es was consider ed be yond the scope of this

chap ter. Exc ellen t reviews of the teratogenic e

ects of alcohol using anima l

models are availab le (see Guerr i & Han nigan, 1996 ). For metha nol, few

report s are available descri bing exposu re e

ects in hum an infants. The weight

of evidence to determ ine the risk of adverse e

ects on developm ent from

prenata l expo sure to metha nol, theref ore, comes large ly from studi es using

anima l models.

II. ETHANO L

Ethano l (EtOH) is a small molecule compou nd that is solubl e in water an d

lipid s, easily passin g throu gh ce ll membran es in the body ( Ram chan dani

et al., 2001 ). Ethano l selective ly concentra tes in highly vascul arized organs

such as the lungs and the brain and these organs have higher EtOH con-

centra tions a fter exposure. Metabol ism of EtOH is depen dent on enzymes in

the liver that initiate its metab olic breakdo wn. Ethanol is metab olized by the

enzyme alcohol deh ydrogenas e (AD H) to acetald ehyde, whi ch, in turn, is

meta bolize d by the enzyme, aldehyde dehyd rogenase , to aceti c acid, an d

ultimat ely to wat er and carbon dioxide . Women meta bolize EtOH di

er-

ently from men and have higher blood levels of EtOH due to higher fat

content, smaller body size, and less gastric

ADH activity ( Frezza et al., 1990;

Seitz et al., 1993 ). In general, women are at increased risk for EtOH

‐

induced

brain injury (see revie w by Pr endergas t, 2004 ). Female a lcoholics show

measurable brain shrinkage after shorter periods of EtOH exposure than

male subjects ( Mann et al., 1992 ). The enhanced sensitivity of women to the

adverse e

‐

ects of alcoholism is not limited to the brain but includes higher

rates of advanced liver disease and other EtOH

related disorders ( Morgan &

‐

Sherlock, 1977 ).

Prenatal exposure to EtOH is the leading cause of preventable birth

defects and mental retardation in the United States, if not the world. The

consumption of beer, wine, or spirits during pregnancy can have a profound

impact on the processes of normal child development. The e

ects of EtOH

are dose

abusing

mothers are at the highest risk for poor developmental outcome ( Stratton

et al., 1996 ). Developmental e

dependent and children born to alcoholic or EtOH

‐

ects are widespread and range from struc-

tural malformations (skeleton, heart, kidney) to delays in physical growth

and deﬁcits in neurobehavioral development (learning, memory, language,

Thomas M. Burbacher and Kimberly S. Grant

and social behavior ) ( American Academ y of Pediatr ics, 2000; Matt son &

Riley, 1998; Matt son et al., 2001 ). The Unit ed State s has made great

strides in educati ng wom en of reproduc tive age abou t the dangers of

drinki ng EtOH during pregnancy. The rate of drinki ng among pregn ant

wom en in the Unit ed State s de clined from 16.3% in 1995 to 12.8% in 19 99

( MMWR, 2002 ). The rate of binge

drinki ng an d frequent EtOH abuse

rates, howeve r, remai ned stable dur ing the same period (2.7 an d 3.3% ,

respect ively).

‐

A. Histor ical Per specti ve

Throu ghout hist ory, matern al drinkin g during pregnancy has been sus-

pected of causing adverse e

spring . M entione d by the

Hebrew s in the Book of Judges 13:4, the ha rmful e

ects in exposed o

ects of drinki ng hav e

been know n since bibli cal times when couples were forbi dden to drink win e

on their weddi ng nigh t so that a

ected infant s woul d not be conceived

( Hag gard & Jell inek, 19 42 ) . A report on drunken ness to the British Hou se

of Commons in the 1800s indicated that o

spring of alcoholic women were

frequently ‘‘born weak and silly

shriveled and old, as though they had

numbered many years’’ ( Goodacre, 1965 ). In 1900, a published report noted

that alcoholic women had increased rates of spontaneous miscarriage and

delivery of stillborn infants and exposed o

...

spring were at high risk for

epilepsy ( Sullivan, 1900 ). Although historical writings warned of the dangers

of drinking during pregnancy, physicians during the post

prohibition era in

the United States dismissed these concerns as moralism and interest in the

subject sharply declined ( Warner & Rosett, 1975 ).

In the late 1960s, a team of French investigators published a report

indicating that children born to alcoholic mothers shared a number of

distinguishing physical characteristics ( Lemoine et al., 1968 ). International

attention was not, however, directed at this constellation of birth defects

until the clinical observations of Jones and Smith were published in 1973.

These investigators coined the term ‘‘fetal alcohol syndrome’’ (FAS) to

describe the prenatal and postnatal growth deﬁciencies and physical mal-

formations observed in infants born to alcoholic mothers. The death of one

of the study subjects allowed for the ﬁrst necropsy of an FAS infant and

neuropathology results conﬁrmed that there was severe damage to both

neuronal and glial cells as well as absence of the corpus callosum. The

pioneering work of these Seattle dysmorphologists triggered new clinical

and scientiﬁc interest in EtOH as a serious teratogen and prospective re-

search programs were initiated in the cities of Seattle, Detroit, Cleveland,

Atlanta, and Pittsburgh ( Streissguth et al., 1981; Jacobson et al., 1993a;

Greene et al., 1991a; Coles et al., 1991; Day et al., 1989 ) .

‐

NEURODEVELOPMENTAL EFFECTS OF ALCOHOL

B. Clinical Features of Fetal Alcohol Syndrome and

Related Disorders

The most serious outcome for the children of drinking mothers is

fetal alcohol syndrome (FAS). As detailed in the 1996 report from the

Institute of Medicine (IOM) ( Stratton et al., 1996 ), clinical diagnosis of this

syndrome is based on three required criteria: (1) a deﬁciency in prenatal and

postnatal physical growth, (2) impairment of the central nervous system

(CNS), and (3) speciﬁc craniofacial malformations. The diagnostic criteria

for FAS and alcohol

related e

ects from the 1996 IOM report are displayed

‐

in Table II .

The diagnosis of FAS requires that the height, weight, and/or length of the

child be less than the 10th percentile. Physical growth in FAS infants is

characterized by growth retardation and may include reductions in birth

weight, loss of weight over time not associated with nutrition, and body

weight that is disproportional to height, length, and head circumference.

Damage to the CNS is required for the FAS diagnosis and e

V-

spring include mental retardation, neurological abnormalities, or develop-

mental delays. The diagnosis of FAS also requires the presence of a distinct

facial dysmorphology, often involving abnormalities of the eyes and the nose

(see Figs. 1 and 2 ).

In addition to microcephaly, facial features of the syndrome include short

palpebral ﬁssures, ﬂattened midface, indistinct philtrum, thin upper lip,

and upturned nose ( Abel, 1984 ). Common features of the FAS face that

are not required for a formal diagnosis include epicanthal folds, low nasal

bridge, minor ear anomalies, and micrognathia. In addition to the diagnostic

criteria set forth in the 1996 IOM report, a second set of clinical diagnostic

criteria have been published by Astley and Clarren (2000) . This system is

known as the Washington criteria and is based on a four

ects in o

digit code that

corresponds to the requisite diagnostic features of FAS. While vastly helpful

in accurate diagnoses of a

‐

ected infants, a number of weaknesses with both

coding schemes have been pointed out ( Hoyme et al., 2005 ). Limitations

include failing to adequately integrate the family/genetic history of the

child into the criteria, confusing terminology, and inadequate deﬁnitions of

clinical diagnoses (encephalopathy, neurobehavioral disorder). Hoyme and

colleagues (2005) have proposed a clariﬁcation of the 1996 IOM criteria to

enhance the identiﬁcation and treatment of children with fetal alcohol

spectrum disorders. These changes allow for more accurate diagnoses in

routine clinical settings.

Many children born to mothers who drink heavily during pregnancy do not

meet the criteria for a formal diagnosis of FAS. It is now well recognized that

there can be signiﬁcant behavioral changes in children born to drinking

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