often catalyze the reverse reaction, the reduction of aldehydes and ketones to alcohols. Consumption of beverage alcohol, known chemically as ethanol, perturbs this natural process and other metabolic processes. Such perturbations may produce a variety of clinical complications.

Study findings suggest that women may metabolize alcohol less efficiently than men, a difference that leads to higher blood alcohol concentrations in women over a shorter period of time.

Ethanol is absorbed from the stomach and intestinal tract into the circulatory system and transported to the liver for metabolism; alcohol metabolism may also occur in the stomach. In the first step of ethanol metabolism, ethanol is oxidized to acetaldehyde by alcohol dehydrogenase. Distinctly different forms, or isoenzymes, of alcohol dehydrogenase are found in the liver and stomach; each varies dramatically in its activity on alcohol. Researchers have identified as many as 17 alcohol dehydrogenase isoenzymes in the human liver. Differences in these isoenzymes may collectively permit these varied enzymes to oxidize a variety of alcohols over a wide range of alcohol concentrations.

At least five alcohol dehydrogenase subunits synthesized in the liver subsequently combine to produce active dimeric isoenzymes (i.e., enzymes that contain two subunits). Different beta subunit forms of alcohol dehydrogenase have been found in different racial groups. Whereas the alcohol dehydrogenase isoenzyme known as B1 occurs predominantly in the Caucasian population, ẞ2 appears in 65 percent of the Asian population, and ẞ3 occurs in 15 percent of the African-American population. Although these B subunits differ by only a single amino acid substitution, the resulting isoenzymes vary substantially in their ability to oxidize alcohol. For example, people with the ẞ2 isoenzyme (predominantly Asians) appear to oxidize ethanol at a faster rate than those with the ẞi isoenzyme (predominantly Caucasians). These different rates lead to variations in acetaldehyde concentrations that may contribute to tissue injury.

Gender may be a factor in alcohol metabolism. Study findings suggest that women may

metabolize alcohol less efficiently than men, a difference that leads to higher blood alcohol concentrations (BACs) in women over a shorter period of time. This difference may make women more vulnerable than men to alcohol-induced liver damage. Ingesting aspirin or cimetidine (a drug used to inhibit gastric secretion in ulcerafflicted individuals) with alcohol enhances BACS; this effect is believed to result from inhibition of alcohol dehydrogenase isoenzymes in the stomach. Accordingly, people should be careful about using alcohol with agents that may decrease alcohol metabolism in the stomach and thus increase circulating alcohol concentrations.

The immediate product of alcohol oxidation, acetaldehyde, is oxidized to acetic acid by a class of enzymes known as aldehyde dehydrogenases. Four distinct aldehyde dehydrogenase isoenzymes have been purified from the human liver, the major site of acetaldehyde synthesis. A genetic variant of one of these enzymes, the mitochondrial aldehyde dehydrogenase isoenzyme, has drastically reduced enzyme activity; this variant appears in approximately 50 percent of the Asian population. Circulating acetaldehyde levels can be 20 times higher in individuals who produce this inactive variant than in those who produce the active form of the enzyme. High acetaldehyde concentration causes a variety of unpleasant effects-facial flushing, palpitations, dizziness, and nausea-which probably deter individuals who produce the inactive isoenzyme from heavy drinking.

Recent research suggests that alcohol itself may interfere with the activity of aldehyde dehydrogenase. Findings from in vitro studies demonstrate that alcohol can slow the movement of large proteins across the mitochondrial membrane. Because aldehyde dehydrogenase is one of the enzymes that must be transported from the cytoplasm into the mitochondria, impaired membrane transport of this enzyme may result in less efficient acetaldehyde oxidation, thus increasing the risk for liver injury from increased acetaldehyde levels.

Ethylcocaine, which is made from cocaine and ethanol, has been found in individuals who use both drugs simultaneously. This unnatural compound appears to be pharmacologically active and may enhance the toxicity of cocaine and alcohol co-use.

Excessive alcohol use may cause deficiencies in a number of vitamins, including B1 (thiamine) and B6, A, folate, D, and E. Chronic drinkers may lose weight despite being well fed. The dramatic

weight loss exhibited by alcoholics indicates that they expend more energy than they can obtain from ethanol as a food source. The mechanisms that underlie this net energy loss have not been clearly defined.

Chapter 8: Effects of Alcohol on Health and Body Systems

Heavy and chronic drinking can harm virtually every organ and system in the body. As the primary site for alcohol metabolism, however, the liver is particularly vulnerable to alcohol's harmful effects. The injurious effects of alcohol on the liver can lead to the development of fatty liver, alcoholic hepatitis and fibrosis, and cirrhosis.

Various factors contribute to the risk for alcoholic liver damage, including quantity and patterns of alcohol consumption, gender, nutrition, and hormones. Although researchers have yet to completely define the mechanisms that underlie this damage, recent studies have focused on examining the role of free radicals, reactive oxygen molecules that oxidize lipids in various liver cell constituents. Another possible mechanism for the pathogenesis of alcohol-induced liver damage could be the increased production of free radicals and the decreased availability of antioxidants. Findings suggest that the normal antioxidant protective mechanisms may be impaired in alcoholics. Acetaldehyde, the major metabolite of alcohol, may also contribute to the pathogenesis of alcoholic liver disease. This compound may damage the cellular microstructure of the liver, induce fibrosis, affect energy metabolism, and generate free radicals. Other factors involved in alcohol-induced liver injury include cytokine activation, immune mechanisms, and oxygen deficiency.

Alcohol can have harmful effects on the cardiovascular system. Heavy drinking is associated with hypertension, weakened heart muscle, an increased risk of hemorrhagic stroke, and arrhythmias. In fact, arrhythmias may account, in part, for the high incidence of sudden death in alcoholics. On the other hand, moderate drinking may lessen the risk for coronary heart disease, possibly by increasing the level of highdensity lipoproteins, interfering with thrombosis, and enhancing estrogen levels in postmenopausal

women.

Chronic alcohol abuse appears to adversely affect the immune system. Research suggests that alcohol depresses immune function, thus placing

heavy drinkers at increased risk for infectious diseases. This effect may be significant in immunocompromised patients, such as people who are infected with human immunodeficiency virus (HIV).

Numerous studies have found that alcohol has deleterious effects on the endocrine system and reproductive function. In men, alcohol can suppress testosterone levels, among other effects. In women, chronic alcohol use is associated with menstrual cycle disturbances. Studies using animal models have reported that alcohol can impair fertility, either by preventing pregnancy or increasing the chance for spontaneous abortion.

With the development of new imaging technologies, researchers are able to follow the natural progression of neurochemical and structural changes from the early stages of acute intoxication to more chronic alcohol-related neurologic conditions.

Acute and chronic drinking have multiple neurologic effects. Neurological consequences of alcohol exposure include acute alcohol intoxication, alcohol withdrawal, nutritional diseases of the nervous system secondary to alcoholism (e.g., Wernicke-Korsakoff syndrome, pellagra, and polyneuropathy), neurologic disorders consequent to alcohol-induced liver disease, and disruption of cognitive and motor functioning.

With the development of new imaging technologies, researchers are able to follow the natural progression of neurochemical and structural changes from the early stages of acute intoxication to more chronic alcohol-related neurologic conditions. This knowledge can enhance the opportunity to prevent and treat severe neurologic disorders through early diagnosis.

Chapter 9: Effects of Alcohol on Fetal and Postnatal Development Studies have established that alcohol is a physical and behavioral teratogen that can produce a spectrum of deleterious effects, ranging from gross morphological anomalies and mental impairment (including mental retardation) to more subtle cognitive and behavioral dysfunctions. The most severe alcohol-related birth injuries are known as fetal alcohol syn

drome (FAS). The minimal diagnostic criteria for FAS are prenatal and postnatal growth retardation, central nervous system involvement, and characteristic craniofacial anomalies. If only some of these features are present in cases in which there is a history of prenatal alcohol exposure, the children may be identified as having fetal alcohol effects (FAE) or alcohol-related birth defects.

FAS has been identified only in children born to mothers who drank heavily while pregnant. Although such drinking increases the risk for FAS in offspring, not all women who abuse alcohol during pregnancy give birth to children with FAS. The reasons for the apparent variability in risk are not fully understood; however, studies suggest that various biological and environmental factors coupled with the amount of alcohol consumed by the mother may govern vulnerability to FAS and FAE. At present, researchers are striving to identify the factors that place some children at increased risk.

Research has repeatedly documented high rates of alcohol involvement in an array of serious and fatal injuries, including motor vehicle crashes, general aviation crashes, drownings, suicide, and homicide.

A number of prospective longitudinal studies conducted in the United States and Canada have contributed to current knowledge of the relationship between prenatal alcohol exposure and fetal development. These studies have produced some inconsistent findings; however, in general, results have shown a positive relationship between the degree of prenatal alcohol exposure and physical birth injuries, growth deficiencies, and numerous cognitive and behavioral deficits.

At present, our knowledge of threshold doses and critical periods of exposure is limited. Through the use of animal models, researchers are examining these critical issues. Animal models allow for control over such variables as dose, pattern, timing, duration of alcohol exposure, and various potentially confounding factors commonly associated with chronic alcohol use. Findings from these studies suggest that binge-like exposure to alcohol may be more harmful than exposure to the same or larger amounts of alcohol spread out more evenly over time.

Animal studies have also yielded a wealth of information on the effects of prenatal alcohol exposure on sensorimotor, neuroanatomical, neurochemical, neurohormonal, and immunological systems. In addition, these studies have provided insight about structure-function relationships between alcohol-induced perturbation of these systems and abnormal behavioral manifestations that result from prenatal alcohol exposure.

The mechanisms that underlie alcoholinduced fetal injury have not been clarified. Recent experiments have examined the possible role of acetaldehyde toxicity, impaired placental transfer of essential nutrients, fetal hypoxia, and perturbation of prostaglandins. It is likely that more than one mechanism is involved in alcoholinduced fetal injury.

Chapter 10: Effects of Alcohol on
Behavior and Safety

Research has repeatedly documented high rates of alcohol involvement in an array of serious and fatal injuries, including motor vehicle crashes, general aviation crashes, drownings, suicide, and homicide. Data from this research reflect the seriousness of alcohol's role in accidental injuries and deaths: Estimates suggest that relative risk of accidental death is 2.5 to 8 times greater among heavy-drinking or alcoholdependent males compared with the general population. Alcohol appears to play a role in both intentional and unintentional injuries and is thought to be associated with high-risk behavior that promotes sexually transmitted disease.

Coroners' reports have been a resource for determining alcohol involvement in different fatal alcohol injury events. These reports allow for comparative study of the role of alcohol in various types of injuries and analysis of data by gender, age, and ethnicity. For example, a recent study examining death certificates from Oklahoma during the period of 1978 to 1984 found that nearly 24 percent of suicide victims, 34 percent of homicide victims, and 38 percent of unintentional injury victims had BACs of .10 percent or greater. Only 20 percent of individuals who died of natural causes were alcohol positive. Evidence from coroners' reports also suggests that males are disproportionately represented in most serious and fatal injury events.

Alcohol continues to be involved in a large number of traffic deaths and injuries. In 1989, 22,413 people were killed in alcohol-related motor vehicle crashes, representing approximately

49 percent of all traffic fatalities. However, the past decade has seen some progress in this area. A slight downward trend in fatal crashes involving BACS of .10 percent or greater has been observed for drivers in all age categories. In addition, a declining pattern has been identified with alcohol involvement for all drivers involved in fatal crashes between 1982 and 1989. Yet, even though women drivers are less likely than men to be involved in alcohol-related traffic crashes, noted changes in drinking and driving behavior of young women point to a population that potentially is at increasing risk of involvement in alcohol-involved motor vehicle crashes.

Compared with motor vehicle crashes, aviation crashes are quite rare. Study findings suggest that alcohol plays a more prominent role in general aviation accidents than in commercial airline crashes, although the number of studies focused on alcohol and air traffic safety are limited. Studies have reported that even low BACS affect pilot safety by impairing a range of perceptual, cognitive, and psychomotor skills. In addition, pilot performance can be impaired long after detectable blood alcohol is eliminated from the body.

The AIDS pandemic has increased public concern about factors that contribute to the spread of sexually transmitted diseases. Research has established that alcohol and other drug use is associated with high-risk sexual behavior. At present, various research efforts are aimed at identifying the complex processes and mechanisms that underlie this relationship.

Studies of domestic and criminal violence often document high rates of alcohol involvement. One study reported that alcohol was most likely to be detected in situations that emerged spontaneously from personal disputes. Further, very high rates of problem drinking have been reported among property offenders and violent offenders.

Chapter 11: Economic Issues in Alcohol Use and Abuse

Virtually all of alcohol's effects have an economic dimension. In 1988, the cost to society of alcohol abuse was estimated to be $85.8 billion. Included in this amount are expenditures for the treatment for alcoholism and the medical consequences associated with abusive drinking; productivity losses from alcohol-related morbidity and premature mortality; and costs associated

with alcohol-related crime, motor vehicle crashes, and fires.

The tools of economic analysis have provided new and valuable perspectives on the problems of alcohol abuse. Recent advances include refinement of estimates of the economic costs of alcohol abuse, new estimates of the costs that heavy drinkers impose on others, and development of a theoretical framework for determining optimal tax rates based on estimates of these costs. Other studies have examined the cost consequences of alcoholism treatment and the effects of addiction on rational economic decisionmaking. These areas of research are in their infancy; yet, they hold much promise for advancing our understanding of the personal and social costs of alcohol abuse and our continuing efforts to reduce these costs.

Section IV-Prevention and Early Intervention

Chapter 12: Prevention of Alcohol-Related Problems

The past 10 to 15 years have seen an explosion of interest both in refining educational programs aimed at informing people of the dangers of alcohol abuse and alcoholism and in complementing these approaches with broad-based strategies aimed at altering the social, legal, and economic context in which drinking occurs. The problems that are associated with drinking occur across a wide variety of human activities and can be experienced by anyone who drinks alcohol. Among the objectives of prevention strategies are reducing the incidence of adverse consequences of acute and chronic drinking, preventing the development of alcohol abuse and alcohol dependence, delaying the onset of drinking, and encouraging abstinence among those who should not drink for various reasons.

The complexity of alcohol's interaction with so many common activities has prompted researchers to emphasize the environmental contexts of alcohol-related problems and how these contexts might have implications for prevention. Moreover, the recognition that alcohol-related problems can be experienced by light, moderate, and heavy drinkers has influenced the conceptual development of prevention approaches: It has been deemed advisable to conduct both targeted interventions that focus on high-risk subgroups and primary prevention strategies that

are directed at all drinkers. Despite the potential benefits of the multilevel approach, most prevention research has focused either on strategies to change individual behavior or on environmental approaches.

Understanding the etiology of alcohol use and related problems among youth is key to developing effective school-based prevention strategies. The causes and correlates of early alcohol use are complex and may be influenced by factors ranging from individual characteristics to societal-level regulatory factors. Accordingly, approaches to prevent alcohol-related problems among young people are varied.

The increase of the minimum drinking age to 21 years has achieved promising results: Levels of alcohol consumption and traffic accidents among people below the age of 21 have declined in response to the higher minimum drinking age.

Curricular prevention approaches that address individual characteristics and peer influence are by far the most common approaches to preventing the onset and use of abusable substances among children and adolescents. They range from those that focus exclusively within schools to those that also attempt to involve families. School-based programs have engendered mixed results; often the effects are small and short term. However, the inclusion of several elements appears to improve outcomes. For example, programs that involve social influence factors, such as resistance training, have proved to be relatively successful. Approaches that supplement classroom intervention with parent education and media campaigns have also produced promising results, although the impact of parent participation in programs on children's alcohol and other drug use behavior is not firmly established.

Media campaigns are the primary vehicle used to transmit prevention messages to the adult population. These efforts have had some success when coupled with such supplementary interventions as mail contacts, dissemination of BAC charts, or community organization campaigns.

The placement of warning labels on alcoholic beverage containers is a new development in communicating the prevention message to the

general public. Early evidence indicates that a large proportion of the population has failed to notice these labels. Studies have suggested several factors that may improve the label's noticeability, including the combined use of a pictorial, an icon, and a contrasting color.

Findings from several studies have suggested that alcohol use is related to physical availability of alcoholic beverages. Similarly, levels of consumption or of alcohol-related problems co-vary with higher prices for alcoholic beverages. Less information is available about the differential effects of price and availability on heavy drinkers compared with light and moderate drinkers.

Efforts to avert alcohol-related driving injuries and deaths are central to prevention research. The increase of the minimum drinking age to 21 years has achieved promising results: Levels of alcohol consumption and traffic accidents among people below the age of 21 have declined in response to the higher minimum drinking age. In general, initiatives to deter drinking and driving have swung away from emphasizing the severity of penalties and toward making penalties swifter and more certain. For example, approaches involving random breath testing illustrate the principle of certainty of penalties; administrative license revocation works on the principle of making penalties swifter.

"Dram shop" or liquor liability laws hold the server of alcoholic beverages liable for injuries caused by a person who had been sold alcohol when service should have been refused. These laws are also aimed at deterring drinking and driving. Recent studies have noted that these measures have some deterrent potential, although State-by-State variations in the degree of liability make this a difficult area to study.

Alcohol use appears to be involved in a high proportion of crimes. For example, studies indicate that alcohol is involved in 50 percent to 70 percent of robberies and assaults. However, methodological problems have impeded research progress toward understanding whether or how alcohol use contributes to crime or victimization. To develop effective prevention aimed at alcohol's role in criminal acts, research is needed to determine whether the observed association between alcohol and crime is correlational or causal, whether alcohol use facilitates criminal acts, or whether a mechanism exists that leads from alcohol use to crime.

An emerging area involves studies of communitywide interventions to prevent alcohol-related problems. Community prevention projects are