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STATE OF THE SCIENCE REPORT ON THE EFFECTS OF MODERATE DRINKING

NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

NATIONAL INSTITUTES OF HEALTH

DEPARTMENT OF HEALTH AND HUMAN SERVICES

DECEMBER 19, 2003

PURPOSE/CHARGE

In support of the planned 2005 update of the Dietary Guidelines, NIAAA has been asked to assess the strength of the evidence related to health risks and potential benefits of moderate alcohol consumption, with particular focus on the areas of cardiovascular disease, breast cancer, obesity, birth defects, breastfeeding, and aging.

The following report was prepared by NIAAA scientific staff experts in areas of basic research (e.g., metabolism, toxicity, neuroscience), nutrition, and epidemiology, and was reviewed by external researchers with extensive research backgrounds on the consequences and benefits of alcohol consumption. (Participating staff and external reviewers are listed in the Appendix).

The report consists of several sections:

I. Background Information

II. Areas of Specific Focus

III. Additional Areas of Potential Risks and Benefits

IV. Conclusions

V. Cited References

Appendix. Participating Authors and Reviewers

I. BACKGROUND INFORMATION

About 35% of the adult US population abstains from alcohol use, about 60% are occasional to moderate drinkers, and about 5 to 7 % are diagnosable with alcohol abuse or dependence (NIAAA, 1997). Of the some 16 million Americans who meet the diagnostic criteria for abuse or dependence, only about 1.5 million seek and receive treatment (SAMHSA, 2003).

Alcohol consumption causes some 100,000 deaths annually in the US, including more than 16,000 alcohol related traffic fatalities (Meister et al., 2000; NIAAA, 2000). Compared with abstainers, drinkers – particularly heavy or excessive drinkers – have higher death rates from injuries, violence, suicide, poisoning, cirrhosis, certain cancers, and possibly hemorrhagic strokes (Gutjahr et al., 2001; Thun et al., 1997).

However, because of alcohol’s apparent protective effect against coronary heart disease (CHD) and other atherosclerotic diseases, which are the most common causes of death in the US, the consequences of alcohol use must be evaluated in conjunction with its potential benefits. For example, at least one estimate predicts that if all current consumers of alcohol abstained from drinking, another approximately 80,000 CHD deaths would occur each year (Pearson & Terry, 1994).

Over the past 50 years, numerous studies have investigated the relationship of alcohol consumption and the development of many medical conditions including cancers, cardiovascular disease, diabetes and dementia. Studies have also investigated the relationship of maternal alcohol consumption during pregnancy and breast feeding to the health and development of infants and children. Many of these studies have evaluated dose response relationships and therefore may provide comparative information about zero, low, moderate and heavy levels of ethanol consumption and the various outcomes of interest. Both epidemiologic and basic science studies have addressed the relationship of moderate alcohol consumption and medical consequences and both must be considered in evaluating the relationship of moderate drinking and health. However, certain complications are inherent in interpreting this literature. “Moderate” drinking is the only level of drinking that has been shown to have potential health benefits, and the levels of drinking that are classified as “moderate” and “heavy” have not been defined consistently across studies (Gaziano et al., 2000; Klatsky, 2002; NIAAA, 1992). Further, they are not always consistent with the definition of moderate drinking in the USDA/DHHS Dietary Guidelines (2000; i.e., no more than one drink per day for women and no more than two drinks per day for men). Furthermore, the amount considered moderate in some situations may be excessive under other circumstances (e.g., pregnancy; intent to drive). Also, it is important to note that many “moderate drinkers” have occasions of high-risk drinking, including heavy episodic drinking and acute intoxication leading to injuries and violence (Gutjahr et al., 2001).

The difficulty in defining moderate drinking is to some extent a result of individual differences. The amount a person can drink without intoxication may vary according to drinking experience and tolerance (Bondy et al., 1999). Individual metabolic differences can lead to a wide range of blood alcohol content (BAC) levels for the same consumption (Ramchandani et al., 2001a). Also important is the time over which the alcohol is consumed: 3 drinks in one hour will produce a much higher BAC than 3 drinks over the course of 3 hours, and therefore different effects. Thus, definitions solely based on the number of drinks are not the best approach.

Another complicating factor in the interpretation of this complex literature is the interaction of genetic vulnerability to a particular medical condition with the effects of alcohol consumption: risk and protection from alcohol's effects may vary considerably across groups or individuals in the population. Confounding and modification by lifestyle variables also could be a factor in the observed health differences between drinkers and nondrinkers. Various studies have found that nondrinkers are less likely to exercise regularly and have a higher body mass index than their drinking counterparts; they also report lower vegetable intakes and higher fat consumption (Barefoot et al., 2002). Moderate drinkers are found to monitor their health (e.g., blood pressure and preventive dental care) more often than abstainers and heavy drinkers, and female drinkers over age 50 report significantly higher mammography rates than nondrinkers (Green & Polen, 2001). Studies suggest that life-long abstainers tend to be older, poorer, religious, disabled or in poor health, less physically and socially active, and to have more symptoms of depression (Ashley et al., 1994); while some of these traits (e.g. health status) may stem from their abstention, others obviously do not.

Research on basic mechanisms of alcohol effects may explain observed epidemiological phenomena associated with moderate drinking. In this report, we summarize both the epidemiological and selected basic research studies that may contribute to the understanding of the consequences and benefits of moderate drinking. However, it is important to note that there is a difference between epidemiological data (e.g., population-based averages) and experimental/clinical data (e.g. looking at specific individuals in specific confounding or co-occurring environmental, physiological, and genetic contexts). Moreover, the interpretation of and conclusions drawn from all of these studies must be tempered by the following considerations:

Pharmacokinetics and Pharmacodynamics

The variation in host responses to alcohol is exemplified in the variability in the rate and extent of absorption, distribution and the metabolism of ethanol, (i.e. the pharmacokinetics), and in the effects (i.e., the pharmacodynamics) of alcohol. To date, researchers have found as much as 3- to 4-fold differences in metabolic and 2- to 3-fold differences in behavioral responses to alcohol between different individuals (Ramchandani et al., 2001a). In other words, whereas alcoholic drinks may be standardized, drinkers are not. There are genetic as well as environmental contributions to this variation. For example, alcohol elimination rates have shown as much as an average 45% increase following the environmental factor of food consumption, compared with that following fasting (Ramchandani et al., 2001b).

Demographics

Alcohol’s influence on mortality risk is influenced by age, because the leading causes of death differ by age group (Ashley et al., 1997; Gronbaek, 2001; Meister et al., 2000; Thun et al., 1997). For example, among US men aged 15-29, deaths from injuries and other external causes predominate, accounting for 75% of all deaths; only 4 % are from cardiovascular conditions. On the other hand, for men over 60, only 3% of deaths are from external causes, and over 45% are from cardiovascular conditions (Thun et al., 1997). This affects the balance of risks and benefits.

The effects of moderate drinking, as well as the level deemed moderate, may also vary by age and by gender due to the metabolic and pharmacokinetic effects described above. Likewise, the risks and benefits of alcohol use may fluctuate according to genetic-based susceptibility to various diseases (including alcoholism itself), which in turn may be associated with ethnic background or gender.

Definition of "moderate”

Moderate drinking can mean drinking in moderation, where the term “moderation” is defined by Webster’s Dictionary (1984) as “within limits; reasonable; of average or medium quantity or extent” that is, drinking such that there is no ensuing harm. Alternatively, the term moderate drinking can be used as a descriptor of quantity/frequency of intake, particularly in comparison to the “extremes” of total abstinence and heavy drinking. Both of these definitions share the problem of not accounting for the pattern of intake over time, which can be a major determinant of whether drinking is harmful or beneficial. Other conceptions of moderate include nonintoxicating; noninjurious; or statistically “normal” (Eckardt et al., 1998), definitions which can vary by individual or by socio-cultural context. Studies cited throughout this report use a wide range of consumption levels to represent moderate drinking: some consider it to be 1 drink per week or less (e.g., Berger et al., 1999) while others use as many as 4 drinks per day (e.g., Nicolas et al., 2002) making comparisons and generalizations across studies and across areas of harm difficult.

Drinking Patterns

Drinking patterns are as important as total consumption, not only in terms of alcohol’s benefits, but also its harmful consequences. Risks for alcohol abuse and/or dependence jump dramatically for men who exceed 4 drinks per occasion and for women who exceed 3 drinks per occasion (NIAAA/NLAES 1992). Some of the studies addressed in this report have specifically looked at the differences between low per-occasion consumption occurring regularly (e.g., 1or 2 drink per day, 4 days per week) and the same total weekly consumption occurring all at once (e.g., Mukamal et al., 2003a). However, the pattern of drinking was not assessed by many of the studies, and so the consumption level of “an average of 1 drink per day” could reflect either a true “daily” drinker; a 3-times-per-week, 2-drinks-per-occasion pattern; or a weekend heavy drinker, making comparison across studies and the determination of clear conclusions difficult.

Drink size

Because some researchers present results in terms of number of drinks and others in terms of “grams of alcohol” (which differs across alcoholic beverage types and according to portion sizes), this report will use the approximation of 1 drink = 15 grams of alcohol in presenting all data in order to facilitate evaluations. However, drink sizes vary by country, alcohol content varies by type of beverage, and recall/reporting by the study participants may be inaccurate (intentionally or not). Thus, while this report “standardizes” drink size for ease of readability, a true comparison of actual alcohol ingestion level across studies is unreliable.

In summary, discrepancies in findings across studies can arise from pattern of alcohol consumption and differences in modes of administration, differences in definition of drink size or in the number of drinks that constitutes “moderate” use, differences between in vivo and in vitro reactivity, and the use of different animal models and the validity of their extrapolation to humans. In human studies, gene-environment interactions, co-morbidity, medications, age, self-reporting and alcohol use assessment, gender and lifestyle effects further complicate interpretation.

II. AREAS OF SPECIFIC FOCUS

A. Cardiovascular Disease

Cardiovascular disease, in particular coronary heart disease (CHD) and associated myocardial infarction (MI), is the leading cause of death among adults in the United States (CDC, 2002). Cardiovascular causes account for about 45% of all deaths among men over 35 years old and 37% of all deaths among women over 35 (Thun et al., 1997). In numerous studies – cross-sectional, longitudinal, cohort, case-control, individual, meta-analysis – differing considerably in their adjustments for confounding risk factors, the data on CHD-related death are remarkably consistent: the relationship between alcohol consumption and mortality follows a J-shaped or U-shaped curve, with one to four drinks daily significantly reducing risk and five or more drinks daily significantly increasing risk (Booyse & Parks, 2001; Corrao et al., 2000; Hines & Rimm, 2001; Murray et al., 2002; Perret et al., 2002; Rehm et al., 2001; Rehm et al., 2003; Rimm, 2000; Rotondo et al., 2001). This inverse association between light-to-moderate alcohol consumption and CHD morbidity and mortality had been demonstrated independent of age, sex, smoking habits, and body mass index.

Most recent studies have found that the trend for beneficial CHD effects first appears when daily drinking exceeds 1 and 1.5 drinks per day for women and men, respectively (Baer et al.; 2002; Hines & Rimm, 2001; Murray et al., 2002; Sillanaukee et al., 2000). The relative risk of MI is reduced by 25% in men consuming up to 2 drinks per day and by 50% in those consuming more than 2 drinks. The association holds even for men with a prior history of MI (Shaper & Wannamethee, 2000). Lower levels of consumption were not significantly associated with CHD (Murray et al., 2002). However, recently Mukamal et al. (2003a) found that the protective effect was more a function of frequency of consumption than of volume; small amounts consumed several times a week reduced risk to a greater extent than the same amount consumed over fewer occasions. In pre-menopausal women, for whom overall CHD risk is lower, the effects of alcohol are less likely to reach significance, although there have been studies showing significant HDL cholesterol-increasing and LDL cholesterol-decreasing effects (Baer et al., 2002). However, in one of the few studies large enough to offset the rarity of CHD in younger women (age 34-59 at start), a 20-40% lower CHD risk was found for moderate drinkers as compared with nondrinkers (Stampfer et al., 1988). In post-menopausal women, for whom CHD risk is higher than for their younger counterparts, similar lipid profile effects, as well as reduced CHD risk, have been found to correspond with moderate (1-2 drinks/day) alcohol consumption (Baer et al., 2002). However, for both men and women, any report of heavy episodic drinking was associated with a significantly increased risk of CHD, at 2.26 for men and 1.10 for women (Murray et al., 2002; Rehm et al., 2001).

There are also cardiovascular risks associated with alcohol consumption, at least at heavier drinking levels. Consistent heavy consumption of alcohol often leads to impairment of left ventricular function, which can result in cardiomyopathy (Walsh et al., 2002). Although most likely pluri-causal with at least some genetic component, alcoholic cardiomyopathy is often a complication of longstanding alcohol abuse, related to a person’s lifetime dose of ethanol; it can eventually lead to congestive heart failure (Meister et al., 2000). Alcoholism is one of the most important factors in dilative cardiomyopathy, associated with up to 30% of the cases and typically occurring in men between age 30 and 55 who have regularly consumed more than 5 drinks per day for more than 10 years (Flesch et al., 2001; Walsh et al., 2002). Total abstinence has been the standard treatment for alcoholic cardiomyopathy, based on the assumption that any further alcohol consumption is deleterious. However, an evaluation of the effect of reduced drinking in patients with cardiomyopathy found that cardiac contractility improved in all patients who reduced their daily intake to 1-4 drinks/day (n = 15). Drinking at a level of 4-5 drinks/day had mixed results, and functional deterioration continued in most of those who continued to exceed 5 drinks/day (Nicolas et al., 2002). An exception within the last (i.e., > 5 drinks) group were those who, although exceeding 5 drinks/day, nonetheless decreased their previous intake by 50% or more; these 4 patients actually demonstrated a functional improvement.

The observed cardioprotective effect of moderate alcohol consumption may be related to alcohol-induced changes in lipids, lipoproteins, fibrinogen and insulin resistance, as well as to other unknown mechanisms or combinations of mechanisms. Approximately 50% of the reduction in risk has been attributed to moderate alcohol-induced increases in high-density lipoprotein cholesterol (HDL-C) (e.g., De Oliveira e Silva et al., 2000; Gronbaek, 2002; Sillanaukee et al., 2000; van der Gaag et al., 2001). Several other biological mechanisms proposed as alcohol-related contributors to CHD risk reduction include decreased low-density lipoprotein (LDL) oxidation (Durrington et al., 2001; Griffin, 1999; Serafini et al., 2000; Sierksma et al., 2002) and reduced blood clotting and platelet aggregation (Dimmitt et al., 1998; Grenett et al., 1998; Lacoste et al., 2001; Mukamal et al., 2001b; Pellegrini et al., 1996; Ruf, 1999; Sierksma et al., 2001; Tabengwa et al., 2002).

Summary -- CHD

The J-shaped curve has accumulated considerable evidence in cohorts of individuals 40 and over, and it persists after the empirical testing of major alternative explanations such as lifestyle and dietary factors, or composition of abstainer group (Corrao et al., 2000; Rehm et al., 2001). The largest potential benefits of alcohol use in terms of CHD mortality and morbidity apply to older individuals and those otherwise at risk for heart disease (Mukamal, 2003; Mukamal & Rimm, 2001); insufficient research has been done on the lifetime accumulation of CHD benefits – or risks – that may accompany moderate drinking begun in young adulthood.

B. Breast Cancer

The effect of alcohol on the risk for breast cancer remains controversial. Methodological problems are common, including the lack of reporting information about other breast cancer risk factors such as family history and estrogen replacement therapy (ERT). Even in well done case control and cohort studies, researchers use a variety of somewhat arbitrary cutoffs in assessing levels, doses, or amounts of alcohol consumed (Ginsburg, 1999). Thus, when comparing the outcomes of various studies, results for pre- and post-menopausal women are inconclusive; there is no clear evidence of a dose-response relationship; there is a large range of threshold values (between <1/2 and 4 or 5 drinks per day); and, as the strength of the association seems to decrease with an increase in follow-up time, results from 5 year versus 15 year follow-ups are often in conflict (Mannisto et al., 2000).

Although some studies have found a positive correlation between alcohol and breast cancer, others have not (Clavel-Chapelon et al., 2002; Colditz & Rosner, 2000; Ellison et al., 2001; Feigelson et al., 2003; Garland et al.; 1999; Gronbaek, 2001; Horn-Ross et al., 2002; Lash & Aschengrau, 2000; Lenz et al., 2002; Rohan et al., 2000; Smith-Warner et al., 1998; Tjonneland et al., 2003; Zhang et al., 1999); there have even been a few findings of lowered relative risk among light-to-moderate drinkers as compared with abstainers (Baumgartner et al., 2002; Kropp et al., 2001). A substantial number of the “positive” findings have failed to reach standard levels of statistical significance; the researchers generally attribute this to their study’s sample size and subsequent limited power to detect associations of the low magnitude observed for alcohol and breast cancer. Other studies report a “significant trend for increasing risk with increasing consumption”, although none of the individual levels of consumption actually demonstrate a statistically significant risk. Even when results are statistically significant, in some studies the magnitude of the change in risk for an individual woman is quite small, making the clinical importance of such findings debatable; however, the public health implications, when the change in risk level is applied across 150 million US women, may be substantial.

In a large collaborative re-analysis of 53 studies, one of the larger analyses with statistically significant findings, compared with women who reported drinking no alcohol, the relative risk of breast cancer was increased by a third for an intake of 2 ½ to 3 drinks per day and by nearly half for more than 3 drinks per day. Specifically, the relative risk of breast cancer increased by 7% for each additional two-thirds drink per day (Hamajima et al., 2002). This means that the cumulative incidence of breast cancer by 80 years is estimated to increase from 8.8 per 100 women in non-drinkers to 9.4, 10.1, 10.8, 11.6, 12.4, and 13.3 per 100 women consuming an average of 1, 2, 3, 4, 5, and 6 drinks per day (Hamajima et al., 2002). The risk at higher doses (e.g., 7-8 drinks per day) is difficult to determine, because in most studies the vast majority of participants report less than 4 drinks per day.

One group that does seem to be at substantially increased risk even at low doses is women with a family history of breast cancer. Vachon et al. (2001) found a risk ratio of 2.45 in daily drinkers who were first-degree relatives of breast cancer probands, as compared with never-drinkers. The risk for second degree relatives was not significant, and there was no association for women who had married into the families (i.e., were not biologically related).

A number of pooled studies and meta-analyses have been undertaken to provide the level of statistical power needed to resolve the issue of nonsignificant findings. One pooled analysis of 6 cohort studies found a significant dose response effect with 1 or more drinks per day increasing breast cancer risk by 9%, and 2-5 drinks per day increasing it by 41%. (Smith-Warner et al., 1998). A meta-analysis of 38 studies indicates a steady but modest increase in risk of breast cancer with increasing daily alcohol consumption (Ashley et al., 1997). However, the association is a relatively weak one, and researchers have suggested that, not only can associations of this magnitude be due to bias or measurement error, but that investigation of other factors that may differ by alcohol use (e.g., age, obesity, smoking, reproductive factors, etc.) is necessary before any conclusions can be drawn (Meister et al., 2000). There is some evidence of a monotonic increase in the relative risk of breast cancer with alcohol consumption; however, the magnitude of the risk was modest – in comparison with non-drinkers, there is a 10% increase in risk for women averaging 1 drink/day (Ellison et al., 2001).

The picture for older women is slightly different. Although there is no consensus on the comparative risks for premenopausal versus postmenopausal women overall, findings for a subset of postmenopausal women have been consistent. Epidemiological evidence indicates that estrogen replacement therapy (ERT) after menopause increases breast cancer risk, and there are data suggesting that ERT combined with alcohol use magnifies that risk (Ginsburg, 1999). In particular, a significant risk is associated with intake of more than 2 drinks/day over a period of years (Stoll, 1999). However, in some studies, even lower levels of alcohol consumption add risk. The Iowa Women’s Health Study found that women who consumed an average of one-half drink per day or more manifested increased risk of breast cancer with estrogen administration; lesser consumption or none at all showed no increased risk (Zumoff, 1997). A prospective cohort of 44,187 post menopausal women found that, while there was no significant increase in risk for women who drank at least 1 ½ drinks per day but did not use ERT, the women consuming that amount of alcohol and also using ERT for 5 or more years had a relative risk twice that of non-drinking, non ERT users, i.e., a woman whose lifetime risk for breast cancer is 4% would increase her risk to 8% with 5 or more years of current ERT use and the consumption of > 1 ½ drinks daily (Chen et al., 2002).

The underlying mechanisms of association between alcohol consumption and breast cancer risk are not clear. The role of estrogen and its metabolism is one candidate for causality. Several studies have reported acute and chronic effects of alcohol in raising levels of circulating estrogen (Ginsburg et al., 1996; Ginsburg, 1999), but other studies have failed to observe this effect (Purohit, 1998). Zumoff (1997) proposed that estrogen levels modulate breast cancer risk in individuals with particular genotypes or dietary and exposure history, which may account for conflicting findings across studies.

Several studies have suggested a role for genetic polymorphisms in the alcohol/breast cancer association. Premenopausal (but not postmenopausal) women with the ADH1C 1-1 genotype with even quite low alcohol intake (> 1 ½ drinks per week ) regularly over a period of 20 years had a breast cancer odds ratio of 3.6 in relation to women with the ADH1C 1-2 or 2-2 genotypes (Freudenheim et al., 1999). A recent case-control study on glutathione S-transferase (GST) M1 and T1 polymorphisms (Zheng et al., 2003) found that ever-drinking women with the GST M1A genotype had a 2.5 fold increased risk of breast cancer compared to never-drinking GST M1A women, a risk that increased with daily amount and/or duration of alcohol consumption. Postmenopausal women with the GST T1-null genotype and a lifetime consumption of more than 1500 drinks (e.g., 3 drinks per week for a duration of 10 years, or 1 drink per week for 30 years) had an almost seven-fold increase in breast cancer risk. Women at that consumption level with both the GST M1A and the GST T1-null had an even greater odds ratio, 8.2. These findings are consistent with mechanisms that may not necessarily involve estrogen. For example, Rundle et al. (2003) reported that for nontumor tissue of breast cancer cases, current drinkers possessing the GST M1-null genotype exhibited significantly higher levels of DNA damage from polycyclic aromatic hydrocarbons, compared to nondrinkers.

Summary – Breast Cancer

In summary, overall evidence from epidemiologic data seems to indicate that alcohol may be associated with an increase in the risk of breast cancer in the population overall, but that the relative effect of moderate consumption is small at the individual level but can be substantial at the population level; the increase in risk is most clearly evident for women with a family history of breast cancer, and for those using ERT. A degree of uncertainty remains about the effect of a given amount of alcohol on the risk of developing breast cancer in the absence of confounding risk factors, as well as whether there may be a threshold dose below which alcohol has no effect. Although not well-investigated other than via consideration as confounds, individual genetic variations in metabolism and their interaction with carcinogens and dietary factors may play a role. Individual women, with the help of their physicians, must weigh their potential increased risk for breast cancer against their potential reduced risk for CHD in determining whether alcohol consumption should be reduced.

C. Obesity

Obesity results from an imbalance between energy intake and energy expenditure over a prolonged period of time. Given the energy content of alcohol (7.1 kcal/g, as compared to 4.5 kcal/g for protein, 5 kcal/g for carbohydrate and 9 kcal/g for fat), weight gain attributable to drinking could arise if corresponding food intake was not adjusted sufficiently to maintain energy balance. DeCastro and Orozco (1990) found that alcohol supplements rather than displaces food-supplied calories. However, a recent animal model study designed to evaluate the effects of chronic moderate alcohol intake (5% ethanol in drinking water) on energy balance using male rats that are maintained on either a low-fat or a high-fat diet suggests that rats fully compensate for the excess calories associated with alcohol and maintain energy balance regardless of the fat content of the diet (Cornier et al., 2002). Looking at actual changes in weight or body mass index (BMI) rather than calorie-source replacement, a prospective study by Wannamethee and Shaper (2003) found that, over a five year follow-up period, mean body mass index and the prevalence of men with a BMI of 28 or greater (i.e., top quintile of the BMI distribution) increased significantly from the light-moderate to the very heavy alcohol (defined in this study as 2 or more drinks per day) intake group even after adjustment for potential confounding factors. However, a prospective study with a ten year follow-up (Koh-Banerjee et al., 2003) found that changes in levels of alcohol consumption were not associated with changes in waist circumference. Over a shorter timeframe, Cordain et al. (2000) found that the addition of two glasses of red wine to the evening meals for 6 weeks did not adversely affect body weight. Thus far, the evidence on the relationship between moderate alcohol consumption and obesity remains inconclusive.

Metabolic Syndrome:

Metabolic syndrome, which predisposes people to CHD and diabetes and is frequently associated with obesity, has been defined as reaching (or exceeding) threshold levels for any three of five conditions: abdominal obesity, elevated fasting blood triglycerides, low levels of HDL or "good" cholesterol, high fasting blood sugar (glucose) and high blood pressure (National Cholesterol Education Program, cited in Sattar et al, 2003.). An earlier World Health Organization definition also included evidence of insulin resistance in people with normal glucose tolerance as a required factor for diagnosis.

A recent study that examined the association between the quantity and type of alcohol intake with clinical and biochemical markers of metabolic syndrome (e.g. lipid profile, fasting blood glucose, hemoglobin A1c, and fasting serum insulin) in severely obese individuals, revealed that light alcohol consumers (< 7 drinks/week) showed a marked reduction in relative risk of developing Type II diabetes (a frequent complication of obesity) compared with rare or non-consumers, and the frequency of consumption did not influence metabolic syndrome measures (Dixon et al., 2002). Kroenke et al. (2003) found an inverse association of alcohol intake and insulin, but only for women with a BMI >= 25. Insulin levels were lowest for episodic drinkers consuming 2 or more drinks per day, up to 3 days per week, suggesting that moderate alcohol consumption of 1-2 drinks per day on a few to several days per week may have a beneficial glycemic effect, particularly among overweight women.

Diabetes:

The relationship between alcohol intake and the relative risk of developing Type II diabetes is U- or J-shaped. Several studies have demonstrated that moderate drinking is associated with a reduced incidence of Type 2 diabetes in both men and women (Ajani et al., 2000; Rimm et al., 1995). The risk is lower by about 1/3 in moderate drinkers as compared to abstainers, and the association is even stronger for those who drink at levels somewhat beyond the limits of moderation, with the risk decreasing progressively up to 6 drinks/day (Meister et al., 2000; Wannamethee et al., 2002) in some populations. In a 10 year follow-up study, Wannamethee et al. (2003) found a progressively decreasing risk for those consuming ½ (20% reduction) through 2 drinks (nearly 60% reduction) per day, but 3 or more drinks per day conferred the same level of risk as total abstention. Looking at Native American Indian populations, Lu et al. (2003) found a similar pattern, but at lower consumption levels: light (3 drinks/week) and moderate (4-12 drinks/week) drinkers had a lower relative risk of developing Type 2 diabetes while heavier drinkers had an increased risk.

The diabetes-related benefits seem to derive from alcohol’s effects on insulin secretion, resistance and sensitivity (Davies et al, 2002; Rimm, 2000). Regular moderate alcohol consumption (4.5 to 11.5 drinks/week) is associated with decreased insulin resistance (Flanagan et al., 2000). Alcohol consumption of 1-2 drinks per day by both men and women was associated with enhanced insulin-mediated glucose uptake, lower plasma glucose and insulin concentrations in response to oral glucose (Facchini et al., 1994). The exact mechanism underlying the insulin sensitizing action of alcohol remains unresolved.

Summary – Obesity & Related Conditions

The relationship between moderate alcohol consumption and weight gain, BMI, or obesity remains inconclusive. However, there appears to be some protective effect of moderate consumption on two of the major sequelae of obesity, i.e., metabolic syndrome and diabetes.

D. Birth Defects

Research over three decades in both human epidemiological studies and animal models has clearly established that alcohol at high consumption levels can cause both physical and neurobehavioral birth defects (Institute of Medicine report -- Stratton et al., 1996). These findings have led to the issuance of a Health Advisory from the Surgeon General of the United States (U.S. Public Health Service, 1981). A specific dysmorphic syndrome, named “fetal alcohol syndrome” (FAS) (Jones and Smith, 1973) was identified and confirmed through research (Stratton et al., 1996). As research has clearly identified three domains of deficits in FAS -- in growth, physical malformations, and neurological/cognitive effects -- it is principally in these domains that potential effects of moderate alcohol exposure could be looked for. However, to date few studies have been undertaken on the effects of low-or-moderate alcohol exposure levels and therefore findings are more limited.

Effects on Growth:

A longitudinal study of alcohol exposure in pregnancy reported a 4 pound decrease in weight at ages 10 and 14 resulting from first trimester exposure to an average daily volume of one drink compared with zero exposure (Day et al., 1999 and 2002). Among women who drank one or more drinks per day during the third trimester, Day et al. (1991) observed continuing smaller size of offspring, including a 1.6 pound decrease in weight at age 3, compared to the offspring of abstainers. In a longitudinal study Sampson et al. (1994) found that effects on size were observable at birth and at 8 months, but not thereafter. A recent case-control study by Yang et al. (2001), provided no evidence of an independent association between moderate maternal alcohol consumption (<14 drinks per week) and risk for intrauterine growth retardation (IUGR). However, unlike the previous studies cited, Yang et al. (2001) collected the maternal alcohol data retrospectively rather than during pregnancy, an approach that appears to be less effective in detecting subtle alcohol effects (S. Jacobson et al., 2002). Additionally, the outcome measure used was a major growth deficit rather than continuous measures of growth, another difficulty in determining subtle effects. Therefore, studies on the risks of moderate prenatal alcohol exposure associated with effects on growth have not yet been definitive.

Morphological Effects:

In general, studies have not found dysmorphology or physical malformation at low to moderate prenatal alcohol exposure levels. In a longitudinal study Sampson et al. (1994) found that dysmorphology of facial features occurred only at the highest levels of consumption. Moreover, the results of a meta-analysis combining seven case-control and cohort studies suggested that moderate alcohol consumption in the first trimester of pregnancy does not increase the risk of major fetal malformations (Polygenis et al. 1998).

Although oral cleft defects are not typically associated with FAS, a case-control study undertaken by Lorente et al. (2000) found a greater than two-fold increase in cleft palate associated with more than 1 drink per day during the first trimester. However, a case-control study by Natsume et al. (2000) found significantly more defects when mothers had less than 1 drink per week than in comparison to the offspring of mothers with higher levels of consumption.

Neurological/Cognitive Effects:

It is the behavioral teratogenic effects of prenatal alcohol exposure (i.e., Alcohol-Related Neurodevelopmental Disorder, or ARND -- the low end of the Fetal Alcohol Spectrum Disorders continuum) that appear to be more sensitive on a dose response basis than the physical teratogenic effects of alcohol, and therefore, are more important in the context of assessing lower dose injury from alcohol. A study examining exposure during the first trimester to an average daily volume of one drink found there were significant effects in verbal learning and memory as measured by the Wide Range Assessment of Memory and Learning (Richardson et al., 2002).

Several other studies have also found deficits in neurodevelopmental parameters at levels averaging 1 to 2 drinks per day. Sampson et al. (1994) found that neurobehavioral functioning was affected from birth through age 14 particularly in the areas of attention, speed of information processing, and learning problems, especially in arithmetic. Goldschmidt et al. (1996) found that children whose mothers consumed seven or more drinks per week during pregnancy had poorer performance in reading and spelling at 7 years of age.

A meta-analytical review by Testa et al. (2003) found effects which differed substantially according to infant age at the time of assessment. While there was a significant negative effect of alcohol exposure on Bayley MDI scores in 12-13 month old infants, there was no association among either 6-8 month olds or 18-24 month olds. Because there are differences in MDI item content for assessing children at different ages, the results may indicate that some skills (i.e., those measured in 1-year olds) are more affected by fetal alcohol exposure than others. Another study (McCarver et al., 1997), which specifically looked at allelic effects, found that drinking during pregnancy was only associated with lower MDI scores in the offspring of mothers without an ADH1B*3 allele.

Important findings have resulted from other, more specific and localized neurocognitive tests that assess specific functional domains of the brain. In one series of studies, infants whose mothers drank seven drinks per week or more on average during pregnancy were more than twice as likely to perform poorly -- in the bottom 16th percentile -- on five different neuropsychological tests, including processing speed on the Fagan Test of Infant Intelligence; elicited (imitative) play on the Belsky scale; and reaction time on the Haith Visual Expectancy Paradigm, as well as the Bayley Mental and Motor Scales; (Jacobson J et al., 1993; Jacobson S et al., 1993; Jacobson S et al., 1994) .

However, research suggests that it is the drinking pattern, rather than average number of drinks per week, which is likely to be the most significant factor affecting adverse pregnancy outcomes. Some investigators who have looked at the distribution of drinking over the week have found that the risk of deficits or defects is highest when women concentrate their weekly drinking by having five drinks or more in one day, while maintaining a weekly consumption of at least seven drinks (Jacobson & Jacobson, 1994; Jacobson J et al., 1998; Streissguth et al., 1993; 1994). Nevertheless, due to individual differences in sensitivity to alcohol, and the likelihood that at certain development time points the fetus is more sensitive to the effects of alcohol, it cannot be assumed that drinking fewer than five drinks per day is a safe threshold.

Impact on Stillbirths:

With respect to risk for the adverse outcome of stillbirth, Kesmodel et al. (2002) found a nearly 3-fold increase in risk of stillbirth among women who reported consuming five or more drinks weekly. The mechanism of action was unclear, as the increased risk could not be attributed to low birth weight, preterm delivery, or malformation, and there was no association between fetal alcohol exposure and risk of first-year death for live-born infants.

Animal Studies:

Animal models have been particularly useful because the dose and pattern of alcohol consumption, as well as many confounding variables associated with human studies, can be more precisely controlled. Nevertheless, the generalizability of findings from animal studies can be challenging. Studies have used a variety of animal species/strains as well as different alcohol administration paradigms. An important consideration is what constitutes moderate drinking in animal studies versus humans.

The majority of animal studies assessed the effects of moderate alcohol exposure on brain growth, structure, and function. Bonthius and West (1990) demonstrated that a smaller absolute amount of ethanol (4.5 g/kg body wt) administered over a short period of time induced a high blood alcohol concentration (BAC) (mean 362 mg/dl), simulating heavy episodic exposure, whereas a higher daily dose (6.6 g/kg) administered continuously resulted in a low BAC (mean 39 mg/dl). Unlike the high BAC condition, low BACs did not induce microcephaly or cell loss in hippocampus and cerebellum. Another area of active investigation is the impact of moderate alcohol exposure on learning and memory tasks. Recently, Savage et al. (2002) determined that the threshold for maternal BAC that elicits subtle, yet significant learning deficits in adult offspring was 30 mg/dl. This is roughly equivalent to 2 to 3 drinks/day for humans.

Alcohol has been shown to impair the function of the L1 cell adhesion molecule with half maximal inhibition occurring at an alcohol concentration of 7 mM (approximate 35 mg percent), a concentration that can be achieved in blood and brain after one drink. Cell adhesion molecules are critical in the development of the brain as they are involved in the mechanism by which newly developing brain cells migrate to their appropriate location and form appropriate connections to other brain cells. Failure to migrate to the proper location can result in the death of the brain cell by a process called apoptosis. Although this research was conducted in tissue culture systems, the high sensitivity at alcohol dose levels that clearly correspond to low to moderate drinking calls for increased attention, and suggest a potential underlying mechanism explaining the behavioral teratogenic effects of alcohol (Ramanthan et al., 1996).

In research with a chick model of alcohol-induced teratogenic injury, exposure of the developing chick embryo to an alcohol dose equivalent to 35-42 mg/dl, a dose in a human model which would correspond to low to moderate exposure, caused apoptosic cell death of cells from the cranial neural crest. The loss of these specific cells is consistent with the phenotypic characteristics of fetal alcohol injury, including FAS. (Cartwright & Smith, 1995).

Summary – Birth Defects

There is no question about the effects of excessive consumption: heavy drinking during pregnancy can produce a range of behavioral and psychosocial problems, malformations, and mental retardation in the offspring (Kesmodel et al., 2002; Meister et al., 2000; NIAAA, 1992). The question of whether there is a safe level of drinking during pregnancy still remains to be established, with studies indicating that low-to-moderate drinking during pregnancy does not appear to be associated with an increased risk of fetal physical malformations, but may have behavioral or neurocognitive consequences. There is some evidence for a dose-response association, but so far there is not an established threshold level below which consumption is not teratogenic. In the absence of definitive information on low- or moderate-level drinking, in 1981 the Surgeon General recommended that women maintain abstinence during pregnancy.

E. Breastfeeding

Epidemiological data on the effects of moderate drinking throughout the lactation period on the human infant are limited, but there are a larger number of animal studies and human experimental data. Little et al. (1989) reported a slight but statistically significant deficit in motor development at one year of age, as measured by the Bayley Scales of Infant Development, when the lactating mother had an average of 2 drinks daily in the first three months postpartum. The association persisted even after controlling for more than 100 potential confounding variables (e.g., smoking, alcohol/drug exposure during pregnancy, etc.). However, the authors questioned the clinical relevance of the finding, noting that, while very low Bayley scores can be indicative of abnormal developmental progression, small differences (i.e., 7 points, in this case) are not predictive of future patterns, given that infant development scales are not precise measures. Moreover, Little et al. (2002) did not replicate the motor development findings in a later study assessing a larger cohort of infants at 18 months with the Griffiths Scales of Mental Development. The 2002 study actually showed a small but significant “abstainer effect”, with the offspring of non-drinkers having lower scores on 3 of the 5 scales. The discrepant findings may reflect a combination of age differences (12-month -olds in the 1989 study; 18-month-olds in 2002), use of different outcome measures (Bayley Scales versus Griffiths Scale), and the instability of the relatively slight effects found in both studies. Additionally, mothers in the two studies differed in terms of diet, demographics, and lifestyle, adding even more confounds to the mix.

Research indicates that a small amount of alcohol consumed by the mother shortly before the beginning of a breast feeding session can have short term effects on lactational performance and infant behaviors (see review by Mennella, 2001a). Two small human laboratory experimental studies (Mennella and Beauchamp, 1991; 1993) showed that breast-fed infants consumed about 20% less milk on average when the mothers consumed a beverage fortified with 0.3 g ethanol per kg body weight, the equivalent of approximately 1 – 2 drinks. The reduction in milk consumption was due to a slight, but statistically significant, decrease in the mother's milk yield (Mennella 1998), a finding in agreement with an earlier study on rats (Subramanian and Abel, 1988), which demonstrated that the decrease resulted from an inhibition by alcohol of suckling-induced prolactin release. More recently, Mennella (2001b) confirmed the original observation, but reported a compensatory increase in milk consumption by the infant in the 8-16 hr period after exposure to alcohol in the milk resulting from one drink, suggesting that any brief nutritional deficits to the infant are likely to be self-correcting, as long as the mother is only an occasional (as opposed to chronic) moderate drinker. This is confirmed by epidemiologic studies that found no significant differences in weight at 3 and 6 months in infants with lactation-alcohol exposure compared to controls (Flores-Huerta et al. 1992; Villalpando et al. 1993).

The infant’s sleep-wake patterns are also disrupted by acute exposure to 32 mg alcohol in 100 ml of breast milk, resulting in significantly less sleep time during the 3.5 hours immediately after exposure (Mennella and Gerrish, 1998). This finding was replicated in a follow-up study (Mennella and Garcia-Gomez, 2001), which showed that, as with the milk consumption deficits noted above, infants can also compensate for the sleep deficit by increasing the amount of time spent in active (REM) sleep during the 20.5 hr. following the sleep deficit period (i.e., within the same 24-hour cycle). Additionally, as both the reduced milk production/reduced consumption and the infant sleep deficits occur only when breast feeding follows shortly after the mother’s alcohol consumption, it appears that a nursing woman who drinks occasionally can limit her infant’s exposure to alcohol by timing breast feeding in relation to her drinking.

Experience with the sensory qualities of alcohol in mother’s milk during nursing may influence early learning, resulting in altered behavioral responses to alcohol. Mennella (1997) has shown that human infants can detect the flavor of alcohol in milk, even when the alcohol is present in small amounts (32 mg/dL - the average concentration in breast milk one hour after a single drink). Infants who had relatively more exposure to alcohol because of the mother’s drinking pattern responded differently to an alcohol-scented toy than infants with less exposure (Mennella and Beauchamp, 1998). Rodent studies have also shown that exposure to alcohol in a nursing context results in learned, enhanced responses to ethanol in the preweanling animal (Hunt et al., 1993). There as yet have been no longitudinal studies assessing whether this early experience has any effect on the individual’s later (i.e., as an adolescent or an adult) sensitivity or tolerance to alcohol.

The effects of ethanol on the lactation process and on the breast-fed infant have received much less attention than the effects of prenatal alcohol exposure. Several studies (reviewed by Mennella, 2001a), have shown that the concentration and elimination rate of ethanol in human milk closely parallels that of the blood. Peak alcohol levels occur between 0.5 and one hr after a low to moderate dose of alcohol, and the clearance rate is linear. Not surprisingly, variability between individuals on these parameters was observed.

Rodent models of lactational exposure have contributed to our knowledge of the potential effects of chronic exposure to low dose alcohol in breast milk (infant BAC ~ 15-30 mg/dL) on the offspring. However, caution must be exercised in evaluating lactational alcohol effects on brain and behavior of the offspring, because rodent brain development during the immediate postnatal period is more comparable to the third trimester of human gestation, and there are species and strain differences in developmental sensitivity to alcohol. The most consistent finding has been a reduction in overall growth of pups, accompanied by reductions in some organ weights; however, brain weight does not appear to be affected (Lancaster et al., 1984, 1986; Oyama and Oller do Nascimento, 2003). Additional parameters of brain development have been examined. Alterations in brain myelin content (Lancaster et al., 1984), brain glucose metabolism (Oyama and Oller do Nascimento, 2003), and developmental profiles of enzyme activities in dopaminergic and cholinergic systems of the corpus striatum (Lancaster et al. (1986) have been reported. These changes could potentially give rise to impaired neurotransmitter function leading to altered behavior such as hyperactivity.

Summary – Breastfeeding

Because the level of alcohol in breast milk mirrors the mother’s blood alcohol content (i.e., it decreases as time-since-consumption lengthens), nursing mothers can limit their infants’ exposure to alcohol by timing their drinking so it does not coincide with feeding schedules. However, while folklore has perpetuated the belief that alcohol is an aid to lactation, and new mothers have often been encouraged to use low or moderate consumption as a way to increase milk production, the research indicates that alcohol ingestion does not enhance lactational performance, and may actually decrease it, at least in the several hours immediately following the consumption period.

F. Aging

Cognitive Effects

Alcohol and its metabolites are known to affect tissues of the central nervous system, and prolonged or excessive alcohol intake has been associated with an increased risk of dementia, both through direct neurotoxic effects and through external causes such as malnutrition and trauma (Brust, 2002; Truelsen et al., 2002). Thus, as life expectancy increases, the effect of alcohol use on cognitive functioning and dementia in older adults has become an important area of investigation. The two most common types of dementia in Western populations are Alzheimer dementia (AD) and vascular dementia (VD). There has been some indication that low to moderate alcohol consumption decreases the risk of VD (Brust, 2002; Peele & Brodsky, 2000; Truelsen et al., 2002). Some studies indicate that levels of consumption less than 1 drink per day, or greater than 4 drinks per day is not significant (Ruitenberg et al., 2002; Mukamal et al., 2003b), while the risk of VD is significantly lowered (RR = 0.30) by consumption of 1 –3 drinks per day (Ruitenberg et al., 2002). Others (Truelsen et al., 2002) found protective effects arising from intake as sporadic as monthly or weekly.

At moderate levels of alcohol consumption (e.g., up to 2 ½ or 3 drinks per day), meta-analyses and epidemiological reviews have failed to find significant effects in relation to AD (English & Holman, 1995; Graves et al., 1991; Tyas, 2001). Among individual studies, consumption levels ranging from 1 drink per week up to 2 drinks per day reduced risk by up to 60% in some studies (Huang et al., 2002; Mukamal et al., 2003b; Orgogozo et al., 1997). No consumption levels demonstrated increased risk.

A number of studies have looked at cognitive function, a different level of assessment than dementia. Moderate alcohol intake was found to be associated with improved cognitive performance (or decreased cognitive impairment) by some researchers (Galanis et al., 2000; Peele & Brodsky, 2000; Zuccala et al., 2001); however, the level of intake that was found to be optimal varies widely across studies, ranging from fewer than 4 drinks per week up to 5 ½ per day for men ( up to 2 ½ per day for women). In other studies, levels of consumption from 1 through 30 drinks per week (i.e., as high as 4 drinks per day) were not significantly associated with cognitive impairment or benefit (Broe et al., 1998; Cervilla et al., 2000; Eckardt et al., 1998; Huang et al., 2002).

Macular Degeneration

Because of its relation to vascular risk factors, age-related macular degeneration (AMD) has been postulated to be influenced by moderate alcohol consumption (Ajani et al., 1999; Hiratsuka & Li, 2001). Although one research group (Obisesan et al., 1998) found moderate consumption to be associated with decreased odds of developing AMD, most studies have found no appreciable association in either direction (Ajani et al., 1999; Cho et al., 2000; Moss et al., 1998).

Sensitivity and Tolerance

Tupler et al. (1995) found differences in the pattern but not in the magnitude of skill/task impairment for elderly subjects as compared to younger individuals, with the elderly demonstrating earlier decrements (i.e., impairment), more rapid acute tolerance, and less pharmacodynamic sensitivity. Regression analyses indicated that age and impairment were negatively related, rather than supporting the assumption of synergistic intoxication effects as a function of aging. Although the elderly subjects reached higher BACs than their younger counterparts under equivalent doses, their baseline performance versus their performance at legally intoxicating BACs reflected no age effects. Results failed to confirm that impairment would be either more severe, or more sustained, as a function of age.

Lucey et al. (1997) confirmed the influence of age on blood ethanol response (i.e., BAC level) after a moderate dose of ethanol. However, neither gastric metabolism nor motility accounted for the age/BAC effects, since they were independent of administration route (orally or IV).

Nishimura et al. (2003) compared younger versus older adults stratified according to ALDH2 genotype, looking at ALDH2-normal (NN) versus heterozygote ALDH2-deficient (ND) individuals. Alcohol consumption markedly increased EEG power (especially in theta and slow-alpha power) in the NN subjects but not in the ND subjects of the older group, in comparison to their younger counterparts. As there were no differences between the two age groups in blood ethanol and acetaldehyde concentrations at 30 minutes after alcohol ingestion, the researchers suggest that the rate of alcohol metabolism was not influenced by age. However, sensitivity to alcohol in the central nervous system of the NN subjects seems to have been modified with age, resulting in greater increases in EEG energy after alcohol ingestion in the older group. The findings suggest that both ALDH2 genotype and age modify alcohol sensitivity in the central nervous system.

Summary – Aging

There is some indication that moderate alcohol consumption may reduce risk for vascular dementia, while effects on Alzheimer’s dementia and on macular degeneration remain inconclusive. Although elderly drinkers reach higher BACs with lower levels of consumption than their younger counterparts (possibly due to changes in body mass/body water or to decreased hepatic function that affects first pass metabolism), their level of impairment at any given BAC level does not differ from that of younger drinkers.

III. ADDITIONAL AREAS OF POTENTIAL RISKS AND BENEFITS

Alcohol Abuse and Dependence

The likelihood exists that some portion of current abstainers and very infrequent drinkers may succumb to alcohol abuse or dependence if they begin or increase consumption. A number of factors come into play in considering the risk for development of alcohol dependence or abuse, including genetic makeup, environmental contributions, and the interaction of the two. A low estimate might be that 5 to 7 % of current abstainers and/or infrequent drinkers could develop diagnosable alcohol problems with upon beginning usage --- a percentage similar to that in the overall population. However, people’s reasons for not drinking vary; if someone abstains because of a family history of alcohol problems or an awareness of their own limitations, he or she is also someone who likely would be at greater than “average” risk for developing dependence (Dawson, 2000; Hasin et al., 2001; Schuckit & Smith, 2001). Epidemiologic data indicate that the greatest risk for the development of alcohol dependence occurs between ages 18 and 25, for the general population as a whole (NIAAA/NLAES, 1992). It is worth noting, however, that most people who do drink have begun by that age, which coincides with legal age requirements, moving away from home, etc. It perhaps is more a situation of the development of dependence occurring within 5-10 years of first regular use, rather than being tied to an actual age. Thus we cannot predict whether abstainers or very infrequent drinkers who take up regular alcohol use later in life based on an expectation of “health benefits” have managed to avoid a developmentally-based high-risk period, or whether the timeframe of risk simply shifts to the 5-10 years that follow their start-up.

Cerebrovascular Effects

Cerebrovascular events (i.e., strokes) are the third leading cause of death and the leading cause of disability in the US (CDC, 2002). The risk of stroke increases with age, with only about 25% of strokes occurring in persons younger than 65 (eMedicine, 2001) . Hemorrhagic strokes account for about 10-15% of all cases, and are more common than ischemic strokes for younger persons (eMedicine 2002). Because blood pressure increases with heavy alcohol consumption, excessive intake levels can be expected to increase the risk of stroke. At lower levels of consumption, however, alcohol’s effects on blood lipoproteins and blood clotting might be expected to reduce the risk of ischemic stroke, although the same anti-clotting effects could increase the risk of hemorrhagic stroke (Meister et al., 2000). While heavy alcohol drinking (about 5 drinks/day) is associated with higher relative risk for both ischemic and hemorrhagic stroke, research suggests that moderate drinking lowers the risk of ischemic stroke via a J-shaped curve with the nadir at just under 2 drinks per day, with the consumption of 7 or more drinks per day increasing the risk about 3-fold (Hillbom et al., 1999; Reynolds et al., 2003; Rotondo et al., 2001). The empirical evidence regarding hemorrhagic stroke is mixed; some studies have found no statistically significant association, some have found a J-shaped relationship, and others indicate a linear relationship (Berger et al., 1999; Klatsky, 2002; Reynolds et al., 2003; Rimm, 2000). Overall, the evidence suggests that moderate alcohol intake reduces the risk of stroke in populations where ischemic stroke predominates (i.e., the middle-aged and elderly), but may increase the risk in populations where hemorrhagic strokes are more common, such as young adults (Meister et al., 2000).

Magnetic resonance imaging (MRI) of brains of elderly individuals free of known cerebrovascular disease who consumed moderate amounts of alcohol (1 - <7 drinks/week) showed a lower prevalence of cerebral infarcts and white matter abnormalities (Mukamal et al., 2001a). There is a paucity of experimental data from animal models of ethanol and stroke that might illuminate possible mechanisms underlying these observations.

The vascular endothelium is likely a target for and mediator of many of ethanol's effects both deleterious as well as protective. Low dose alcohol has been shown to be involved in modulating many endothelial cell functions including increased release of nitric oxide, and adhesion receptor expression (Puddey et al., 2001). Treatment with low concentrations of ethanol (2-20 mM) promotes endothelial cell survival (Liu et al., 2002) and may stimulate angiogenesis at 10 and 20 mM (Gu et al., 2001). Studies in animals demonstrate that low dose alcohol augments endothelium-mediated vasodilation whereas higher doses impair endothelium-mediated relaxation. A study examining moderate or heavy alcohol consumption and circulating adhesion molecules (Sacanella et al., 2002) found that moderate drinkers (1½ to 3 drinks /day) showed lower serum adhesion molecule levels than did abstainers and heavy drinkers. The authors suggested that moderate alcohol consumption may have an anti-inflammatory effect on the endothelium, contributing to its vaso-protective effect.

Hepatic Effects

Alcohol abuse is the leading cause of liver-related mortality in the US, accounting for at least 40%, and perhaps as many as 90%, of cirrhosis deaths (Meister et al., 2000). The level of alcohol consumption associated with increased risk for liver disease is uncertain; some studies have suggested levels as low as 14 drinks per week for men and 7 for women (Pequignot and Tuyns, 1980) while others have observed considerably higher thresholds (e.g., see Meister et al., 2000). However, the largest body of evidence suggests that intake of at least 5 drinks/day over a period of at least 5 years is necessary for the development of cirrhosis, while the odds ratio for hepatocellular carcinoma shows a linear increase after more than 4 drinks/day, and becomes statistically significant when consumption levels exceed 5 ½ drinks/day (Donato et al., 2002; Montalto et al., 2002).

Although chronic heavy alcohol consumption leads to the development of alcoholic liver disease, studies in animals showed no significant effects with moderate amounts of alcohol. However, moderate alcohol consumption may potentiate the carcinogenic potency of other hepatotoxins. For example, daily consumption of 1 ½ to 2 drinks per day increased by 35-fold the risk of developing hepatocellular carcinoma induced by dietary aflatoxin B1 (Bulatao-Jayme et al., 1982).

Heavy alcohol intake is also known to impair hepatic regeneration (e.g. Diehl et al., 1990). Recently, data were published reporting the effect of light (1g/kg), moderate (2 g/kg), and heavy (4 g/kg) alcohol intake on hepatic regeneration after partial hepatectomy in rats (Zhang et al., 2000). While heavy alcohol impaired liver regeneration, moderate alcohol had no effect, and light alcohol enhanced liver regeneration. The mechanisms of these effects are not known.

Individuals with Pre-existing Hepatitis C:

Several studies (Bellentani et al., 1999; Harris et al., 2002; Poynard et al., 1997; Thomas et al., 2000) have demonstrated an increased risk for cirrhosis in HCV-infected patients who consume more than 4 drinks per day, with some studies suggesting an increased risk to patients who consume more than 2 drinks per day. However, the hepatotoxic effects of light and moderate amounts of alcohol on HCV infection, progression, and severity need further exploration.

Three studies examined the relationship between moderate levels of alcohol consumption and fibrosis progression in patients with hepatitis C infection (Hezode et al., 2003; Westin et al., 2002; Wiley, et al., 1998). In each instance, moderate alcohol consumption worsened the degree of biopsy confirmed fibrosis. These studies are somewhat comparable since alcohol consumption was defined as less than 2 ½ drinks per day. One study showed a dose dependent increase in fibrosis for an intake between 2 and 3 ½ drinks per day (Hezode et al., 2003).

Oxidative stress is increased in patients with alcoholic liver disease and in patients with HCV. A number of reports link low and moderate alcohol intake with increased oxidative stress and liver fibrosis progression in chronic hepatitis C. Rigamonti et al. (2003) evaluated serum markers of oxidative stress and concluded that moderate alcohol consumption, defined as less than 4 drinks per day, promotes oxidative stress in patients with chronic hepatitis C. However, this was a retrospective analysis on stored serum samples in which auto-oxidation had occurred. Results were compared with freshly obtained control specimens. The presence of steatosis in patients with hepatitis C increased progression rates when low to moderate (1 ½ to 2 drinks per day) amounts of alcohol were consumed (Serfaty et al., 2002).

Oral/Upper Digestive Tract Cancers

Associations have been reported between drinking and cancers of the mouth, pharynx, larynx, and esophagus (Holman et al., 1996; Seitz et al., 1998; 2001). Risk appears to increase directly with consumption level, although it may increase more rapidly at higher drinking levels (Ashley et al., 1997; Gronbaek et al., 1998). In most studies “moderate” drinking per se was not studied, but results were statistically extrapolated; however, some studies have found that alcohol had adverse effects on these diseases even when the usual level of intake was classified as “responsible”, with risks increasing by 26% to 83% (Holman et al., 1996).

One hypothesis is that the responsible agent is acetaldehyde, (i.e., the first metabolite of ethanol) which has been shown to be carcinogenic (International Agency for Research on Cancer, 1999). Acetaldehyde can be formed by microbial alcohol dehydrogenases (ADHs) in the upper GI tract (Salaspuro, 1996). High acetaldehyde levels of microbial origin were found in human saliva after a moderate dose of alcohol (Homann et al., 1997). Furthermore, moderate alcohol consumption (0.5 g/kg of body weight) resulted in three-fold higher salivary acetaldehyde levels in Asians with deficient aldehyde dehydrogenase -2 (ALDH2) allele (flushers) than with Asians with normal ALDH2 (nonflushers) (Vakevainen et al., 2000). Higher levels of acetaldehyde in flushers may contribute to the higher incidence of alcohol-associated cancers of the upper digestive tract.

Colorectal Cancer

Estimates of relative risk based on meta-analyses have found modest but statistically significant risk of cancer of the colon and/or rectum at lower levels of alcohol consumption. For consumption up to 2 drinks per day, estimated relative risks range from 1.08 to 1.14 (Bagnardi et al. 2001a; 2001b; English & Holman, 1995). Individual cohort and case/control studies found no increased risk for colon cancer at up to 2 drinks per day, while the risk for rectal cancer was inconsistent across studies, with some studies finding no association and others finding an increased risk for rectal cancer (RR = 1.7) at 1-2 drinks per day (Flood et al., 2002; Ji et al., 2002; Pedersen et al. 2003). Yet another study (Murata et al., 1999) found a significant protective effect for colorectal cancer, as well as colon cancer alone, from consumption of up to 2 drinks per day. Overall, the relationship between moderate alcohol consumption and colorectal cancer is inconclusive, with studies demonstrating some minor effects and many modifying or confounding factors.

Cancer - General

Considering all cancers combined, an American Cancer Society study of middle-aged men found that mortality from cancer was significantly lower among those consuming up to one drink daily, as compared to abstainers (Ashley et al., 1994). However, it seems that any cancer-related benefits conferred occur only at the lower end of the “moderate drinking” range.

Injuries/Accidents

Studies on the role of alcohol in injury from falls and violence/abuse frequently do not distinguish between moderate and excessive drinking (e.g., Cunningham et al., 2003; Humphrey et al., 2003; Vinson et al., 2003; Wells & Graham, 2003; Zautcke et al, 2002). However, many “moderate drinkers” have episodes of high-risk drinking, including heavy episodic drinking and acute intoxication leading to injuries and violence (Gutjahr et al., 2001). Additionally, studies of the acute effects of alcohol show that even moderate-dose consumption compromises brain performance in terms of error detection, processing speed, and response time (Ridderinkhof et al., 2002), impairments that may be particularly important in terms of driving-related risk. Several reports (Deery & Love, 1996; Hingson et al., 1999; Midanik et al. 1996) have indicated that low levels of drinking (e.g., 1 or fewer per day) and BACs below the legal limit of 0.08% (e.g., 0.05%) increase risk of driving-related accidents.

Total (All-Cause) Mortality

A meta-analysis on all cause-mortality (Gmel et al., 2003) using approximately 50 studies demonstrated an inverse association between light to moderate drinking and total mortality under all scenarios, although the extent of the effect (i.e., nadir of risk curve; magnitude of effect) may differ according to demographics (e.g., women versus men; older populations versus younger). The resulting J-shaped curve, with the lowest mortality risk occurring at the level of 1-2 drinks per day, is likely due primarily to the protective effects of alcohol consumption on CHD and ischemic stroke, which comprise the leading cause of death in the US (CDC, 2002).

IV. CONCLUSIONS:

Government dietary guidelines commonly indicate a minimum daily requirement necessary for good health. Health care consumers are familiar with this approach and may easily confuse low-risk guidelines for alcohol use with recommended levels of intake for good health. Thus, “moderate alcohol use” should not be construed as “healthy alcohol use” (Masters 2003).

Furthermore, as described in the “Background” section of this report, the relationship between moderate alcohol consumption and disease outcome is confounded and modified by numerous individual differences – age, gender, genetic susceptibility, metabolic rate, co-morbid conditions, lifestyle factors, and patterns of consumption, just to name a few. Protective and detrimental levels of alcohol consumption cannot be generalized across the population, but instead should be determined by an individual in consultation with her or his physician.

Finally, most of the research refers to the risk of disease occurrence. Some of these illnesses may detract from quality of life without increasing mortality; most differ in prognosis, either via the natural history of the disease or due to currently available treatment options. The potential for moderate alcohol consumption to increase risk for one disease may be offset or outweighed by its potential to decrease risk for another disease, depending on the individual’s family history, medical history, genetic makeup, and lifestyle.

While keeping these issues in mind as caveats, the current scientific literature suggests the importance of the following points:

The lowest total all-cause mortality occurs at the level of 1 - 2 drinks per day.

Current scientific data continue to show that moderate levels of alcohol consumption do not increase risk for heart failure/ myocardial infarction or ischemic stroke, and in fact provide protective effects along a J-shaped curve.

There is evidence of a monotonic increase in relative risk of breast cancer with alcohol consumption. Compared to nondrinkers, there appears to be a 10% increase in risk for women averaging 1 drink per day; the risk may be higher for women with a family history of breast cancer and for those on hormone replacement therapy.

The data on the relationship between moderate alcohol consumption and weight gain/obesity are inconclusive. However, there is some evidence for reduced risk of diabetes and metabolic syndrome, which often co-exist with or develop from obesity.

Low-to-moderate drinking during pregnancy does not appear to be associated with an increased risk of fetal physical malformations, but may have behavioral or neurocognitive consequences. There is some evidence for a dose-response association but, so far, there is not an established threshold level below which consumption may be safe. There is no question about the effects of excessive consumption: heavy drinking during pregnancy can produce a range of behavioral and psychosocial problems, malformations, and mental retardation in the offspring.

Alcohol ingestion by nursing mothers does not enhance lactational performance, and may actually decrease it, at least in the several hours immediately following the consumption period. Effects on the infant appear to be short-term and reversible; however, as alcohol dissipates from breast milk over time, the safest course would be to allow sufficient time between drinking occasion and feeding session for the mother to fully metabolize the alcohol.

There is no evidence that cognitive functioning is negatively affected by moderate alcohol consumption as one ages, and there may be a protective effect against vascular dementia.

Summary – Conclusions

The current scientific knowledge on the risks and benefits related to various levels of alcohol consumption does not suggest a need to modify the existing guidelines on moderate alcohol use. Except for those individuals at particular risk (as are described in the current guidelines), consumption of 2 drinks a day for men and 1 for women is unlikely to increase health risks. As risks for some conditions and diseases do increase at higher levels of consumption, men should be cautioned to not exceed 4 drinks on any day and women to not exceed 3 on any day.

V. CITED REFERENCES

Ajani UA, Christen WG, Manson JE, Glynn RJ, Schaumberg D, Buring JE, Hennekens CH (1999). A prospective study of alcohol consumption and the risk of age-related macular degeneration. Ann Epidemiol 9: 172-177.

Ajani UA, Hennekens CH, Spelsberg A, Manson JE (2000). Alcohol consumption and risk of type 2 diabetes mellitus among US male physicians Arch Intern Med 160: 1025-1030.

Ashley MJ, Ferrence R, Room R, Bondy S, Rehm J, Single E (1997). Moderate drinking and health: Implications of recent evidence. Can Fam Physician, 43: 687-694.

Ashley MJ, Ferrence R, Room R, Rankin J, Single E (1994). Moderate drinking and health: Report of an international symposium. Can Med Assoc 151, 809-828.

Baer DJ, Judd JT, Clevidence BA, Muesing RA, Campbell WS, Brown ED, Taylor PR (2002). Moderate alcohol consumption lowers risk factors for cardiovascular disease in postmenopausal women fed a controlled diet. Am J Clin Nutr, 75: 593-599.

Bagnardi V, Blangiardo M, La Vecchia C, Corrao G. (2001a). A meta-analysis of alcohol drinking and cancer risk. Br J Cancer 85(11):1700-1705.

Bagnardi V, Blangiardo M, La Vecchia C, Corrao G. (2001b). Alcohol consumption and the risk of cancer: a meta-analysis. Alcohol Res Health 25(4):263-270.

Barefoot JC, Gronbaek M, Feaganes JR, McPherson RS, Williams RB, Siegler IC (2002). Alcoholic beverage preference, diet, and health habits in the UNC alumni heart study. Am J Clin Nutr, 76: 466-472.

Baumgartner KB, Annegers JF, McPherson RS, Frankowski RF, Gilliland FD, Samet JM. (2002). Is alcohol intake associated with breast cancer in Hispanic women? Ethnicity & Disease; 12:460-469.

Bellentani S, Pozzato G, Saccoccio G, Crovatto M, Croce LS, Mazzoran L, Masutti F et al. (1999). Clinical course and risk factors of hepatitis C virus related liver disease in the general population. Gut 44: 874-880.

Berger K, Ajani UA, Kase CS, Gaziano JM, Buring JE, Glynn RJ, Hennekens CH (1999). Light-to-moderate alcohol consumption and risk of stroke among U.S. male physicians. N Engl J Med. 341:1557-64.

Bondy SJ, Rehm J, Ashley MJ, Walsh G, Single E, Room R (1999). Low-risk drinking guidelines: the scientific evidence. Canadian J Public Health, 90; 264-270.

Bonthius DJ, West JR (1990) Alcohol-induced neuronal loss in developing rats: increased brain damage with binge exposure. Alcohol Clin Exp Res 14:107-118.

Booyse FM, Parks DA (2001). Moderate wine and alcohol consumption: Beneficial effects on cardiovascular disease. Thromb Haemost, 86: 517-528.

Broe GA, Creasey H, Jorm AF, Bennett HP, Casey B, Waite LM et al.. (1998). Health habits and risk of cognitive impairment and dementia in old age: a prospective study on the effects of exercise, smoking and alcohol consumption. Aust N Z J Public Health 22(5):621-623.

Brust JCM (2002). Wine, flavonoids, and the “water of life”. Neurology, 59: 1300-1301.

Bulatao-Jayme L, Almero EM, Castro MCA, Jardeleza MTR, Salamat LA (1982) A case-control dietary study of primary liver cancer risk from aflatoxin exposure. Int J Epidemiol 11:112-119.

Cartwright MM, Smith SM (1995). Increased cell death and reduced neural crest cell numbers in ethanol-exposed embryos: partial basis for the fetal alcohol syndrome phenotype. Alcoholism Clin and Exp Res. 19: 378-386.

CDC (2002). National Vital Statistics Report, 50(16).

Cervilla JA, Prince M, Joels S, Lovestone S, Mann A. (2000) Long-term predictors of cognitive outcome in a cohort of older people with hypertension. Br J Psychiatry 177:66-71.

Chen WY, Colditz GA, Rosner B, Hankinson SE et al. (2002). Use of postmenopausal hormones, alcohol, and risk for invasive breast cancer. Ann Intern Med; 137:798-804.

Cho E, Hankinson SE, Willett WC, Stampfer MJ, Spiegelman D, Speizer FE, Rimm EB, Seddon JM (2000). Prospective study of alcohol consumption and the risk of age-related macular degeneration. Arch Opthalmol 118: 681-688.

Clavel-Chapelon F, Thiebaut A, Berrino F. (2002). Alcohol consumption and breast cancer risk. IARC Scientific Publications 156: 155-160.

Colditz GA, Rosner B. (2000). Cumulative risk of breast cancer to age 70 years according to risk factor status. Am J Epidemiol; 152:950-964.

Cordain L, Melby CL, Hamamoto AE, O’Neill DS, et al.(2000) Influence of moderate chronic wine consumption on insulin sensitivity and other correlates of syndrome X in moderately obese women. Metabolism 49:1473-1478, 2000

Cornier MA, Gayles EC, Bessesen DH (2002) Effects of chronic ethanol consumption on energy balance in rats. Metabolism 51:787-791.

Corrao G, Rubbiai L, Bagnardi V, Zambon A, Poikolainen K (2000). Alcohol and coronary heart disease: a meta-analysis. Addiction 95: 1505-1523.

Cunningham R, Walton MA, Maio RF, Blow FC, Weber JE, Mirel L (2003). Violence and substance use among an injured emergency department population. Acad Emerg Med 10: 764-775.

Davies MJ, Baer DJ, Judd JT, Brown ED, Campbell WS, Taylor PR (2002). Effects of moderate alcohol intake on fasting insulin and glucose concentrations and insulin sensitivity in postmenopausal women. JAMA, 287: 2559-2562.

Dawson DA. (2000). The link between family history and early onset alcoholism: earlier initiation of drinking or more rapid development of dependence? J Stud Alcohol. 2000 61:637-646.

Day NL, Leech SL, Richardson GA, Cornelius MD, Robles N, Larkby C. (2002) Prenatal alcohol exposure predicts continued deficits in offspring size at 14 years of age. Alcoholism: Clinical and Experimental Research; 26(10):1584-1591.

Day NL, Zuo Y, Richardson GA, Goldschmidt L, Larkby CA, Cornelius MD (1999). Prenatal alcohol use and offspring size at 10 years of age. Alcoholism: Clinical and Experimental Research; 23(5):863-869.

Day NL, Robles N., Richardson G., Geva D., Taylor P., Scher M. et al. (1991) Effects of prenatal alcohol use on the growth of children at three years of age. Alcoholism: Clinical and Experimental Research; 15(1):67-71.

DeCastro JM, Orozco S (1990) Moderate alcohol intake and spontaneous eating patterns of humans: Evidence of unregulated supplementation. Am. J. Clin. Nutr. 52:246-253.

Deery HA, Love AW (1996). The effect of moderate dose alcohol on the traffic hazard perception profile of young drink-drivers. Addiction 91: 815-827.

De Oliveira e Silva ER, Foster D, McGee HM, Seidman CE, Smith JD, Breslow JL, Brinton EA (2000) Alcohol consumption raises HDL cholesterol by increasing the transport rate of apolipoproteins AI and AII. Circulation 102:2347-2352.

Diehl AM, Thorgeirsson SS, Steer CJ (1990) Ethanol inhibits liver regeneration in rats without reducing transcripts of protooncogenes. Gastroenterology 99:1105-1112.

Dimmitt SB, Rakic V, Puddey IB, Baker R, Oostryck R, Adams MJ, Chesterman CN, Burke V, Beilin LJ (1998) The effects of alcohol on coagulation and fibrinolytic factors: a controlled trial. Blook Coagul Fibrinolysis. Jan;9(1):39-45.

Dixon JB, Dixon ME, O’Brien PE (2002) Alcohol consumption in the severely obese: Relationship with the metabolic syndrome. Obesity Res. 10:245-252.

Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, Albertini A, Decarli A, Trevisi P, Ribero ML, Martelli C, Porru S, Nardi G (2002). Alcohol and hepatocellular carcinoma: The effect of lifetime intake and hepatitis virus infections in men and women. AmJ Epidemiol, 155: 323-331.

Durrington PN, Mackness B, Mackness MI (2001) Paraoxonase and atherosclerosis. Arterioscl. Thromb. Vasc. Biol. 21:473-480.

Eckardt MJ, File SE, Gessa GL, Grant KA et al (1998). Effects of moderate alcohol consumption on the central nervous system. Alcoholism: Clinical and Experimental Research; 22(5):998-1040.

Ellison RC, Zhang Y, McLennan CE, Rothman KJ.(2001). Exploring the relation of alcohol consumption to risk of breast cancer. Am J Epidemiol; 154(8):740-747.

English D.R., Holman D.D.J. (1995). The quantification of drug-caused mortality and morbidity in Australia. Canberra: Commonwealth Department of Human Services and Health .

eMedicine (2001). Website: http://www.emedicine.com/EMERG/topic558.htm

eMedicine (2002). Website: http://www.emedicine.com/EMERG/topic557.htm

Facchini F, Chen YD, Reaven GM (1994) Light to moderate alcohol intake is associated with enhanced insulin sensitivity. Diabetes Care 17:115-119; 1994.

Feigelson H, Jonas C, Robertson A, McCullough M, Thun M, Calle E (2003). Alcohol, folate, methione and risk of incident breast cancer in the American Cancer Society Cancer Prevention Study II nutrition cohort. Cancer Epidem Biomark Prev 12: 161-164.

Flanagan DE, Moore VM, Godsland IF, Cockington RA, Robinson JS, Phillips DI. (2000) Alcohol consumption and insulin resistance in young adults. Eur. J. Clin. Invest. 30:297-301.

Flesch M, Rosenkranz S, Erdmann E, Bohm M (2001). Alcohol and the risk of myocardial infarction. Bas Res Cardiol, 96: 128-135.

Flood A, Caprario L., Chaterjee N., Lacey J.V.Jr., Schairer C., Schatzkin A. (2002). Folate, methionine, alcohol, and colorectal cancer in a prospective study of women in the United States. Cancer Causes and Control 13(6):551-561.

Flores-Heuerta S, Hernandez-Montes H, Argote RM, Villalpando S (1992). Effects of ethanol consumption during pregnancy and lactation on the outcome and postnatal group of the offspring. Ann Nutr Metab 36; 121-128.

Freudenheim JL, Ambrosone CB, Moysich KB, Vena JE et al. (1999). Alcohol dehydrogenase 3 genotype modification of the association of alcohol consumption with breast cancer risk. Cancer Causes and Control 10, 369-377.

Galanis DJ, Joseph C, Masaki KH, Petrovitch H, Ross GW, White L. (2000). A longitudinal study of drinking and cognitive performance in elderly Japanese American men. Am J Public Health; 90:1254-1259.

Garland M, Hunter DJ, Colditz GA, Spiegelman DL, Manson JE, Stampfer MJ, Willett WC (1999). Alcohol consumption in relation to breast cancer risk in a cohort of United States women 25-42 years of age. Cancer Epidemiology, Biomarkers & Prevention; 8: 1017-1021.

Gaziano JM, Gaziano TA, Glynn RJ, Sesso HD, Ajani UA, Stampfer MJ, Manson JE, Hennekens CH, Buring JE (2000). Light-to-moderate alcohol consumption and mortality in the physicians’ health study enrollment cohort. J Am Coll Cardiol, 35: 96-105.

Ginsburg ES (1999). Estrogen, alcohol and breast cancer risk. J Steroid Biochem & Molecular Biol, 69: 299-306.

Ginsburg ES, Mello NK, Mendelson et al (1996). Effects of alcohol ingestion on estrogens in postmenopausal women. JAMA; 276:1747-1751.

Gmel G, Gutjahr E, Rehm J (2003). How stable is the risk curve between alcohol and all-cause mortality and what factors influence the shape? A precision-weighted hierarchical meta-analysis. Eur J Epidemiology, 18: 631-642.

Goldschmidt L, Richardson GA, Stoffer DS, Geva D, Day NL. (1996). Prenatal alcohol exposure and academic achievement at age six: a nonlinear fit. Alcohol Clin Exp Res, 20:763-770.

Green CA, Polen MR (2001). The health and health behaviors of people who do not drink alcohol. Am J Prev Med, 21: 298-305.

Grenett HE, Aikens ML, Tabengwa EM, Davis GC, Booyse FM (1998) Ethanol transcriptionally upregulates t-PA and u-PA gene expression in cultured human endothelial cells. Alcoholism Clin. Exp. Res. 22:849-853, 1998.

Griffin BA (1999) Lipoprotein atherogenecity: an overview of current mechanisms Proc. Nutr. Soc. 58:163-169.

Gronbaek M (2001). Factors influencing the relation between alcohol and mortality – with focus on wine. J Intern Med, 250: 291-308.

Gronbaek M (2002). Alcohol, type of alcohol, and all-cause and coronary heart disease mortality. Ann NY Acad Sci 957: 16-20.

Gronbaek M, Becker U, Johansen D, Tonnesen H, Jensen G, Sorensen TI (1998). Population based cohort study of the association between alcohol intake and cancer of the upper digestive tract. BMJ 317: 844-847.

Gu, J-W, Elam J, Sartin A, Li W, Roach R, Adair TH (2001) Moderate levels of ethanol induce expression of vascular endothelial growth factor and stimulate angiogenesis. Am J Physio 281: R365-R371.

Gutjahr E, Gmel G, Rehm J (2001). Relation between average alcohol consumption and disease: An overview. Eur Addict Res, 7: 117-127.

Hamajima N, Hirose K, Tajima K, Rohan T, Calle EE, Heath CW Jr, et al. [the Collaborative Group on Hormonal Factors in Breast Cancer] (2002). Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer. 87(11):1234-45.

Harris DR, Gonin R, Alter HJ, Wright EC, Buskell ZJ, Hollinger FB, Seeff LB (2001). The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse. Ann Intern Med 134: 120-124.

Hasin D, Paykin A, Endicott J. (2001). Course of DSM-IV alcohol dependence in a community sample: effects of parental history and binge drinking. Alcohol Clin Exp Res. 25:411-414.

Hezode C., Lonjon I, Roudot-Thorval F, Pawlotsky JM, Zafrani ES, Dhumeaux D (2003) Impact of moderate alcohol consumption on histological activity and fibrosis in patients with chronic hepatitis C, and specific influence of steatosis: a prospective study. Aliment Pharma Therapeu 17:1031-1037.

Hillbom M, Juvela S, Numminen H (1999). Alcohol intake and the risk of stroke. J Cardiovasc Risk, 6: 223-228.

Hines LM, Rimm EB (2001). Moderate alcohol consumption and coronary heart disease: a review. Postgrad Med J, 77: 747-752.

Hingson RW, Heeren T, Winter MR (1999). Preventing impaired driving. Alcohol Res Health 23: 31-39.

Hiratsuka Y, Li G (2001). Alcohol and eye diseases: a review of epidemiologic studies. J Stud Alcohol. 62:397-402.

Holman CDJ, English DR, Milne E, Winter MG (1996). Meta-analysis of alcohol and all-cause mortality. MJA 164, 141-145.

Homann N, Jousimies-Somer H, Jokelainen K, Heine R, Salaspuro M (1997) High acetaldehyde levels in saliva after ethanol consumption: methodological aspects and pathogenetic implications. Carcinogenesis 18:1739-1743.

Horn-Ross PL, Hoggatt KJ, West DW, Krone MR, Stewart SL, Anton-Culver H, et al. (2002). Recent diet and breast cancer risk: the California Teachers Study. Cancer Causes and Control 13: 407-415.

Huang W, Qiu C, Winblad B, Fratiglioni L. (2002). Alcohol consumption and incidence of dementia in a community sample aged 75 years and older. J Clin Epidemiol; 55(10):959-964.

Humphrey G, Casswell S, Han DY (2003). Alcohol and injury among attendees at a New Zealand emergency department. NZ Med J 116: U298.

Hunt PS, Kraebel KS, Rabine H, Spear LP, Spear NE (1993) Enhanced ethanol intake in preweanling rats following exposure to ethanol in a nursing context. Dev Psychobiol 26:133-153.

International Agency for Research on Cancer (1999) Acetaldehyde, in IARC monographs on the evaluation of the carcinogenic risk to humans: re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide, vol 71, part 2, pp319-335. International Agency for Research on Cancer, Lyon, France.

Jacobson SW, Chiodo LM., Sokol RJ, Jacobson JL (2002). Validity of maternal report of alcohol, cocaine, and smoking during pregnancy in relation to neurobehavioral outcome. Pediatrics, 109: 815-825

Jacobson JL, Jacobson, SW (1994). Prenatal alcohol exposure and neurobehavioral development: Where is the threshold? Alcohol Health and Research World, 18: 30-36.

Jacobson JL, Jacobson SW, Sokol RJ, Ager JW Jr. (1998). Relation of maternal age and pattern of pregnancy drinking to functionally significant cognitive deficit in infancy. Alcohol Clin Exp Res, 22:345-351.

Jacobson JL, Jacobson SW, Sokol RJ, Martier SS, Ager JW, Kaplan-Estrin MG. (1993). Teratogenic effects of alcohol on infant development. Alcohol Clin Exp Res, 17:174-183.

Jacobson SW, Jacobson JL, Sokol RJ. (1994). Effects of fetal alcohol exposure on infant reaction time. Alcohol Clin Exp Res, 18:1125-1132.

Jacobson SW, Jacobson JL, Sokol RJ, Martier SS, Ager JW (1993). Prenatal alcohol exposure and infant information processing ability. Child Dev, 64:1706-1721.

Ji BT, Dai Q., Gao Y.T., Hsing A.W., McLaughlin J.K., Fraumeni J.F.Jr. et al. (2002). Cigarette and alcohol consumption and the risk of colorectal cancer in Shanghai, China. European Journal of Cancer Prevention; 11(3):237-244.

Jones KL, Smith, DW. (1973) Recognition of the fetal alcohol syndrome in early infancy. Lancet 2:999-1001.

Kesmodel U, Wisborg K, Olsen SF, Henriksen TB, Secher NJ (2002). Moderate alcohol intake during pregnancy and the risk of stillbirth and death in the first year of life. Am J Epidemiol, 155: 305-312.

Klatsky AL (2002). Alcohol and cardiovascular diseases. Ann NY Acad Sci 957: 7-15.

Klein R, Klein BE, Tomany SC, Moss SE (2002). Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 156: 589-598.

Koh-Banerjee P, Chu NF, Spiegelman D, Rosner B, Colditz G, Willett W, Rimm E (2003). Prospective study of the association of changes in dietary intake, physical acivity, alcohol consumption, and smoking with 9-y gain in waist circumference among 16587 US men. Am J Clin Nutr 78: 719-727.

Kroenke CH, Chu N-F, Rifai N, Spiegelman D, Hankinson SE, Manson JE, Rimm EB (2003). A cross-sectional study of alcohol consumption patterns and biologic markers of glycemic control among 459 women. Diabetes Care: 26(7) 1971-1978.

Kropp S, Becher H, Nieters A, Chang-Claude J. (2001). Low-to-moderate alcohol consumption and breast cancer risk by age 50 years among women in Germany. Am J Epidemiol 154:624-634.

Lacoste L, Huang J, Lam JY (2001) Acute and delayed antithrombotic effects of alcohol in humans. Am. J. Cardiol. 87:82-85.

Lancaster FE, Phillips SM, Patsalos PN, Wiggins RC (1984) Brain myelination in the offspring of ethanol-treated rats: in utero versus lactational exposure by crossfostering offspring of control, paired and ethanol treated dams. Brain Res 309:209-216.

Lancaster FE, Selvanayagam PF, Hsu LL (1986) Lactational ethanol exposure: brain enzymes and [3H]spiroperidol binding. Int J Dev Neurosci 4:151-160.

Lash TL, Aschengrau A. (2000). Alcohol drinking and risk of breast cancer. The Breast Journal; 6:396-399.

Lenz SK, Goldberg MS, Labreche F, Parent M-E, Valois M-F. (2002). Association between alcohol consumption and postmenopausal breast cancer. Cancer Causes and Control; 13:701-710.

Little RE, Anderson KW, Ervin CH, Worthington-Roberts B, Clarren SK (1989) Maternal alcohol use during breast-feeding and infant mental and motor development at one year. N Engl J Med 321:425-430.

Little RE, Northstone K., Golding J. (2002). The ALSPAC Team. Alcohol, breastfeeding, and development at 18 months. Pediatrics; 109(5):1-6.

Liu J, Tian Z, Gao B, Kunos G (2002) Dose-dependent activation of antiapoptotic and proapoptotic pathways by ethanol treatment in human vascular endothelial cells. J Biol Chem 277:20927-20933.

Lorente C, Cordier S, Goujard J, Ayme S, et al. (2000). Tobacco and alcohol use during pregnancy and risk of oral clefts. Am J Public Health 90:415-419.

Lu W, Jablonski KA, Resnick HE, Jain AK, et al.(2003) Alcohol intake and glycemia in American Indians: The Strong Heart Study Metabolism 52:129-135.

Lucey MR, Hill EM, Young JP, Demo-Dananberg L, Beresford TP. (1999). The influence of age and gender on blood ethanol concentrations in healthy humans. J Stud Alcohol 60: 103-110.

Mannisto S, Virtanen M, Kataja V, Uusitupa M, Pietinen P (2000). Lifetime alcohol consumption and breast cancer: a case-control study in Finland. Public Health Nutrition; 3: 11-18.

Maters JA (2003). Moderate alcohol consumption and unappreciated risk for alcohol-related harm among ethnically diverse, urban-dwelling elders. Geriatric Nursing 24: 155-161.

McCarver DG, Thomasson HR, Martier SS, Sokol RJ, Li TK. (1997). Alcohol dehydrogenase-2*3 allele protects against alcohol-related birth defects among African Americans. J Pharmacology & Experimental Therapeutics; 283:1095-1101.

Meister KA, Whelan EM, Kava R (2000). The health effects of moderate alcohol intake in humans: An epidemiologic review. Critical Reviews in Clinical Laboratory Sciences, 37: 261-296.

Mennella JA (1997) Infants' suckling responses to the flavor of alcohol in mothers' milk. Alcohol Clin Exp Res 21:581-585.

Mennella JA. (1998).Short-term effects of maternal alcohol consumption on lactational performance. Alcoholism: Clinical and Experimental Research; 22(7):1389-1392.

Mennella JA (2001a) Alcohol’s effect on lactation. Alcohol Res Health 25:230-234.

Mennella JA (2001b) Regulation of milk intake after exposure to alcohol in mothers' milk. Alcohol Clin Exp Res 25:590-593.

Mennella JA, Beauchamp GK. (1991). The transfer of alcohol to human milk. Effects on flavor and the infant's behavior. N Engl J Med; 325(14):981-985.

Mennella JA, Beauchamp GK (1993) Beer, breast feeding and folklore. Dev Psychobiol 26:459-466.

Mennella JA, Beauchamp GK (1998) Infants’ exploration of scented toys: effects of prior experiences. Chem Senses 23:11-17.

Mennella JA, Garcia-Gomez PL. (2001). Sleep disturbances after acute exposure to alcohol in mother's milk. Alcohol: An International Biomedical Journal; 25(3):153-158.

Mennella JA, Gerrish CJ (1998) Effects of exposure to alcohol in mother's milk on infant sleep. Pediatrics 101:E2.

Midanik LT, Tam TW, Greenfield TK, Caetano R (1996). Risk functions for alcohol-related problems in a 1988 US national sample. Addiction 91: 1427-1437.

Montalto G, Cervello M, Giannitrapani L, Dantona F, Terranova A, Castagnetta LAM (2002). Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann NY Acad Sci, 963: 13-20.

Moss SE, Klein R, Klein BE, Jensen SC, Meuer SM (1998). Alcohol consumption and the 5-year incidence of age-related maculopathy. Opthamology 105: 789-794.

Mukamal KJ. (2003). Alcohol use and prognosis in patients with coronary heart disease. Prev Cardiol 6: 93-98.

Mukamal KJ, Conigrave KM, Mittleman MA, Camargo CA, Stampfer MJ, Willett WC, Rimm EB (2003a). Roles of drinking pattern and type of alcohol consumed in coronary heart disease in men. N Engl J Med, 348: 109-118.

Mukamal K.J., Jadhav P.P., D’Agostino R.B., Massaro JM, Mittleman MA, Lipinska I, Sutherland PA, Matheney T, Levy D, Wilson PW, Ellison RC, Silbershatz H, Muller JE, Tofler GH (2001b) Alcohol consumption and hemostatic factors: analysis of the Framingham Offspring cohort. Circulation. 104:1367-73.

Mukamal KJ, Kuller LH, Fitzpatrick AL, Longstreth WT, Jr., Mittleman MA, Siscovick DS. (2003b). Prospective study of alcohol consumption and risk of dementia in older adults. JAMA; 289(11):1405-1413.

Mukamal KJ, Longstreth WT, Murray MA, Crum RM, Siscovick DS (2001a) Alcohol consumption and subclinical findings on magnetic resonance imaging of the brain in older adults. Stroke 32:1939-1946.

Mukamal KJ, Rimm EB (2001). Alcohol’s effects on the risk of coronary heart disease. Alcohol Res Health 25: 255-261.

Murata M, Tagawa M., Watanabe S., Kimura H., Takeshita T., Morimoto K. (1999). Genotype difference of aldehyde dehydrogenase 2 gene in alcohol drinkers influences the incidence of Japanese colorectal cancer patients. Japanese Jounal of Cancer Research; 90(7):711-719.

Murray RP, Connett JE, Tyas SL, Bond R, Ekuma O, Silversides CK, Barnes GE (2002). Alcohol volume, drinking pattern, and cardiovascular disease morbidity and mortality: Is there a U-shaped function? Am J Epidemiol 155: 242-248.

Natsume N, Kawai T, Ogi N, Yoshida W. (2000). Maternal risk factors in cleft lip and palate: case control study. Br J of Oral and Maxillofacial Surgery; 38:23-25.

NIAAA (1992) Moderate drinking. Alcohol Alert # 16.

NIAAA (1997) 9th special report to the US Congress on alcohol and health.

NIAAA (2000) 10th special report to the US Congress on alcohol and health.

NIAAA/NLAES (2002) Alcohol consumption and problems in the general population: Findings from the 1992 NLAES.

Nicolas JM, Fernandez-Sola J, Estruch R, Pare JC, Sacanella E, Urbano-Marquez A, Rubin E (2002). The effect of controlled drinking in alcoholic cardiomyopathy. Ann Int Med, 136: 192-200.

Nishimura FT, Fukunaga T, Yokomukai Y, Kajiura H, Ono T, Nishijo H. (2003). Age-dependent changes in electroencephalographic responses to alcohol consumption in subjects with aldehyde dehydrogenase-2 genetic variations. Alcohol Clin Exp Res 27: 841-848.

Obisesan TO, Hirsch R, Kosoko O, Carlson I, Parrott M (1998). Moderate wine consumption is associated with decreased odds of developing age-related macular degeneration in NHANES-1. J Am Geriatr Soc 46: 1-7.

Orgogozo JM, Dartigues JF, Lafont S, Letenneur L, Commenges D, Salamon R et al. (1997). Wine consumption and dementia in the elderly: a prospective community study in the Bordeaux area. Rev Neurol (Paris); 153(3):185-192.

Oyama LM, Oller do Nascimento CM (2003) Effect of ethanol intake during lactation on male and female pups’ liver and brain metabolism during the suckling-weaning transition period. Nutr Neurosci 6:183-188.

Pearson TA, Terry P (1994). What to advise patients about drinking alcohol. JAMA, 272:967-968.

Pedersen A, Johansen C, Gronbaek M. (2003). Relations between amount and type of alcohol and colon and rectal cancer in a Danish population based cohort study. Gut; 52(6):861-867.

Peele S, Brodsky A (2000). Exploring psychological benefits associated with moderate alcohol use: a necessary corrective to assessments of drinking outcomes? Drug and Alcohol Dependence, 60: 221-247.

Pellegrini N, Pareti FI, Stable F, Brusamolino A, Simonetti P (1996) Effects of moderate consumption of red wine on platelet aggregation and haemostatic variables in healthy volunteers. Eur J Clin Nutr 50:209-13.

Pequignot G, Tuyns AJ (1980). Compared toxicity of ethanol on various organs. In Stock C, Bode JC, Sarles H eds., Alcohol and the Gastrointestinal Tract. Paris: Editions INSERM 95: 17-32.

Perret B, Ruidavets J-B, Vieu C, Jaspard B, Cambou J-P, Terce F, Collet X (2002). Alcohol consumption is associated with enrichment of high-density lipoprotein particles in polyunsaturated lipids and increased cholesterol esterification rate. Alcohol Clin Exp Res, 26: 1134-1140.

Peters MG, Terrault NA (2002). Alcohol use and hepatitis C. Hepatology 36: S220-S225.

Polygenis D, Wharton S., Malmberg C., Sherman N., Kennedy D., Koren G. et al. (1998). Moderate alcohol consumption during pregnancy and the incidence of fetal malformations: A meta-analysis. Neurotoxicology and Teratology; 20(1):61-67.

Poynard T, Bedossa P, Opolon P. (1997). Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 349: 825-832.

Puddey IB, Zilkens RR, Croft KD, Beilin LJ (2001) Alcohol and endothelial function: A brief review. Clin Exp Pharma Physiol 28: 1020-1024.

Purohit V (1998) Moderate alcohol consumption and estrogen levels in postmenopausal women: A review. Alcohol Clin Exp Res 22:994-997.

Ramanathan, R, Wilkemeyer, MF, Mittal B, Perides G, Charness ME (1996). Alcohol inhibits cell-cell adhesion mediated by human L1. J. Biol Chem. 1996 133: 1139-40.

Ramchandani VA, Bosron WF, Li TK (2001a). Research advances in ethanol metabolism. Pathol Biol 49: 676-682.

Ramchandani VA, Kwo PY, Li TK (2001b). Effect of food and food composition on alcohol elimination rates in healthy men and women. J Clin Pharmacol 41: 1345-1350.

Rehm J, Greenfield TK, Rogers JD (2001). Average volume of alcohol consumption, patterns of drinking, and all-cause mortality: Results from the US national alcohol survey. Am J Epidemiol, 153: 64-71.

Rehm J, Sempos CT, TTrevisan M (2003). Average volume of alcohol consumption, patterns of drinking and risk of coronary heart disease – a review. J Cardiovasc Risk 10: 15-20.

Reynolds K, Lewis B, Nolen JD, Kinney GL, Sathya B, He J. (2003). Alcohol consumption and risk of stroke: a meta-analysis. JAMA; 289(5):579-588.

Richardson GA, Ryan C, Willford J, Day NL, Goldschmidt L. (2002) Prenatal alcohol and marijuana exposure. Effects on neuropsychological outcomes at 10 years. Neurotoxicology and Teratology; 24(3):309-320.

Ridderinkhof KR, de Vlugt Y, Bramlage A, Spaan M, Elton M, Snel J, Band GPH (2002). Alcohol consumption impairs detection of performance errors in mediofrontal cortex. Sciencexpress, 7 November 2002; 10.1126/science.1076929.

Rigamonti C, Mottaran E, Reale E, Rolla R, Cipriani V, Capelli F, Boldorini R, Vidali M, Sartori M, Albano E (2003) Moderate alcohol consumption increases oxidative stress in patients with chronic hepatitis C. Hepatology 38:42-49.

Rimm E (2000). Alcohol and cardiovascular disease. Current Atherosclerosis Reports, 2: 529-535.

Rimm EB, Chan J, Stampfler MJ, Colditz GA, Willett WC (1995) Prospective study of cigarette smoking, alcohol use and the risk of diabetes in men. BMJ 310:555-559.

Rohan TE, Jain M, Howe GR, Miller AB. (2000). Alcohol consumption and risk of breast cancer: a cohort study. Cancer Causes and Control 11:239-247.

Rotondo S, DiCastelnuovo A, de Gaetano G (2001). The relationship between wine consumption and cardiovascular risk: From epidemiological evidence to biological plausibility. Ital Heart J, 2: 1-8.

Ruf JC (1999) Wine and polyphenols related to platelet aggregation and atherothrombosis. Drugs: Exp. Clin. Res. 25:125-131

Ruitenberg A, van Swieten JC, Witteman JC, Mehta KM, van Duijn CM, Hofman A et al. (2002). Alcohol consumption and risk of dementia: the Rotterdam Study. Lancet; 359(9303):281-286.

Rundle A, Tang D, Mooney L, Grumet S, Perera F (2003). The interaction between alcohol consumption and GSTM1 genotype on polycyclic aromatic hydrocarbon-DNA adduct levels in breast tissue. Cancer Epidem Biomark Prev 12: 911-914.

Sacanella E, Badia E, Nicolas JM, Fernandez-Sola J, Antunez E, Urbano-Marquez A, Estruch R (2002) Differential effects of moderate or heavy alcohol consumption on circulating adhesion molecule levels. Throm Haemost 88:52-55.

Salaspuro M (1996) Bacteriocolonic pathway for ethanol oxidation: characteristics and clinical implications. Ann Med 28:195-200.

SAMHSA [Substance Abuse and Mental Health Services Administration] (2003). Overview of Findings from the 2002 National Survey on Drug Use and Health (Office of Applied Studies, NHSDA Series H-21, DHHS Publication No. SMA 03-3774). Rockville, MD.

Sampson PD, Bookstein FL, Barr HM, Streissguth AP. (1994). Prenatal alcohol exposure: Birthweight, and measures of child size from birth to age 14 years. American Journal of Public Health; 84(9):1421-1428.

Sattar N, Gaw A, Scherbakova O, Ford I, et al (2003). Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 108: 414-419.

Savage DD, Becher M, de la Torre AJ, Sutherland RJ (2002) Dose-dependent effects of prenatal ethanol exposure on synaptic plasticity and learning in mature offspring. Alcohol Clin Exp Res 26:1752-1758.

Schuckit MA, Smith TL. A comparison of correlates of DSM-IV alcohol abuse or dependence among more than 400 sons of alcoholics and controls. Alcohol Clin Exp Res. 25:1-8.

Seitz HK, Poschl G, Simanowski UA (1998) Alcohol and Cancer in: Recent Developments in Alcoholism, Vol 14, Galanter ed., New York, Plenum Press, pp.67-95.

Seitz HK, Matsuzaki S, Yokoyama A, Homann N, Vakevainen S, Wang X-D (2001) Alcohol and Cancer. Alcohol Clin Exp Res 25:137S-143S.

Serafini M, Laranjinha JA, Almeida LM, Maiani G (2000) Inhibition of human LDL lipid peroxidation by phenol-rich beverages and their impact on plasma total antioxidant capacity in humans. J. Nutr. Biochem. 11:585-590.

Serfaty L, Poujol-Robert A, Carbonell N, Chazouilleres O, Poupon RE, Poupon R (2002) Effect of the interaction between steatosis and alcohol intake on liver fibrosis progression in chronic hepatitis C. Am J Gastroenterol 97:1807-1812.

Shaper AG, Wannamethee SG (2000). Alcohol intake and mortality in middle aged men with diagnosed coronary heart disease. Heart, 83: 394-399.

Sierksma A, van der Gaag MS, Kluft C, Hendriks HF (2001) Effect of moderate alcohol consumption on fibrinogen levels in healthy volunteers is discordant with effects on C-reactive prote. Ann N Y Acad Sci 936:630-3.

Sierksma A, van der Gaag MS, van Tol A, James RW, Hendriks, HFJ (2002) Kinetics of HDL Cholesterol and Paraoxonase Activity in Moderate Alcohol Consumers. Alcohol Clin Exp Res 26:1430-1435.

Sillanaukee P, Koivula T, Jokela H, Pitkajarvi T, Seppa K (2000). Alcohol consumption and its relation to lipid-based cardiovascular risk factors among middle-aged women. Atherosclerosis, 152: 503-510.

Smith-Warner SA, Spiegelman D, Yaun SS et al (1998) Alcohol and breast cancer in women: a pooled analysis of cohort studies. J Am Med Assoc 279:535-540.

Stampfer MJ, Colditz GA, Willett WC, Speizer FE, Hennekens CH (1988). A prospective study of moderate alcohol consumption and the risk of coronary heart disease and stroke in women. N Eng J Med, 319: 267-273.

Stoll BA. (1999). Alcohol intake and late-stage promotion of breast cancer. Eur J Cancer 35:1653-1658.

Stratton, K.; Howe, C.; and Battaglia, F., eds. Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention, and Treatment -- The Institute of Medicine Report. Washington, DC: National Academy Press, 1996.

Streissguth AP, Bookstein FL, Sampson PD, Barr HM (1993). The Enduring Effects of Prenatal Alcohol Exposure on Child Development, Birth Through 7 Years: A Partial Least Squares Solution. Ann Arbor: University of Michigan Press.

Streissguth AP, Sampson PD, Olson HC, Bookstein FL, Barr HM, Scott M, Feldman J, Mirsky AF. (1994). Maternal drinking during pregnancy: attention and short-term memory in 14-year-old offspring--a longitudinal prospective study. Alcohol Clin Exp Res, 18:202-218.

Subramanian MG, Abel EL (1988) Alcohol inhibits suckling-induced prolactin release and milk yield. Alcohol 5:95-98.

Tabengwa EM, Wheeler CG, Yancey DA, Grenett HE, Booyse FM (2002) Alcohol-induced up-regulation of fibrinolytic activity and plasminogen activators in human monocytes. Alcoholism Clin. Exp. Res. 26:1121-1127.

Testa M, Quigley BM, Eiden RD (2003). The effects of prenatal alcohol exposure on infant mental development: a meta-analytical review. Alcohol & Alcoholism; 38(4) 295-304.

Thomas DL, Astemborski J, Rai RM, Anania FA, Schaeffer M, Galai N, Nolt K, et al (2000). The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA 284: 450-456.

Thun MJ, Peto R, Lopez AD, Monaco JH, Henley SJ, Heath Jr CW, Doll R (1997). Alcohol consumption and mortality among middle-aged and elderly US adults. N Engl J Med, 337: 1705-1714.

Tjonneland A, Thomsen BL, Stripp C, Christensen J, Overvad K, Mellemkjaer L, et al. (2003). Alcohol intake, drinking patterns and risk of postmenopausal breast cancer in Denmark. Cancer Causes and Control 14: 277-284.

Truelsen T, Thudium D, Gronbaek M (2002). Amount and type of alcohol and risk of dementia. Neurology, 59: 1313-1319.

Tupler LA, Hege S, Ellinwood Jr. EH. (1995). Alcohol pharmacodynamics in young-elderly adults contrasted with young and middle-aged subjects. Psychopharmacology 118: 460-470.

Tyas SL (2001). Alcohol use and the risk of developing Alzheimer’s disease. Alcohol Res & Health, 25: 299-306.

U.S. Public Health Service (1981). Surgeon General's Advisory on Alcohol and Pregnancy. Federal Drug Administration Bulletin 1981; 11:9-10.

U.S. Department of Health and Human Services and U.S. Department of Agriculture (USDA) (2000) Nutrition and Your Health: Dietary Guidelines for Americans, 5th ed.

Vachon CM, Cerhan JR, Vierkant RA, Sellers TA. (2001). Investigation of an interaction of alcohol intake and family history on breast cancer risk in the Minnesota breast cancer family study. Cancer;92:240-248.

Vakevainen S, Tillonen J, Agarwal DP, Srivastava, N, Saspuro M (2000) High salivary acetaldehyde after a moderate dose of alcohol in ALDH2-deficient subjects: strong evidence for the local carcinogenic action of acetaldehyde. Alcohol Clin Exp Res 24:873-877.

van der Gaag MS, van Tol A, Vermunt SHF, Scheck LM, Schaafsma G, Hendriks HFJ (2001) Alcohol consumption stimulates early steps in reverse cholesterol transport. J Lipid Res 42: 2077-2083.

Villalpando S, Flores-Huerta S, Fajardo A, Hernandez-Beltran M (1993). Ethanol consumption during pregnancy and lactation: Changes in the nutritional status of predominantly breastfeeding mothers. Arch Med Res 24; 333-338.

Vinson DC, Borges G, Cherpitel CJ (2003). The risk of intentional injury with acute and chronic alcohol exposures: a case-control and case-crossover study. J Stud Alcohol 64: 350-357.

Walsh CR, Larson MG, Evans JC, Djousse L, Ellison RC, Vasan RS, Levy D (2002). Alcohol consumption and risk for congestive heart failure in the Framingham heart study. Ann Int Med, 136: 181-191.

Wannamethee SG, Camargo CA, Jr., Manson JE, Willett WC, Rimm EB. (2003). Alcohol drinking patterns and risk of type 2 diabetes mellitus among younger women. Arch Intern Med; 163(11):1329-1336.

Wannamethee SG, Shaper AG (2002). Taking up regular drinking in middle age: effect on major coronary heart disease events and mortality. Heart, 87: 32-26.

Wannamethee SG, Shaper AG, Perry IJ, Alberti KGMM (2002). Alcohol consumption and the incidence of type II diabetes. J Epidemiol Community Health, 56: 542-548.

Wannamethee SG, Shaper AG (2003). Alcohol, body weight, and weight gain in middle-aged men. Am J Clin Nutr, 77: 1312-1317.

Websters II New Riverside University Dictionary (1984). Boston: Houghton Mifflin.

Wells S, Graham K (2003). Aggression involving alcohol: relationship to drinking patterns and social context. Addiction 98: 33-42.

Westin J, Laggin LM, Spak F, Aires N, Svensson E, Lindh M, Dhillon AP, Norkrans G, Wejstal R (2002) Moderate alcohol intake increases fibrosis progression in untreated patients with hepatitis C virus infection. J Vir Hepatitis 9:235-241.

Wiley TE, McCarthy M, Breidi L, McCarthy M, Layden T (1998) Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatol 28:805-809.

Yang Q, Witkiewicz B.B., Olney R.S., Liu Y., Davis M., Khoury M.J. et al. (2001).Case-control study of maternal alcohol consumption and intrauterine growth retardation. Annals of Epidemiology; 11(7):497-503.

Zautcke et al (2002). Geriatric trauma in the state of Illinois: substance use and injury patterns. Am J Emergency Medicine; 20: 14-17.

Zhang M, Gong Y, Corbin I et al. (2000) Light ethanol consumption enhances liver regeneration after partial hepatectomy in rats. Gastroenterology 119:1333-1339.

Zhang Y, Kreger BE, Dorgan JF, Splansky GL et al. (1999). Alcohol consumption and risk of breast cancer: the Framingham study revisited. Am J. Epidemiol. 149:93-101.

Zheng T, Holford TR, Zahm SH, Owens PH et al. (2003). Glutathione S-transferase M1 and T1 genetic polymorphisms, alcohol consumption and breast cancer risk. Br J Cancer 88:58-62.

Zuccala G, Onder G, Pedone C, Cesari M, et al. (2001). Dose-related impact of alcohol consumption on cognitive function in advanced age: Results of a multicenter study. Alcohol: Clin Exp Res 25: 1743-1748.

Zumoff B (1997). Editorial: the critical role of alcohol consumption in determining the risk of breast cancer with postmenopausal estrogen administration. J Clinical Endocrinology & Metabolism; 82: 1656-1657.

APPENDIX

PARTICIPATING AUTHORS (NIAAA STAFF):

Rosalind Breslow, Ph.D., Division of Epidemiology & Prevention Research

Ricardo Brown, Ph.D., Division of Metabolism & Health Effects

Page Chiapella, Ph.D., Division of Treatment and Recovery Research

Mary Dufour, MD, MPH (retired; formerly of Division of Biometry & Epidemiology)

Mark Egli, Ph.D., Division of Neuroscience & Behavior

Vivian Faden, Ph.D., Division of Epidemiology & Prevention Research

Susan Farrell, Ph.D. (retired; formerly of Division of Biometry & Epidemiology)

Laurie Foudin, Ph.D., Division of Metabolism & Health Effects

Lorraine Gunzerath, Ph.D., Office of Extramural Activities

Diane Lucas, Ph.D., Division of Metabolism & Health Effects

Vishnudutt Purohit, Ph.D., Division of Metabolism & Health Effects

Denise Russo, Ph.D., Division of Metabolism & Health Effects

Barbara Smothers, Ph.D., Division of Epidemiology & Prevention Research

Kenneth Warren, Ph.D., Office of Scientific Affairs

Ellen Witt, Ph.D., Division of Neuroscience & Behavior

Harold Yahr, Ph.D., Division of Epidemiology & Prevention Research

Samir Zakhari, Ph.D., Division of Metabolism & Health Effects

 

NIAAA ADVISORY COUNCIL TASK FORCE REVIEWERS:

Caetano, Raul, M.D., Ph.D., School of Public Health, University of Texas

Edenberg, Howard J., Ph.D., Indiana University School of Medicine

Taylor, Robert E., M.D., Ph.D., Department of Pharmacology, Howard University College of Medicine

 

EXTERNAL REVIEWERS:

Michael Charness, M.D., Department of Neurology, Harvard Medical School

R. Curtis Ellison, M.D., Department of Medicine, Boston University School of Medicine

Thomas D. Giles, M.D., Cardiovascular Research Section, Louisiana State University School of Medicine

Sandra W. Jacobson, Ph.D., Department of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University

Charles S. Lieber, M.D., Bronx VA Medical Center

Matthew P. Longnecker, M.D., Epidemiology Branch, National Institute of Environmental Health Sciences

Julie Mennella, Ph.D., Monell Chemical Senses Center

Jurgen Rehm, Ph.D., University of Toronto Public Health Sciences, & Centre for Addiction and Mental Health

Eric Rimm, Sc.D., Departments of Epidemiology and Nutrition, Harvard School of Public Health

Keith W. Singletary, Ph.D., Department of Food Science and Human Nutrition, University of Illinois

Andrew Thomas, Ph.D., Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey


Updated: February 2, 2007