Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study.

OBJECTIVE: To estimate risks of major congenital anomaly (MCA) among children of mothers prescribed antidepressants during early pregnancy or diagnosed with depression but without antidepressant prescriptions. DESIGN: Population-based cohort study. SETTING: Linked UK maternal-child primary care records. POPULATION: A total of 349,127 singletons liveborn between 1990 and 2009. METHODS: Odds ratios adjusted for maternal sociodemographics and comorbidities (aORs) were calculated for MCAs, comparing women with first-trimester selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) and women with diagnosed but unmedicated depression, or women without diagnosed depression. MAIN OUTCOME MEASURES: Fourteen system-specific MCA groups classified according to the European Surveillance of Congenital Anomalies and five specific heart anomaly groups. RESULTS: Absolute risks of MCA were 2.7% (95% confidence interval, 95% CI, 2.6-2.8%) in children of mothers without diagnosed depression, 2.8% (95% CI 2.5-3.2%) in children of mothers with unmedicated depression, and 2.7% (95% CI 2.2-3.2%) and 3.1% (95% CI 2.2-4.1%) in children of mothers with SSRIs or TCAs, respectively. Compared with women without depression, MCA overall was not associated with unmedicated depression (aOR 1.07, 95% CI 0.96-1.18), SSRIs (aOR 1.01, 95% CI 0.88-1.17), or TCAs (aOR 1.09, 95% CI 0.87-1.38). Paroxetine was associated with increased heart anomalies (absolute risk 1.4% in the exposed group compared with 0.8% in women without depression; aOR 1.78, 95% CI 1.09-2.88), which decreased marginally when compared with women with diagnosed but unmedicated depression (aOR 1.67, 95% CI 1.00-2.80). CONCLUSIONS: Overall MCA risk did not increase with maternal depression or with antidepressant prescriptions. Paroxetine was associated with increases of heart anomalies, although this could represent a chance finding from a large number of comparisons undertaken.

Regional variations of basal cell carcinoma incidence in the U.K. using The Health Improvement Network database (2004-10).

BACKGROUND: Basal cell carcinoma (BCC) is one of the most common types of nonmelanoma skin cancer affecting the white population; however, little is known about how the incidence varies across the U.K. OBJECTIVES: To determine the variation in BCC throughout the U.K. METHODS: Data from 2004 to 2010 were obtained from The Health Improvement Network database. European and world age-standardized incidence rates (EASRs and WASRs, respectively) were obtained for country-level estimates and levels of socioeconomic deprivation, while strategic health-authority-level estimates were directly age and sex standardized to the U.K. standard population. Incidence-rate ratios were estimated using multivariable Poisson regression models. RESULTS: The overall EASR and WASR of BCC in the U.K. were 98.6 per 100,000 person-years and 66.9 per 100,000 person-years, respectively. Regional-level incidence rates indicated a significant geographical variation in the distribution of BCC, which was more pronounced in the southern parts of the country. The South East Coast had the highest BCC rate followed by South Central, Wales and the South West. Incidence rates were substantially higher in the least deprived groups and we observed a trend of decreasing incidence with increasing levels of deprivation (P < 0.001). Finally, in terms of age groups, the largest annual increase was observed among those aged 30-49 years. CONCLUSIONS: Basal cell carcinoma is an increasing health problem in the U.K.; the southern regions of the U.K. and those in the least deprived groups had a higher incidence of BCC. Our findings indicate an increased incidence of BCC for younger age groups below 49 years.

Incidence of depression and antidepressant prescription in patients with COPD: A large UK population-based cohort study.

BACKGROUND: Depression is frequently reported in patients with Chronic Obstructive Pulmonary Disease (COPD). However, there is little information available on the incidence of depression following a COPD diagnosis. OBJECTIVE: To determine the incidence of a new diagnosis of depression or antidepressant prescription in people with and without a COPD diagnosis. METHODS: A matched cohort study was conducted using The Health Improvement Network database. Patients with confirmed COPD diagnosis were matched to up to four subjects without a COPD diagnosis by age, sex and GP practice. Cox proportional hazards models were used to assess the incidence rates of depression and antidepressant prescription. RESULTS: 44,362 patients with COPD and 124,140 subjects without COPD were included. The incidence rate of depression per 1000 person-years following COPD diagnosis was greater (11.4; 95% CI: 10.9-11.8) compared to subjects without COPD (5.7; 95% CI: 5.5-5.8) (p < 0.001). Patients with COPD were 42% more likely to have an incident depression (adjusted hazard ratio [aHR]: 1.42; 95% CI: 1.32-1.53; p < 0.001), and 40% more likely to be prescribed an antidepressant (aHR: 1.40; 95% CI: 1.35-1.45; p < 0.001). The incidence to either depression or antidepressant prescription was also greater for patients with COPD (aHR: 1.41; 95% CI: 1.36-1.46; p < 0.001). Patients with COPD and worse breathlessness had a higher risk of incident depression compared to patients with less breathlessness. CONCLUSION: Healthcare providers managing patients with COPD should be alert to the existence of depression and aware of its symptoms and consequences.

Risk of incident dementia and cognitive impairment in patients with chronic obstructive pulmonary disease (COPD): A large UK population-based study.

BACKGROUND: Although cognitive impairment and dementia are common comorbidities in patients with chronic obstructive pulmonary disease (COPD), estimates of incidence following a diagnosis of COPD are inconclusive. OBJECTIVE: To determine the incidence of cognitive impairment and dementia in people with and without a COPD diagnosis. METHODS: A population-based study using UK General Practice (GP) health records from The Health Improvement Network database was conducted. Patients with confirmed COPD diagnosis, ≥40 years old, were matched to up to four subjects without a COPD diagnosis by age, sex and GP practice. Cox proportional hazards models were used to assess the incidence rates of cognitive impairment and dementia. RESULTS: Of patients with COPD (n = 62,148), 9% developed cognitive impairment, compared with 7% of subjects without COPD (n = 230,076), p < 0.001. The incidence of cognitive impairment following COPD diagnosis was greater than in subjects without COPD following index date (adjusted Hazard Ratio (aHR), 1.21; 95% CI: 1.16 ─ 1.26, p < 0.001). The coded incidence of either cognitive impairment or dementia was also greater in patients with COPD following adjustment for confounders (aHR: 1.13, 95% CI: 1.09 ─ 1.18, p < 0.001). Coded incident dementia alone was not different between patients with COPD and subjects without COPD (aHR, 0.91, 95% CI: 0.83 ─ 1.01, p = 0.053). CONCLUSION: Despite the increased incidence of cognitive impairment in patients with COPD, incidence of dementia was not as frequently recorded in patients with COPD. This raises the concern of undiagnosed dementia and emphasises the need for a systematic assessment in this population.

Debonding of Leucite-reinforced Glass-ceramic Veneers Using Er, Cr:YSGG Laser Device: Optimizing Speed with Thermal Safety.

CLINICAL RELEVANCE: Removing laminate veneers on anterior teeth by using an Er,Cr:YSGG dental laser can be completed faster than previously reported while maintaining thermal safety.

Bone mineral density reference ranges for Australian men: Geelong Osteoporosis Study.

SUMMARY: A large population-based random sample of Australian white men was used to provide normative bone mineral density (BMD) data at multiple anatomical sites. The femoral neck BMD data are very similar to those obtained in USA non-Hispanic white males participating in the National Health and Nutrition Examination Survey III (NHANES III). The reference ranges will be suitable for similar populations. INTRODUCTION: To provide normative BMD data for Australian men derived from a large population-based random sample. METHODS: An age-stratified random sample of men was recruited from the Australian electoral rolls (n = 1,467 aged 20-97 years). BMD was quantified at multiple sites using Lunar densitometers. RESULTS: Age-related differences in BMD were best predicted by linear relationships at the spine and hip and by quadratic functions at the whole body and forearm. At the spine, a small age-related increase in mean BMD was observed. Although in the subset with no spinal abnormalities, there was a decrease of 0.003 g/cm(2) per year from age 20. At the hip sites, mean BMD decreased at 0.001-0.006 g/cm(2) per year from age 20. At the forearm and whole body, BMD peaked at 41-47 years. Apart from a small difference in men greater than or equal to 80 years, the Australian femoral neck BMD data are not different to those obtained in USA non-Hispanic white males participating in NHANES III and were generally similar to those of large studies from Canada (CaMos) and Spain. CONCLUSIONS: These data supply BMD reference ranges at multiple anatomical sites that will be applicable to white Australian men and similar populations such as USA non-Hispanic white men.

Effect of maternal asthma, exacerbations and asthma medication use on congenital malformations in offspring: a UK population-based study.

BACKGROUND: Clinical advice to pregnant women with asthma is to maintain optimal therapeutic management; however, potential adverse effects of asthma treatments on fetal development remain uncertain. A study was undertaken to assess the association between maternal asthma and gestational exposure to asthma medications with risk of congenital malformation in offspring. METHODS: A matched case-control study was performed using The Health Improvement Network primary care database. Children with malformations were matched to control children on birth year, general practice and singleton or twin delivery. RESULTS: 5124 cases of liveborn children with major congenital malformations and 30,053 controls were included in the study. The risk of any malformation in children born to women with asthma was marginally higher than that in children born to women without asthma (adjusted OR 1.10, 95% CI 1.01 to 1.20). However, no association was present in children born to mothers receiving asthma treatment in the year before or during pregnancy (OR 1.06, 95% CI 0.94 to 1.20). In assessing teratogenicity of medications, no increased risk of malformation was found with gestational exposures to short- or long-acting beta agonists, inhaled corticosteroids, oral corticosteroids, other bronchodilators or cromones. These findings were similar for each of 11 system-specific malformation groups, except for an increase in musculo-skeletal system malformation associated with cromone exposure. CONCLUSIONS: Gestational exposure to commonly used asthma medications was found to be safe overall, although a moderate teratogenic risk of cromones cannot be excluded. There was some evidence of a small increased risk of congenital malformation in children born to women with asthma, but this was not explained by gestational exposure to asthma drugs.

The inhibition of CHO-K1-BH4 cell proliferation and induction of chromosomal aberrations by brevetoxins in vitro.

Brevetoxins (PbTxs) are highly potent trans-syn polyether neurotoxins produced during blooms of several species of marine dinoflagellates, most notably Karenia brevis. These neurotoxins act on voltage-sensitive sodium channels prolonging the active state. During red tides, the commercial fishing and tourism industries experience millions of dollars of lost revenue. Human consumption of shellfish contaminated with PbTxs results in neurotoxic shellfish poisoning (NSP). Additionally, blooms of K. brevis are potentially responsible for adverse human health effects such as respiratory irritation and airway constriction in coastal residents. There is little information regarding the full range of potential toxic effects caused by PbTxs. Recent evidence suggests that PbTxs are genotoxic substances. The purpose of this study was to determine if PbTxs could induce chromosomal aberrations and inhibit cellular proliferation in CHO-K1-BH4 cells, and if so, could the damage be negated or reduced by the PbTx antagonist brevenal. Results from the chromosomal aberrations assay demonstrated that PbTxs are potent inducers of CHO-K1-BH4 chromosome damage. Results from the inhibition of cellular proliferation assays demonstrated that PbTxs inhibit the ability of CHO-K1-BH4 cells to proliferate, an effect which can be reduced with brevenal.

Correlation of regional and nonlinear formaldehyde-induced nasal cancer with proliferating populations of cells.

Formaldehyde induces nonlinear, concentration-related increases in nasal epithelial cell proliferation and squamous cell carcinomas (SCC) in rats. A formaldehyde carcinogenicity study was conducted in which a major end point was correlation of cell proliferation indices with sites of formaldehyde-induced SCC. A poor correlation in certain sites led to incorporation of the number of cells in each site into the correlation. Rats were exposed (6h/day, 5 days/week) to formaldehyde (0, 0.7, 2, 6, 10 or 15 ppm) for up to 24 months with interim sacrifice time points at 3, 6, 12, and 18 mo. A unit length labeling index (ULLI; S-phase nuclei/mm basement membrane) was determined for specific nasal regions in addition to a population-weighted ULLI (PWULLI). The PWULLI was defined as the product of regional ULLI and total number of nasal epithelial cells in the respective site. Nasal SCC sites of origin were mapped. Formaldehyde induced SCC in a highly nonlinear fashion, with no observed effect at the level of 2 ppm, a minimal response at 6 ppm, and a sharp increase at 10 and 15 ppm. The tumor incidence was 1, 22, and 47% at 6, 10 and 15 ppm, respectively. ULLI was significantly (P<0.05) increased at 10 and 15 ppm but not at the lower concentrations. There was a good correlation between PWULLI and regional tumor incidence (R(2) = 0.88), while the correlation of regional SCC with ULLI was relatively poor (R(2) = 0.46). We conclude that target cell population size and sustained increases of cell proliferation in these populations, determined by differences in regional airflow-driven formaldehyde binding to DNA dose to these sites, coupled with the known nonlinear kinetics of formaldehyde binding to DNA, can together account for the nonlinearity and site specificity of formaldehyde-induced nasal SCC in rats.

Perinatal nephropathies.

The purpose of this paper is to review the development of the mammalian kidney and to assess the influence that various perinatal manipulations may have on the developmental process either morphologically or functionally. Immature kidneys in general have less functional capacity than adult kidneys and a low rate of glomerular filtration, perhaps related to renal blood flow, which appears to limit the disposition of a fluid or solute load. Tubular reabsorption is also limited leading to the urinary loss of glucose, amino acids, bicarbonate and phosphate. Although the relatively low function of the immature kidney is a normal part of development, its capacity to respond under conditions of stress may be less adequate than in adults. An additional concern is that a variety of perinatal manipulations, such as the incidental or accidental ingestion of a chemical, may lead to varying degrees of altered morphogenesis or functional development of the kidney. Chemical induced renal anomalies may be of several types, but in typical teratology experiments hydronephrosis may be the most frequent observation. The functional consequences of these renal malformations may be lethal or inconsequential or while an animal may be able to survive and develop normally in the presence of a renal malformation, it is possible that a stressful situation would unmask a functional malformation which could compromise survival. Thus, some renal abnormalities may be subtle enough to go unnoticed without experimental tests. Without such tests it is impossible to evaluate the effect of functional alterations on successful adaptation.

Opportunities for improving techniques for interspecies extrapolation in the risk assessment process.

Quantitative estimates of human carcinogenic risk from chemical exposure are currently derived primarily from linearized multistage model analyses of the tumor response as observed in chronic laboratory animal bioassays versus administered dose. The numerous ad hoc assumptions that provide a rationale for this generic approach to carcinogenic risk assessment can only be evaluated critically when mechanistic data directly relevant to the low-dose and interspecies extrapolation problems are available. Clear needs exist to develop such ancillary data bases and the means for explicitly incorporating them into the risk estimation process. Target site dosimetry provides one useful organizing concept. Physiological response modeling can account systematically for interspecies variations in the distribution and disposition of chemicals in relation to external measures of exposure. Direct measurements of interactions of chemicals and their metabolites with specific target macromolecules can provide sensitive and biologically meaningful exposure indices. Alternatively, quantitation of toxic effects such as altered cell regulation and differentiation can serve the same purpose. Virus and oncogene activation, DNA damage and repair, and enhanced cell proliferation provide additional biological markers of exposure. They may also comprise critical elements of the carcinogenic process. Identification of the actual mechanisms involved should eventually lead to the development of risk assessment models that adequately reflect the unique biological and toxicological characteristics of different species-chemical combinations.

Effect of polybrominated biphenyls on hepatic excretory function in rats and mice.

The purpose of this investigation was to determine the influence of polybrominated biphenyls (PBBs) on hepatic excretory function in developing and adult rats and mice. Prenatal or postnatal dietary exposure to PBBs (50 ppm in diet of pregnant or lactating mother or in diet of rat weanlings) resulted in elevated liver weight in developing rats. In 15-day-old rats that had been treated with PBBs increased liver weight correlated to enhanced ouabain transport from plasma into bile. Liver weight was also elevated in 21, 35, and 49-day-old rats exposed to PBBs, but this effect was not associated with stimulation of ouabain transport in these animals. However, adult rats fed 100 ppm PBBs for two weeks had significantly lower plasma concentrations of sulfobromophthalein (BSP) and increased biliary excretion of BSP, when compared to controls. PBBs-fed adult rats also excreted a greater percentage conjugated BSP (BSP-GSH) into bile. Two week dietary treatment of 100, 150, and 200 ppm PBBs resulted in enhanced initial disappearance of indocyanine green (ICG) from plasma of adult mice. However, dietary doses of 100 and 200 ppm PBBs to adult mice was not associated with enhanced capacity for ouabain excretion. In contrast, treatment with PBBs through the mother's diet (50 ppm) resulted in an almost twofold increase in cumulative ouabain excretion in 15-day-old mice. The results suggest that PBBs stimulate hepatic drug elimination in rats and mice, but the magnitude of the effect is dependent on age and transported compound.

Paraquat: model for oxidant-initiated toxicity.

Paraquat, a quaternary ammonium bipyridyl herbicide, produces degenerative lesions in the lung after systemic administration to man and animals. The pulmonary toxicity of paraquat resembles in several ways the toxicity of several other lung toxins, including oxygen, nitrofurantoin and bleomycin. Although a definitive mechanism of toxicity of paraquat has not been delineated, a cyclic single electron reduction/oxidation of the parent molecule is a critical mechanistic event. The redox cycling of paraquat has two potentially important consequences relevant to the development of toxicity: generation of "activated oxygen" (e.g., superoxide anion, hydrogen peroxide, hydroxyl radical) which is highly reactive to cellular macromolecules; and/or oxidation of reducing equivalents (e.g., NADPH, reduced glutathione) necessary for normal cell function. Paraquat-induced pulmonary toxicity, therefore, is a potentially useful model for evaluation of oxidant mechanisms of toxicity. Furthermore, characterization of the consequences of intracellular redox cycling of xenobiotics will no doubt provide basic information regarding the role of this phenomena in the development of chemical toxicity.

Human exposure and risk from indoor use of chlorpyrifos.

The toxicity, exposure, and risk from chlorpyrifos are briefly discussed in juxtaposition with two recent articles in Environmental Health Perspectives concerning potential exposures to children. In studies conducted according to EPA guidelines, chlorpyrifos has been shown not to be mutagenic, carcinogenic, or teratogenic, nor does it adversely affect reproduction. Chlorpyrifos toxicity does not occur in the absence of significant cholinesterase inhibition. If exposures are less than those that cause significant cholinesterase depression, then no signs or symptoms related to chlorpyrifos exposure occur. The weight of empirical evidence indicates that the risk of adults or children experiencing an adverse health effect from exposure to chlorpyrifos through both nondietary and dietary sources is negligible. Both the research supporting the registration of these products and their long history of widespread use suggest that unless these products are seriously misused, their margins of safety are wide enough to protect everyone with the potential to be exposed. A weight-of-evidence review of the entire scientific knowledge base relating to chlorpyrifos products supports these conclusions.

Paraquat toxicity: proposed mechanism of action involving lipid peroxidation.

The purpose of this study was to investigate the hypothesis that paraquat pulmonary toxicity results from cyclic reduction-oxidation of paraquat with sequential generation of superoxide radicals and singlet oxygen and initiation of lipid peroxidation. In vitro mouse lung microsomes catalyzed an NADPH-dependent, single-electron reduction of paraquat. Incubation of paraquat with NADPH, NADPH-cytochrome c reductase, and purified microsomal lipid increased malondialdehyde production is a concentration dependent manner. Addition of either superoxide dismutase or a single oxygen trapping agent 1,3-dipheylisobenzo furan inhibited paraquat stimulated lipid peroxidation. In vivo, pretreatment of mice with phenobarbital decreased paraquat toxicity, possibly by competing for electrons which might otherwise reduce paraquat. In contrast, paraquat toxicity in mice was increased by exposure to 100% oxygen and by deficiencies of the antioxidants selenium, vitamin E, or reduced glutahione (GSH). Paraquat, given IP to mice, at 30 mg/kg, decreased concentrations of the water-soluble antioxidant GSH in liver and lipid soluble antioxidants in lung. Oxygen-tolerant rats, which hae increased activities of pulmonary enzymes which combat lipid peroxidation, were also tolerant to lethal doses of paraquat as indicated by an increased paraquat LT50. Furthermore, rats chronically exposed to 100 ppm paraquat in the water had elevated pulmonary activities of glucose-6-phosphate dehydrogenase and GSH reductase. These results were consistent with the hypothesis that lipid peroxidation is involved in the toxicity of paraquat.

Distribution of polybrominated biphenyls after dietary exposure in pregnant and lactating rats and their offspring.

Female rats were fed PBBs in the diet (50 ppm) from day 8 of gestation to day 21 of gestation, from day 1 postpartum to day 14 postpartum or from day 8 of gestation through day 14 postpartum. Levels of PBBs were measured in various tissues. Small concentrations of PBBs (less than 5 microgram/g) were found in the brain, heart, lung, liver, small intestine, placenta, and gravid uterus. Larger concentrations (less than 30 microgram/g) were found in kidneys, the nongravid uterus, skin, mammary tissue, and fat. Lactation did not significantly alter the concentrations of PBBs found in tissues other than mammary tissue. Offspring were subjected to several exposure regimens by cross-fostering. Concentrations of PBBs in the neonatal livers were higher than in the adults nursing them. Transfer of PBBs via the milk appears to be much more important to appearance of PBBs in newborns than does placental transfer.

The effects of a mixed fish diet on platelet function, fatty acids and serum lipids.

Eight healthy subjects were fed a diet containing 1-4 g eicosapentaenoic acid (EPA) daily for 8-21 days. The EPA was derived from 300-400 g per day of sardines, pilchards, herring and/or kabeljou. Sources of arachidonic acid (AA) in the diet were reduced. At the end of the experimental period there was an increase in the ratio of EPA to AA in the platelets and a decrease in platelet aggregation to ADP, epinephrine and collagen. Aggregation to AA was not reduced. Thromboxane production in response to all four agonists was reduced. Serum total and HDL cholesterol levels fell significantly but platelet counts, LDL cholesterol and triglyceride values did not change. We conclude that even a relatively modest intake of EPA derived from a mixed fish diet together with a reduction in AA intake can alter in vitro platelet function and serum lipids significantly. A long term controlled trial of a palatable mixed fish diet to assess possible antithrombotic and antiatherogenic effects is justifiable.

Reanalysis with optimized power of red blood cell acetylcholinesterase activity from a 1-year dietary treatment of dogs to chlorpyrifos.

A no-observed-effect level (NOEL) of 0.1 mg/kg/day was reported for inhibition of red blood cell (RBC) acetylcholinesterase (AChE) in two groups of Beagle dogs fed chlorpyrifos (0, 0.01, 0.03, 0.1, 1 or 3 mg/kg/day) in the diet for 1 or 2 years (McCollister et al., Food Cosmet. Toxicol. 12 (1974) 45-61). The statistical analyses were by t-test that had low statistical power due to small sample sizes. Common time points for blood samples in both phases allowed a reanalysis of the grouped data over a 1-year time period. The reanalysis increased statistical power by increasing the sample size to n=14 from n=3 or 4, and decreasing the variance, by statistical step-by-step aggregation of the data from both phases, both sexes, and four sample periods. Factors retained in the ANOVA were dose, sex, and phase (sex-by-dose was not significant). Contrasts with one-sided t-tests indicated the 1 and 3 mg/kg/day groups had significantly inhibited RBC AChE (P<0.0001). At alpha=0.05, the uncorrected one-sided model had 80% power to detect a 12% decrease, 93% power for a 15% decrease, and 99.5% power for a 20% decrease in AChE activity. Overall, the reanalysis had high power to detect a clinically significant decrease in RBC AChE activity, and substantiated the original NOEL for chronic treatment of dogs to dietary chlorpyrifos at 0.1 mg/kg/day.

Effects of duration and timing of environmental enrichment on voluntary ethanol intake in rats.

The effects of exposure to five environmental rearing conditions on subsequent voluntary ethanol intake was examined. Male weanling rats were reared for 60 days in either an enriched environment, individually, or in a smaller enriched environment (quasienriched). The quasienriched environment was employed to allow for a group measurement of ethanol intake. Following the initial 60-day environmental exposure period, the three initial groups (Enriched, Isolation, Quasienriched) were randomly subdivided into five groups (Enriched/Isolation, Isolation, Isolation/Quasienriched, Quasienriched, Quasienriched/Isolation) and exposed to increasing concentrations of ethanol (3-9% v/v) in a free choice with water. Results indicated that exposure to an enriched environment for 60 days does not alter ethanol intake. In contrast, rats exposed to the quasienriched environment while having access to ethanol demonstrated a significant increase in voluntary ethanol intake as compared to all other groups. Exposure to different environmental conditions while having access to ethanol was not by itself sufficient to alter ethanol intake. These data are discussed in terms of the amount and timing of exposure to an enriched environment necessary to alter voluntary ethanol intake.