Pathology (environmental 2)

• Work-related accidents are the biggest problem in developing countries, while work-related diseases are more frequent in industrialized countries.
• The fraction of global disease attributed to occupational exposures includes 13% of all cases of chronic obstructive pulmonary disease, 9% of lung cancers, and 2 % of leukemias.

• Some, such as chloroform and carbon tetrachloride, are found in degreasing and dry cleaning agents and paint removers.
• Acute exposure to high levels of vapors from these agents can cause dizziness and confusion, leading to CNS depression and even coma.
• Lower levels are toxic for the liver and kidneys.
• Occupational exposure of rubber workers to benzene and 1,3-butadiene increases the risk of leukemia. Benzene is oxidized by hepatic CYP2E1 to toxic metabolites that disrupt the differentiation of hematopoietic cells in the bone marrow, leading to dose-dependent marrow aplasia and an increased risk of acute myeloid leukemia

Benzene is oxidized by hepatic CYP2E1 to toxic metabolites that disrupt the differentiation of hematopoietic cells in the bone marrow, leading to dose-dependent marrow aplasia and an increased risk of AML

• Polycyclic hydrocarbons may be released during the combustion of fossil fuels, particularly when coal and gas are burned at high temperatures (such as in steel foundries), and are also present in tar and soot.
• Polycyclic hydrocarbons are among the most potent carcinogens, and industrial exposures have been implicated in the development of lung and bladder cancer

• Organochlorines (and halogenated organic compounds in general) are synthetic lipophilic products that resist degradation.
• Important organochlorines used as pesticides include DDT (dichlorodiphenyltrichloroethane), Lindane, Aldrin, and Dieldrin. Nonpesticide organochlorines include polychlorinated biphenyls (PCBs) and dioxin (TCDD; 2,3,7,8-tetrachlorodibenzo-p-dioxin).
• DDT was banned in the United States in 1973, but more than half of the U.S. population has detectable levels ofp, p′-DDE, a long-lasting DDT metabolite.
• PCB (another banned substance), dioxin, and PBDEs (polybrominated diphenyl ethers used as flame retardants) are also detectable in a large proportion of the U.S. population. Most organochlorines are endocrine disruptors with anti-estrogenic or anti-androgenic activity

CO

• Very very stable
• Dioxins and PCBs can cause skin disorders such as folliculitis and a dermatosis known as chloracne (mainly dioxin) that is characterized by acne, cyst formation, hyperpigmentation, and hyperkeratosis, generally around the face and behind the ears.
• These toxins can also cause abnormalities in the liver and central nervous system.
• Because PCBs induce CYPs, workers exposed to these substances may show abnormal drug metabolism.

• halogenated solvents such as carbon tetrachloride, chloroform, and trichloroethylene
• Acute--> CNS
• Chronic--> hepatic dysfunction and nephrotoxicity

• Benzene, toluene, and xylene are important aromatic hydrocarbons
• Acute-->CNS depression
• Long-term exposure to benzene is associated with hematotoxicity (thrombocytopenia, aplastic anemia, pancytopenia) and leukemia

chlorinated hydrocarbons (DDT and its analogs), acetylcholinesterase inhibitors (carbamates, organophosphates), and botanical agents (nicotine, rotenone, pyrethrum alkaloids).

• Persistent, poorly metabolized, lipophilic chemicals that exhibit significant bioaccumulation.
• Chlorinated hydrocarbons block physiologic inactivation in the sodium channels of nerve membranes and cause uncontrolled firing of action potentials.
• Tremor is usually the first sign of acute toxicity and may progress to seizures. Recent evidence suggests an association with brain and testicular cancer

The carbamates (eg, aldicarb, carbaryl) and organophosphates (eg, dichlorvos, malathion, parathion) are effective pesticides with short environmental half-lives used in agriculture

• cholinesterase inhibitors increase muscarinic and nicotinic activity.
• The signs and symptoms include pinpoint pupils, sweating, salivation, bronchoconstriction, vomiting and diarrhea, CNS stimulation followed by depression, and muscle fasciculations, weakness, and paralysis.
• The most common cause of death is respiratory failure.
• Chronic exposure to some organophosphates (not carbamates) has resulted in a delayed neurotoxicity with axonal degeneration

• Atropine is used in large doses to control muscarinic excess;
• pralidoxime is used to regenerate cholinesterase.
• Mechanical ventilation may be necessary

• Nicotine
• Rotenone
• PYRETHRUM

• NICOTINE: excitation followed by paralysis of ganglionic, CNS, and neuromuscular transmission). Treatment is supportive.
• ROTENONE: GI distress when ingested and conjunctivitis and dermatitis after direct contact
• PYRETHRUM: contact dermatitis (MC). Ingestion or inhalation of large quantities may cause CNS excitation (including seizures) and peripheral neurotoxicity.

• Chlorophenoxy Acids: The 2 most important members of this group are 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid, the compound in Agent Orange.( Acute--> muscle hypotonia and coma. Long-term -->NHL)
• Glyphosate (the most widely used herbicide in the world)--> skin and eye irritation
• Paraquat, a bipyridyl herbicide, is used extensively to kill weeds on farms and for highway maintenance. nontoxic unless ingested. After ingestion, the initial effect is GI irritation with hematemesis and bloody stools. Within a few days, signs of pulmonary impairment occur and are usually progressive, resulting in severe pulmonary fibrosis and often death

• Causes chronic, non-neoplastic lung diseases known as pneumoconioses.
• This term also includes diseases induced by organic and inorganic particulates, and chemical fume- and vapor-induced non-neoplastic lung diseases.
• The most common pneumoconioses are caused by exposures to coal dust (from mining of hard coal), silica (sandblasting, stone cutting, etc.), asbestos (mining, fabrication, insulation work), and beryllium (mining, fabrication).
• Exposure to these agents nearly always occurs in the workplace. However, the increased risk of cancer as a result of asbestos exposure extends to the family members of asbestos workers and to other individuals exposed outside the workplace

• Used in the synthesis of polyvinyl resins
• angiosarcoma of the liver

CO, lead, solvents, cobalt

• Nasal cancer: Isopropyl alcohol, wood dust
• Lung cancer: Radon, asbestos, silica, bis(chloromethyl)ether, nickel, arsenic, chromium, mustard gas, uranium
• Chronic obstructive lung disease: Grain dust, coal dust, cadmium
• Hypersensitivity: Beryllium, isocyanates
• Irritation: Ammonia, sulfur oxides, formaldehyde
• Fibrosis: Silica, asbestos, cobalt

• Peripheral neuropathies/ataxic gait: Solvents, mercury, lead, arsenic, DDT(tremor seizure)
• Central nervous system depression: Chlordane, toluene, mercury
• Cataracts: Alcohols, ketones, aldehydes,  Ultraviolet radiation

• Toxicity: lead, glycol ethers, solvents, cadmium
• Bladder cancer: Naphthylamines, 4-aminobiphenyl, benzidine, rubber products

• Male infertility: Lead
• Female infertility/stillbirths: Lead, mercury
• Teratogenesis: Mercury, polychlorinated biphenyls

• Folliculitis and acneiform dermatosis: PCB, dioxins, herbicides
• Cancer: UV, arsenic

• oral succimer in outpatients and with parenteral agents (eg, EDTA with or without dimercaprol) in more severe cases.
• Succimer is generally used in such children.
• In workers exposed to lead, prophylaxis with oral chelating agents is contraindicated because some evidence suggests that lead absorption may be enhanced by the presence of chelators.
• In contrast, high dietary calcium is indicated because it impedes lead absorption

dimercaprol

• ACUTE ARSENIC POISONING: severe GI discomfort, vomiting, "rice-water" stools, and capillary damage with dehydration and shock. A sweet, garlicky odor may be detected in the breath and the stools.
• CHRONIC ARSENIC POISONING: skin changes, hair loss, bone marrow depression and anemia, and chronic nausea and gastrointestinal disturbances. Arsenic is a known human carcinogen.
• ARSINE GAS: an occupational hazard, is formed during the refinement and processing of certain metals and is used in the semiconductor industry. Arsine causes a unique form of toxicity characterized by massive hemolysis. Pigment overload from erythrocyte breakdown can cause renal failure.

• ACUTE MERCURY POISONING: through inhalation of inorganic elemental mercury. It causes chest pain, shortness of breath, nausea and vomiting, kidney damage, gastroenteritis, and CNS damage. Acute ingestion of mercuric chloride causes a severe, life-threatening hemorrhagic gastroenteritis followed by renal failure.
• CHRONIC MERCURY POISONING: may occur with inorganic or organic mercury. Poisoning from inhalation of mercury vapor presents as a diffuse set of symptoms involving the gums and teeth, gastrointestinal disturbances, and neurologic and behavioral changes (erethism).
• ORGANIC MERCURY POISONING:Minimata

• oral succimer or with intramuscular dimercaprol (for acute)
• Dimercaprol may redistribute mercury to the CNS and should not be used in chronic exposure to elemental mercury

The initial symptoms of iron poisoning include vomiting, gastrointestinal bleeding, lethargy, and gray cyanosis. These can be followed by signs of severe gastrointestinal necrosis, pneumonitis, jaundice, seizures, and coma

Tobacco

• The main culprit is cigarette smoking, but smokeless tobacco (snuff, chewing tobacco, etc.) is also harmful to health and an important cause of oral cancer.
• The use of tobacco products not only creates personal risks, but passive tobacco inhalation from the environment (“second-hand smoke”) can cause lung cancer in nonsmokers.

Smoking

Cessation of smoking greatly reduces, within 5 years, the overall mortality and the risk of death from cardiovascular diseases. Lung cancer mortality decreases by 21% within 5 years, but the excess risk lasts for 30 years.

• Colorectal
• Head and neck cancers, including esophagus
• Kidney
• Liver
• Lower urinary tract, including renal pelvis, ureter, and bladder
• Lung
• Mesothelioma
• Myeloid leukemia
• Nasal cavity and paranasal sinuses
• Pancreas
• Penis
• Stomach
• Uterine cervix

• Mainly addictive
• Nicotine binds to receptors in the brain, and through the release of catecholamines, is responsible for the acute effects of smoking, such as the increase in heart rate and blood pressure, and the elevation in cardiac contractility and output

• The most common diseases caused by cigarette smoking involve the lung and include COPD, and lung cancer. 
• Cigarette smoking is also strongly associated with the development of atherosclerosis, myocardial infarcts, and cancers of the lip, mouth, pharynx, esophagus, pancreas, bladder, kidney, and cervix
• 

• Tar
• Polycyclic aromatic hydrocarbons
• Benzopyrene
• Nitrosamine

Phenol

• Formaldehyde
• Oxides of nitrogen
• Phenol (also promoter)

Carbon monoxide

Ganglionic stimulation and depression

• Agents in smoke have a direct irritant effect on the tracheobronchial mucosa, producing inflammation and increased mucus production (bronchitis). 
• Cigarette smoke also causes the recruitment of leukocytes to the lung, with increased local elastase production and subsequent injury to lung tissue, leading to emphysema.

• Components of cigarette smoke, particularly polycyclic hydrocarbons and nitrosamines, are potent carcinogens are likely involved in the development of lung cancer in humans.
• CYPs (cytochrome P-450 phase I enzymes) and phase II enzymes increase the water solubility of the carcinogens, facilitating their excretion
• However, some intermediates produced by CYPs are electrophilic and form DNA adducts. If such adducts persist, they can cause mutations in oncogenes and tumor suppressors such as K-Ras and p53,.
• The risk of developing lung cancer is related to the intensity of exposure, frequently expressed in terms of “pack years”.
• Moreover, smoking multiplies the risk of other carcinogenic influences. Witness the ten-fold higher incidence of lung carcinomas in asbestos workers and uranium miners who smoke over those who do not smoke, and the interaction between tobacco consumption and alcohol in the development of oral cancers

• Lung, larynx: Polycyclic aromatic hydrocarbons 4-(Methylnitrosoamino)-1-(3-pyridyl)-1-buta-none (NNK), polonium 210
• Esophagus: N′-Nitrosonornicotine (NNN)
• Bladder: 4-Aminobiphenyl, 2-naphthylamine
• Oral cavity (smoking): Polycyclic aromatic hydrocarbons, NNK, NNN
• Oral cavity (snuff): NNK, NNN, polonium 210

• The causal mechanisms probably relate to several factors, including increased platelet aggregation, decreased myocardial oxygen supply (because of significant lung disease coupled with the hypoxia related to the CO content of cigarette smoke) accompanied by an increased oxygen demand, and a decreased threshold for ventricular fibrillation.
• Smoking has a multiplicative effect on the incidence of myocardial infarction when combined with hypertension and hypercholesterolemia.

• Maternal smoking increases the risk of spontaneous abortions and preterm births and results in intrauterine growth retardation.
• Birth weights of infants born to mothers who stopped smoking before pregnancy are, however, normal

• increased risk of coronary atherosclerosis and fatal myocardial infarction
• Risk of lung cancer
• respiratory illnesses and asthma

cotinine, a metabolite of nicotine

• Problematic pattern of tobacco use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:
• 1. Tobacco is often taken in larger amounts or over a longer period than was intended.
• 2. There is a persistent desire or unsuccessful efforts to cut down or control tobacco use.
• 3. A great deal of time is spent in activities necessary to obtain or use tobacco.
• 4. Craving, or a strong desire or urge to use tobacco.
• 5. Recurrent tobacco use resulting in a failure to fulfill major role obligations at work, school, or home (e.g., interference with work).
• 6. Continued tobacco use despite having persistent or recurrent social or interper­sonal problems caused or exacerbated by the effects of tobacco (e.g., arguments with others about tobacco use).
• 7. important social, occupational, or recreational activities are given up or reduced be­cause of tobacco use.
• 8. Recurrent tobacco use in situations in which it is physically hazardous (e.g., smok­ing in bed).
• 9. Tobacco use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by tobacco 
• 10. Tolerance, as defined by either of the following:a. A need for markedly increased amounts of tobacco to achieve the desired effect.b. A markedly diminished effect with continued use of the same amount of tobacco.
• 11. Withdrawal, as manifested by either of the following:a. The characteristic withdrawal syndrome for tobacco (refer to Criteria A and B of the criteria set for tobacco withdrawal).b. Tobacco (or a closely related substance, such as nicotine) is taken to relieve or avoid withdrawal symptoms

• A. Daily use of tobacco for at least several weeks.
• B. Abrupt cessation of tobacco use, or reduction in the amount of tobacco used, followed within 24 hours by four (or more) of the following signs or symptoms:1. Irritability, frustration, or anger.2. Anxiety.3. Difficulty concentrating.4. Increased appetite.5. Restlessness.6. Depressed mood.7. Insomnia.

• A problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:
• 1. Alcohol is often taken in larger amounts or over a longer period than was intended.
• 2. There is a persistent desire or unsuccessful efforts to cut down or control alcohol use.
• 3. A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recovôr from its effects.
• 4. Craving, or a strong desire or urge to use alcohol.
• 5. Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home.
• 6. Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol.
• 7. Important social, occupational, or recreational activities are given up or reduced be­cause of alcohol use.
• 8. Recurrent alcohol use in situations in which it is physically hazardous.
• 9. Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol
• 10. Tolerance, as defined by either of the following:a. A need for markedly increased amounts of alcohol to achieve intoxication or de­sired effect.b. A markedly diminished effect with continued use of the same amount of alcohol.
• 11. Withdrawal, as manifested by either of the following:a. The characteristic withdrawal syndrome for alcohol (refer to Criteria A and B of the criteria set for alcohol withdrawal, pp. 499-500).b. Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms

• blood alcohol concentration (>200 in non tolerant--> severe intoxication): can judge the degree of tolerance
•  GGT and CDT--> sensitive and return to normal upon abstinence
• MCV (elevated): not normalized readily
• LFT
• Elevated TG, uric acid and HDL

• A. Recent ingestion of alcohol.
• B. Clinically significant problematic beliavioral or psychological changes (e.g., inappropri­ate sexual or aggressive behavior, mood lability, impaired judgment) that developed during, or shortly after, alcohol ingestion.
• C. One (or more) of the following signs or symptoms developing during, or shortly after, alcohol use:1. Slurred speech.2. Incoordination. 3. Unsteady gait.4. Nystagmus.5. Impairment in attention or memory.6. Stupor or coma.

other substance intoxication, especially in individuals with conduct disorder or antisocial personality disorder

• A. Cessation of (or reduction in) alcohol use that has been heavy and prolonged.
• B. Two (or more) of the following, developing within several hours to a few days after the cessation of (or reduction in) alcohol use described in Criterion A:1. Autonomic hyperactivity (e.g., sweating or pulse rate greater than 100 bpm).2. Increased hand tremor.3. Insomnia.4. Nausea or vomiting.5. Transient visual, tactile, or auditory hallucinations or illusions.6. Psychomotor agitation.7. Anxiety.8. Generalized tonic-clonic seizures.

accidents caused by drunken driving and alcohol-related homicides and suicides

• After consumption, ethanol is absorbed unaltered in the stomach and small intestine. It is then distributed to all the tissues and fluids of the body in direct proportion to the blood level.
• Less than 10% is excreted unchanged in the urine, sweat, and breath.

The amount exhaled is proportional to the blood level and forms the basis of the breath test used by law enforcement agencies. A concentration of 80 mg/dL in the blood constitutes the legal definition of drunk driving in the United States. For an average individual, this alcohol concentration may be reached after consumption of three standard drinks, contained in about 3 (12 ounce) bottles of beer, 15 ounces of wine, or 4–5 ounces of 80 proof distilled spirits

Drowsiness/ Stupor

• Most of the alcohol in the blood is biotransformed to acetaldehyde in the liver by three enzyme systems consisting of alcohol dehydrogenase (ADH), the microsomal ethanol-oxidizing system (MEOS), and catalase.
• The main enzyme system involved in alcohol metabolism is ADH, located in the cytosol of hepatocytes. 
• At high blood alcohol levels, the microsomal ethanol-oxidizing system participates in its metabolism.
• Catalase, which uses hydrogen peroxide as substrate, is of minor importance, since it metabolizes no more than 5% of ethanol in the liver.
• Acetaldehyde produced by alcohol metabolism through ADH or MEOS is converted to acetate by acetaldehyde dehydrogenase (ALDH), which is then utilized in the mitochondrial respiratory chain
• 

• This cytosolic, NAD+-dependent enzyme, found mainly in the liver and gut, accounts for the metabolism of low to moderate doses of ethanol.
• Because of the limited supply of the coenzyme NAD+, the reaction has zero-order kinetics, resulting in a fixed capacity for ethanol metabolism of 7–10 g/h.
• Gastrointestinal metabolism of ethanol is lower in women than in men

acetate by acetaldehyde dehydrogenase (ALDH), which is then utilized in the mitochondrial respiratory chain

• At blood ethanol levels higher than 100 mg/dL, the liver microsomal mixed function oxidase system that catalyzes most phase I drug-metabolizing reactions  contributes significantly to ethanol metabolism.
• Chronic ethanol consumption induces cytochrome P450 enzyme synthesis and MEOS activity; this increase may be partially responsible for the development of tolerance to ethanol.
• The primary isoform of cytochrome P450 induced by ethanol—2E1—converts acetaminophen to a hepatotoxic metabolite

2E1 which converts acetaminophen to a hepatotoxic metabolite

• Aldehyde dehydrogenase, a mitochondrial enzyme found in the liver and many other tissues.
• Aldehyde dehydrogenase is inhibited by disulfiram and metronidazole, oral hypoglycemics (chlorpropamide), and some cephalosporins (Cefoperazone ). 
• Some individuals, primarily of Asian descent, have genetic deficiency of aldehyde dehydrogenase.
• After consumption of even small quantities of ethanol, these persons experience nausea and a flushing reaction from accumulation of acetaldehyde

• Located in SER
• Induction of CYPs by alcohol explains the increased susceptibility of alcoholics to other compounds metabolized by the same enzyme system, which include drugs, anesthetics, carcinogens, and industrial solvents.
• When alcohol is present in the blood at high concentrations, it competes with other CYP2E1 substrates and delays drug catabolism, potentiating the depressant effects of narcotic, sedative, and psychoactive drugs in the central nervous system

• Acetaldehyde has many toxic effects and is responsible for some of the acute effects of alcohol and for the development of oral cancers.
• The efficiency of alcohol metabolism varies between populations, depending on the expression levels of ADH and ALDH isozymes, and the presence of genetic variants that alter enzyme activity.
• About 50% of Asians have very low ALDH activity, due to the substitution of lysine for glutamine at residue 487 (the normal allele is termed ALDH2*1 and the inactive variant is designated as ALDH2*2).
• The ALDH2*2 protein has dominant-negative activity, such that even one copy of the ALDH2*2 allele reduces ALDH activity significantly. 
• Individuals homozygous for the ALDH2*2 allele are completely unable to oxidize acetaldehyde and cannot tolerate alcohol, experiencing nausea, flushing, tachycardia, and hyperventilation after its ingestion

• Alcohol oxidation by ADH causes the reduction of NAD to NADH, with a consequent decrease in NAD and increase in NADH.
• NAD is required for fatty acid oxidation in the liver and for the conversion of lactate into pyruvate.
• Its deficiency is a main cause of the accumulation of fat in the liver of alcoholics.
• The increase in the NADH/NAD ratio in alcoholics also causes lactic acidosis

fatty acid oxidation in the liver and for the conversion of lactate into pyruvate

• produces reactive oxygen species and causes lipid peroxidation of cell membranes.
• Alcohol also causes the release of endotoxin (lipopolysaccharide) from gram-negative bacteria in the intestinal flora, which stimulates the production of TNF and other cytokines from macrophages and Kupffer cells, leading to hepatic injury

CNS

• Acute alcoholism exerts its effects mainly on the CNS, but it may induce hepatic and gastric changes that are reversible if alcohol consumption is discontinued.
• Even with moderate intake of alcohol, multiple fat droplets accumulate in the cytoplasm of hepatocytes (fatty change or hepatic steatosis).
• The gastric changes are acute gastritis and ulceration.
• In the CNS, alcohol is a depressant, first affecting subcortical structures (probably the high brain stem reticular formation) that modulate cerebral cortical activity. Consequently, there is stimulation and disordered cortical, motor, and intellectual behavior.
• At progressively higher blood levels, cortical neurons and then lower medullary centers are depressed, including those that regulate respiration. Respiratory arrest may follow

liver

• Liver
• Stomach
• Peripheral neuropathies and the Wernicke-Korsakoff syndrome
• Dilated congestive cardiomyopathy
• HTN
• Acute and chronic pancreatitis
• fetal alcohol syndrome
• Increased incidence of cancer of the oral cavity, esophagus, liver, and, possibly, breast in females
• Malnutrition and nutritional deficiencies, particularly of the B vitamins

• The liver is the main site of chronic injury. In addition to fatty change, chronic alcoholism causes alcoholic hepatitis and cirrhosis.
• Cirrhosis is associated with portal hypertension and an increased risk for the development of HCC

massive bleeding from gastritis, gastric ulcer, or esophageal varices (associated with cirrhosis), which may prove fatal

Thiamine (vitamin B1) deficiency.

The principal lesions resulting from this deficiency are peripheral neuropathies and the Wernicke-Korsakoff syndrome; cerebral atrophy, cerebellar degeneration, and optic neuropathy

• Direct Injury to the myocardium may produce dilated congestive cardiomyopathy (alcoholic cardiomyopathy).
• HTN
• Moderate amounts of alcohol (about 20–30 gm of daily intake, corresponding to approximately 250 mL of wine) have been reported to increase HDL levels and inhibit platelet aggregation, thus protecting against coronary heart disease.
• However, heavy alcohol consumption, with attendant liver injury, results in decreased levels of HDL, increasing the likelihood of coronary heart disease.

• It consists of microcephaly, growth retardation, and facial abnormalities in the newborn, and reduction in mental functions as the child grows older.
• It is difficult to establish the minimal amount of alcohol consumption that can cause fetal alcohol syndrome, but consumption during the first trimester of pregnancy is particularly harmful

Acetaldehyde

• Chronic alcohol consumption is associated with an increased incidence of cancer of the oral cavity, esophagus, liver, and, possibly, breast in females.
• Acetaldehyde is considered to be the main agent associated with alcohol-induced laryngeal and esophageal cancer, in that acetaldehyde-DNA adducts have been detected in some tumors from these tissues.
• Individuals with one copy of the ALDH2*2 allele who drink are at a higher risk of developing cancer of the esophagus

resveratrol

its activation of protein deacetylases of the Sir2 (sirtuin) family of enzymes, which include histone deacetylases

• It facilitates the action of GABA at GABAA receptors, inhibits the ability of glutamate to activate NMDA (N-methyl-D-aspartate) receptors, and modifies the activities of adenylyl cyclase, phospho-lipase C, and ion channels.
• It has been suggested that alcohol "blackouts" may result from interference with NMDA receptors.

Vascular smooth muscle is relaxed, which leads to vasodilation, sometimes with marked hypothermia. Ethanol relaxes uterine smooth muscle

Reduced gluconeogenesis can lead to hypoglycemia

Gynecomastia, testicular atrophy, and salt retention occur, partly because of altered steroid metabolism in the cirrhotic liver

BZD

• The opioid receptor antagonist naltrexone has proved to be useful in some patients, presumably through its ability to decrease the effects of endogenous opioid peptides in the brain. 
• Acamprosate , an NMDA glutamate receptor antagonist, is also FDA approved for treatment of alcoholism.
• The aldehyde dehydrogenase inhibitor disulfiram is used adjunctively in some treatment programs. If ethanol is consumed by a patient who has taken disulfiram, acetaldehyde accumulation leads to nausea, headache, flushing, and hypotension 

• A component of visual pigment, Maintenance of specialized epithelia, Maintenance of resistance to infection
• Def: Night blindness, xerophthalmia, blindness, Squamous metaplasia, Vulnerability to infection, particularly measles

• Facilitates intestinal absorption of calcium and phosphorus and mineralization of bone
• Def: Rickets in children/ Osteomalacia in adults

• Major antioxidant; scavenges free radicals
• DEf: Spinocerebellar degeneration

• Cofactor in hepatic carboxylation of procoagulants—factors II (prothrombin), VII, IX, and X; and protein C and protein S
• Def: Bleeding diathesis

• As pyrophosphate, is coenzyme in decarboxylation reactions
• Def: Dry and wet beriberi, Wernicke syndrome, Korsakoff syndrome

• Converted to coenzymes flavin mononucleotide and flavin adenine dinucleotide, cofactors for many enzymes in intermediary metabolism
• Def: Ariboflavinosis, cheilosis, stomatitis, glossitis, dermatitis, corneal vascularization

• Incorporated into nicotinamide adenine dinucleotide (NAD) and NAD phosphate, involved in a variety of redox reactions
• Def: Pellagra—“three Ds”: dementia, dermatitis, diarrhea

• Derivatives serve as coenzymes in many intermediary reactions
• Def: Cheilosis, glossitis, dermatitis, peripheral neuropathy

• B12: Required for normal folate metabolism and DNA synthesis/ Maintenance of myelinization of spinal cord tracts Def: Megaloblastic pernicious anemia and degeneration of posterolateral spinal cord tracts
• Folate: Essential for transfer and use of one-carbon units in DNA synthesis Def: Megaloblastic anemia, neural tube defects
• Pantothenic acid: Incorporated in coenzyme A
• Biotin: Cofactor in carboxylation reactions

• Serves in many oxidation-reduction (redox) reactions and hydroxylation of collagen
• Def: Scurvy

CDH (elevated)