Vitamin A deficient lung – COPD – hospice in home senior care

Last night, I massaged the chest and back of an 80-yr old male hospice senior in the bay area with apricot oil with essential oil of eucalyptus and lemon. Vitamin A deficiency is prevalent among those with lung disease. I instructed the caregiver to get sunshine in the morning and continue on healing massage in other parts of the body too especially the heart, feet, lungs, and liver area.

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Natural Remedies

As we’ve mentioned above, holistic medicine is the practice of treating the body itself to treat the illness. For example, in treating a headache, a holistic method of treatment might be to try hydrotherapy, which involves water for pain relief. In the case of chronic lung diseases, a variety of natural remedies may be used to promote airway clearance and to reduce mucus such as:

  • Lobelia– believed to stimulate the adrenal glands to release epinephrine, in effect, this relaxes the airways and allows for easier breathing.
  • Osha root– has been used to relieve congestion and make breathing easier.
  • Lungwort– known to reduce irritation and provide soothing qualities.
  • Elecampane– used to relieve coughs.
  • Oregano– known to benefit the respiratory tract, coughing reflex, and nasal passage airflow.
  • Orange peel– provides support for the respiratory system by breaking down and expelling congestion.
  • Chaparral– protects the body from harmful bacterial agents.
  • Eucalyptus– strengthens the immune system against infection.
  • Ginger– relieves congestion and improves circulation within the lungs.
  • Rosemary– contains healing vitamins A and C, and minerals calcium, magnesium, iron, potassium, sodium and zinc and helps blood flow.

Remember, however, to always consult with your primary doctor or physician before adding any new natural remedies to your diet.

4. Natural Supplements

In the case of natural supplements for COPD, there are a variety of vitamins and nutrients used by the body to reduce inflammation within the airways as well as promote more natural breathing from within. Here are a few examples with their properties and benefits:

  • NAC (N-Acetylcysteine) – a powerful antioxidant that has been shown to reduce inflammation, phlegm and cough, as well as thin mucus and ease expectoration.
  • Vitamin D – a sun-derived vitamin that has been linked to better lung function tests.
  • Bromelain – a chemical enzyme found in pineapple juice, believed to reduce inflammation and has shown in some studies to be an effective supplement for COPD relief.


Lung cancer and heavy metal toxins

lung cancer.JPGHeavy metals are naturally occurring elements that have a high atomic weight and a density at least 5 times greater than that of water. Their multiple industrial, domestic, agricultural, medical and technological applications have led to their wide distribution in the environment; raising concerns over their potential effects on human health and the environment. Their toxicity depends on several factors including the dose, route of exposure, and chemical species, as well as the age, gender, genetics, and nutritional status of exposed individuals. Because of their high degree of toxicity, arsenic, cadmium, chromium, lead, and mercury rank among the priority metals that are of public health significance. These metallic elements are considered systemic toxicants that are known to induce multiple organ damage, even at lower levels of exposure. They are also classified as human carcinogens (known or probable) according to the U.S. Environmental Protection Agency, and the International Agency for Research on Cancer. This review provides an analysis of their environmental occurrence, production and use, potential for human exposure, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity.


Heavy metals are defined as metallic elements that have a relatively high density compared to water [1]. With the assumption that heaviness and toxicity are inter-related, heavy metals also include metalloids, such as arsenic, that are able to induce toxicity at low level of exposure [2]. In recent years, there has been an increasing ecological and global public health concern associated with environmental contamination by these metals. Also, human exposure has risen dramatically as a result of an exponential increase of their use in several industrial, agricultural, domestic and technological applications [3]. Reported sources of heavy metals in the environment include geogenic, industrial, agricultural, pharmaceutical, domestic effluents, and atmospheric sources [4]. Environmental pollution is very prominent in point source areas such as mining, foundries and smelters, and other metal-based industrial operations [1, 3, 4].

Although heavy metals are naturally occurring elements that are found throughout the earth’s crust, most environmental contamination and human exposure result from anthropogenic activities such as mining and smelting operations, industrial production and use, and domestic and agricultural use of metals and metal-containing compounds [47]. Environmental contamination can also occur through metal corrosion, atmospheric deposition, soil erosion of metal ions and leaching of heavy metals, sediment re-suspension and metal evaporation from water resources to soil and ground water [8]. Natural phenomena such as weathering and volcanic eruptions have also been reported to significantly contribute to heavy metal pollution [1, 3, 4, 7, 8]. Industrial sources include metal processing in refineries, coal burning in power plants, petroleum combustion, nuclear power stations and high tension lines, plastics, textiles, microelectronics, wood preservation and paper processing plants [911].

It has been reported that metals such as cobalt (Co), copper (Cu), chromium (Cr), iron (Fe), magnesium (Mg), manganese (Mn), molybdenum (Mo), nickel (Ni), selenium (Se) and zinc (Zn) are essential nutrients that are required for various biochemical and physiological functions [12]. Inadequate supply of these micro-nutrients results in a variety of deficiency diseases or syndromes [12].

Heavy metals are also considered as trace elements because of their presence in trace concentrations (ppb range to less than 10ppm) in various environmental matrices [13]. Their bioavailability is influenced by physical factors such as temperature, phase association, adsorption and sequestration. It is also affected by chemical factors that influence speciation at thermodynamic equilibrium, complexation kinetics, lipid solubility and octanol/water partition coefficients [14]. Biological factors such as species characteristics, trophic interactions, and biochemical/physiological adaptation, also play an important role [15].

The essential heavy metals exert biochemical and physiological functions in plants and animals. They are important constituents of several key enzymes and play important roles in various oxidation-reduction reactions [12]. Copper for example serves as an essential co-factor for several oxidative stress-related enzymes including catalase, superoxide dismutase, peroxidase, cytochrome c oxidases, ferroxidases, monoamine oxidase, and dopamine β-monooxygenase [1618]. Hence, it is an essential nutrient that is incorporated into a number of metalloenzymes involved in hemoglobin formation, carbohydrate metabolism, catecholamine biosynthesis, and cross-linking of collagen, elastin, and hair keratin. The ability of copper to cycle between an oxidized state, Cu(II), and reduced state, Cu(I), is used by cuproenzymes involved in redox reactions [1618]. However, it is this property of copper that also makes it potentially toxic because the transitions between Cu(II) and Cu(I) can result in the generation of superoxide and hydroxyl radicals [1619]. Also, excessive exposure to copper has been linked to cellular damage leading to Wilson disease in humans [18, 19]. Similar to copper, several other essential elements are required for biologic functioning, however, an excess amount of such metals produces cellular and tissue damage leading to a variety of adverse effects and human diseases. For some including chromium and copper, there is a very narrow range of concentrations between beneficial and toxic effects [19, 20]. Other metals such as aluminium (Al), antinomy (Sb), arsenic (As), barium (Ba), beryllium (Be), bismuth (Bi), cadmium (Cd), gallium (Ga), germanium (Ge), gold (Au), indium (In), lead (Pb), lithium (Li), mercury (Hg), nickel (Ni), platinum (Pt), silver (Ag), strontium (Sr), tellurium (Te), thallium (Tl), tin (Sn), titanium (Ti), vanadium (V) and uranium (U) have no established biological functions and are considered as non-essential metals [20].

In biological systems, heavy metals have been reported to affect cellular organelles and components such as cell membrane, mitochondrial, lysosome, endoplasmic reticulum, nuclei, and some enzymes involved in metabolism, detoxification, and damage repair [21]. Metal ions have been found to interact with cell components such as DNA and nuclear proteins, causing DNA damage and conformational changes that may lead to cell cycle modulation, carcinogenesis or apoptosis [2022]. Several studies from our laboratory have demonstrated that reactive oxygen species (ROS) production and oxidative stress play a key role in the toxicity and carcinogenicity of metals such as arsenic [23, 24, 25], cadmium [26], chromium [27, 28], lead [29, 30], and mercury [31, 32]. Because of their high degree of toxicity, these five elements rank among the priority metals that are of great public health significance. They are all systemic toxicants that are known to induce multiple organ damage, even at lower levels of exposure. According to the United States Environmental Protection Agency (U.S. EPA), and the International Agency for Research on Cancer (IARC), these metals are also classified as either “known” or “probable” human carcinogens based on epidemiological and experimental studies showing an association between exposure and cancer incidence in humans and animals.

Heavy metal-induced toxicity and carcinogenicity involves many mechanistic aspects, some of which are not clearly elucidated or understood. However, each metal is known to have unique features and physic-chemical properties that confer to its specific toxicological mechanisms of action. This review provides an analysis of the environmental occurrence, production and use, potential for human exposure, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity of arsenic, cadmium, chromium, lead, and mercury.


Environmental Occurrence, Industrial Production and Use

Arsenic is a ubiquitous element that is detected at low concentrations in virtually all environmental matrices [33]. The major inorganic forms of arsenic include the trivalent arsenite and the pentavalent arsenate. The organic forms are the methylated metabolites – monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and trimethylarsine oxide. Environmental pollution by arsenic occurs as a result of natural phenomena such as volcanic eruptions and soil erosion, and anthropogenic activities [33]. Several arsenic-containing compounds are produced industrially, and have been used to manufacture products with agricultural applications such as insecticides, herbicides, fungicides, algicides, sheep dips, wood preservatives, and dye-stuffs. They have also been used in veterinary medicine for the eradication of tapeworms in sheep and cattle [34]. Arsenic compounds have also been used in the medical field for at least a century in the treatment of syphilis, yaws, amoebic dysentery, and trypanosomaiasis [34,35]. Arsenic-based drugs are still used in treating certain tropical diseases such as African sleeping sickness and amoebic dysentery, and in veterinary medicine to treat parasitic diseases, including filariasis in dogs and black head in turkeys and chickens [35]. Recently, arsenic trioxide has been approved by the Food and Drug Administration as an anticancer agent in the treatment of acute promeylocytic leukemia [36]. Its therapeutic action has been attributed to the induction of programmed cell death (apoptosis) in leukemia cells [24].

Potential for Human Exposure

It is estimated that several million people are exposed to arsenic chronically throughout the world, especially in countries like Bangladesh, India, Chile, Uruguay, Mexico, Taiwan, where the ground water is contaminated with high concentrations of arsenic. Exposure to arsenic occurs via the oral route (ingestion), inhalation, dermal contact, and the parenteral route to some extent [33,34,37]. Arsenic concentrations in air range from 1 to 3 ng/m3 in remote locations (away from human releases), and from 20 to 100 ng/m3 in cities. Its water concentration is usually less than 10µg/L, although higher levels can occur near natural mineral deposits or mining sites. Its concentration in various foods ranges from 20 to 140 ng/kg [38]. Natural levels of arsenic in soil usually range from 1 to 40 mg/kg, but pesticide application or waste disposal can produce much higher values [25].

Diet, for most individuals, is the largest source of exposure, with an average intake of about 50 µg per day. Intake from air, water and soil are usually much smaller, but exposure from these media may become significant in areas of arsenic contamination. Workers who produce or use arsenic compounds in such occupations as vineyards, ceramics, glass-making, smelting, refining of metallic ores, pesticide manufacturing and application, wood preservation, semiconductor manufacturing can be exposed to substantially higher levels of arsenic [39]. Arsenic has also been identified at 781 sites of the 1,300 hazardous waste sites that have been proposed by the U.S. EPA for inclusion on the national priority list [33,39]. Human exposure at these sites may occur by a variety of pathways, including inhalation of dusts in air, ingestion of contaminated water or soil, or through the food chain [40].

Contamination with high levels of arsenic is of concern because arsenic can cause a number of human health effects. Several epidemiological studies have reported a strong association between arsenic exposure and increased risks of both carcinogenic and systemic health effects [41]. Interest in the toxicity of arsenic has been heightened by recent reports of large populations in West Bengal, Bangladesh, Thailand, Inner Mongolia, Taiwan, China, Mexico, Argentina, Chile, Finland and Hungary that have been exposed to high concentrations of arsenic in their drinking water and are displaying various clinico-pathological conditions including cardiovascular and peripheral vascular disease, developmental anomalies, neurologic and neurobehavioural disorders, diabetes, hearing loss, portal fibrosis, hematologic disorders (anemia, leukopenia and eosinophilia) and carcinoma [25, 33, 35, 39]. Arsenic exposure affects virtually all organ systems including the cardiovascular, dermatologic, nervous, hepatobilliary, renal, gastro-intestinal, and respiratory systems [41]. Research has also pointed to significantly higher standardized mortality rates for cancers of the bladder, kidney, skin, and liver in many areas of arsenic pollution. The severity of adverse health effects is related to the chemical form of arsenic, and is also time- and dose-dependent [42,43]. Although the evidence of carcinogenicity of arsenic in humans seems strong, the mechanism by which it produces tumors in humans is not completely understood [44].

Mechanisms of Toxicity and Carcinogenicity

Analyzing the toxic effects of arsenic is complicated because the toxicity is highly influenced by its oxidation state and solubility, as well as many other intrinsic and extrinsic factors [45]. Several studies have indicated that the toxicity of arsenic depends on the exposure dose, frequency and duration, the biological species, age, and gender, as well as on individual susceptibilities, genetic and nutritional factors [46]. Most cases of human toxicity from arsenic have been associated with exposure to inorganic arsenic. Inorganic trivalent arsenite (AsIII) is 2–10 times more toxic than pentavalent arsenate (AsV) [5]. By binding to thiol or sulfhydryl groups on proteins, As (III) can inactivate over 200 enzymes. This is the likely mechanism responsible for arsenic’s widespread effects on different organ systems. As (V) can replace phosphate, which is involved in many biochemical pathways [5, 47].

One of the mechanisms by which arsenic exerts its toxic effect is through impairment of cellular respiration by the inhibition of various mitochondrial enzymes, and the uncoupling of oxidative phosphorylation. Most toxicity of arsenic results from its ability to interact with sulfhydryl groups of proteins and enzymes, and to substitute phosphorous in a variety of biochemical reactions [48]. Arsenic in vitro reacts with protein sulfhydryl groups to inactivate enzymes, such as dihydrolipoyl dehydrogenase and thiolase, thereby producing inhibited oxidation of pyruvate and betaoxidation of fatty acids [49]. The major metabolic pathway for inorganic arsenic in humans is methylation. Arsenic trioxide is methylated to two major metabolites via a non-enzymatic process to monomethylarsonic acid (MMA), which is further methylated enzymatically to dimethyl arsenic acid (DMA) before excretion in the urine [40, 47]. It was previously thought that this methylation process is a pathway of arsenic detoxification, however, recent studies have pointed out that some methylated metabolites may be more toxic than arsenite if they contain trivalent forms of arsenic [41].

Tests for genotoxicity have indicated that arsenic compounds inhibit DNA repair, and induce chromosomal aberrations, sister-chromatid exchanges, and micronuclei formation in both human and rodent cells in culture [5052] and in cells of exposed humans [53]. Reversion assays with Salmonella typhimurium fail to detect mutations that are induced by arsenic compounds. Although arsenic compounds are generally perceived as weak mutagens in bacterial and animal cells, they exhibit clastogenic properties in many cell types in vivo and in vitro [54]. In the absence of animal models, in vitro cell transformation studies become a useful means of obtaining information on the carcinogenic mechanisms of arsenic toxicity. Arsenic and arsenical compounds are cytotoxic and induce morphological transformations of Syrian hamster embryo (SHE) cells as well as mouse C3H10T1/2 cells and BALB/3T3 cells [55, 56].

Based on the comet assay, it has been reported that arsenic trioxide induces DNA damage in human lymphophytes [57] and also in mice leukocytes [58]. Arsenic compounds have also been shown to induce gene amplification, arrest cells in mitosis, inhibit DNA repair, and induce expression of the c-fos gene and the oxidative stress protein heme oxygenase in mammalian cells [58, 59]. They have been implicated as promoters and comutagens for a variety of toxic agents [60]. Recent studies in our laboratory have demonstrated that arsenic trioxide is cytotoxic and able to transcriptionally induce a significant number of stress genes and related proteins in human liver carcinoma cells [61].

Epidemiological investigations have indicated that long-term arsenic exposure results in promotion of carcinogenesis. Several hypotheses have been proposed to describe the mechanism of arsenic-induced carcinogenesis. Zhao et al. [62] reported that arsenic may act as a carcinogen by inducing DNA hypomethylation, which in turn facilitates aberrant gene expression. Additionally, it was found that arsenic is a potent stimulator of extracellular signal-regulated protein kinase Erk1 and AP-1 transactivational activity, and an efficient inducer of c-fos and c-jun gene expression [63]. Induction of c-jun and c-fos by arsenic is associated with activation of JNK [64]. However, the role of JNK activation by arsenite in cell transformation or tumor promotion is unclear.

In another study, Trouba et al. [65] concluded that long-term exposure to high levels of arsenic might make cells more susceptible to mitogenic stimulation and that alterations in mitogenic signaling proteins might contribute to the carcinogenic action of arsenic. Collectively, several recent studies have demonstrated that arsenic can interfere with cell signaling pathways (e.g., the p53 signaling pathway) that are frequently implicated in the promotion and progression of a variety of tumor types in experimental animal models, and of some human tumors [66, 68]. However, the specific alterations in signal transduction pathways or the actual targets that contribute to the development of arsenic-induced tumors in humans following chronic consumption of arsenic remains uncertain.

Recent clinical trials have found that arsenic trioxide has therapeutic value in the treatment of acute promyelocytic leukemia, and there is interest in exploring its effectiveness in the treatment of a variety of other cancers [69,70]. In acute promyelocytic leukemia, the specific molecular event critical to the formation of malignant cells is known. A study by Puccetti et al. [71] found that forced overexpression of BCR-ABL susceptibility in human lymphoblasts cells resulted in greatly enhanced sensitivity to arsenic-induced apoptosis. They also concluded that arsenic trioxide is a tumor specific agent capable of inducing apoptosis selectively in acute promyelocytic leukemia cells. Several recent studies have shown that arsenic can induce apoptosis through alterations in other cell signaling pathways [72,73]. In addition to acute peomyelocytic leukemia, arsenic is thought to have therapeutic potential for myeloma [74]. In summary, numerous cancer chemotherapy studies in cell cultures and in patients with acute promyelocytic leukemia demonstrate that arsenic trioxide administration can lead to cell-cycle arrest and apoptosis in malignant cells.

Previous studies have also examined p53 gene expression and mutation in tumors obtained from subjects with a history of arsenic ingestion. p53 participates in many cellular functions, cell-cycle control, DNA repair, differentiation, genomic plasticity and programmed cell death. Additional support for the hypothesis that arsenic can modulate gene expression has been provided by several different studies [75,76]. Collectively, these studies provide further evidence that various forms of arsenic can alter gene expression and that such changes could contribute substantially to the toxic and carcinogenic actions of arsenic treatment in human populations [77].

Several in vitro studies in our laboratory have demonstrated that arsenic modulates DNA synthesis, gene and protein expression, genotoxicity, mitosis and/or apoptotic mechanisms in various cell lines including keratinocytes, melanocytes, dendritic cells, dermal fibroblasts, microvascular endothelial cells, monocytes, and T-cells [78], colon cancer cells [79], lung cancer cells [80], human leukemia cells [81], Jurkat-T lymphocytes [82], and human liver carcinoma cells [83]. We have also shown that oxidative stress plays a key role in arsenic induced cytotoxicity, a process that is modulated by pro- and/or anti-oxidants such as ascorbic acid and n-acetyl cysteine [8486]. We have further demonstrated that the toxicity of arsenic depends on its chemical form, the inorganic form being more toxic than the organic one [42].

Various hypotheses have been proposed to explain the carcinogenicity of inorganic arsenic. Nevertheless, the molecular mechanisms by which this arsenical induces cancer are still poorly understood. Results of previous studies have indicated that inorganic arsenic does not act through classic genotoxic and mutagenic mechanisms, but rather may be a tumor promoter that modifies signal transduction pathways involved in cell growth and proliferation [68]. Although much progress has been recently made in the area of arsenic’s possible mode(s) of carcinogenic action, a scientific consensus has not yet reached. A recent review discusses nine different possible modes of action of arsenic carcinogenesis: induced chromosomal abnormalities, oxidative stress, altered DNA repair, altered DNA methylation patterns, altered growth factors, enhanced cell proliferation, promotion/progression, suppression of p53, and gene amplification [87]. Presently, three modes (chromosomal abnormality, oxidative stress, and altered growth factors) of arsenic carcinogenesis have shown a degree of positive evidence, both in experimental systems (animal and human cells) and in human tissues. The remaining possible modes of carcinogenic action (progression of carcinogenesis, altered DNA repair, p53 suppression, altered DNA methylation patterns and gene amplification) do not have as much evidence, particularly from in vivo studies with laboratory animals, in vitro studies with cultured human cells, or human data from case or population studies. Thus, the mode-of-action studies suggest that arsenic might be acting as a cocarcinogen, a promoter, or a progressor of carcinogenesis.


Environmental Occurrence, Industrial Production and Use

Cadmium is a heavy metal of considerable environmental and occupational concern. It is widely distributed in the earth’s crust at an average concentration of about 0.1 mg/kg. The highest level of cadmium compounds in the environment is accumulated in sedimentary rocks, and marine phosphates contain about 15 mg cadmium/kg [88].

Cadmium is frequently used in various industrial activities. The major industrial applications of cadmium include the production of alloys, pigments, and batteries [89]. Although the use of cadmium in batteries has shown considerable growth in recent years, its commercial use has declined in developed countries in response to environmental concerns. In the United States for example, the daily cadmium intake is about 0.4µg/kg/day, less than half of the U.S. EPA’s oral reference dose [90]. This decline has been linked to the introduction of stringent effluent limits from plating works and, more recently, to the introduction of general restrictions on cadmium consumption in certain countries.

Potential for Human Exposure

The main routes of exposure to cadmium are via inhalation or cigarette smoke, and ingestion of food. Skin absorption is rare. Human exposure to cadmium is possible through a number of several sources including employment in primary metal industries, eating contaminated food, smoking cigarettes, and working in cadmium-contaminated work places, with smoking being a major contributor [91, 92]. Other sources of cadmium include emissions from industrial activities, including mining, smelting, and manufacturing of batteries, pigments, stabilizers, and alloys [93]. Cadmium is also present in trace amounts in certain foods such as leafy vegetables, potatoes, grains and seeds, liver and kidney, and crustaceans and mollusks [94]. In addition, foodstuffs that are rich in cadmium can greatly increase the cadmium concentration in human bodies. Examples are liver, mushrooms, shellfish, mussels, cocoa powder and dried seaweed. An important distribution route is the circulatory system whereas blood vessels are considered to be main stream organs of cadmium toxicity. Chronic inhalation exposure to cadmium particulates is generally associated with changes in pulmonary function and chest radiographs that are consistent with emphysema [95]. Workplace exposure to airborne cadmium particulates has been associated with decreases in olfactory function [96]. Several epidemiologic studies have documented an association of chronic low-level cadmium exposure with decreases in bone mineral density and osteoporosis [9799].

Exposure to cadmium is commonly determined by measuring cadmium levels in blood or urine. Blood cadmium reflects recent cadmium exposure (from smoking, for example). Cadmium in urine (usually adjusted for dilution by calculating the cadmium/creatinine ratio) indicates accumulation, or kidney burden of cadmium [100, 101]. It is estimated that about 2.3% of the U.S. population has elevated levels of urine cadmium (>2µg/g creatinine), a marker of chronic exposure and body burden [102]. Blood and urine cadmium levels are typically higher in cigarette smokers, intermediate in former smokers and lower in nonsmokers [102, 103]. Because of continuing use of cadmium in industrial applications, the environmental contamination and human exposure to cadmium have dramatically increased during the past century [104].

Molecular Mechanisms of Toxicity and Carcinogenicity

Cadmium is a severe pulmonary and gastrointestinal irritant, which can be fatal if inhaled or ingested. After acute ingestion, symptoms such as abdominal pain, burning sensation, nausea, vomiting, salivation, muscle cramps, vertigo, shock, loss of consciousness and convulsions usually appear within 15 to 30 min [105]. Acute cadmium ingestion can also cause gastrointestinal tract erosion, pulmonary, hepatic or renal injury and coma, depending on the route of poisoning [105, 106]. Chronic exposure to cadmium has a depressive effect on levels of norepinephrine, serotonin, and acetylcholine [107]. Rodent studies have shown that chronic inhalation of cadmium causes pulmonary adenocarcinomas [108, 109]. It can also cause prostatic proliferative lesions including adenocarcinomas, after systemic or direct exposure [110].

Although the mechanisms of cadmium toxicity are poorly understood, it has been speculated that cadmium causes damage to cells primarily through the generation of ROS [111], which causes single-strand DNA damage and disrupts the synthesis of nucleic acids and proteins [112]. Studies using two-dimensional gel electrophoresis have shown that several stress response systems are expressed in response to cadmium exposure, including those for heat shock, oxidative stress, stringent response, cold shock, and SOS [113115]. In vitro studies indicate that cadmium induces cytotoxic effects at the concentrations 0.1 to 10 mM and free radical-dependent DNA damage [116, 117]. In vivo studies have shown that cadmium modulates male reproduction in mice model at a concentration of 1 mg/kg body weight [118]. However, cadmium is a weak mutagen when compared with other carcinogenic metals [119]. Previous reports have indicated that cadmium affects signal transduction pathways; inducing inositol polyphosphate formation, increasing cytosolic free calcium levels in various cell types [120], and blocking calcium channels [121, 122]. At lower concentrations (1–100 µM), cadmium binds to proteins, decreases DNA repair [123], activates protein degradation, up-regulates cytokines and proto-oncogenes such as c-fos, c-jun, and c-myc [124], and induces expression of several genes including metallothioneins [125], heme oxygenases, glutathione transferases, heat-shock proteins, acute-phase reactants, and DNA polymerase β [126].

Cadmium compounds are classified as human carcinogens by several regulatory agencies. The International Agency for Research on Cancer [91] and the U.S. National Toxicology Program have concluded that there is adequate evidence that cadmium is a human carcinogen. This designation as a human carcinogen is based primarily on repeated findings of an association between occupational cadmium exposure and lung cancer, as well as on very strong rodent data showing the pulmonary system as a target site [91]. Thus, the lung is the most definitively established site of human carcinogenesis from cadmium exposure. Other target tissues of cadmium carcinogenesis in animals include injection sites, adrenals, testes, and the hemopoietic system [91, 108, 109]. In some studies, occupational or environmental cadmium exposure has also been associated with development of cancers of the prostate, kidney, liver, hematopoietic system and stomach [108, 109]. Carcinogenic metals including arsenic, cadmium, chromium, and nickel have all been associated with DNA damage through base pair mutation, deletion, or oxygen radical attack on DNA [126]. Animal studies have demonstrated reproductive and teratogenic effects. Small epidemiologic studies have noted an inverse relationship between cadmium in cord blood, maternal blood or maternal urine and birth weight and length at birth [127, 128].


Environmental Occurrence, Industrial Production and Use

Chromium (Cr) is a naturally occurring element present in the earth’s crust, with oxidation states (or valence states) ranging from chromium (II) to chromium (VI) [129]. Chromium compounds are stable in the trivalent [Cr(III)] form and occur in nature in this state in ores, such as ferrochromite. The hexavalent [Cr(VI)] form is the second-most stable state [28]. Elemental chromium [Cr(0)] does not occur naturally. Chromium enters into various environmental matrices (air, water, and soil) from a wide variety of natural and anthropogenic sources with the largest release coming from industrial establishments. Industries with the largest contribution to chromium release include metal processing, tannery facilities, chromate production, stainless steel welding, and ferrochrome and chrome pigment production. The increase in the environmental concentrations of chromium has been linked to air and wastewater release of chromium, mainly from metallurgical, refractory, and chemical industries. Chromium released into the environment from anthropogenic activity occurs mainly in the hexavalent form [Cr(VI)] [130]. Hexavalent chromium [Cr(VI)] is a toxic industrial pollutant that is classified as human carcinogen by several regulatory and non-regulatory agencies [130132]. The health hazard associated with exposure to chromium depends on its oxidation state, ranging from the low toxicity of the metal form to the high toxicity of the hexavalent form. All Cr(VI)-containing compounds were once thought to be man-made, with only Cr(III) naturally ubiquitous in air, water, soil and biological materials. Recently, however, naturally occurring Cr(VI) has been found in ground and surface waters at values exceeding the World Health Organization limit for drinking water of 50 µg of Cr(VI) per liter [133]. Chromium is widely used in numerous industrial processes and as a result, is a contaminant of many environmental systems [134]. Commercially chromium compounds are used in industrial welding, chrome plating, dyes and pigments, leather tanning and wood preservation. Chromium is also used as anticorrosive in cooking systems and boilers [135, 136].

Potential for Human Exposure

It is estimated that more than 300,000 workers are exposed annually to chromium and chromium-containing compounds in the workplace. In humans and animals, [Cr(III)] is an essential nutrient that plays a role in glucose, fat and protein metabolism by potentiating the action of insulin [5]. However, occupational exposure has been a major concern because of the high risk of Cr-induced diseases in industrial workers occupationally exposed to Cr(VI) [137]. Also, the general human population and some wildlife may also be at risk. It is estimated that 33 tons of total Cr are released annually into the environment [130]. The U.S. Occupational Safety and Health Administration (OSHA) recently set a “safe” level of 5µg/m3, for an 8-hr time-weighted average, even though this revised level may still pose a carcinogenic risk [138]. For the general human population, atmospheric levels range from 1 to 100 ng/cm3[139], but can exceed this range in areas that are close to Cr manufacturing.

Non-occupational exposure occurs via ingestion of chromium containing food and water whereas occupational exposure occurs via inhalation [140]. Chromium concentrations range between 1 and 3000 mg/kg in soil, 5 to 800 µg/L in sea water, and 26 µg/L to 5.2 mg/L in rivers and lakes [129]. Chromium content in foods varies greatly and depends on the processing and preparation. In general, most fresh foods typically contain chromium levels ranging from <10 to 1,300 µg/kg. Present day workers in chromium-related industries can be exposed to chromium concentrations two orders of magnitude higher than the general population [141]. Even though the principal route of human exposure to chromium is through inhalation, and the lung is the primary target organ, significant human exposure to chromium has also been reported to take place through the skin [142, 143]. For example, the widespread incidence of dermatitis noticed among construction workers is attributed to their exposure to chromium present in cement [143]. Occupational and environmental exposure to Cr(VI)-containing compounds is known to cause multiorgan toxicity such as renal damage, allergy and asthma, and cancer of the respiratory tract in humans [5, 144].

Breathing high levels of chromium (VI) can cause irritation to the lining of the nose, and nose ulcers. The main health problems seen in animals following ingestion of chromium (VI) compounds are irritation and ulcers in the stomach and small intestine, anemia, sperm damage and male reproductive system damage. Chromium (III) compounds are much less toxic and do not appear to cause these problems. Some individuals are extremely sensitive to chromium(VI) or chromium(III), allergic reactions consisting of severe redness and swelling of the skin have been noted. An increase in stomach tumors was observed in humans and animals exposed to chromium(VI) in drinking water. Accidental or intentional ingestion of extremely high doses of chromium (VI) compounds by humans has resulted in severe respiratory, cardiovascular, gastrointestinal, hematological, hepatic, renal, and neurological effects as part of the sequelae leading to death or in patients who survived because of medical treatment [141]. Although the evidence of carcinogenicity of chromium in humans and terrestrial mammals seems strong, the mechanism by which it causes cancer is not completely understood [145].

Mechanisms of Toxicity and Carcinogenicity

Major factors governing the toxicity of chromium compounds are oxidation state and solubility. Cr(VI) compounds, which are powerful oxidizing agents and thus tend to be irritating and corrosive, appear to be much more toxic systemically than Cr(III) compounds, given similar amount and solubility [146, 147]. Although the mechanisms of biological interaction are uncertain, the variation in toxicity may be related to the ease with which Cr(VI) can pass through cell membranes and its subsequent intracellular reduction to reactive intermediates. Since Cr(III) is poorly absorbed by any route, the toxicity of chromium is mainly attributable to the Cr(VI) form. It can be absorbed by the lung and gastrointestinal tract, and even to a certain extent by intact skin. The reduction of Cr(VI) is considered as being a detoxification process when it occurs at a distance from the target site for toxic or genotoxic effect while reduction of Cr(VI) may serve to activate chromium toxicity if it takes place in or near the cell nucleus of target organs [148]. If Cr(VI) is reduced to Cr(III) extracellularly, this form of the metal is not readily transported into cells and so toxicity is not observed. The balance that exists between extracellular Cr(VI) and intracellular Cr(III) is what ultimately dictates the amount and rate at which Cr(VI) can enter cells and impart its toxic effects [134].

Cr(VI) enters many types of cells and under physiological conditions can be reduced by hydrogen peroxide (H2O2), glutathione (GSH) reductase, ascorbic acid, and GSH to produce reactive intermediates, including Cr(V), Cr(IV), thiylradicals, hydroxyl radicals, and ultimately, Cr(III). Any of these species could attack DNA, proteins, and membrane lipids, thereby disrupting cellular integrity and functions [149, 150].

Studies with animal models have also reported many harmful effects of Cr (VI) on mammals. Subcutaneous administration of Cr (VI) to rats caused severe progressive proteinuria, urea nitrogen and creatinine, as well as elevation in serum alanine aminotransferase activity and hepatic lipid peroxide formation [151]. Similar studies reported by Gumbleton and Nicholls [152] found that Cr (VI) induced renal damage in rats when administered by single sub-cutaneous injections. Bagchi et al. demonstrated that rats received Cr (VI) orally in water induced hepatic mitochondrial and microsomal lipid peroxidation, as well as enhanced excretion of urinary lipid metabolites including malondialdehyde [153, 154].

Adverse health effects induced by Cr (VI) have also been reported in humans. Epidemiological investigations have reported respiratory cancers in workers occupationally exposed to Cr (VI)-containing compounds [142, 148]. DNA strand breaks in peripheral lymphocytes and lipid peroxidation products in urine observed in chromium-exposed workers also support the evidence of Cr (VI)-induced toxicity to humans [155, 156]. Oxidative damage is considered to be the underlying cause of these genotoxic effects including chromosomal abnormalities [157, 158], and DNA strand breaks [159]. Nevertheless, recent studies indicate a biological relevance of non-oxidative mechanisms in Cr(VI) carcinogenesis [160].

Carcinogenicity appears to be associated with the inhalation of the less soluble/insoluble Cr(VI) compounds. The toxicology of Cr(VI) does not reside with the elemental form. It varies greatly among a wide variety of very different Cr(VI) compounds [161]. Epidemiological evidence strongly points to Cr(VI) as the agent in carcinogenesis. Solubility and other characteristics of chromium, such as size, crystal modification, surface charge, and the ability to be phagocytized might be important in determining cancer risk [135].

Studies in our laboratory have indicated that chromium (VI) is cytotoxic and able to induce DNA damaging effects such as chromosomal abnormalities [162], DNA strand breaks, DNA fragmentation and oxidative stress in Sprague-Dawley rats and human liver carcinoma cells [27, 28]. Recently, our laboratory has also demonstrated that chromium (VI) induces biochemical, genotoxic and histopathologic effects in liver and kidney of goldfish, carassius auratus [163].

Various hypotheses have been proposed to explain the carcinogenicity of chromium and its salts, however some inherent difficulties exist when discussing metal carcinogenesis. A metal cannot be classified as carcinogenic per se since its different compounds may have different potencies. Because of the multiple chemical exposure in industrial establishments, it is difficult from an epidemiological standpoint to relate the carcinogenic effect to a single compound. Thus, the carcinogenic risk must often be related to a process or to a group of metal compounds rather than to a single substance. Differences in carcinogenic potential are related not only to different chemical forms of the same metal but also to the particle size of the inhaled aerosol and to physical characteristics of the particle such as surface charge and crystal modification [164].


Environmental Occurrence, Industrial Production and Use

Lead is a naturally occurring bluish-gray metal present in small amounts in the earth’s crust. Although lead occurs naturally in the environment, anthropogenic activities such as fossil fuels burning, mining, and manufacturing contribute to the release of high concentrations. Lead has many different industrial, agricultural and domestic applications. It is currently used in the production of lead-acid batteries, ammunitions, metal products (solder and pipes), and devices to shield X-rays. An estimated 1.52 million metric tons of lead were used for various industrial applications in the United Stated in 2004. Of that amount, lead-acid batteries production accounted for 83 percent, and the remaining usage covered a range of products such as ammunitions (3.5 percent), oxides for paint, glass, pigments and chemicals (2.6 percent), and sheet lead (1.7 percent) [165, 166].

In recent years, the industrial use of lead has been significantly reduced from paints and ceramic products, caulking, and pipe solder [167]. Despite this progress, it has been reported that among 16.4 million United States homes with more than one child younger than 6 years per household, 25% of homes still had significant amounts of lead-contaminated deteriorated paint, dust, or adjacent bare soil [168]. Lead in dust and soil often re-contaminates cleaned houses [169] and contributes to elevating blood lead concentrations in children who play on bare, contaminated soil [170]. Today, the largest source of lead poisoning in children comes from dust and chips from deteriorating lead paint on interior surfaces [171]. Children who live in homes with deteriorating lead paint can achieve blood lead concentrations of 20µg/dL or greater [172].

Potential for Human Exposure

Exposure to lead occurs mainly via inhalation of lead-contaminated dust particles or aerosols, and ingestion of lead-contaminated food, water, and paints [173, 174]. Adults absorb 35 to 50% of lead through drinking water and the absorption rate for children may be greater than 50%. Lead absorption is influenced by factors such as age and physiological status. In the human body, the greatest percentage of lead is taken into the kidney, followed by the liver and the other soft tissues such as heart and brain, however, the lead in the skeleton represents the major body fraction [175]. The nervous system is the most vulnerable target of lead poisoning. Headache, poor attention spam, irritability, loss of memory and dullness are the early symptoms of the effects of lead exposure on the central nervous system [170, 173].

Since the late 1970’s, lead exposure has decreased significantly as a result of multiple efforts including the elimination of lead in gasoline, and the reduction of lead levels in residential paints, food and drink cans, and plumbing systems [173, 174]. Several federal programs implemented by state and local health governments have not only focused on banning lead in gasoline, paint and soldered cans, but have also supported screening programs for lead poisoning in children and lead abatement in housing [167]. Despite the progress in these programs, human exposure to lead remains a serious health problem [176, 177]. Lead is the most systemic toxicant that affects several organs in the body including the kidneys, liver, central nervous system, hematopoetic system, endocrine system, and reproductive system [173].

Lead exposure usually results from lead in deteriorating household paints, lead in the work place, lead in crystals and ceramic containers that leaches into water and food, lead use in hobbies, and lead use in some traditional medicines and cosmetics [167, 174]. Several studies conducted by the National Health and Nutrition Examination surveys (NHANES) have measured blood lead levels in the U.S. populations and have assessed the magnitude of lead exposure by age, gender, race, income and degree of urbanization [176]. Although the results of these surveys have demonstrated a general decline in blood lead levels since the 1970s, they have also shown that large populations of children continue to have elevated blood lead levels (> 10µg/dL). Hence, lead poisoning remains one of the most common pediatric health problems in the United States today [167, 173, 174, 176179]. Exposure to lead is of special concern among women particularly during pregnancy. Lead absorbed by the pregnant mother is readily transferred to the developing fetus [180]. Human evidence corroborates animal findings [181], linking prenatal exposure to lead with reduced birth weight and preterm delivery [182], and with neuro-developmental abnormalities in offspring [183].

Molecular Mechanisms of Toxicity and Carcinogenicity

There are many published studies that have documented the adverse effects of lead in children and the adult population. In children, these studies have shown an association between blood level poisoning and diminished intelligence, lower intelligence quotient-IQ, delayed or impaired neurobehavioral development, decreased hearing acuity, speech and language handicaps, growth retardation, poor attention span, and anti social and diligent behaviors [178, 179, 184, 185]. In the adult population, reproductive effects, such as decreased sperm count in men and spontaneous abortions in women have been associated with high lead exposure [186, 187]. Acute exposure to lead induces brain damage, kidney damage, and gastrointestinal diseases, while chronic exposure may cause adverse effects on the blood, central nervous system, blood pressure, kidneys, and vitamin D metabolism [173, 174, 178, 179, 184187].

One of the major mechanisms by which lead exerts its toxic effect is through biochemical processes that include lead’s ability to inhibit or mimic the actions of calcium and to interact with proteins [173]. Within the skeleton, lead is incorporated into the mineral in place of calcium. Lead binds to biological molecules and thereby interfering with their function by a number of mechanisms. Lead binds to sulfhydryl and amide groups of enzymes, altering their configuration and diminishing their activities. Lead may also compete with essential metallic cations for binding sites, inhibiting enzyme activity, or altering the transport of essential cations such as calcium [188]. Many investigators have demonstrated that lead intoxication induces a cellular damage mediated by the formation of reactive oxygen species (ROS) [189]. In addition, Jiun and Hseien [190] demonstrated that the levels of malondialdehyde (MDA) in blood strongly correlate with lead concentration in the blood of exposed workers. Other studies showed that the activities of antioxidant enzymes, including superoxide dismutase (SOD), and glutathione peroxidase in erythrocytes of workers exposed to lead are remarkably higher than that in non-exposed workers [191]. A series of recent studies in our laboratory demonstrated that lead-induced toxicity and apoptosis in human cancer cells involved several cellular and molecular processes including induction of cell death and oxidative stress [29, 192], transcriptional activation of stress genes [30], DNA damage [29], externalization of phosphatidylserine and activation of caspase-3 [193].

A large body of research has indicated that lead acts by interfering with calcium-dependent processes related to neuronal signaling and intracellular signal transduction. Lead perturbs intracellular calcium cycling, altering releasability of organelle stores, such as endoplasmic reticulum and mitochondria [194, 195]. In some cases lead inhibits calcium-dependent events, including calcium-dependent release of several neurotransmitters and receptor-coupled ionophores in glutamatergic neurons [196]. In other cases lead appears to augment calcium-dependent events, such as protein kinase C and calmodulin [194, 197].

Experimental studies have indicated that lead is potentially carcinogenic, inducing renal tumors in rats and mice [198, 199], and is therefore considered by the IARC as a probable human carcinogen [200]. Lead exposure is also known to induce gene mutations and sister chromatid exchanges [201, 202], morphological transformations in cultured rodent cells [203], and to enhance anchorage independence in diploid human fibroblasts [204]. In vitro and in vivo studies indicated that lead compounds cause genetic damage through various indirect mechanisms that include inhibition of DNA synthesis and repair, oxidative damage, and interaction with DNA-binding proteins and tumor suppressor proteins. Studies by Roy and his group showed that lead acetate induced mutagenicity at a toxic dose at the E. coli gpt locus transfected to V79 cells [205]. They also reported that toxic doses of lead acetate and lead nitrate induced DNA breaks at the E. coli gpt locus transfected to V79 cells [205]. Another study by Wise and his collaborators found no evidence for direct genotoxic or DNA-damaging effects of lead except for lead chromate. They pointed out that the genotoxicity may be due to hexavalent chromate rather than lead [206].


Environmental Occurrence, Industrial Production and Use

Mercury is a heavy metal belonging to the transition element series of the periodic table. It is unique in that it exists or is found in nature in three forms (elemental, inorganic, and organic), with each having its own profile of toxicity [207]. At room temperature elemental mercury exists as a liquid which has a high vapor pressure and is released into the environment as mercury vapor. Mercury also exists as a cation with oxidation states of +1 (mercurous) or +2 (mercuric) [208]. Methylmercury is the most frequently encountered compound of the organic form found in the environment, and is formed as a result of the methylation of inorganic (mercuric) forms of mercury by microorganisms found in soil and water [209].

Mercury is a widespread environmental toxicant and pollutant which induces severe alterations in the body tissues and causes a wide range of adverse health effects [210]. Both humans and animals are exposed to various chemical forms of mercury in the environment. These include elemental mercury vapor (Hg0), inorganic mercurous (Hg+1), mercuric (Hg+2), and the organic mercury compounds [211]. Because mercury is ubiquitous in the environment, humans, plants and animals are all unable to avoid exposure to some form of mercury [212].

Mercury is utilized in the electrical industry (switches, thermostats, batteries), dentistry (dental amalgams), and numerous industrial processes including the production of caustic soda, in nuclear reactors, as antifungal agents for wood processing, as a solvent for reactive and precious metal, and as a preservative of pharmaceutical products [213]. The industrial demand for mercury peaked in 1964 and began to sharply decline between 1980 and 1994 as a result of federal bans on mercury additives in paints, pesticides, and the reduction of its use in batteries [214].

Potential for Human Exposure

Humans are exposed to all forms of mercury through accidents, environmental pollution, food contamination, dental care, preventive medical practices, industrial and agricultural operations, and occupational operations [215]. The major sources of chronic, low level mercury exposure are dental amalgams and fish consumption. Mercury enters water as a natural process of off-gassing from the earth’s crust and also through industrial pollution [216]. Algae and bacteria methylate the mercury entering the waterways. Methyl mercury then makes its way through the food chain into fish, shellfish, and eventually into humans [217].

The two most highly absorbed species are elemental mercury (Hg0) and methyl mercury (MeHg). Dental amalgams contain over 50% elemental mercury [218]. The elemental vapor is highly lipophilic and is effectively absorbed through the lungs and tissues lining the mouth. After Hg0 enters the blood, it rapidly passes through cell membranes, which include both the blood-brain barrier and the placental barrier [219]. Once it gains entry into the cell, Hg0 is oxidized and becomes highly reactive Hg2+. Methyl mercury derived from eating fish is readily absorbed in the gastrointestinal tract and because of its lipid solubility, can easily cross both the placental and blood-brain barriers. Once mercury is absorbed it has a very low excretion rate. A major proportion of what is absorbed accumulates in the kidneys, neurological tissue and the liver. All forms of mercury are toxic and their effects include gastrointestinal toxicity, neurotoxicity, and nephrotoxicity [213].

Molecular Mechanisms of Mercury Toxicity and Carcingenicity

The molecular mechanisms of toxicity of mercury are based on its chemical activity and biological features which suggest that oxidative stress is involved in its toxicity [220]. Through oxidative stress mercury has shown mechanisms of sulfhydryl reactivity. Once in the cell both Hg2+ and MeHg form covalent bonds with cysteine residues of proteins and deplete cellular antioxidants. Antioxidant enzymes serve as a line of cellular defense against mercury compounds [221]. The interaction of mercury compounds suggests the production of oxidative damage through the accumulation of reactive oxygen species (ROS) which would normally be eliminated by cellular antioxidants.

In eukaryotic organisms the primary site for the production of reactive oxygen species (ROS) occurs in the mitochondria through normal metabolism [222]. Inorganic mercury has been reported to increase the production of these ROS by causing defects in oxidative phosphorylation and electron transport at the ubiquinone-cytochrome b5 step [223]. Through the acceleration of the rate of electron transfer in the electron transport chain in the mitochondria, mercury induces the premature shedding of electrons to molecular oxygen which causes an increase in the generation of reactive oxygen species [224].

Oxidative stress appears to also have an effect on calcium homeostasis. The role of calcium in the activation of proteases, endonucleases and phospholipases is well established. The activation of phospholipase A2 has been shown to result in an increase in reactive oxygen species through the increase generation of arachidonic acid. Arachidonic acid has also been shown to be an important target of reactive oxygen species [225]. Both organic and inorganic mercury have been shown to alter calcium homeostasis but through different mechanisms. Organic mercury compounds (MeHg) are believed to increase intracellular calcium by accelerating the influx of calcium from the extracellular medium and mobilizing intracellular stores, while inorganic mercury (Hg2+) compounds increase intracellular calcium stores only through the influx of calcium from the extracellular medium [226]. Mercury compounds have also been shown to induce increased levels of MDA in both the livers, kidneys, lungs and testes of rats treated with HgCl2 [227]. This increase in concentration was shown to correlate with the severity of hepatotoxicity and nephrotoxicity [228]. HgCl2-induced lipid peroxidation was shown to be significantly reduced by antioxidant pretreatment with selenium. Selenium has been shown to achieve this protective effect through direct binding to mercury or serving as a cofactor for glutathione peroxidase and facilitating its ability to scavenge ROS [229]. Vitamin E has also been reported to protect against HgCl2-induced lipid peroxidation in the liver [230].

Metal-induced carcinogenicity has been a research subject of great public health interest. Generally, carcinogenesis is considered to have three stages including initiation, promotion, and progression and metastasis. Although mutations of DNA, which can activate oncogenesis or inhibit tumor suppression, were traditionally thought to be crucial factors for the initiation of carcinogenesis, recent studies have demonstrated that other molecular events such as transcription activation, signal transduction, oncogene amplification, and recombination, also constitute significant contributing factors [231, 232]. Studies have shown that mercury and other toxic metals effect cellular organelles and adversely affect their biologic functions [231, 233]. Accumulating evidence also suggests that ROS play a major role in the mediation of metal-induced cellular responses and carcinogenesis [234236].

The connection between mercury exposure and carcinogenesis is very controversial. While some studies have confirmed its genotoxic potential, others have not shown an association between mercury exposure and genotoxic damage [237]. In studies implicating mercury as a genotoxic agent, oxidative stress has been described has the molecular mechanism of toxicity. Hence, mercury has been shown to induce the formation of ROS known to cause DNA damage in cells, a process which can lead to the initiation of carcinogenic processes [238, 239]. The direct action of these free radicals on nucleic acids may generate genetic mutations. Although mercury-containing compounds are not mutagenic in bacterial assays, inorganic mercury has been shown to induce mutational events in eukaryotic cell lines with doses as low as 0.5 µM [240]. These free radicals may also induce conformational changes in proteins that are responsible for DNA repair, mitotic spindle, and chromosomal segregation [241]. To combat these effects, cells have antioxidant mechanisms that work to correct and avoid the formation of ROS (free radicals) in excess. These antioxidant mechanisms involve low molecular weight compounds such as vitamins C and E, melatonin, glutathione, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase that protect the cells by chelating mercury and reducing its oxidative stress potential [242].

Glutathione levels in human populations exposed to methylmercury intoxication by eating contaminated fish have been shown to be higher than normal [243]. These studies were also able to confirm a direct and positive correlation between mercury and glutathione levels in blood. They also confirmed an increased mitotic index and polyploidal aberrations associated with mercury exposure [243]. Epidemiological studies have demonstrated that enzymatic activity was altered in populations exposed to mercury; producing genotoxic alterations, and suggesting that both chronic and relatively low level mercury exposures may inhibit enzyme activity and induce oxidative stress in the cells [244]. There is no doubt that the connection between mercury exposure and carcinogenesis is very controversial. However, in-vitro studies suggest that the susceptibility to DNA damage exists as a result of cellular exposure to mercury. These studies also indicate that mercury-induced toxicity and carcinogenicity may be cell-, organ- and/or species- specific.


A comprehensive analysis of published data indicates that heavy metals such as arsenic cadmium, chromium, lead, and mercury, occur naturally. However, anthropogenic activities contribute significantly to environmental contamination. These metals are systemic toxicants known to induce adverse health effects in humans, including cardiovascular diseases, developmental abnormalities, neurologic and neurobehavioral disorders, diabetes, hearing loss, hematologic and immunologic disorders, and various types of cancer. The main pathways of exposure include ingestion, inhalation, and dermal contact.

Lung Cancer genes

lung-cancer-genesMolecular Profiling of Lung Cancer

Lung cancer is the leading cause of cancer related mortality in the United States, with an estimated 224,390 new cases and 158,080 deaths anticipated in 2016 (ACS 2016). Classically, treatment decisions have been empiric and based upon histology of the tumor. Platinum based chemotherapy remains the cornerstone of treatment. However, survival rates remain low. Novel therapies and treatment strategies are needed.

Lung cancer is comprised of two main histologic subtypes: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Over the past decade, it has become evident that subsets of NSCLC can be further defined at the molecular level by recurrent ‘driver’ mutations that occur in multiple oncogenes, including AKT1, ALK, BRAF, EGFR, HER2, KRAS, MEK1, MET, NRAS, PIK3CA, RET, and ROS1 (Table 1). Another altered kinase gene involves MET. ‘Driver’ mutations lead to constitutive activation of mutant signaling proteins that induce and sustain tumorigenesis. These mutations are rarely found concurrently in the same tumor. Mutations can be found in all NSCLC histologies (including adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma) and in current, former, and never smokers (defined by individuals who smoked less than 100 cigarettes in a lifetime). Never smokers with adenocarcinoma have the highest incidence of EGFR, HER2, ALK, RET, and ROS1 mutations. Importantly, targeted small molecule inhibitors are currently available or being developed for specific molecularly defined subsets of lung cancer patients.

Historically, efforts at characterizing the molecular underpinnings of SCC of the lung have lagged behind those of adenocarcinoma of the lung. Many of the ‘driver’ mutations found in lung adenocarcinoma are only rarely found in lung SCC. Moreover, newer agents, such as bevacizumab (Avastin) and pemetrexed (Alimta) are not approved for or exhibit diminished efficacy in SCC (Sandler et al. 2006; Scagliotti et al. 2008). Thus, patients with metastatic SCC have fewer treatment options than those with non-squamous NSCLC. Despite these caveats, however, ‘driver’ mutations that may be linked to outcomes with targeted therapies in SCC are emerging. Altered genes include FGFR1 and DDR2 as well as PIK3CA. In addition, results from a recent large genomic study in lung SCC have added a variety of potential therapeutic targets that await validation in prospective clinical trials (Hammerman et al. 2012).

The following text is meant to provide a broad overview of several of the oncogenes known to be important for lung cancer pathogenesis. Where possible, the presence of a specific mutation is correlated to clinical parameters as well as response to both conventional chemotherapy and targeted agents. At present, only data for treatment of advanced (stage IIIB/IV) disease is presented.

Table 1. Frequency of Mutations and Availability of Targeted Therapies in NSCLC.

Gene Alteration Frequency in NSCLC
AKT1 Mutation 1%
ALK Rearrangement 3–7%
BRAF Mutation 1–3%
DDR2 Mutation ~4%
EGFR Mutation 10–35%
FGFR1 Amplification 20%
HER2 Mutation 2–4%
KRAS Mutation 15–25%
MEK1 Mutation 1%
METa Amplification 2–4%
NRAS Mutation 1%
PIK3CA Mutation 1–3%
PTEN Mutation 4–8%
RET Rearrangement 1%
ROS1a Rearrangement 1%

Drugs approved in NSCLC.
Drugs approved in NSCLC but for other molecular subtype.
Drugs approved in other cancer.
Drugs in clinical development.

Note: a Crizotinib is a dual ALK/MET tyrosine kinase inhibitor which is currently FDA approved for ALK positive and ROS1 positive NSCLC. However, there is a case report of a patient with NSCLC harboring MET amplification who responded to this agent (Ou et al. 2011). In addition, one patient with NSCLC harboring a ROS1 gene rearrangement had a partial response to crizotinib, which has ‘off-target’ anti-ROS1 activity (Bergethon et al. 2012).


Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2016. Molecular Profiling of Lung Cancer. My Cancer Genome (Updated March 28).

Last Updated: March 28, 2016

Disclaimer: The information presented at is compiled from sources believed to be reliable. Extensive efforts have been made to make this information as accurate and as up-to-date as possible. However, the accuracy and completeness of this information cannot be guaranteed. Despite our best efforts, this information may contain typographical errors and omissions. The contents are to be used only as a guide, and health care providers should employ sound clinical judgment in interpreting this information for individual patient care.

Lung cancer in the Philippines

In the Philippines, cancer ranks third in leading causes of morbidity and mortality after communicable diseases and cardiovascular diseases (Department of Health–Health Intelligence Service or DOH–HIS, 1992, 1996) (1). Over the period 1942–96, communicable disease mortality has shown a gradually decreasing trend, in contrast to the increasing trends of heart disease and cancer (non-communicable diseases).

In the Philippines, 75% of all cancers occur after age 50 years, and only about 3% occur at age 14 years and below. If the current low cancer prevention consciousness persists, it is estimated that for every 1800 Filipinos, one will develop cancer annually. At present, most Filipino cancer patients seek medical advice only when symptomatic or at advanced stages: for every two new cancer cases diagnosed annually, one will die within the year.

The Philippine Cancer Control Program, begun in 1988, is an integrated approach utilizing primary, secondary and tertiary prevention in different regions of the country at both hospital and community levels. Six leading cancers (lung, breast, liver, cervix, oral cavity, colon and rectum) are discussed.


The top cancer sites in the Philippines include those cancers whose major causes are known (where action can therefore be taken for primary prevention), such as cancers of the lung/larynx (anti-smoking campaign), liver (vaccination against hepatitis B virus), cervix (safe sex) and colon/rectum/stomach (healthy diet). Except for the liver, the top Philippine cancer sites are also the top cancers worldwide.

Survival from Cancer in the Philippines

The survival experience, regardless of treatment, of patients with top cancer sites diagnosed in 1987 and included in the DOH–RCR was evaluated as the first population-based survival data for Filipinos (5). Lung cancer had the lowest survival and breast cancer had the highest (Table 4). Five-year survival in excess of 40% was observed for only three cancer sites: oral cavity, colon and breast. For all other sites, survival was less than 30%. Owing to the small number of cases in each category, no distinct impact of age on relative survival could be perceived for most cancer sites. However, both observed and relative survival rates were low for breast cancer patients less than 35 years old.

A study in 1999 (11) estimated 17.9 million Filipinos to have a history of smoking (46.5% of the adult population). At least another 26.4 million are passive smokers. The economic burden resulting from lung cancer, chronic obstructive pulmonary disease, coronary artery disease and cerebrovascular disease adds up to approximately US$ 1 billion (59% from health care costs, 39% from premature deaths and 2% from productivity loss).

Second-hand smoking, effects to non-smokers

The group renewed its call for stricter implementation of tobacco control measures in the country that will address the many dangers of smoking, including its effect on non-smokers.

The call comes as the World Health Organization (WHO) on Friday, February 27 celebrated the 10th anniversary of the Framework Convention on Tobacco Control (FCTC), of which the Philippines is a signatory.

Among other tobacco control measures, the FCTC calls for protection from exposure to tobacco smoke.

Yet despite the Philippines’ Tobacco Regulation Act of 2003 (Republic Act 9211), the figures are still alarming: 24 million Filipinos are exposed to tobacco smoke every day, with 66.7% inhaling second-hand smoke at work, and 75.7% in places without an anti-tobacco policy.

Citing the Philippine Cancer Society, NVAP said 3,000 Filipinos die of lung cancer each year because of second-hand smoke. Lung cancer is the leading cause of cancer deaths in the Philippines and worldwide. (READ: What you should know about lung cancer).

Air pollution in Manila

air pi.JPG

Lung cancer – top cancer in the Philippines

Dietary needs of toxic lungs

Avoid the following to create an anti-fungal or anti-mold diet that helps detox your lungs

  • Alcoholic beverages: Alcohol is the mycotoxin of Saccharomyces yeast (brewer’s yeast), and often contains other mycotoxins from mold-containing fruits and grains
  • Wheat and all wheat products
  • Rye
  • Peanuts: Often contaminated with dozens of mold types, one of which is cancer-causing aflatoxin (also in 4-day old RICE)
  • Cottonseed and cottonseed oil
  • Corn: Universally contaminated with a variety of fungal toxins
  • Barley
  • Sorghum: Used in a variety of grain products and alcoholic beverages
  • Sugar from sugar cane and sugar beets
  • Hard cheeses. Discard dairy.

What to eat

  • Include probiotics such as pickled veggies and probiotic such as raw garlic.

Garlic is a potent antifungal, antibacterial, antiviral, immune system stimulant, and detoxification agent. Garlic also helps clean out the respiratory tract. The best form is raw, whole garlic, rather than a supplement derived from garlic, as it is the synergism of the whole food that makes it so clinically active. Eat the cloves whole, or run them through your juicer alongside your veggies.

Garlic has remained a staple for various natural health practices because of its anti-inflammatory properties. The high level of allicin reduces inflammation and fight infection. It destroys free radicals and may help to improve asthma. It can help to reduce the risk for lung cancer.

  • Increase intake of Vitamin C and/or Vit C rich foods such as citrus/lemons.

Rosemary herb (rich in Vit C, like lemon and citrus fruits) and add the following ingredients in your salad: bunch watercress, cucumber, turnip, large carrots, clove garlic, lemon and mint leaves.

  • Green papaya added in soups of chicken broth/grass-fed beef.

My father drink a juice of green papaya and green apples during her bout with lung cancer.

  • Ginger

Ginger is also an antifungal and antibacterial. It helps dislodge congestion in your respiratory tract, and is also a great digestive aid. Ginger also makes a great addition to fresh juice.

This spice is incredibly easy to incorporate into your meal for an added flavor and health boost. The anti-inflammatory function clears your lungs of lingering pollution that could lead to health issues. You may also be interested to read my article how to use ginger as a medicine for great health.

  • Cayenne

Cayenne is a catalyst for the other herbs.

  • Goldenseal

Goldenseal, with its active ingredient berberine, has antibacterial and immune-enhancing properties. However, it should not be used for long periods of time.

  • Lifestyle: The best way to avoid most chemicals, GMOs, artificial sweeteners, high fructose corn syrup (HFCS), excess sugar and bad salt is to eliminate junk and processed foods and sodas. Minimize meat, dairy and wheat to reduce excess mucus. Adding ginger, onions, garlic and cayenne helps eliminate excess mucus as well.
  • Exercise more outdoors, away from traffic if possible. Breathing exercises can be used to help strengthen lung tissue. Yoga offers some, and there are others as well. Natural News has a plethora of information here (
  • Eliminate household toxins that are part of detergents, cleansers, bleaches and chemically scented “air fresheners” (

There are many chemical free substitutes available at health food stores, even Target has a few on hand. Ditto for cosmetics and bodycare products. Buy only aluminum free deodorants for starters.

Pesticides must go as well, and there are alternatives that aren’t toxic for humans.

All toxic commercial pesticides emit caustic gases or vapors (off-gassing) that irritate the lungs.

  • Improve your indoor air, which can be even worse than outdoor air. Try to replace carpeting with other flooring or at least vacuum and steam clean often. Beware of furniture or clothing that’s been fire proofed. Flame retardants off-gas carcinogenic compounds.

You may want to look into commercial air cleaners . Or simply get some nice indoor plants that add life to your dwelling while removing toxins .

  • Herbal remedies for lung issues are abundant. You’ll need to determine which type of herb is appropriate for your situation.

Antitussive herbs reduce respiratory spasms; expectorant herbs loosen mucus; demulcent herbs sooth irritated tissue; and antimicrobial herbs resolve infections.

  •  Detoxing is necessary for any regeneration or rebuilding. Eliminating or reducing your toxic load relieves your immune system and allows the process of growing new tissue to occur.
  • Cilantro foods such as chlorella and cilantro consumed often can help detoxify heavy metals, especially from the liver. Zeolite in its raw powder form (not liquid) is very useful.
  • Make sure you drink plenty of purified fluoride free water and find ways to sweat more. If you can, use a far infrared sauna somewhere; you’ll have the best level of sauna. But conventional sauna’s still do the job.
  • Serrapeptase enzymes are very powerful enzymes capable of eating up scar tissue, heavily calcified tissue or hardened mucus deposits. It provided a dramatic turn-around for a British emphysema patient a few years ago.
  • Cruciferous Vegetables

A cruciferous vegetable is any food that is a member of the cabbage family. They are generally packed with antioxidants that naturally help your body cleanse toxins. Some of the most popular choices for people pursuing lung health is broccoli, cauliflower, and cabbage. Read also my article about the incredible health benefits of cruciferous vegetables.

  • Foods With Carotenoids

Carotenoid is an orange antioxidant pigment that have been shown to cut the risks of developing lung cancer.  Carotenoids are found in fruits and vegetables characterized with orange or red colors. Carrots are a great option because of the beta-carotene in them. This antioxidant is converted to vitamin A which can help reduce the incident of asthma.

Bring on the green tea! Drink carrot juice.  Get your potassium kick.  Load on the antioxidants.

  • Foods With Omega-3 Fatty Acids

This fatty acid is crucial for your overall health. Preliminary studies suggest that foods that are rich in the fatty acid have beneficial effect on asthma. If you can’t get enough of it through fish, nuts or flaxseed, try taking one of the many supplements available. See also my article about the amazing health benefits of omega 3 fish oil. Taking omega 3 is also one of the 70 habits featured in my e-book 70 Powerful Habits For A Great Health which will guide you how to take positive steps to improve your wellness and overall health.

  • Foods With Folate

These foods are great for fighting the process of lung carcinogens and preventing forms of cancer. Some great choices include spinach, asparagus, beets, and lentils.

  • Foods With Vitamin C

Foods that contain high amounts of vitamin C help your lungs effectively transport oxygen throughout the body. Foods that are good sources of vitamin C and popular choices for lung health are: kiwifruit, red and green capsicums (bell peppers), citrus fruits like oranges, lemons, and grapefruits, vegetable and tomato juice, strawberries, broccoli, pineapples, mango and cantaloupe melon.

  • Berries

Berries are one of the richest antioxidant fruits, containing the polyphenols anthocyanins and the flavonoids beta-carotene, lutein and zeaxanthin. These antioxidants protect your lungs from cancer, disease and infection. Livestrong website mentions that fruit juice that contains dark berries such as raspberries, blackberries or blueberries, may help to reduce the risk of developing lung cancer. You can find more information about the amazing healing properties of berries in my e-book The Healing Berry Guide. This e-book will teach you how to transform your health with berries, and is a must for berry lovers.

  • Apples

Now we have yet another use for this nutrient packed fruit. The flavonoids and variety of vitamins maintain healthy respiratory function and prevent the development of lung diseases. Apple is also one of the superfoods mentioned in my e-book about superfoods which is part of the Natural Health Revolution Program. This program will help you to achieve your health, nutrition and weight loss goals.

  • Turmeric

This spice is similar to ginger in its lung health benefits with anti-inflammatory properties. As an added bonus the high amounts of curcumin can lead to the elimination of cancer cells. Find here more about the fantastic health benefits of turmeric.

  • Grapefruit

If you can stomach the bitter taste of this fruit, you will benefit from the wealth of lung supporting vitamins and minerals in it. Health experts suggest that the flavonoids in the fruit are great for cleaning out lungs that have been effected by carcinogens. DO NOT TAKE WITH MEDICATIONS.

  • Pomegranates

This fruit contains many antioxidants that are good to include into your diet. The nutritionally dense properties of this tasty fruit can slow down the development of lung issues including tumor development.

  • Foods With Magnesium

Magnesium is a mineral that is commonly recommended to people who suffer from asthma issues. It can increase lung capacity and build on the efficiency of the respiratory process. An easy way to get this mineral is through seeds, nuts, or beans.

  • Water

Once again, when it comes to natural health the number one remedy will usually be water. Though it may seem bland, our bodies crave it for many different reasons. More water in your diet can make your circulatory process working while keeping your lungs hydrated and ready to flush out unwanted toxins.

  • ASupplements
    • Glutathione is mentioned by Kurt and Lee Ann Billings as being helpful. Glutathione is your body’s most powerful antioxidant and has even been called the “master antioxidant” because it maximizes the activity of all the other antioxidants. The best way to increase your glutathione level is by consuming a high quality whey protein. It should be cold pressed, undenatured, derived from grass-fed cows, and free of hormones, chemicals and sugar.
    • Omega-3 fats are also very important, from a mixture of plant and animal sources. The best source of animal-based omega-3s comes from krill oil.
    • Artichoke leaf extract: A study published in the Journal of Agricultural Food Chemistry in 20044 found that extract of artichoke leaf was toxic to many types of fungi, including both molds and yeasts.
    • Vitamin D: Research suggests vitamin D may prevent mold allergies, so make sure your vitamin D levels are optimal.
  • Herbs

    Licorice root is one that pretty much covers all those attributes. It can create side effects for some because of its glycyrrhizin content. But licorice extract products are available with the glycyrrhizin removed. This is known as deglycyrrhizinated licorice or DGL licorice.  Lobelia, ironically known as Indian tobacco, helps clear the airways for easier breathing. It even works for asthma attacks (

  • Amino Acids for lung disease

According to some researchers and there are a few amino acids for lung disease that exist and may help such issues. COPD (chronic obstructive pulmonary disease) is one of these lung conditions may be aided by amino acid supplements; in particular, those with even severe COPD. This lung disease affects the ability to breath and also reduces energy levels in those who have it. COPD may have different causes, but it can be a result of smoking cigarettes long term, as well as conditions such as emphysema. 

According to one study by RW Dal Negro, A Testa, et al., in Italy it was amino acids for lung disease that helped the patients with COPD. By supplementing COPD patients with certain essential amino acids they were able to determine if pulmonary rehabilitation might have improved health status and produce higher rates of physical performance.

Essential amino acids are several of the 22 commonly known amino acids. “Essential” means that they have to be gotten through diet since the body cannot produce them on its own. The list of essential amino acids may include:Valine, Threonine, Methionine, Leucine, Isoleucine, Phenylalanine, Tryptophan, Lysine, and Histidine.

Amino acids for lung disease – chronic COPD

A total of 88 COPD out-patients who had a 23 BMI (body mass index) or less were selected randomly to receive essential amino acids for lung disease (COPD) for a period of three months. After 12 weeks of the test period the patients receiving amino acids for lung disease had showed significant improvements in physical performance.

Also, the COPD patients scored higher on the SGRQ score (which measures breathing). Additionally, other areas were affected positively, as compared to the placebo group, who had taken the essential amino acids for lung disease (COPD), including improvements in: fat-free mass, serum albumin, increased muscle strength, oxygen saturation, and cognitive dysfunction.

The results produced greater confidence levels in the patients and the researchers for improvements in these symptoms that COPD usually negatively affects its patients. Essential amino acids may, then, help reduce symptoms of COPD, so it is clear that amino acids for lung disease can aid the patient in breathing easier as well as help their physical performance in a number of areas.


Lung disease: COPD among white and black women

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Change in death rate among white women in the USA:

  • Klamath, OR: +16%
  • Dallas, TX: +20%
  • SF: -29%
  • LA: -18%
  • Tulsa OK: +20%
  • Salt Lake, UT: +9%
  • Fresno, CA: +8%
  • Santa Clara: -15%

44% History of Asthma ; 38% smokers

10M white women with COPD, 1.4M Black women, 1M Hispanic women

1991-1995: Heart disease death rate: Asian, white, black and Hispanic women (shown in the pictures above)

Dr Axe wrote:

  • Eucalyptus oil can be very helpful for people with COPD. A study in Respiratory Research showed that cineole, the main constituent of eucalyptus essential oil, actually reduced exacerbations in people with COPD. It also reduced dyspnea (shortness of breath), and improved lung function as well as health status overall. Furthermore, the research suggested that cineole is an active controller and reducer of airway inflammation in COPD. To get the benefits of cineole, you can use eucalyptus oil in a diffuser and/or humidifier and breath in the anti-inflammatory air.
  • Consume Ginseng: Ginseng is an herbal supplement that improves lung function and also decrease bacteria in the lungs. Panax ginseng in particular has a long history of use in Chinese medicine for respiratory conditions, including asthma and COPD.  A recent study published in the journal Complementary Therapies in Medicine highlighted therapeutic ginseng benefits. Panax ginseng and ginsenosides (active components of ginseng) appear to inhibit processes related to the development of COPD. (10)
  • Take N-Acetylcysteine (NAC): Supplementing with NAC helps decrease the severity and frequency of asthma attacks and improves overall lung function by increasing glutathione levels and thinning bronchial mucus. Glutathione fights against oxidative stress in the respiratory tract, which can make NAC a powerful and effective natural treatment for COPD.  Inhaled Nebulized Glutathione


Dr. Jonathan V. Wright from the Tahoma Medical Clinic wrote about COPD in the August 2002 “Nutrition and Healing”  COPD Natural Treatments Jonathan V Wright Aug 2002.  The mainstay of his treatment for COPD is nebulized glutathione, a natural treatment which restores glutathione levels to the lung tissue.

Altered Glutathione Levels is Primary Abnormality in COPD

“Alterations in alveolar and lung GSH (glutathione) metabolism are widely recognized as a central feature of many inflammatory lung diseases including chronic obstructive pulmonary disease (COPD).”  (14)

Inhaled Glutathione: Inhaled Glutathione may be taken in a nebulizer.  Originally, the glutathione is made up by a compounding phamacy and shipped to the user.  “Inhaled glutathione requires a prescription and is available from compounding pharmacies such as McGuff Compounding Pharmacy and Wellness Pharmacy. The usual starting dose is 300 mg of glutathione (200 mg/cc, draw 1.5 cc and place in nebulizer) twice a day.  ” (7)  Quote from Julian Whitaker’s newsletter (7).

Glutathione capsules: A more practical method has been devised by Dr Bishop, using capsules.  (Glutathione  capsules from Thera Naturals ) .  Dr. Sircus wrote an article on  Glutathione & Bicarbonate Nebulization using the Glutathione capsules.

Clark T. Bishop, M.D. devised this protocol: Protocol for Augmentation of GSH Levels in Cystic Fibrosis Patients, and Related Information.  Here is a clinical study on the use of Glutathione: by Dr Alfredo Visca, and Clark Bishop, et al. Improvement in clinical markers in CF patients using a reduced glutathione Clark Bishop 2008  Journal of Cystic Fibrosis 7.5 (2008): 433-436.  (8-12)

SSKI to Liquify Secretions: 004001 SSKI (Potassium Iodide Oral Solution, USP), 1gm per mL, 240mL Dropper Bottle McGuffMedical.comThe second treatment is SSKI to liquify secretions and allow clearance of mucous,  SSKI stands for super saturated potassium iodine, an old remedy which works quite well.  Although SSKI has been available at the corner drug store for over 80 years, and is generally considered safe, iodine can suppress thyroid function with an increase in the TSH lab value on thyroid testing.  This elevation of TSH is usually temporary and returns to normal after discontinuing the SSKI. (6)    There is much misinformation or disinformation about the safety of SSKI (see this news report).  The elevation of TSH from SSKI is not life  threatening and is of little or no clinical consequence.  As with most other medical treatments, it is best to work with a knowledgeable doctor who can monitor thyroid function while under treatment.   Left image bottle of SSKI courtesy of McGuff medical Supply.

Resveratrol:  An extract from grapes, Resveratrol, is useful in COPD. see: Antioxidant and anti-inflammatory effects of resveratrol in airway disease. by Wood .   “We conclude that resveratrol has potential as a therapeutic agent in respiratory disease”.  Buy Resveratrol.

Dr Wright’s List of recommended treatments for COPD

  • 120-200 milligrams of nebulized, inhaled Glutathione, two times per day
  • 500 milligrams of N-acetylcysteine, three times per day
  • 30 milligrams of Zinc Picolinate per day
  • Three to six drops of potassium iodide (SSKI) per day
  • 200-400 milligrams of Goldenseal twice a day
  • 2 grams of vitamin C twice a day
  • 300-400 milligrams of Magnesium per day (in the form of magnesium citrate, aspartate, taurate, or glycinate)
  • 50,000 units of vitamin A per day
  • 1 1/2 tablespoons of lecithin per day
  • 1 1/2 tablespoons of flaxseed oil per day
  • 400-600 units of vitamin E per day
  • 2 milligrams of copper glycinate per day
  • multiple vitamin-mineral supplement

Serrapeptidase: mucolytic enzyme shown to be useful in COPD.  see:

Effect of the proteolytic enzyme Serrapeptase in patients with chronic airway disease. by Nakamura S Department of Respiratory Medicine, Tokyo. Respirology. 2003 Sep;8(3):316-20.

Oregano Oil Joy of the Mountains Oregano Oil: Oregano Oil has antimicrobial and anti-inflammatory qualities, and is of use in COPD to prevent pulmonary infection and reduce pulmonary inflammation.

The Oregano oil may be diluted in juice or mixed with olive oil to dilute further.  Start with one drop and gradually work up as tolerates.  Some people report good results with inhaled organo oil in a steamer or nebulizer.  However use with caution as the oil may be very strong undiluted.

Useful Books on Natural Treatments for COPD

  • Natural Therapies for COPD and Emphysema: Natural Therapies for Emphysema and COPD: Relief and Healing for Chronic Pulmonary Disorders April 4, 2007, by Robert J. Green Jr.

Credit and Thanks goes to Dr. Jonathan Wright and Dr Julian Whitaker for much of the information in this article.

Jeffrey Dach MD

7450 Griffin Road Suite 190

Davie, Fl 33314


Links and References

  • 2001 Jun;119(6):1661-70. Salmeterol plus theophylline combination therapy in the treatment of COPD. ZuWallack RL1, Mahler DA, Reilly D, Church N, Emmett A, Rickard K, Knobil K.


Patients with COPD often require multiple therapies to improve lung function and decrease symptoms and exacerbations. Salmeterol and theophylline are indicated for the treatment of COPD, but the use of these agents in combination has not been extensively studied.

OBJECTIVES:  To compare the efficacy and safety of salmeterol plus theophylline vs either agent alone in COPD.

METHODS:  Randomized, double-blind, double-dummy, parallel-group trial in 943 patients with COPD. After an open-label theophylline titration period (serum levels, 10 to 20 microg/mL), patients were randomly assigned to receive salmeterol (42 microg bid) plus theophylline, salmeterol (42 microg bid), or theophylline for 12 weeks. Serial pulmonary function tests were completed on day 1 and treatment week 12. Patients kept diary cards and noted their peak flow rates, symptom scores, and albuterol use, and periodically completed quality-of-life and dyspnea questionnaires.

RESULTS:  All three groups significantly improved compared with baseline. Combination treatment with salmeterol plus theophylline provided significantly (p < or = 0.045) greater improvements in pulmonary function; significantly (p < or = 0.048) greater decreases in symptoms, dyspnea, and albuterol use; and significantly fewer COPD exacerbations (p = 0.023 vs theophylline). In general, treatment with salmeterol provided greater improvement in lung function and satisfaction with treatment compared with theophylline. Salmeterol treatment was also associated with significantly fewer drug-related adverse events (p < or = 0.042) than either treatment that included theophylline. The safety profile (adverse events, vital signs, and ECG findings) of the two treatments that included theophylline were similar.

CONCLUSION:  Patients with COPD may benefit from combination treatment with salmeterol plus theophylline, without a resulting increase in adverse events or other adverse sequelae.

Links and References

  • Medications for COPD: A Review of Effectiveness. GIL C. GRIMES, MD; JOHN L. MANNING, MD; PARITA PATEL, MD, and R. MARC VIA, MD Texas A&M University Health Science Center, Temple, Texas Am Fam Physician. 2007 Oct 15;76(8):1141-1148.
  • James F. Donohue “Combination Therapy for Chronic Obstructive Pulmonary Disease“, Proceedings of the American Thoracic Society, Vol. 2, SYMPOSIUM: THE SCIENCE OF COPD: OPPORTUNITIES FOR COMBINATION THERAPY (2005), pp. 272-281.
  • Thorax 1999;54:730-736 doi:10.1136/thx.54.8.730
  • Long acting β2 agonists and theophylline in stable chronic obstructive pulmonary disease Mario Cazzola, Claudio Ferdinando Donner, Maria Gabriella Matera
  • Nebulized Glutathione for Emphysema Davis Lamson Alt Med Review 2000: a Case Report Davis W. Lamson, ND, Matthew S. Brignall, ND
  • Alternative Medicine Review. 2000;5(5):429-431)
  • JUBIZ, WILLIAM, SHIRLEY CARLILE, and LYNN D. LAGERQUIST. “Serum thyrotropin and thyroid hormone levels in humans receiving chronic potassium iodide.” The Journal of Clinical Endocrinology & Metabolism 44.2 (1977): 379-382.
  • Natural Treatments for COPD by Dr. Julian Whitaker:
  • Inhaled glutathione requires a prescription and is available from compounding pharmacies such as McGuff Compounding Pharmacy and Wellness Pharmacy. The usual starting dose is 300 mg of glutathione (200 mg/cc, draw 1.5 cc and place in nebulizer) twice a day.
  • Help for COPD Julian Whitaker, MD ;
  • Glutathione Articles – COPD (Chronic Obstructive Pulmonary Disease) & Lung Disorders
  • Glutathione & Bicarbonate Nebulization Posted by Dr Sircus on December 9, 2010 | Filed under Glutathione, Medicine, Sodium Bicarbonate (Baking Soda) ; Reduced L Glutathione Plus Thera Naturals
  • Clark T. Bishop, M.D.: Protocol for Augmentation of GSH Levels in Cystic Fibrosis Patients, and Related Information
  • Visca, Alfredo, et al. Improvement in clinical markers in CF patients using a reduced glutathione Clark Bishop 2008 “Improvement in clinical markers in CF patients using a reduced glutathione regimen: an uncontrolled, observational study.” Journal of Cystic Fibrosis 7.5 (2008): 433-436.
  • Leonard Nimoy, Also Known As Dr. Spock Dies of COPD 30 Years After Giving UP Smoking –
  • Lung glutathione and oxidative stress: implications in cigarette smoke-induced airway disease. Irfan Rahman , William MacNee
  • American Journal of Physiology – Lung Cellular and Molecular Physiology Published 1 December 1999 Vol. 277 no. 6, L1067-L1088
  • Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many inflammatory lung diseases including chronic obstructive pulmonary disease (COPD).

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Source:  Jeffrey Dach