2A - Triad 4 and 1 - Smith - XX-B - Nov12 [Read-Only]glvhealth.com/LargeFiles/Mod 20b CD/6 Slides BW/2A... · Sources of Environmental Toxins • The large chemical load on the environment

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Triad 4: Stacking with Triad 1The Role of Environmental Pollutants in Disrupting

Thyroid‐Adrenal‐Pancreas Relationships

Pamela W. Smith, M.D., MPHThe following potential conflict of interest relationships are

germane to my presentation.

Equipment: NoneSpeakers Bureau: PCCA, Spectracell, ZRT & Orthomolecular

Stock Shareholder: NoneGrant/Research Support: None

Consultant: CustomVite, Pathway & Thorne

Status of FDA devices used for the material being presented: NA/Non‐Clinical

Status of off‐label use of devices, drugs or other materials that constitute the subject of this presentation: NA/Non‐Clinical

Module XX‐BEnvironmental Toxins

Pamela W. Smith, M.D., MPH, MS

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Copyright © 2012 James B. LaValle, Integrative Health Resources, LLC.

All rights reserved. No part of this material may be used or reproduced in any manner whatsoever, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior permission of the author.

This material is provided for educational and informational purposes only to licensed health care professionals. This information is obtained from sources believed to be reliable, but its accuracy cannot be guaranteed. Herbs and other natural substances are very powerful and can occasionally cause dangerous allergic reactions in a small percentage of the population. Licensed health care professionals should rely on sound professional judgment when recommending herbs and natural medicines to specific individuals. Individual use of herbs and natural medicines should be supervised by an appropriate health care professional. The use of any specific product should always be in accordance with the manufacturer's directions.

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Toxic Exposure

• According to the EPA, more than 4 billion pounds of chemicals were released into the ground in the year 2000, threatening the natural ground water sources.

• The average American unknowingly eats about 124 pounds of additives a year.

• Each year over 2.5 billion pounds of pesticides are dumped on crop lands, forests, lawns, and fields.– The Importance of Detoxification, Advanced Nutritional Publications, Inc., 2002.

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Exposure To Toxins Is Increased By

• Eating a diet high in processed foods and fat

• Drinking tap water

• Excessive consumption of caffeine containing beverages

• Excessive alcohol consumption

• Tobacco use

• Chronic use of medication6

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Exposure To Toxins Is Increased By (Cont.)

• Lack of exercise

• Liver dysfunction

• Kidney problems

• Intestinal dysfunction

• Occupational exposure

• Using pesticides, paint, and other toxic substances without adequate protective gear

• Living or working near areas of high vehicle traffic or industrial plants

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Sources of Environmental Toxins

• The large chemical load on the environment is due to many years of chemical exposure from food, water, and contaminated air.

• The EPA since 1976 has conducted a study called the National Human Adipose Tissue Survey (NHATS).– Environmental Protection Agency, Office of Toxic Substances, EPA‐560/5‐86‐035, Broad scan analysis of the FY82 National Human Adipose Tissue Survey specimens. Washington, DC: EPA, 1986.

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Sources of Environmental Toxins (Cont.)

• In 1982 the EPA expanded its list to look for 54 environmental chemical toxins.

• Five chemicals were present in all of the samples.

– Octachlorodibenzo‐p‐dioxin (OCDD)

– Styrene

– 1,4, dichlorobenzene

– Xylene

– Ethylphenol

• Ibid., EPA9


• Nine other chemicals were found in more than 90% of the samples.– Benzene

– Toluene

– Chlorobenzene

– Ethylbenzene

– Dichlorodiphenyldicholoroethylene (DDE)

– Three dioxins

– One furan• Ibid., EPA.

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• Also found in the study in greater than 80%

– Polychlorinated biphenyl (PCB)

– Beta‐benzene hexachloride (BHC)

• Ibid., EPA.

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• A study from the CDC showed that cadmium, cesium, cobalt, lead, mercury, and thallium were present in almost all of the samples that they took which were from healthy people and had no known exposure to chemicals besides the environment.– National report on human exposure to environmental chemicals. Department of Health and Human Services, Centers for Disease Control. March 2001.

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• The load of xenobiotics has also been examined.

• This study tested more compounds in each person than any previous study.

• It tested for 210 xenobiotics and found 167.

• The average number was 91.

– Houlihan, J., et al., “Body burden, the pollution in people,” http://www.ewg.org/reports/bodyburden/index.php (accessed October 17, 2011).

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• Studies looking at chemical residues on foods have not found any foods chemical free.

• Foods with the highest level of DDE– Fresh or frozen spinach

– Butter

– Collards

– Pork sausage

– Lamb chops

– Canned spinach14

Reference

– Gunderson, E., FDA diet survey, April 1982‐April 1986, dietary intakes of pesticides, selected elements and other chemicals. Washington, DC: Food and Drug Administration, Division of Contaminants Chemistry.

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Sources of Environmental Toxins

• DDT and DDE were banned in the U.S. in 1972. Some of the high levels may be due to residual pesticide and some may be contamination from food brought in from other countries.

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Common Environmental Toxins

• Organohalogens are chemicals that are very persistent in the environment and in the human body.

• Major sources of organohalogens– Organochlorine pesticides e.g., DDT (dichlorodiphenyltrichloroethane)

– Polychlorinated biphenyls (PCBs)– Polybrominated diphenyl ethers (PBDEs)– Plastic residues– Dioxins– Organic byproducts of water chlorination

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Reference

– Crinnion, W., Environmental Medicine. In Pizzorno, J., et al. (Eds). Textbook of Natural Medicine. St. Louis: Elsevier, 2006, p. 339‐353.

– Lyon, M., Functional Toxicology. In Pizzorno, J., et al. (Eds). Textbook of Natural Medicine. St. Louis: Elsevier, 2006, p. 593‐607.

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Xenobiotics

• A xenobiotic is a chemical which found in an organism which is not usually produced or expected to be present in it.

• The term can also cover substances that are in higher concentrations than what they are usually found.

• The term also refers to toxins such as dioxins and polychlorinated biphenyls.

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Mechanisms of Toxic Injury

• Xenobiotic‐initiated injury usually affects three targets.

– Alter, remove or impair the synthesis of specific molecules‐‐‐e.g., glutathione

– Alter structural entities—e.g., mitochondria

– Create disturbances in cell signaling‐‐‐e.g., cytokines

• Ibid., Lyon.

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Biotransformation

• Many metals, drugs, and xenobiotics undergo biotransformation before being excreted from the body.

• Biotransformation commonly involves phase I and phase II detoxification in the liver.

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The Detoxification Process

• Detoxification is a process by which the body transforms toxins and medications into harmless molecules that can be eliminated.

• It takes place primarily in the liver and to a smaller degree in other tissues.

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Detoxification Is Accomplished In Two Phases

• Phase I—Certain enzymes change toxins into intermediate compounds

• Phase II—Other enzymes convert the intermediate compounds created in Phase I into harmless molecules that are eliminated by the body.

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Phase I• Enzymes in the cytochrome P‐450 system use oxygen to modify toxic compounds, medications, and steroid hormones.

• This is the first line of defense for the detoxification of all environmental toxins, medications, supplements including vitamins, as well as many waste products that the body produces.

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Reference

– Fortney, L., Detoxification. In Rakel, D., (Ed.) Integrative Medicine. 3rd Ed., Philadelphia: Elsevier, 2012, p. 923.

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Phase I (Cont.)

• Occurs in the liver and usually involved oxidation

• May also involve demethylation, hydroxylation, or dehalogenation

• If there is increased Phase I clearance without increased Phase II clearance, this can lead to the build up of intermediates that may be more toxic than the original substance.

• Decreased Phase I clearance will cause toxic accumulation in the body.

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Phase I (Cont.)

• Adverse drug reactions can be due to decreased clearance of Phase I.

• Within the genetic makeup are variations called single nucleotide polymorphisms, (SNPs).

• SNPs code for a particular enzyme that can increase or decrease the activity of that enzyme.

• Therefore, SNPs may increase or decrease the clearance rate. Both can be toxic.

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References

– Ibid., Lyon.

– Guengerich, F., “Role of cytochrome P450 in drug‐drug interactions,” Adv Pharmacol 1997; 43:7‐35.

– Schuetz E., “Induction of cytochromes P450,” CurrDrug Metabl 2001; 2:139‐47.

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Phase I Detoxification Requires

• Niacin

• Magnesium

• Copper

• Zinc

• Vitamin C

• Vitamins B2, B3, B6, B12

• Folic acid

• Flavonoids30

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Phase II

• In this phase large water‐soluble molecules are added to toxins, usually at the reactive site formed by Phase I reactions.

• After Phase II modifications, the body is able to eliminate the transformed toxins in the urine or the feces.

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Reference

– Ibid., Fortney.

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Phase II Detoxification Has Six Phases

• Glutathione conjugation

• Amino acid conjugation

• Methylation

• Sulfation

• Acetylation

• Glucuronidation

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Glutathione Conjugation

• Glutathione is the strongest antioxidant that the body makes

• Requires glutathione and B6

• Conjugates with organic xenobiotics and heavy metals to eliminate them from the body

• Makes toxic substances more water soluble and allows them to be excreted via the bile or kidney.

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Glutathione Conjugation (Cont.)

• If mercury accumulates in the hepatocytes, the excretion of mercury and other toxic substances is decreased.

– Gregus, Z., et al., “Role of glutathione and hepatic glutathione S‐transferase in the biliary excretion of methyl mercury, cadmium and zinc: a study with enzyme inducers and glutathione depletors,” ActaPharmacol Toxicol (Copenh) 1985; 56:298‐403.

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• Supplementing with alpha lipoic acid increases the level of intracellular glutathione if there is adequate sulfur amino acid intake present.

– Ibid., Lyons.

– Han, D., et al., “Lipoic acid increases de novo synthesis of cellular glutathione by improving cysteine utilization,” Biofactors 1997; 6:321‐38.

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• Undenatured whey protein which is rich in glutathione precursors can increase cellular plasma glutathione.

– Ibid., Lyon.

– Micke, P., et al., “Effects of long‐term supplementation with whey proteins on plasma glutathione levels of HIV‐infected patients,” EurJour Nutr 2002; 41:12‐8.

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Amino Acid Conjugation

• Requires glycine, taurine, and glutamine

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Methylation

• Needed for many reactions in the body

• Requires folic acid, choline, methionine, trimethylglycine, s‐adenosylmethionine(SAMe)

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Sulfation

• Requires cysteine, methionine, and molybdenum

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Acetylation

• Requires acetyl CoA

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Glucuronidation

• Requires glucuronic acid

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References

– Birdsall, T., “Therapeutic applications of taurine,” Altern Med Rev 1998; 3:129‐136.

– Kelly, G., “Clinical applications of N‐acetylcysteine,” Altern Med Rev 1998; 3:114‐27.

– Gregus, Z., et al., “Dependence of glycine conjugation on availability of glycine: role of the glycine cleavage system,” Xenobiotica 1993; 23:141‐53.

– Hong, R., et al., “Glutamine preserves liver glutathione after lethal hepatic injury,” Ann Surg 1992; 215:114‐19.

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Upregulation of Phase II

• Cruciferous vegetables significantly increase phase 2 enzyme activity.

– Ibid., Lyon.

– Nho, C., et al., “The synergistic upregulation of phase II detoxification enzymes by glucosinolatebreakdown products in cruciferous vegetables,” Toxicol Appl Pharmacol 2001; 174:146‐52.

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Antioxidants and Liver Detoxification

• Antioxidants also play a major role in liver detoxification by decreasing oxidative stress which results from phase I activity and preventing glutathione consumption by ROS.

– Milk thistle

– Curcumin

– Green tea

• Ibid. Lyon.

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References

– Zhao, J., et al., “Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: implications in cancer chemoprevention,” Carcinogenesis 1999; 20:2101‐08.

– Rukkumani, R., et al., “Comparative effects of curcumin and an analog of curcumin on alcohol and PUFA induced oxidative stress,” Jour Pharm Pharm Sci2004; 7:274‐83.

– Cai, Y., et al., “Antioxidant effects of green tea polyphenols on free radical initiated peroxidation of rat liver microsomes,” Chem Phys Lipids 2002; 120:109‐17.

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Toxic Response

• Nutritional and environmental factors also can modify a patients susceptibility to environmental toxins.

• These factors for detoxification may be very modifiable when it comes to nutrition, environment, and lifestyle factors.

– Ibid., Lyon.

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Toxic Response (Cont.)

• High carbohydrate diets downregulate P450 system which may decrease the reduction in the metabolism of drugs and hormones.

– Guengerich, R., “Role of cytochrome P450 enzymes in drug‐drug interactions,” AdvPharmacol 1997; 43:7‐35.

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Other Nutritional Factors and Detoxification

• Intestinal dysbiosis inhibits the P450 system.– Veihelmann, A., et al., “Inhibition of nitric oxide synthesis improves detoxification in inflammatory liver dysfunction in vivo,” Amer Jour Physiol 1997; 273:G53‐36.

• Supplementing with probiotics reduces the effects of bacterial endotoxins on the liver along with decreases gut permeability.– Nanji, As., et al., “Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease),” Proc Soc Exp Biol med 1994; 205:243‐47.

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Other Nutritional Factors and Detoxification (Cont.)

• Some dietary fibers enhance the activity of both phase I and phase II.

– Roland, NM., et al., “Hepatic and intestinal cytochrome P‐450, glutathione‐S‐transferase and UDP‐glucuronosyl transferase are affected by six types of dietary fiber in rats inoculated with human whole fecal flora,” Jour Nutr 1994; 124:1581‐87.

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Other Nutritional Factors and Detoxification (Cont.)

• Fiber also decreases stool transit time which aids in the sequestration of conjugated xenobiotics and endobiotics located in the bile and reduces the amount of bacterial deconjugating enzymes in the stool.

• All of these reduce the recycling of xenobioticsand endobiotics throughout the enterohepaticcirculation.

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References

– Ibid., Lyon.

– Reddy, B., et al., “Effect of dietary fiber on colonic bacterial enzymes and bile acids in relation to colon cancer,” Gastroenterology 1992; 102:1475‐82.

– Story, J., et al., “Dietary fiber and bile acid metabolism‐‐‐an update,” Adv Exp Med Biol 1997; 427:259‐66.

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Exercise and Detoxification

• Exercise, along with adequate calories and protein, has been shown to increase detoxification.

• Exercise has also been shown to increase antioxidant enzymes.

• Exercise also increases reduced glutathione.

– Ibid., Lyon.

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References

– Leeuwenburghm C., et al., “Adaptations of glutathione antioxidant system to endurance training are tissue and muscle fiber specific,” Amer Jour Physiol 1997; 272:R363‐69.

– Yiamouyiannis, C., et al., “Chronic physical activity: hepatic hypertrophy and increased total biotransformation enzyme activity,” BiochemPharmacol 1992; 44:121‐27.

– Duncan, K., et al., “Running exercise may reduce risk for lung and liver cancer by inducing activity of antioxidant and phase II enzymes,” Cancer Lett 1997; 116:151‐58.

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• Exercise also mobilizes extracellular fluid and lymph where xenobiotics may tend to accumulate after being released from the cells.

• Sweating also increases the detox mechanisms of the liver.

• Exercise also aids in the elimination of organic and metallic toxicants.– Ibid., Lyon.

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References

– Schnare, S., et al., “reduction of the human body burdens of hexachlorobenzene and polychlorinated biphenyls,” IARC Sci Pub 1986; 77:596‐603.

– Schnare, D., et al., “Evaluation of a detoxification regimen for fat stored xenobiotics,” med Hypotheses 1982; 9:265‐82.

– Lovejoy, H., et al., “Mercury exposure evaluations and their correlation with urine mercury excretions,” 4. Elimination of mercury by sweating,” Jour Occup Med 1973; 15:590‐91.

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• Exercise may be helpful to accelerate the movement of mercury from the extracellular fluid through the lymph and into the bloodstream.

– Ibid, Lyon.

• Hyperthermic therapy with a sauna may also help mobilize mercury.

– Ibid., Lovejoy.58

Toxic Response

• There are a significant number of genetic polymorphisms that determine the patients ability to detoxify.– This subject will be covered fully in module XXII: Genomics and Proteonomics.

• Some toxins act in a simple manner, where others are multifunctional with a large pattern of induction and inhibition, or both, of several phase I and phase II enzyme systems.

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Summary of Phase I and Phase II

• Phase I and Phase II enzymes are the engines that run the detoxification process.

• They are fueled by vitamins, minerals, and other key food components.

• Therefore, if one is undernourished or lacks key vitamins or nutrients, they may not be able to adequately detoxify.

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Toxic Exposure History

• Community– City and neighborhood air quality, noise, electromagnetic fields

• Home– Home heating and ventilation, cleaning chemicals, pesticides, paints, carpets, building materials, molds, allergens, water

• Hobbies– Toxic chemicals, paints, solvents, metal fumes

• Ibid., Lyon.

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Toxic Exposure History (Cont.)

• Occupation– Workplace air quality, toxic chemicals

• Personal habits– Smoking, drinking, drug use, sun exposure exercise, stress management

• Diet– Overall quality of diet, amount of food consumed, organic or not, fast foods, snacks, deep‐fried foods, fish or seafood, meat or not, food allergies, or intolerances, leaky gut syndrome, abnormal gut flora

• Ibid., Lyon. 62

Toxic Exposure History (Cont.)

• Drugs– Prescription, OTC, recreational

• Dental– Amalgams placed and removed, extractions, root canals

• Development– Mother’s pregnancy and exposures, childhood exposures

• Ibid., Lyon.

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Symptoms of Dysfunctional Detoxification

• The symptoms of a dysfunction of the body’s ability to detoxify may be vague and not specific.

• It is important to rule out a serious medical condition causing that may cause these symptoms as well.

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Symptoms of Dysfunctional Detoxification (Cont.)

• Fatigue with sleep disruption and brain fog

• Mood disturbance, especially depression, anxiety, fear, and anger

• Muscle aches and joint pain

• Sinus congestion, dark circles under the eyes, and postnasal drip

• Headaches with neck and shoulder pain

• Bloating and gas

• Irritable bowel, foul‐smelling stools and dark urine

• Weight changes and loss of muscle tone

– Ibid., Fortney.65

Symptoms of Dysfunctional Detoxification (Cont.)

• Heartburn

• Infertility and low libido

• Premature aging and weakness

• Fluid retention and excess weight

• Rash and canker sores

• Bad breath

• Body odor

• Recurrent colds and persistent infections

• Recurrent colds and persistent infections

– Ibid., Fortney.

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Detoxification Testing

• Detoxification of Phase I and Phase II can be measured.

• SNPs can be evaluated.– For example, CYP3A4, affects an enzyme that the body uses to detoxify over 50% of all drugs.

– These medications include many antidepressants, steroid hormones, and cholesterol lowering medications.

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Heavy Metal Intoxication

• Toxic metals like cadmium, mercury, lead, aluminum, and nickel poison the intracellular enzymatic systems that keep the body working optimally.

• They are not biodegradable.

• They have a high affinity for sulfhydryl (SH) groups and consequently displace essential metals like zinc and selenium from the active sites of proteins.

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Heavy Metal Intoxication (Cont.)

• Enzymatic dysfunction can occur (e.g., GSH‐Px) with suppression of the following

– Protein synthesis

– Inhibition of mitochondrial enzymes

– Production of free radicals

• Grober, U., Micronutrients. Stuttgard, Germany, 2009, p. 357‐59.

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Heavy Metal Intoxication (Cont.)

• Heavy metal intoxication also

– Destroys the architecture of cell membranes and mitochondria which may result in the following

• Increase in DNA damage and cancer

• Neuron decay and cognitive decline

• Mitochondrial decay with accelerated aging and degenerative diseases

– Ibid., Grober.

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Sources of Heavy Metals

• Vehicle exhaust fumes (lead)

• Lead piping

• Aluminum‐based antacids

• Aluminum pots and pans

• Sachets of instant coffee

• Canned food

• Fish

• Mussels

• Shellfish

• Pesticides

• Dental amalgams (mercury)

• Cigarettes (cadmium)• Ibid., Grober.

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Toxicity of Heavy Metals

• Furthermore, metals that are not nutrient may bind to molecular areas where they are involved in inappropriate catalytic activities including the generation of free radicals.

– Stohs, S., et al., “Oxidative mechanisms in the toxicity of metal ions,” Free Radic Biol Med 1995; 18:321‐36.

– Ibid., Lyons.

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Reference

– Gregus, Z., et al., “Role of glutathione and hepatic glutathione S‐transferase in the biliary excretion of methyl mercury, cadmium and zinc: a study with enzyme inducers and glutathione depletors,” ActaPharmacol Toxic (Copenh) 1985; 56:398‐403.

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Toxins and the Thyroid Gland

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PCBs, Dioxins, Furans

• Are all highly persistent, lipophilic, organochlorine pollutants.

• About 90% of exposure from intake—mainly meat, fish, dairy

• Breast feeding accounts for 12%‐14% of exposure

• Can affect the ability to convert T4 to T3

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Reference

– Patandin, S., et al., “Dietary exposure to polychlorinated biphenyls and dioxins from infancy until adulthood: a comparison between breast‐feeding toddler, and long‐term exposure,” Environ Health Perspect 1999; 107:45‐51.

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Polybrominated Biphenyls (PBBs)

• An increase in rate of primary hypothyroidism has been shown in a group of workers exposed to PBBs.

– Bahn, A., et., al., “Hypothyroidism in workers exposed to polybrominated biphenyls,” NEJM 1980; 310:31‐3.

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TCDD

• In another study, elevated levels of free T4 index were seen in workers with exposed to the highest body burdens of 2,3,7,8‐TCDD which is a dioxin‐like compound.

– Calvert, G., et al., “Evaluation of diabetes mellitus, serum glucose, and thyroid function among United States workers exposed to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin,” Occup Environ Med 1999; 56:270‐76.

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Polychlorinated Biphenyls

• Hydroxylated metabolites of various polychlorinated biphenyls compete with endogenous ligands for non‐receptor transport proteins

• Binds transthyretin which disrupts thyroid homeostasis

– Ibid., Luderer.

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Thiocyanates and Perchlorates

• Thiocyanates and perchlorates inhibit thyroid synthesis by blocking iodine uptake into the thyroid gland.– Ibid., Luderer.

• Perchlorate contamination of drinking water – Reduced T4

– Increased TSH in newborns• Brechner, R., et al., “Ammonium perchlorate contamination of Colorado river drinking water is associated with abnormal thyroid function in newborns in Arizona,” Jour Occup Environ Med 2000; 42:777‐82.

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Lithium

• Suppresses thyroid hormone release

• Inhibits cyclic AMP‐mediated effects of TSH

– Ibid., Luderer.

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Inhibit Organification of Iodine

• Cobalt

• Cyclic organic compounds

– Substituted phenols

• Ibid., Luderer.

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Thiocyanate

• Chronic cyanide exposure seen in electroplating workers caused an accumulation of thiocyante.

– Decreases free T3

– Decreases free T4

– Elevates TSH

• Banerjee, K., et al., “Evaluation of cyanide exposure and its effects on thyroid function of workers in a cable industry,” Jour Occup Environ Med 1997; 39:258‐60.

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Compounds Associated with Hypothyroidism

• Lead• Carbon disulfide• Polybrominated biphenyls (PBBs)• Polychlorinated biphenyls (PCBs)

– Enhances T4 glucuronidation which increases excretion of thyroid hormone

– Binds to serum thyroid hormone transport proteins

• Dioxins• DDT


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Compounds Associated with Hypothyroidism (Cont.)

• Furans

– Ibid., Luderer.

• Chloroacetanilides (herbicides)


• Methoxychlor (organochlorine insecticide)

– Inhibition of peripheral T4 deiodination

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References

– Ibid., Luderer.– Cheek, A., et al., “Potential mechanisms of action of thyroid disruption in humans: interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid‐binding globulin,” Environ Health Perspect 1999; 107:273‐78.

– Zhou, L., et al., “Cytochrome P450 catalyzed binding of methoxychlor to rat hepatic microsomal iodothyronine 5’‐monodeiodinase, type 1: does exposure to metoxychlor disrupt thyroid hormone metabolism.” Arch Biochem Biophys 1995; 322:390‐94.

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PBBs

• Accidental exposure to PBBs in Michigan in farming communities in the 1970s revealed an increase in non‐goitrogenic thyroid dysfunction.

– Had increase in thyroid antibodies

• Bahn, A., et al., “Hypothyroidism in workers exposed to polybrominated biphenyls,” NEJM 1980; 302:31‐3.

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PCBs

• Study people exposed to PCBs (‘Yusho rice oil’) contaminated with PCBs 16 years earlier.

– Elevated free T3

– Elevated free T4

– TSH normal

– Normal thyroid antibodies

• Murai, K., et al., “Thyroid function in “Yusho” patients exposed to polychlorinated biphenyls (PCB),” Environ Res 1987; 44:179‐87. 88

PCBs (Cont.)

• Human studies are conflicting.

• Recent study of employees in a former PCB plant showed an increase in thyroid volume and increase in positive antibodies.

• No difference in free T4 or TSH was seen.

– Langer, P., et al., “Increased thyroid volume and prevalence of thyroid disorders in an area heavily polluted by polychlorinated biphenyls,” Eur Jour Endocrinol 1998; 139:402‐09. 89

PCBs (Cont.)

• Animal studies there is no conflicting data.

• Studies show a decrease of free T4 by PCBs.

– Ibid., Cheek.

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PCBs (Cont.)

• Study on children revealed a negative relationship between serum PCB levels and serum levels of free T3.

• The same study revealed a positive correlation with TSH.

– Osius, Ns., et al., “Exposure to polychlorinated biphenyls and levels of thyroid hormones in children,” Environ Health Perspect 1999; 107:843‐49.

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PCBs (Cont.)

• Animal study showed that maternal PCB exposure caused lower T4 and T3 levels in fetal brains.

• Motor deficits and impaired learning were also recognized.– Sher, E., et al., “The effects of thyroid hormone level and action in developing brain: are there targets for the actions of polychlorinated biphenyls and dioxins? Toxicol Ind Health 1998; 14:121‐58.

– Porterfield, S., et al., “Impact of PCBs on thyroid hormone directed brain development,” Toxicol IndHealth 1998; 14:103‐20.

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PCBs and Dioxins

• Study showed a positive correlation between breast milk PCBs and dioxins and neonatal TSH, but there was no correlation with TSH.

– Koopman‐Esseboom, C., et al., “Effects of polychlorinated biphenyl/dioxin exposure and feeding type of infants’ mental and psychomotor development,” Pediatrics 1996; 97:700‐06.

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Dioxins

• Study with people exposure to TCDD showed a positive correlation with T4 and free T4 index, but not TSH or thyroid disease.

• This study was done on workers that were exposed to TCDD 15 years earlier.– Calvert, G., et al., “Evaluation of diabetes mellitus, serum glucose, and thyroid function among United States workers exposed to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin,” Occup Environ Med 1999; 56:270‐76.

• Ibid., Luderer.

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Dioxins (Cont.)

• Another study showed an association between serum TCDD concentration and T4 but not TSH in chemical workers.

– Suskind, R., et al., “Human health effects of 2,4,5‐T and its toxic contaminants,” JAMA 1984; 251:2372‐80.

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Dioxins (Cont.)

• Yet another study—this one done on Vietnam veterans exposed to TCDD in Agent Orange.

• Free T4 index did not show any change.

– Ibid., Calvert.

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Cobalt

• Studies were done on women that were exposed to cobalt‐based paints.

– Dose‐related elevation of T4

– Dose‐related elevation of free T4

– Dose‐related elevation of the T4‐to‐T3 ratio.

– No change in TSH or pituitary function was seen

• Results suggest reduced peripheral deiodination of T4 to T3.

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References

– Prescott, E., et al., “Effect of occupational exposure to cobalt blue dyes on the thyroid volume and function of female plate painters,” Scand Jour Work Environ Health 1992; 18:101‐04.

– Christensen, J., et al., “A 1982‐1992 surveillance programme on Danish pottery painters. Biologic levels health effects of following exposure to soluble or insoluble cobalt compounds in cobalt dyes,” Sci Total Environ 1994; 150:95‐104.

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Other Chemicals

• Thyroid dysfunction has been seen also related to the following chemicals– Organophosphates

– Carbamates

– Organochlorines

– Fungicides

– Food colorants

– Mercury• Capen, C., “Mechanisms of chemical injury to the thyroid gland,” Prog Clin Biol Res 1994; 387:173‐91.

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Mercury

• Is one of the most toxic substances

– Clarkson, T., “The toxicology of mercury,” Crit Rev Clin Lab Sci 1997; 34:369‐403.

• When mercury enters the cell it becomes covalently bound to the sulfhydryl groups found in glutathione.

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Mercury (Cont.)

• Mercury binds to a less amount to

– Cysteine

– Biotin

– Lipoic acid

– Coenzyme A

• Ibid., Lyon.

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Mercury (Cont.)

• Causes a reduction in glutathione production and glutathione peroxidase activity

• Glutathione is very important in liver detoxification.

• Also causes free radical production

– Stohs, S., et al., “oxidative mechanisms in the toxicity of metal ions,” Free Radic Biol Med 1995; 18:321‐36.

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Outcomes

• No long‐term studies have been done to look at the potential reversibility of thyroid dysfunction.

• Lead workers removed from exposure appear to have an improvement of depressed T4 levels.

103

Toxins and The Thyroid

• The following toxins decrease T4 and T3 and increase TSH since they are competitive inhibitors of iodine transport.

– Thiocyanates

– Perchlorates

– Pertechnetates

104

Toxins and The Thyroid (Cont.)

• The following are compounds that inhibit thyroid peroxidase which is needed in the second step of thyroid synthesis.– Thiourea– Thiouracil– Propylthiouracil– Carbimazole– Aniline derivatives– Para‐aminobenzoic acid– Substituted phenols like resorcinol– Phloroglucinol

• Ibid., Crinnon.105


• Iodine and lithium block thyroid hormone release from the thyroid.

– Ibid., Crinnion.

106


• Low levels of thyroid hormone have been seen with exposure to the following

– Lead

• Due to problem with hypothalamus

– Carbon disulfide

– PBBs

• Ibid., Crinnion.

107

Lead

• Mild depression in thyroid function has been seen in adult patients chronically and heavily exposed to lead without substantial effects on lower levels.– Ibid., Luderer.– Cullen, M., et al., “Endocrine and reproductive dysfunction in men associated with occupational inorganic lead intoxication,” Arch Environ Health 1984; 39:431‐40.

– Robins, J., et al., “Depressed thyroid indices associated with occupational exposure to lead,” Arch Intern Med 1983; 143:220‐24.

108

19

Reference

– Schumacher, C., et al., “Thyroid function in lead smelter workers: absence of subacute or cumulative effects with moderate lead burdens,” Int Arch Occup Environ Health 1998; 71:453‐58.

109

Lead Toxicity

• Study showed that the bones of humans today contain lead at 1,000 x greater than humans of the pre‐industrial era.

– Patterson, C., et al., “Natural skeletal levels of lead in homo sapiens uncontaminated by technological lead,” Sci Total Environ 1991; 107:205‐36.

110


• These substances are suggested to adversely affect thyroid function.– Organophosphates

– Carbamates

– OCCs

– Fungicides

– Food coloring

– PCBs

– Mercury (animal studies)• Ibid., Crinnion.

111


• Inducers of hepatic cytochrome P450 cause an alteration in thyroid structure and decrease in T4

– Phenobarbital

– Benzodiazepines

– Calcium channel blockers

– Steroids

– Retinoids

– Chlorinated hydrocarbons

– Polyhalogenated biphenyls 112

Reference

– Thrasher, J., et al., “Immunologic abnormalities in humans exposed to chlorpyrifos: preliminary observations,” Arch Environ Health 1993; 48:89‐93.


113

Mitochondrial Disruptions

• Toxic metals and many xenobiotics also may target the membranes of the mitochondria.

• This can result in alterations in energy metabolism and subsequent thyroid function.

– Wallace, K., et al., “Mitochondria‐mediated cell injury. Symposium overview,” Fundam Appl Toxicol1997; 38:23‐37.

– Ibid., Lyon.

114

20

Toxins and Adrenal Function

115


• There are not many studies that look at toxins and adrenal function.

• The zonae reticularis and fasciculata are the main targets for xenobiotic chemicals.

• The adrenal cortex is predisposed to toxic affects due to adrenocortical cell storage of lipids which allows lipophilic compounds to accumulate. – Haschek, W., et al., (Eds.) Fundamentals of ToxicologicPathology. 2nd Ed. New York: Academic Press, 2010, p. 513‐51.

116

Toxins and Adrenal Function (Cont.)

• The lipophilic compounds have enzymes including enzymes of the cytochrome P450 system that are capable of biotransformingxenobiotics.

• May cause increase or decrease in toxicity

• Most chemicals that affect adrenal function do so by altering steroidogenesis.

– Ibid., Haschek.117

PCBs

• Transformer repairmen were studied that were exposed to PCBs (former and current workers).

• Urinary 17‐hydroxycortisone excretion was observed to be lower.

• Also, urinary 17‐hydroxycortisone was negatively correlated with fat cell PCB concentration.

• Serum levels were not measured.118


• The lower urinary 17‐hydrocortisone levels may be reflective of a suppressive effect of PCBs on adrenal glucocorticoid secretion or synthesis which would results in low serum glucocorticoid levels.– Ibid., Luderer.

– Emmett, E., et al., Studies of transformer repair workers exposed to PCBs: II. Results of clinical laboratory investigations,” Amer Jour Ind Med 1988; 14:47‐62.

119

Paraquat

• Is a herbicide

• Is an inhibitor of aldosterone synthesis

• Action similar to spironolactone and metyrapone

• A decrease in aldosterone was seen in animals

– Blanchouin‐Emeric N., et al., “The reoxidation of cytochrome P‐45‐ by paraquat inhibits aldosterone biosynthesis from 18‐hydroxycorticosterone,” Jour Steroid Biochem 1988; 31:331‐35.

– Ibid., Luderer.120

21

Organophosphates

• Malathion and diazinon both organophosphates have been shown to interfere with adrenomedullary function.– Increases production of E and NE

– Results in hyperglycemia

– Glycogen deposition in the liver

– Exhaustion of adrenal stores of these amines• Matin, M., et al., “Modification of diazinon‐induced changes in carbohydrate metabolism by adrenalectomyin rats,” Biochem Pharmacol 1990; 39:1781‐86.

121

Reference

– Liu, P., et al., “Organophosphates inhibit catecholamine secretion and calcium influx in bovine adrenal chromaffin cells,” Toxicology 1994; 90:81‐91.

– Ibid., Luderer.

122

Mirex, Toxaphene, and Dioxin

• All have been shown to cause suppression of glucocorticoid synthesis by the adrenals.

• Results in hypoglycemia that is reversible by cortisone.– Bestervelt, L., et al., “TCDD alters pituitary‐adrenal function. Adrenal responsiveness to exogenous ACTH,” Neurotoxicol Teratol 1993; 15:365‐67.

– Jovanovich, L., et al., “Significance of mirex‐caused hypoglycemia and hyperlipidemia in rats,” Jour Biochem Toxicol 1987; 2:203‐13.

123

Reference

– Mohammed, A., et al., “Toxaphene: accumulation in the adrenal cortex and effect on ACTH‐stimulated corticosteroid synthesis in the rat,” Toxicol Lett 1985; 24:137‐43.

– Ibid., Luderer.

124

1, 1, 1‐trichloroethane

• 1,1,1‐trichloroethane is a solvent.

• It suppresses plasma corticosterone and ACTH concentrations

• May have an effect on hypothalamic corticotropin‐releasing hormone (CRH) in animals.– Pise, V., et al., “Effects of acute inhalation exposure to 1,1,1‐trichloroethane on the hypothalamo‐pituitary‐adrenal axis in male Sprague‐Dawley rats,” Jour ToxicolEnviron Health 1998; 54(Part A):193‐208.

125

Testing for Toxins

126

22

Testing for Toxins

• History of exposure

• Extensive panels are now available to measure the level of organic toxins via blood, urine, or adipose biopsy.– PCBs

– Organochlorine pesticides

– PBDE fire retardants

– Furans

– Dioxins

127

Treatment

128

Treatment

• Avoid toxin

• Supplements to support detoxification and antioxidant protection

• Reducing body burden of xenobiotics– Ibid., Crinnion.

– Rousseau, D., Your Home, Your Health, Your Well‐Being. Vancouver, BC: Hartley & Marks, 1988.

– Golos, N., Success in the clean bedroom: a path to optimal health,” Rochester, Y: Pinnacle, 1992.

129

Avoid

• Solvents• Paints• Exhaust fumes• Perfumes• Hair sprays• New furniture• Carpeting and cabinetry• Plastics• Gas or oil heat

– Ibid., Crinnion. 130

Things to Do

• Eat organic foods

• Use organic cleaners

• Use organic pesticides if pesticides are needed

• Drink purified water

• Use nature air purifiers

– Charcoal or high‐efficiency particulate air filters

– Many plants in home131

Plants That Clean The Air

• The following plants have been shown in a study done by NASA to clean the air.

– Mass cane (Dracaena massangeana)

– Pot mum (Chrysanthemum morifolium)

– Gerbera daisy (Gerbera jamesonii)

– Warnecki (Dracaena deremensis “Warnecki”)

– Ficus (Ficus benjamina)


132

23

Reference

– Wolverton, B., et al., “Interior landscape plants for indoor air pollution abatement,” Stennis Space Center, MS: National Aeronautics and Space Administration, 1989.

133

Nutritional Support

• Nutritional support for detoxification has been focused on two areas.

– Cofactors for enzymatic biotransformation of xenobiotic compounds

– Antioxidants

134

Effects of a Low‐Protein Diet on Detoxification

• Decreased cytochrome P450 content of liver, secondary to decreased quantity of microsomal protein

• Decreased NADPH‐cytochrome P450 (c) reductase

• Decreased cytochrome b5• Decrease in hepatic GSH• Increased liver UDP‐glucuronlytransferase (phase 2)– Ibid., Crinnion.

135

Protein Deficiency

• An increase in chemical toxicity and drug toxicity have been seen with protein deficiency.

• Inadequate protein intake decreases the activity of liver mixed function oxidase (MF0) systems which can result in an increase ½ life of drugs and toxic chemicals. It may also increase drug action and toxicity. – Ibid., Crinnion.

136

Protein Deficiency (Cont.)

• The quality and quantity of protein can alter phase I and phase II detoxification of drugs.

• The toxicity of the following agents has been increased several fold by protein deficiency.– OCCs

– Acetylcholinesterase inhibitors

– Herbicides

– Fungicides• Ibid., Crinnion.

137

Protein Deficiency (Cont.)

• Other items that suppress MFO activity

– Methionine deficiency

• Also affects selenium metabolism by making less selenium available for glutathione peroxidase biosynthesis

– Cysteine deficiency

– Folic acid deficiency

– Choline deficiency


138

24

Avoid Sugar

• High sugar levels have been shown to reduce the clearance of some chemicals from the liver.


139

Vitamin E

• Stabilizes membranes and helps provide a good environment for the making and activity of membrane‐associated enzymes that protect against damage due to toxins.

• Is an antioxidant.

• Helps prevent CCL4 hepatotoxicity.

• Pretreatment with vitamin E before exposure to ozone and nitrous oxide provides partial protection against toxicity.– Ibid., Crinnion. 140

Vitamin A and Beta‐Carotene

• Beta‐carotene is needed for epithelial cell differentiation and regulation of membranes.

• Decreases singlet oxygen species

• Is necessary for normal estrogen cycle

• Protects against singlet oxygen‐induced damage


141

Deficiency of Vitamin A

• Is associated with elevated binding of benzo(a)pyrene to tracheal epithelia

• Toxins that decrease vitamin A in liver which increases their toxic effect

– Organophosphates

– DDT

– PCBs

• Ibid., Crinnion.142

Other Things That Lower Vitamin A

• Alcohol

• Coffee

• Cold weather

• Cortisone

• Diabetes

• Excessive iron

• Infections

• Laxatives

• Liver disease

• Mineral oil

• Nitrates

• Sugar

• Tobacco

• Vitamin D deficiency

• Zinc deficiency


143

Thiamin

• Thiamin depletion can be due to the following– Excessive formaldehyde exposure

– Alcohol (increases aldehydes)

– Candida (increases aldehydes)

• The coenzyme of thiamin pyrophosphate (TPP) is needed to metabolize the aldehyde group as is magnesium.

• Also a coenzyme (TPP) for pyruvate DH and alpha‐ketoglutarate DH– Ibid., Crinnion. 144

25

Thiamin (Cont.)

• Used in phase II pathways

• Needed to restore oxidized GSH

• Thiamin deficiency increases the toxicity of the following. They also can lead to lead to thiamine deficiency which further increases their toxicity.– PCBs

– Dieldrin

– Heptachlor

– Aniline dyes• Ibid., Crinnion. 145

Riboflavin

• Component of the coenzymes in flavoprotein

• enzymes needed for oxidation/reduction reactions

• Liver microsomal flavoprotein reduced nicotinamide adenine dinucleotide phosphate (NADPH)‐cytochrome reductase supplies reducing equivalents to cytochrome P450.

– Ibid., Crinnion.146

Riboflavin (Cont.)

• These are very important for the functioning of phase I biotransformation.

• Riboflavin helps destroy azo dyes in the liver by MFO which protects against azo dye‐induced cancer.

• The GSH reductase pathways also use riboflavin. They work with superoxide dismutase to block the production of free radicals.


Niacin

• Nicotinamide is a part of NAD and NADP.

• Both of these are oxidized to NAD+ and NADP+ and are reduced to NADH and NADPH.

• Needed for phase I detoxification.

• Used in the deamination of amino acids, fatty acids, and beta‐oxidation of fatty acids.

• Used in steroid formation and drug metabolism.

148

Pyridoxine

• Exposure to carbon disulfide, PCBs, and penicillamine all can disrupt the optimal function of vitamin B6 and chronic exposure can cause B6 deficiency.

• Chemically sensitive patients are commonly deficient in pyridoxine even if they are taking supplemental B6.– Rea, W.,, Chemical Sensitivity. 3rd Ed., Boca Raton, FL: Lewis Publications, 1996, Vols 1‐3.

149

Pyridoxine (Cont.)

• Low levels of pyridoxine can cause low levels of taurine.

• If the patient’s taurine is low, extreme sensitivities to the following may occur.– Chlorine– Chlorite (bleach)– Aldehydes– Alcohols– Solvents– Ammonia

• Ibid., Crinnion.150

26

Pyridoxine (Cont.)

• Deficiencies of pyridoxine may lead to a decreased ability to conjugate E and serotonin.


151

Vitamin C

• Is a cellular antioxidant

• Scavenges free radical superoxides and hydroxyl radicals

• Protects against the following toxicities– Phenol

– Phenylqumotin

– Carboxylic acid

– Barbiturate toxicity• Ibid., Crinnion. 152

Vitamin C (Cont.)

• Also protects against– Ozone‐reduced pulmonary edema– O2 toxicity– CCL4 toxicity

• Reduces the toxicity of the following– Pesticides– Heavy metals– Hydrocarbons– PCB– Acetaminophen

• Ibid., Crinnion. 153

Vitamin C (Cont.)

• Increases MFO activity since there is decreased cytochrome P450 activity with vitamin C deficiency

• Increases the incorporation of iron into heme

• Prevents nitrosamine formation from nitrites in the GI tract

• Protects against lead and cadmium toxicity


Vitamin C (Cont.)

• Higher levels of vitamin C may help facilitate the breakdown of xenobiotics by liver MFO (mixed function oxidase).

• Also xenobiotics increase vitamin C excretion in the urine.


155

Iron

• Help is important for cytochrome P450 and hemoglobin since they are both hemecontaining.

• Aniline metabolism is very sensitive to low iron levels and increases susceptibility to lead toxicity.


156

27

Magnesium

• In a study done on chemically sensitive patients, low magnesium was found in 40%.

– Ibid., Rea.

• Magnesium deficiency can lead to low

– Cytochrome P450

– NADPH cytochrome reductase

• Both of these are needed for phase I detoxification

• Magnesium supplementation reverse this process– Ibid., Crinnion. 157

Magnesium (Cont.)

• Magnesium deficiency can also lead to decreased hydroxylation of aniline and demethylation of aminopyrine.

– Magnesium supplementation can reverse this process


158

Selenium

• GSH peroxidase helps to maintain the integrity of cellular and subcellular membranes and selenium is s component of GSH peroxidase.

• Selenium is also important for phase 2 xenobiotic conjugation.

• GSH peroxidase levels can also be increased by NAC and L‐cysteine.


Selenium (Cont.)

• Decreases the toxicity of lead

• Increases biliary excretion of cadmium

• Increases biliary excretion of mercury

• Prevents cadmium‐induced decrease of Cytochrome P450

• Low selenium levels increases the toxicity of several xenobiotics.


Zinc

• The metabolism and detoxification of xenobitoics is affected both by low and excessive levels of zinc.

• Low zinc levels decrease enzyme function

• Low zinc levels reduce GSH levels

• High zinc levels decrease cytochrome P450 levels

– Crinnion.161

Glutathione

• GSH– Needed for GSH conjugation in phase II– Needed to quench lipid peroxide molecules

• GSH levels can be increased by – Selenium– NAC– Vitamin A– Vitamin E

• Numan, I., et al., “Protective effects of antioxidants against endrin‐induced lipid peroxidation, glutathione depletion, and lethality in rats,” Arch Environ Contam Toxicol 1990; 19:302‐06.

• Ibid., Crinnion

162

28

Glutathione (Cont.)

• Milk thistle also can increase GSH levels

• Inhibits GSH depletion and lipid peroxidation after endrin exposure

– Vitamin E

– Vitamin C

– Cysteine

163

Botanicals

• Used to treat chemical toxicity

– Silybum marianum (milk thistle)

– Curcuma longa (turmeric)

164

Depuration/Detoxification

• Depuration is the removal of impurities from the body .

• To methods of xenobiotic removal have been described in the literature.– Hubbard Purification Rundown

• Exercise

• High‐temperature saunas

• Increasing doses of niacin

• Electrolyte replacement– Ibid., Crinnion.

165

References

– Schnare, D., et al., “Body burden reductions of PCBs, PBBs, and chlorinated pesticides in human subjects,” Ambio 1984; 13:378‐80.

– Tretjak, Z., et al., “PCB reduction and clinical improvement by detoxification an unexplored approach?” Hum Exp Toxicol 1990; 9:235‐44.

– Schnare, D., et al., “Evaluation of a detoxification regimen for fat stored xenobiotics,” Med Hypotheses 1982; 9:265‐82.

166

Detoxification

• Two methods of xenobiotic removal have been described in the literature (cont.).

– Fasting

• Study on people poisoned by PBB‐contaminated rice bran cooking oil in Taiwan

– Imamura, M., et al., “A trial of fasting cure for PCB‐poisoned patients in Taiwan,” Amer Jour Ind Med 1984; 5:147‐53.

167

Crinnion Depuration Protocol

• Used to treat environmentally poisoned patients

• Developed by Walter Crinnion, ND– Used for 20 years

– Outcome study for various problems treated with this protocol, 83% of patients rated their results as good or great.

• Crinnion, W., “Results of a decade of naturopathic treatment for environmental illness,” Jour Nat Med 1977; 7:21‐8/

168

29

Crinnion Depuration Protocol (Cont.)

• Testing for chlorinated pesticides, PCBs, and solvents using the depuration protocol showed a reduction of body burden.

• Many had a complete clearance of PCBs from the serum.

– Crinnion, W., unpublished data.

169

Crinnion Depuration Protocol

• Exercise daily using exercycle, rebounder, or brisk walking to start lipolysis and diaphoresis.

• Thermal Chamber– Up to three 60‐minute “sauna” sessions with temperatures from 120F to 135Fwith cool‐down periods in between

• Not to be used in patients with CHD or arrhythmias• Glass bottle spring water and electrolyte replacement• Increases the rate of lipolysis in the adipose tissue which releases the lipophilic xenobitoics into the bloodstream

• Substances in the subcu fat pads are mobilized through sweat, as well as into the blood 170


• Constitutional hydrotherapy– Use of alternating hot and cold towels with sine wave stimulation

• Stimulates body self healing properties

• Increases the amount of toxin‐laden bile dumped from the liver into the intestines

– Herbal therapy to increase choleretic and cholagogue action on the liver

• Capsule of a combination of Chelidonium, Chionanthus, Taraxacum, Arctium lappa, Silybum marianum, and Urtica dioca 171


• Colonic irrigation– Gravity‐fed machines are used to gently introduce triple‐filtered water into the large intestines which provides a method for toxic bile and liver byproducts to leave the body

– Chlorinated pesticides have been found in the effluent

• Constitutional homeopathy

• Counseling– Helps to eliminate emotional toxins

– Helps to eliminate physical toxins172


• Body therapies

– Massage

– Shiatsu

– Craniosacral

– Visceral, spinal, and joint adjustment

173


• Protocol is used daily for 4‐8 weeks (5 times a week) with the assistance of their health care provider in the office.

• Therapies are then continued at home for one year.

– Crinnion.

174

30

Treatment Overview of CrinnionProtocol for Environmental Toxins

• Avoidance of further chemical exposure through air, food, and water

• Nutrient support for transformation, elimination, and antioxidant pathways

• Depuration protocol


175

Nutritional Support

• Vitamin C: 6,000 to 12,000 mg/day

• Vitamin E: 400‐1,200 units of D‐alpha‐tocopherol daily

• B complex: once daily

• Vitamin A: 25,000 to 50,000 units/day (unless patient is a smoker or at risk of pregnancy)

• NAC: up to 500 mg/day

• Selenium: 300‐600 micrograms /day176

Nutritional Support (Cont.)

• Silybum marianum (standardized): 100 mg BID to TID

• Adequate protein in diet with each meal

• Magnesium: 300 to 600 mg/day

• Psyllium husks powder: begin with 0.5 tsp in water nightly (to bind bile in the intestines)

177

Testing Methods

• Urine—most accurate

• Stool‐‐‐more of a representation of exposure than actual toxic load

• Hair analysis‐‐‐not viewed by many authors as accurate

– Bencko, V., “Use of human hair as a biomarker in the assessment of exposure to pollutants in occupational and environmental settings,” Toxicology 1995; 101:29‐39. 178

Urine Testing

• The best available way to estimate the amount of toxic metals in the body is a urine test after the administration of a chelating agent.

• Studies have been done since the 1970s on provocation testing for toxic metals determined this was an accurate testing method.

179

References

– Quig, D., Metal Toxicity: Assessment of Exposure and Retention. In Pizzorno, J., et al. (Eds). Textbook of Natural Medicine. St. Louis: Elsevier, 2006, p. 263‐74.

– Centers for Disease Control. “Preventing lead poisoning in young children,” Jour Pediatr 1978; 93:709‐14.

– Chisolm, J., Chelation therapy in children with subclinical plumbism,” Jour Pediatr 1974; 53:441‐49.

180

31

References (Cont.)– Chisolm, J., “The use of chelating agents in the treatment of acute and chronic lead intoxication in childhood,” Jour Pediatr 1968; 73:1‐15.

– Markowitz, M., et al., “Assessment of lead stores in children: validation of an 8 hour CaNa2EDTA provocation test,” Jour Pediatr 1984; 104:337‐41.

181

Measurement of Toxic Metal Levels

• 6‐hour or 24‐hour urine challenge test.

• See handout.

182

Provocation Chelating Agents

• Most commonly used provocation chelating agents for toxic metal screening currently are

– Ca‐Na2‐EDTA

– DMPA

– DMSA

183

Provocation Chelating Agents (Cont.)

• Since most mercury is excreted through the stool and urine as a glutathione conjugate, patients who have had a toxic burden with mercury for a long time (and therefore depleted glutathione production) may NOT show an elevated level of mercury if a challenge test is NOT done.

– Aposhian, H., et al., “Urinary mercury after administration of 2,3‐dimercaptopropane‐1‐sulfonic acid: correlation with dental amalgam score,” FASEB Jour 1992; 6:2472‐76. 184

Ca‐Na2‐EDTA

• Has been approved by the FDA and used IV for years as the provocating item and therapeutic treatment of choice for patients exposed to lead.

• Can also increase excretion of iron, copper, nickel, cadmium, and manganese.

– Rozema, T., “Protocols for chelation therapy,” Jour Adv Med 1997; 10:3‐100.

185

Ca‐Na2‐EDTA (Cont.)

• Will also chelate out zinc if not carefully used

• Check creatinine and GFR before using since Ca‐Na2‐EDTA moved metals are cleared through the kidney.

• Should attend chelation course before using

• Not as effective chelator of mercury

– Ibid., Rozema.

186

32

DMPS

• DMPS (Dimaval, ‐(R,S)‐2,3‐dimercapto‐propropane‐1 sulfonate) is a dithiol.

• Most productive agent to mobilize mercury

– Keith, R., et al., “Utilization of renal slices to evaluate the efficiency of chelating agents for removing mercury from the kidney,” Toxicology 1997; 116:67‐75.

– Clarkson, T., et al., “Tests of efficacy of antidotes for removal of methylmercury in human poisoning during the Iraq outbreak,” Jour Pharmacol Exp Therap 1981; 218:74‐83. 187

DMPS (Cont.)

• Study done on college students

• Subjects with and without mercury fillings were given 300 mg DMPS (PO) and urine was collected.

• A positive correlation was seen between the amount of mercury excreted after the DMPS challenge and amalgam surface area.

– Ibid., Quig.188

Reference

– Aposhian, H., et al., “Urinary mercury after administration of 2,3‐dimercaptopropane‐1‐sulfonic acid: correlation with dental amalgams,” FASEB Jour 1992; 6:2472‐76.

189

DMPS

• Another study also support the value of using DMPS as a provocating agent in patients exposed to mercury vapors.

• Also concluded that a post‐DMPS urinary mercury levels were better indicators of exposure and retention than unprovoked urinary mercury levels.

– Ibid. Quig.

190

Reference

– Gonzalez‐Ramirez, D., et al., “Sodium 2,3‐dimercaptopropane‐1‐sulfonate challenge test for mercury in humans. II. Urinary mercury, porphyrins and neurobehavioral changes of dental workers in Monterey, Mexico,” Jour PharmacolExper Ther 1995; 272:264‐74.

191

DMPS

• The pharmacokinetics of DMPS have been well defined.

– Ibid., Aposhian.

– Aposhian, H., et al., “Mobilization of heavy metals by newer, therapeutically useful chelating agents,” Toxicology 1995; 97:23‐38.

192

33

DMPS (Cont.)

• Efficacy of DMPS as a chelating agents has been found for the following

– Mercury

– Arsenic

– Lead (pediatric)

193

References

– Campbell, J., et al., “The therapeutic use of 2,3‐dimercaptopropane‐1‐sulfonate in two cases of inorganic mercury poisoning,” JAMA 1986; 256:3127‐30.

– Wax, P., et al., “Recovery from severe arsenic‐induced peripheral neuropathy with 2,3‐dimercapto‐1‐propanesulfonic acid,” Clin Toxicol2000; 38:777‐80.

– Dimival (DMPS): Summary of Scientific Literature. Houston: Heyltex Corp, 1991, 6237‐93.

194

DMPS

• Not approved by the FDA

• Is registered in Germany with the German Drug Regulatory Authorities and is available without a prescription

• In the US, DMPS is available by prescription only from compounding pharmacies for oral, IV, and IM use.

• Suggested to take chelation course and use a consent form since it is not FDA approved in US 195

DMPS (Cont.)

• Side effects are rare but could include– Nausea

– Weakness

– Vertigo

– Chills

– Fever

– Cutaneous reactions/itching/erythema multiforme

– Elevations of transaminases196

References

– Ibid., Quig.



– Ibid., Wax.

– Ibid., Heyltex.

197

DMPS Provocation Protocol

• PO detailed provocation protocol can be found


• IV detailed provocation protocol –see handout.

– Crinnion, W., “Environmental Medicine. Part III. Long‐term effects of chronic mercury exposure,” Altern Med Rev 2000; 5:209‐23.

198

34

Common DMPS Provocation Protocol

• Patient is instructed to fast overnight and to collect a urine specimen.

• In the am, fasting, after the bladder is emptied, the patient is given 300 mg (or 10 mg/kg) DMPS PO.

• All the urine is collected for the next 6 hours

• A light meal can be eaten in fours hours that does not contain sea food.

• Encourage fluid intake199

References

– Ibid., Quig.


200

DMPS Effective Chelator of These

• Bismuth

• Mercury (organic and inorganic )

• Copper

• Lead

• Arsenic

• Antimony

• Cadmium

• Nickel

• Tin

• Tungsten

• Thallium

• Gold

– Ibid., Quig

201

DMPS is NOT an Effective Chelator

• Aluminum

• Uranium

– Ibid., Quig.

202

DMPS Chelation

• Mercury is the metal that is predominantly excreted after DMPS chelation

• Copper levels will be elevated after chelation and this is normal.

• As mercury levels go down post chelation, then urinary levels may rise of lead, cadmium, and tin with subsequent challenges.

– Ibid., Quid.203

DMPS Chelation (Cont.)

• The pattern may shift of different metals excreted.

– This is based on a combination of affinities of DMPS for the different metals.

– This is based on the mass competition for metal binding sites.

• Ibid., Quid.

204

35


• There are no established guidelines for the interpretation of the results of a DMPS challenge test.

• Studies have been done to give a range that may be since in your practice.

– Ibid., Heyltex.

205


• Conclusions about toxicity cannot be made from the DMPS test by itself.– Symptoms

– History

– Physical examination

• Results of the DMPS challenge test can be used to compare later challenge tests to evaluate how the treatment is working.– Ibid., Quig.

206


• DMPS does not provide direct information as to the level of mercury in the CNS.

• GFR must be evaluated before beginning chelation therapy.

• Metals chelated out are excreted mostly from the kidney and a small amount from the liver and biliary/fecal system.

– Ibid., Aposhian.207

DMSA

• DMSA (meso‐2,3‐dimercaptosuccinic acid) is a a dithiol like DMPS.

• Widely used for provocating test

• Used as a chelating agent for the following

– Lead

– Mercury

– Arsenic

– Antimony 208

References

– Ibid., Quig.– Graziano, J., et al., “2,3‐dimercaptosuccinic acid as an antidote for lead intoxication,” Clin Pharmacol Ther1985; 37:431‐38.

– Grandjean, P., et al., “Chronic lead poisoning treated with dimercaptosuccinic acid,” Pharmacol Toxicol1991; 68:266‐69.

– Roels, H., et al., “Urinary excretion of mercury after occupational exposure to mercury vapour and influence of the chelating agent meso‐2,3‐dimercaptosuccinic acid (DMSA),” Brit Jour Ind Med 1991; 48:247‐53.

209

DMSA

• Approved by the FDA for lead intoxication and is the method of choice for children and adults.

• Used PO

• About 20% of orally given DMSA is available after one dose.– Ibid., Quig.

– Physicians Desk Reference . 54th Ed. Montvale, NJ: Medical Economics, 2000.

210

36

DMSA (Cont.)

• In animal studies DMSA has been shown to effectively remove lead and mercury from the brain. – Aaseth, J., “Treatment of mercury and lead poisonings with dimercaptosuccinic acid and sodium dimercaptopropane sulfate,” Analyst 1995; 120:853‐54.

– Jones, M., et al., “Comparative in vivo lead mobilization with meso‐ and rac‐2,3 dimercapto‐succinic acids in Albino Wistar rats,” Pharmacol Toxicol1997; 186:182‐86.

211

References

– Gong, Z., et al., “Effects of chelation with meso‐dimercaptosuccinic acid (DMSA) before and after the appearance of lead‐induced neurotoxicity in the rat,” Toxicol Appl Pharmacol 1997; 144:205‐14.

– Smith, D., et al., “Efficiency of succimer chelation for reducing brain lead levels in rodent model,” Environ Res 1998; 78:168‐76.

212

DMSA

• DMSA is usually well tolerated

• Periodic testing of liver enzymes should be done during the course of prolonged treatment

• Possible mild side effects of DMSA– GI bloating and gas

– Occasional loose stools

– Skin rash• Ibid., Quig.

213

DMSA (Cont.)

• There are several reviews of DMSA protocols.




– Miller, A., “Dimercaptosuccinic acid (DMSA), a non‐toxic, water soluble treatment for heavy metal toxicity,” Altern Med Rev 1998; 3:199‐207.

– Ibid., Quig.

214

DMSA (Cont.)

• There is a significant difference between DMSA protocols for acute lead poisoning and chronic low level lead retention.

– Ibid., Physicians Desk Reference.

– Ibid., Quig.

215

Protocol for DMSA Provocation Testing

• There are various protocols.


– Frumkin, H., et al., “Diagnostic chelation challenge with DMSA: a biomarker of long‐term mercury exposure? Environ Health Persp 2001; 109:167‐71.

• Common DMSA provocation protocol

– 10 mg/kg PO TID for three consecutive days

– 24 hour urine collection on day 3

216

37

Protocol for DMSA Provocation Testing (Cont.)

• Most common and convenient protocol

– Single dose of DMSA PO (30 mg/kg) on an empty stomach and then collect the urine for 6 hours

• Ibid., Quig.

– Alternative is DMSA 1,000 mg as a single dose and collect urine for 6 hours

• LaValle, J., Module VII.

217

Reference

– Ibid., Quig.

– Hibberd, A., et al., “Mercury from dental amalgam fillings: studies on oral chelating agents for assessing and reducing mercury burdens in humans,” Jour Nutr Environ Med 1998; 8:219‐31.

218

Protocol for DMSA Provocation Testing

• Some authors suggest if using the single day provocation test that the DMSA leaves behind some metals that have been mobilized but not excreted so consider giving DMSA 10 mg/kg TID for the next two days to clean up the metals that are left behind.

– Ibid., Quid.

• Urine will have a transiently foul, sulfurous odor from the use of DMSA. Let the patient know.

219

Treatment of Toxic Metals

• Chelation

– Suggested best agents

• Arsenic: DMPS excellent

• Lead: Ca‐Na2‐EDTA excellent, DMSA and DMPS good

• Inorganic mercury: DMSA or DMPS excellent

• Organic mercury: DMSA or DMPS excellent

• Tin: DMSA or DMPS good

• Nickel: Ca‐Na2‐EDTA good– Ibid., Quig.

220

Toxic Metals as Chemical Competitors

• Toxic metals can act as “chemical competitors” with trace metals.

– Cadmium competes with zinc

– Lead competes with calcium

– Mercury competes with selenium

• Ibid., Lyon.

• Clarkson, T., “Molecular and ionic mimicry of toxic metals,” Annu Rev Pharmacol Toxicol 1993; 33:545‐71.

221

Toxic Metals as Chemical Competitors (Cont.)

• This may result in high levels of nutritional depletion of competitive metals.

• May also result in inhibition (or overactivation) of metal‐dependent systems such as enzymes.

– Ibid., Lyon.

222

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Micronutrients to Treat Toxic Metal Exposure

• Selenium: AM (4 weeks) 200‐300 ug and long‐term 100‐300 ug

• Zinc: Evening (4 weeks) 25‐50 mg and long‐term 15‐25 mg

• Alpha lipoic acid: 600‐1,200 mg (may affect thyroid function)

• Vitamin C: 500‐3,000 mg• L‐Glutathione: IV 600 mg 2‐3x/week x 6 weeks• NAC: 200‐600 mg • Vitamin E: 200‐500 IU

223

Micronutrients To Treat Toxic Metal Exposure (Cont.)

• Coenzyme Q‐10: 60‐200 mg

• Vitamin B complex

• Folic acid: 400‐1,000 ug

• B12: 1,000‐2,000 ug methylcobalamin

• Taurine: 500‐2,000 mg

• Magnesium: 300‐600 mg

• Calcium 600‐1,000 mg– Ibid., Gorber. 224

Nutrition and Toxic Metal Detox

• Nutrition status has an great influence on absorption, retention, toxicity, and excretion of toxic metals.

– Goyer, R., “Nutrition and essential metal interactions,” Annu Rev Nutr 1997; 17:37‐50.

– Ibid., Lyon.

225

Nutrition and Toxic Metal Detox (Cont.)

• Examples– Absorption of lead and cadmium are increased if iron or calcium levels are low (also iron deficiency can lead to increased intestinal permeability)

– Low levels of some minerals leads to increased retention of toxic metals.

• Calcium deficiency increases both lead and cadmium body burden

• Selenium deficiency increases mercury retention– Ibid., Lyon.

226

Other Lifestyle Modifiers of Toxins

• Moderately high‐protein diets up regulate the cytochrome P450 system which decreases the patient’s susceptibility to pesticides and other xenobiotics.

• Low protein diets increase pesticide toxicity because they down regulate cytochrome P450.

– Ibid., Lyon.

227

Other Lifestyle Modifiers of Toxins (Cont.)

• Cigarette smoking not only increases oxidative stress but also biotransforms some xenobiotics into potent cancer causing agents.

– Mori, Y., et al., “effect of cigarette smoke on the mutagenic activation of various carcinogens in hamster,” Mutat Res 1995; 346:1‐8.

– Ibid., Lyon.

228

39


• The following also help detoxify the body

– Onions and garlic

– Cruciferous vegetables

– Chlorophyll

– Terpenoids

• Citrus

• Ginkgo biloba

• Menthol

• Camphor229


• The following also help detoxify the body (cont.)

– Bioflavonoids

• Citrus

• Pine bark

• Grape seed

• Green tea– Ibid., Lyon.

– Kitts, D., “Bioactive substances in food: identification and potential uses,” Can Jour Physiol Pharmacol 1994; 72:423‐34.

230

The Detoxification Lifestyle

• The mnemonic A NERD helps the patient remember how to lead a detoxification lifestyle.– Avoid exposure

– Nutrition

– Exercise

– Rest

– Detoxification• Ibid., Lyon.

231 232

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