Chapter 35 Environmental Medicine
Environmental Toxic Load
The twentieth century, with its promise of “Better Living Through Chemistry,” brought us a host of chemical toxicant-related illnesses (referred to here as “environmental illnesses”). We are experiencing the new medical diagnoses of sick (closed) building syndrome1,2 and multiple chemical sensitivity,3–5 both of which are known to be related to overexposure to environmental contaminants. The rates of asthma, allergy, autism, attention deficit hyperactivity disorder, and childhood brain tumors, obesity, and diabetes are all skyrocketing. All of these have been linked to the growing environmental burden that is carried by all persons. The primary physiologic action of the major pesticide classes disrupts neurologic function.6 The primary physiologic action of solvents is neurotoxicity7 as well. In addition to being neurotoxic, these compounds are profoundly immunotoxic8–10and are often toxic to the endocrine system as well.11–13 The adverse health effects are not limited to those systems as these compounds can also cause a variety of dermatologic, gastrointestinal, genitourinary, respiratory, musculoskeletal, and cardiologic13–15 problems. A great many of the adverse effects of these environmental toxins appear to be secondary to their mitochondrial damaging capacity.
The Toxic Burden
In an effort to identify what the full burden of environmental chemicals in the U.S. population is, the Centers for Disease Control (CDC) has been performing an ongoing assessment of the levels of environmental chemicals in the U.S. population. This ongoing study utilizes laboratory samples from persons involved in the National Health and Nutrition Examination Survey from the years 1999 to 2000, 2001 to 2002, and 2003 to 2004 (each representing about 2400 persons). In the First National Report on Human Exposure to Environmental Chemicals, 27 different compounds were measured.16 They tested for the presence of 13 different heavy metals, cotinine, six different organophosphorus pesticide (OP) metabolites, and seven phthalates and their metabolites. Nine of the heavy metals (including lead and mercury), three of the organophosphorus metabolites, and three of the phthalate metabolites appeared fairly ubiquitously. The second report was published 2 years later and expanded its scope of measurement by an additional 89 compounds for a total of 116 chemicals for the years 1999 and 2000.17 The second report included measurements of dioxins, furans, polycyclic aromatic hydrocarbons (PAH), herbicides, carbamate pesticides, certain organophosphate pesticides (including chlorpyrifos), phytoestrogens, and organochlorine pesticides. Of the 14 PAHs measured (all from combustion) five were found ubiquitously. In the third report (2005), pyrethroid insecticides were added to the list.18
In the fourth report, 75 new compounds were measured, bringing the grand total of measured xenobiotics to 212.19 This report included blood and urinary levels of eight different forms of arsenic along with several aromatic solvents (a total of 30 different compounds) for the first time. This was also the first of the reports that gave values for mercury in adults rather than juveniles and showed that the majority of mercury in the blood is organic rather than elemental. Acrylamides, trihalomethanes (from water disinfection), bisphenol A, phthalates, triclosan, polybrominated diphenyl ethers (flame retardants), benzophenone from sunblock, perfluorocarbons from nonstick coatings, and a host of other xenobiotics were found in the majority of persons tested in the fourth report. A review of the pertinent findings of the fourth report is available online.20
The Environmental Working Group (www.ewg.org) has funded and published two studies that specifically tested adults and newborns in the United States for xenobiotic burden. They originally tested 9 adults for the presence of 210 environmental toxins.21 These nine adults had an average of 91 of the 210 toxic compounds. Because these compounds can also be passed from mother to child, the EWG did a study to examine how many toxins were passed to babies. The EWG newborn study tested for 423 toxic chemicals in the cord blood of 10 infants born in U.S. hospitals in the year 2004.22 A total of 287 toxic compounds were found in the samples of the cord blood, with an average of 200 per child. One hundred one of these toxic compounds were found in all of the samples, with a range of total chemicals from a low of 154 compounds per child to a high of 231.
Sources of Environmental Toxins
In the previous section, the EWG newborn study22 highlighted the fact that mothers unwittingly pass fat-soluble toxins to their child during gestation. After birth, the toxic exposures primarily come from the air in our homes and the food that we consume. The U.S. Environmental Protection Agency did a number of total exposure assessment methodology studies in the 1980s, which showed that indoor air contains higher levels of environmental chemicals than outdoor air (even in towns with multiple chemical plants).23 The majority of compounds found in the indoor air were solvents that came from smoking, dry cleaned clothes, home furnishings, and home cleaning agents. Pesticide use in the home and garden are also contributing factors to the burden of pollutants in indoor air and dust.24,25
Food is the other route through which the majority of our xenobiotic load is delivered. The U.S. Food and Drug Administration (FDA) has an ongoing total diet survey that measures a set list of foods for a variety of environmental contaminants, including heavy metals and plasticizer compounds.26,27 The U.S. Department of Agriculture (USDA) has also been doing an ongoing measurement of pesticide residues on the most commonly consumed fruits and vegetables.28 The data published in this USDA report form the basis for the “dirty dozen” list of the most toxic fruits and vegetables, which are published on the web by the EWG.29 This listing gives the consumer information on how to avoid their greatest exposures to OPs.
Plasticizers contaminate food from simple contact with plastic food wrap. The movement of plastics from the wrapping to the food increases with the length of time they are in contact with each other, the fat content of the food, and whether or not heat is involved. Microwaving foods in plastic wrap increases migration, depending upon how closely the food is in contact with the wrapping.30 Levels of plasticizers are high in store-wrapped meat, poultry, fish, and cheese, with cheese having the highest level of plasticizers. Contrary to a current internet myth, freezing food in plastic containers does not increase plastic levels in the food. Plastic levels in unheated plastic-wrapped foods only increased in those foods after they were heated.31 Our exposure to some plasticizers, however, comes primarily from fragrances and other personal care products.32
Butter has been used as a sampling agent to assess the regional and global distribution of PCBs and other persistent organic pollutants around the globe. When butter was sampled for these compounds from around the world, the highest levels of PCBs were found in butter from Europe and North America.33 For individuals living in North America, the greatest source of PCB exposure came from butter and fish.34 However, by far, the single greatest source of PCBs and other “halogenated” persistent toxins in food is farmed Atlantic salmon from grocery stores and restaurants. A study done by the Food Safety Authority of Ireland found that farmed salmon had an average of four times the amount of PCBs and dioxins as wild salmon.34a Another study revealed that these farmed salmon had PCB levels over five times higher than those found in a sampling of wild salmon.35
These studies were done on relatively small numbers of fish, but had consistent findings. Their findings were confirmed in a subsequent study done on over 700 salmon, totaling approximately two metric tons of farmed and wild salmon from around the globe.36 Thirteen persistent chlorinated chemical pollutants, including the flame retardant polybrominated diphenyl ether, were found in significantly higher levels in farmed salmon than in wild salmon.
Health Effects of Environmental Toxins
Immunotoxicity
Of the three major systems affected by xenobiotic burden (immune, neurologic, and endocrine), the signs and symptoms of immunotoxicity are very often the first to occur in a patient’s history. This often begins with the appearance of allergies (including adverse food reactions), after which chemical sensitivity begins. Chronic infections (due to cell-mediated immune dysfunction) and autoimmunity can also be present.8,9,37 Rarely will a single individual manifest all of these, but clinicians are well advised to be vigilant in looking for such a constellation.
Cell-Mediated Immune Dysfunction
Unfortunately, many of the xenobiotics that have been identified inside all of us are very potent suppressors of cell-mediated immune responses. Dichlorodiphenyldichloroethylene (DDE) (the main metabolite of DDT) causes apoptosis of peripheral blood mononuclear cells, resulting in fewer macrophages roaming the body to phagocytize invading pathogens and trigger an immune response.38,39 Persons with the highest levels of DDE in their blood also showed reduced mitogen-induced lymphocyte response to concanavalin A.40 Individuals with this commonly found lipophilic toxin could easily have compromised cellular immune responses. Mercury, another commonly found xenobiotic, also increases apoptosis of both monocytes and lymphocytes and reduces phagocytic ability of the monocytes. It has been demonstrated that workers occupationally exposed to mercury vapor exhibited diminished capacity to produce both tumor-necrosis factor-α and interleukin-1.41
The chemicals produced by combustion, PAHs, have been shown to have similar depressing effects on the immune system, including decreased T-cell dependent antibody response, decreased splenic activity, diminished T-cell effector functions, suppression of T-cell cytotoxic induction, and lower natural killer cell activity.42 The OPs, which are not as biologically persistent as chlorinated pesticides, are also toxic to the immune system. They have been found to cause decreased percentages of CD4 and CD5 cells, increased number and percentages of CD26 cells, increased incidence of atopy and antibiotic sensitivity, and high rates of autoimmunity. This elevation in autoimmunity is reflected by high levels of antibodies to smooth muscle, parietal cells, brush border, thyroid, myelin, and elevated antinuclear antibody (ANA).43
Allergy and Asthma
Increased rates of asthma and allergy have been clearly linked to outdoor air pollution.44 A day or two after ambient ozone levels spike, persons with asthma have exacerbations of their breathing problems.45 Hikers who encounter elevated levels of ozone also experience reduced lung function. With each additional 50 ppb of ambient ozone levels, hikers experience a 2.6% decline in forced expiratory volume and a 2.2% decline in forced vital capacity.46 When persons with asthma and allergies encounter diesel exhaust particles, their allergic problems increase.47 Even those individuals without a history of allergies can become allergic when exposed to diesel emissions at the same time as an allergen. Herbicide and pesticide exposures,48 as well as exposure to phthalates (plasticizers) in house dust have also been associated with increased risk for asthma.49
Autoimmunity
The development of autoimmunity has been linked with chemical exposure as well. The notion of chemically-induced autoimmune states is, of course, not new because many chemicals are known to induce the onset of systemic lupus erythematosus. Some chemicals, like formaldehyde and other volatile organic compounds, are thought to induce tissue-specific autoimmune reactions by acting as haptens. These low molecular weight molecules bind to various tissues in the body, making a new antigenic combination. The immune system then makes an antibody to this new combination that can attack the parent tissue with or without the chemicals being present. Chemically exposed individuals will often present with elevated antibodies to certain body tissues, including antimyelin, antiparietal, anti-brush border, and antismooth muscle.50 A study of 298 patients with exposure to industrial chemicals revealed several immunologic abnormalities, including autoantibodies against smooth muscle (odds ratio [OR] 3.99), parietal cells (OR 9.7), and brush border cells in the small intestine (OR 14.45), the thyroid, and myelin sheathing.51
Autoimmune hypothyroidism is becoming a much more commonly seen problem in physicians’ offices and can be secondary to exposures beyond just OPs.52 The presence of elevated levels of antinuclear antibodies has also been associated with pesticide exposures other than organophosphates.53
A number of investigators have reported that mercurials are also capable of immune activation, leading to autoimmunity while simultaneously reducing the cellular immune response leading to increased infection,54–57 which is the classic appearance of immunotoxicity.58 In genetically susceptible mice, the presence of mercury dramatically increased their autoimmune response with increased antifibrillarin antibodies.59
Neurotoxicity
The neurologic system is also a frequent target for xenobiotic compounds. Some patients will present primarily with neurotoxicity symptoms, whereas others may exhibit immunotoxicity signs and symptoms first. The most common neurotoxicity symptoms include reduced cognitive functioning (often referred to by the patient as “brain fog” or “crooked brain”), headache, memory problems, and mood disorders. Tremors, balance problems, and anxiety can also be present (Box 35-1). Although there are indications that xenobiotics may play a role in certain neurologic illnesses, Parkinsonism is the illness that shows the most association.
The nervous system is a unique target for toxic agents in several ways:
1. The adult neuron does not divide and, therefore, replacement of lost neurons is not possible. Nerve cells killed by toxins cannot regenerate.
2. The blood–brain barrier does not block nonpolar substances or items that are actively transported.
3. Because the normal function of the nervous system requires the action of a complex integrated network, damage to even a small portion of the nervous system sometimes can result in marked effects on function.
4. Neurons are dependent on glucose and oxygen, and some cell bodies exist at borderline levels of oxygen. If high energy demands are placed on the system and delivery of oxygen is reduced, then cell death may occur.
5. Because of high lipid content (myelin), there is an accumulation and storage of lipophylic xenobiotics.
6. Neurons have high surface areas and, therefore, increased exposure to toxins.
Unfortunately a great many of the common xenobiotic toxics in our bodies are potent neurotoxins. All of the major classes of pesticides kill pests by virtue of their neurotoxic actions. Chlorinated pesticides and pyrethroids disrupt the ion flow along the axon, whereas organophosphates (which came out of nerve gas research in Germany between the first and second world wars60) and carbamates are potent acetylcholinesterase inhibitors (resulting in excessive acetylcholine levels in the synaptic clefts). Solvents, some of which were originally used as anesthetics, dampen the propagation and transmission of electrical impulses along the nerve axons. All of these agents produce various forms of toxic encephalopathy (acute or chronic, selective, or diffuse toxic encephalopathies). Many environmentally ill patients present to their physicians with chief complaints that fit this diagnostic category.
Pesticide Neurotoxicity
Organophosphates
Greenhouse workers who were exposed to OPs exhibited higher incidences of depression, headache, tremors, and paresthesias.61 Polish female greenhouse workers exposed to OPs exhibited longer reaction time and reduced motor steadiness than unexposed workers. They also reported increased tension, depression, and fatigue more than controls reported.62 Dutch farmers and gardeners who used OPs frequently had much higher risk of developing mild cognitive dysfunction than others.63 Farmers repeatedly exposed to OPs from sheep dip showed much greater vulnerability to psychiatric disorders than controls (quarry workers). They also performed worse than controls on cognitive testing that assessed attention span and how fast they processed information.64 None of the persons in any of these studies fit the definition of acute OP toxicity and none had dramatic reductions of acetylcholinesterase.
Neurologic problems from OP exposure can also persist. A study of persons previously poisoned by OPs revealed many abnormalities, including memory, abstraction, intellectual functioning, mood, and motor reflexes. They also had greater distress and complaints of disability.65 A different study of OP workers also revealed diminished memory, learning, and vigilance, but also found diminished plantar and ankle reflexes.66 The authors noted that the persons with these problems had similar acetylcholine levels as those who did not exhibit these differences. Abnormal deep tendon reflexes were found, along with diminished coordination and muscle strength in Ecuadorian persons exposed to OPs.67
Chlorinated Pesticides
Early controlled trials of airborne exposure to low levels of DDT revealed that exposed subjects would experience neurologic symptoms, including dimming of vision, a drawing sensation at the base of the nose or behind the eyes, a sense of fullness deep inside the skull, headache, slowness of thought, inability to concentrate, and short-term memory loss.68 Various muscle symptoms also occurred, including weakness, fatigue, dysphagia, and ataxia. Demonstrable reductions in electromyographic readings were found after nasal exposure to DDT that might account for such symptoms.69
A study that compared retired malaria control workers with a reference group of retired persons who did not handle DDT revealed that the exposed group had significantly poorer performance on cognitive, sensory, and motor testing. They did particularly poorly on the cognitive testing (verbal attention, visuomotor speed, and sequencing) and reported significantly more psychiatric symptoms than controls reported.70
Neurologic effects of chlordane exposure were studied in a group of persons who lived in an apartment complex where chlordane was used. Seven years after the application occurred, residents and former residents of the complex were assessed. Significant changes were found in the exposed persons, including reduced reaction time, balance dysfunction (shown by increased sway speed), reduction in cognitive function, perceptual motor speed, and immediate and delayed verbal recall. They also had worse scores for mood, including increased tension, depression, anger, and fatigue.71
Solvents
Chronic toxic encephalopathy (CTE) from solvent exposure will often gradually improve in 50% of cases with elimination of solvent exposure (Box 35-2). However, 50% will not improve from mere avoidance in the time frame of 6 to 42 months after initial assessment. It is interesting to note that in one study persons on antidepressants were nearly four times more likely to have persistent CTE than those not on the medications.72 Although the study failed to list which antidepressants were used, many of the antidepressant medications were known to be inhibitors of the CYP system in the liver. Workers with a genetic polymorphism affecting glutathione production had a dramatically increased risk for the development of CTE.73 It is therefore possible that the reason for such poor recovery from CTE after leaving the main source of solvent exposure is the rate at which the liver can clear these compounds from the circulation. In persons with CTE, brain atrophy was noted in over 50% of them using computed tomographic scan.74
BOX 35-2 Chronic Toxic Encephalopathy (CTE): Designations of Solvent-Induced Neurotoxicity
1. Affective syndrome: neuropsychiatric symptoms, no signs of impairment, reversible.
2. Mild chronic toxic encephalopathy: neuropsychiatric symptoms, proven impairments, uncertain reversibility.
3. Severe chronic toxic encephalopathy: more severe neuropsychiatric symptoms, more pronounced impairments, usually irreversible.
Data from World Health Organization meeting on Organic Solvents, Copenhagen, Denmark, 1985.
Shipyard painters were found to have significantly higher scores for neurotic behaviors than controls reported.75 They were also found to have significantly greater problems with short-term memory, concentration, fatigue, dizziness, and insomnia. They also noted more trouble with a feeling of pressure in the chest and perspiration without work. One of the questions most frequently answered affirmatively by the group (in significantly higher levels than controls) was, “Do you often have to go back to check things that you have done, such as turned off the stove, locked the door, etc?”76
Female workers exposed to toluene showed significantly more problems with manual dexterity, visual scanning, and verbal memory.77 The authors of this study noted that the workers who exhibited these changes on neurobehavioral testing showed absolutely no clinical signs of toxicity!
Heavy Metal Neurotoxicity
Lead
Lead is a well-recognized neurotoxin leading to multiple problems in children, including reduced IQ scores,78 and attention79 and behavioral problems. Parents of children with lead burdens report that their children have more somatic complaints and delinquent, aggressive, internalizing, and externalizing behavior. Their teachers report that the children have more problems with anxious/depressed behavior, social problems, attention problems, and delinquent, aggressive, internalizing, and externalizing behavior.80 In Yugoslavian children, specific intelligence testing revealed that lead was most damaging to perceptual–motor aspects of intelligence rather than language-related aspects.81 Lead exposure in children may also be a factor in pervasive developmental disorders, including autism.82 A number of studies have also clearly linked lead burden in children and attention deficit hyperactivity disorder.83–85
When persons who were lead exposed in childhood were studied 20 years later, neurologic deficits were still found. In this group, significant adverse central and peripheral neurologic effects were present. Peripheral nerve function was altered, as were measures of coordination, reaction time, dexterity, learning, and mood.86 As persons with lead exposure grew older, their memory capacity continued to decline, at rates faster than aging could account for.87
Lead workers have consistently shown neuropsychologic problems at levels significantly higher than those of controls. These problems include visuospatial, visuomotor, comprehension, and symptoms of depression, insomnia, fatigue,88,89 and postural sway.90,91 When bone lead burden was measured in older individuals, none of whom had industrial exposures to lead, a clear association was correlated with mental function. As the total bone lead (measured by fluoroscopy of the tibia) increased, cognitive function decreased in a group of older individuals from Baltimore.92
Recently, lead burden has been associated with increased risk for the development of Parkinsonism.93
Mercury-Induced Neurotoxicity
Mercury in both organic and inorganic forms is neurotoxic. Methylmercury accumulates in the brain and is associated with mitochondria, endoplasmic reticulum, Golgi complex, nuclear envelopes, and lysosomes. In nerve fibers, methylmercury is localized primarily in myelin sheaths, where it leads to demyelination.94 Mercury is also known to inhibit the uptake of dopamine,95 serotonin,96 and norepinephrine97 at synaptic sites. Mercury apparently has a higher binding affinity for serotonin-binding sites.
The widespread pollution of Minamata Bay, Japan, by methylmercury in the 1950s provided researchers with a clear picture of methylmercury-induced neurotoxicity. Known as Minamata Disease, the neurotoxic signs included ataxia, speech impairment, constriction of visual fields, hypoesthesia, dysarthria, hearing impairment, and sensory disturbances. These neurologic problems persisted and were found in other areas of Japan as the mercury contamination spread through fish consumption.98 Follow-up studies in the Minamata area almost 40 years after the spill and almost 30 years since a fishing ban was enacted for the area showed the persistence of mercury neurotoxicity. Residents in fishing villages in the area in 1995 reported significantly higher prevalences than “town resident controls” in males for the following complaints: stiffness, dysesthesia, hand tremor, dizziness, loss of pain sensation, cramping, atrophy of the upper arm musculature, arthralgia, insomnia, and lumbago. Female residents of the fishing villages had significantly higher incidents of complaints of leg tremor, tinnitus, loss of touch sensation, leg muscular atrophy, and muscular weakness.99
In the Amazon, children exposed to methylmercury from local gold mining have also been studied for the neurotoxic effect of methylmercury. In the villages studied, more than 80% of the children had hair mercury levels above 10 mcg/g (a level above which adverse effects on brain development are likely to occur). Neuropsychological tests of motor function, attention, and visuospatial performance in these children showed decrements associated with hair mercury concentrations.100 Patients in an internal medicine practice in San Francisco who consumed large fish regularly and had mercury blood levels above 5 mcg/L presented most commonly with fatigue, hair loss, trouble thinking, memory loss, muscle aches, and headaches.101 One peculiar symptom in this group was a metallic taste in the mouth.
Mental health symptoms are also quite common with mercury toxicity. Evidence linking mercury exposure to psychological disorders has been accumulating for the last 60 years. The recognized psychological symptoms of mercury include irritability, excitability, temper outburst, quarreling, fearfulness, restlessness, depression and, in some cases, insomnia. In a study of individuals with amalgam filling who had them removed, the majority noted psychological improvements. The greatest improvements were found in anger outbursts, depression, irritability, and fatigue.102 None of these manifestations were too surprising when related to the effect of mercury on reducing the serotonin effect. The association of mercury to depression has stimulated some interesting questions as to whether mercury toxicity was to blame for Sir Isaac Newton’s health problems of 1692 to 1693.103
Endocrine Toxicity
The most common presentations of toxic damage to the endocrine system are:
1. Sleep disturbances or changes in energy level or mood.
2. Alterations in weight, appetite, and bowel function.
3. Sexual interest and function change; in females, any menstrual change.
4. Changes in temperature perception, sweating, or flushing.
The most common endocrine diagnoses associated with xenobiotic burden include:
Infertility
Pesticides, solvents, aromatic hydrocarbons, heavy metals, and chemical dusts have been associated with both male and female infertility.104
Herbicides and Organophosphate Pesticides
A study of Ontario farmers showed an association of female pesticide use with fecundity,105 and the relative risk of being infertile from pesticide exposure was 3.8. Five compounds reduced females’ fecundity rates 24% to 49%: Dicamba (0.51), glyphosate (0.61), 2,4-D (0.71), organophosphates (0.75), and thiocarbamates (0.76). Glyphosate is commonly known as “Roundup” and is highly advertised in print and on TV for its safety, yet was clearly associated with infertility in this study. In a study of Spanish greenhouse sprayers exposed to OPs, higher spontaneous abortion rates were found, along with higher rates of depression and headaches.106 Although these health problems were clearly evident, no significant decrease in erythrocyte acetylcholinesterase was found. This reproduced other studies showing apparent adverse organophosphate health effects without the expected serum finding indicating an acute OP toxicity. A study in California farming counties showed a clear association with pesticide spraying and fetal death due to congenital anomalies.107 In this study, when an OP or carbamate pesticide was sprayed in one of eight adjacent square miles of women’s residences during the third to eighth week of pregnancy, the OR of fetal death was 1.4. When the spraying occurred within one square mile of a residence, the OR increased to 2.2.
Chlorinated Pesticides and Polychlorinated Biphenyls
Chlorinated compounds were studied in a German clinic for association with reproductive difficulties.108 Hexachlorocyclohexane (HCH) serum levels were significantly associated with miscarriage history and uterine fibroid presence. Higher HCH and PCB levels were also noted more frequently in women with antithyroid and antinuclear antibodies. PCB exposure and elevated antithyroid antibodies have also been reported elsewhere.109 PCB serum levels were significantly associated with endometriosis and increasing DDT levels with reduced conception. Pentachlorophenol (PCP) levels were also found to be associated with increased miscarriage rates and levels of ANA.
A noncontrolled study in Canada looked for the presence of certain xenobiotics in the serum and follicular fluid from infertile females and seminal plasma from their male partners.110 These eighteen couples all attended an in vitro fertilization program in hopes of becoming parents. They found DDE, mirex, HCH, trichlorobenzene, and three different PCBs in more than 50% of all follicular fluid samples. Four different PCBs, DDE, and endosulfan were also found in over 50% of all serum samples. DDE was the most frequently found contaminant, had the highest residue, and was negatively associated with fertilization. Of the couples tested, those who failed to achieve pregnancy with in vitro fertilization methods generally had higher toxic levels than successful couples. It is unfortunate that these authors did not get a matched control group of fertile couples to compare the toxic burden.
In the same Canadian study, women with higher DDE levels had greater trouble conceiving. This finding was also noted in the previously mentioned German study and was recently re-documented as a generational effect as well in a group of women from Oakland, California.111 In this study, serum levels of DDT/DDE were measured from maternal samples at the time of birth. The time it took these daughters to conceive were then followed for 28 to 31 years. Differing generational effects were found for both DDT and DDE. Maternal levels of DDT were associated with reduced fecundity (32% less) in their daughters, whereas DDE levels were associated with increased fecundity (16% greater).
Solvents
Occupational solvent exposure has been associated with infertility (OR 1.76) and tubal-factor infertility (OR 1.95).21 Reduced fecundity has also been shown in female toluene workers (fecundity rate [FR] 0.47)112 and in laboratory workers exposed to organic solvents (FR 0.79).113 Toluene was also associated with a reduction in luteal phase luteinizing hormone in both males and females.114 In laboratory workers, the greatest reduction of fertility was found in association with acetone exposure (FR 0.72). Chronic benzene exposure was associated with abnormally long menstrual cycles.115 Wives of men who worked around organic solvents also showed decreased fecundity (FR 0.36).116 A study in Chinese female chemical plant workers revealed an increased risk (OR 2.9) for spontaneous abortions.117 Of the myriad of petrochemicals they were exposed to, benzene (OR 2.5), gasoline (OR 1.8), and hydrogen sulfide (OR 2.3) all showed independent significant association with miscarriages. A study in pharmaceutic factory workers also showed increased spontaneous abortion risk from multiple solvent exposures.118 The risk increased as the number of solvents used increased, with the greatest risk found in those who were exposed to four or more solvents. In pharmacy assistants, an increased risk was found for stillbirths and perinatal death for those with solvent exposure.119 A National Institute Occupational Safety and Health study of forest service workers exposed to two different paints used to mark trees revealed a 177% and a 181% increased risk of miscarriage over workers who were not exposed to these paints.120 Those forest workers who were exposed to herbicides had an 82% increase in their risk as well. A single case of first-trimester maternal exposure to the solvent N-methyl-2-pyrrolidone, resulting in fetal death in week 31 of gestation, was also reported in the literature.121
Hypothyroidism
PCBs have been closely studied for their possible adverse effects on thyroid hormonal status and function. Both PCBs and thyroxine are made of two connected benzene rings with attached halogens; PCBs having chlorine molecules and thyroxine with iodine. Interestingly, the common human contaminant bisphenol-A is also structurally similar, with two bromine molecules on each of the rings. PCBs have demonstrated in vitro activity in binding transthyretin, a transport protein mechanism for thyroxine.122 This effect of blocking the transport of thyroxine via this molecule (which does not affect thyroxine-binding globulin) is also found with dioxins and furans. They also appear to adversely affect the thyroid hormone metabolizing enzymes (uridine-diphosphate-glucuronyl transferases, iodothyronine deiodinases, and sulfotransferases) found in the liver and brain.123
Elevated antithyroid antibodies, both antiperoxidase and antithyroglobulin, were found in workers in a PCB manufacturing plant.109 This is reflective of the earlier noted study,108 in which PCBs and HCH were frequently found in infertile German women with antithyroid and antinuclear antibodies. Surprisingly, no difference was found in the levels of T4 and thyroid stimulating hormone (TSH) in these 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) workers than in the control group. One of the limitations in this and other studies looking at the effect of toxins on thyroid function is the use of TSH normal ranges. Only TSH levels that are above the upper limit of normal, showing a gross hypothyroidism, would be considered an abnormal finding. Many alternative clinicians have found that TSH levels between 3 and 5, within laboratory normal ranges, typically indicate subclinical hypothyroidism. The use of the term subclinical here can be misleading, because the individuals in questions typically present with symptoms of hypothyroidism and note dramatic symptomatic improvement with proper thyroid hormone replacement. At least some of the workers in this study with elevated antithyroid antibodies would certainly be expected to eventually have elevated TSH and reduced T3 or T4 levels and would have found symptomatic improvement with replacement of these hormones.
A recent study in Sweden examined women who were exposed to PCBs from consuming at least two meals of fish from the Baltic Sea each month. Their PCB serum levels were measured along with their FT3, TT3, FT4, and TT4 levels, which revealed a significant inverse correlation between PCB levels and TT3 and an insignificant inverse correlation with TT4.124 German children showed a significant positive correlation between PCB serum levels and elevation of TSH.126 They also showed a significant inverse correlation between serum PCB levels and FT4, as one would expect to find with increasing TSH levels.
Chlorinated pesticides have also been associated with hypothyroidism. A study of Indian women looked for any association between DDT and dieldrin in women with elevated TSH and depleted T4. DDT was found to be higher in all of the hypothyroid women, though not significantly, but dieldrin was significantly associated with low T4 levels.125 As mentioned previously, pesticide applicators had elevated TSH levels during the seasons in which they sprayed most (summer to fall). These applicators used both OPs and fungicides.
Adult-Onset Diabetes
The incidence of adult-onset diabetes has risen in the last decade at rates much higher than previously recorded.127,128 Although there is clear association with a variety of lifestyle choices to the risk of diabetes, new information is also pointing to a xenobiotic link.129 Arsenic, naturally present in groundwater throughout the world, has been associated with the development of diabetes.129,130 Arsenic is present in some of the following foods: shellfish, chicken, and rice, and is high in cigarette smoke. The presence of chlorinated pesticides and dioxins have also been linked to the development of diabetes.131 In this study, the OR for developing diabetes was 2.5 for those with the lowest levels of PCB 153 in their blood and was 6.8 for those with the highest levels. The chlordanes trans-nonachlor and oxychlordane had ORs of 2.7 (each) for those with the lowest blood levels of these termiticide residues, and ORs 11.8 and 6.5, respectively, for those with the highest blood levels present. When the sum of all six bioaccumulative toxins were combined, the odds of developing diabetes went from a low of 14-fold to a high of 37.7-fold for those with the greatest fat-soluble burden. Studies examining other persistent pollutants have also revealed greater diabetes risk.132
Diagnostic Methods
However, because of the ubiquitous nature of the chemicals in question, a history may not always give a clear picture of exposure. Other laboratory tests may be helpful in these cases. A standard complete blood count and general blood chemistry test is usually nonremarkable in cases of chronic low level exposures (although the author often finds leukopenia present in his population of toxic patients). In his patient population, the author rarely finds elevated levels of liver enzymes, even when solvents and pesticides are present in the serum. This has also been reported in the literature with persons occupationally exposed to solvents.133
Serum tests for the presence of the most common, and most harmful, chlorinated pesticides, PCBs and solvents can prove invaluable. The publication of the CDC’s National Reports has revitalized this area of laboratory medicine, because it provides national reference values for many of these compounds for the clinician. Before the publication of these data, the clinician had to rely on industrial-derived reference values or reference values from the pool of information that the laboratory itself had derived from its clients. For the biologically persistent PCBs and chlorinated pesticides, the CDC gives levels both in parts per billion and as lipid-adjusted (nanogram per gram lipid) values. These fat-soluble toxins are released from adipose tissue along with triglycerides and cholesterol.134 Previously published research actually found that quantifying the fat-soluble xenobiotics according to the amount of lipids in the blood corresponded excellently with the amount of xenobiotics present in adipose biopsies of the same person.135 Using the lipid adjusted values as a glimpse of the adipose burden of these compounds also allows the clinician to monitor the effectiveness of their depuration treatments. Follow-up testing would allow one to see if the body burden was decreasing.
Heavy metals can be measured in the hair, blood, urine, and stool. Blood levels are mostly indicative of current exposure levels and are still considered by many physicians to be the only valid method of heavy metal assessment. Unfortunately, the blood reference values for heavy metals are typically based upon industrial medicine standards for toxicity in the workplace. Fortunately, the CDC national reports again provide the national normal ranges for most of the heavy metals in blood and in urine (given as microgram per liter and microgram per gram creatinine). Utilizing both pre- and post-challenge urine tests for heavy metals can reveal if the patient is currently exposed and provide information on the appropriateness of the chosen heavy metal “chelating” agent.136 When used with an oral chelating agent, doing a pre- and post-challenge test can also reveal information about the absorptive ability of the person (or lack thereof).137
Treatment Methods
1. Avoidance of further chemical exposure. This should not be overlooked, although it is often the most difficult step for compliance. In cases of multiple chemical sensitivity, this step is indispensable. By simply having a chemically-safe dwelling, many persons with chemical sensitivity begin to improve.138 Compounds to be avoided include solvents, paints, exhaust fumes, perfumes, hair sprays, new furniture, carpeting, cabinetry, plastics, gas or oil heat, etc. Because the home is the environment that is most in one’s control, the home must be made a “safe oasis.” If there are building materials that are off-gassing chemicals and these materials cannot be removed, they should be sealed. There are a number of good books available to help with these issues.*
In addition to avoiding environmental chemicals, any foods that cause adverse reactions should be avoided (see Chapter 15 on Food Allergies). Organic foods should be used wherever possible, as well as purified water. Avoiding the “dirty dozen” fruits and vegetables (www.foodnews.org), along with all farmed salmon, high mercury fish, and nonorganic dairy products will significantly reduce toxin exposures by food.
2. Dietary support. The best macro-diet choice (in addition to organic foods) is to consume a diet with high protein, low carbohydrate, and low fat. Such a diet helps Phase 1 biotransformation significantly.
Although protein deficiency clearly reduces the ability of the body to adequately metabolize chemicals,139 the opposite also appears to be true. Isocalorically increasing the ratio of dietary protein to carbohydrate ratio in well-nourished volunteers was shown to enhance clearance of antipyrine and theophylline. Although it was not clear if the effect of the protein was due to the amino acid content alone, it was known that methionine and cysteine deficiency led to reduction of intestinal and hepatic MFO enzyme activity. Hepatic MFO activity can also be suppressed by folic and choline deficiency. Low methionine intake also impacts selenium metabolism by making less selenium available for gluthathione-peroxidase biosynthesis. High sugar intake is also known to reduce the clearance of certain chemicals from the liver.
Rice bran fiber (RBF), which can be found in a diet high in brown rice or using RBF as a fiber supplement, has been shown to have a high binding ability with PCBs and other toxins, including the combustion by-product benzo(a)pyrene in a laboratory setting.140 When measured against other fibers, RBF demonstrated the ability to dramatically reduce the reabsorption (termed “hepatic recycling”) of PCBs from the intestines in animals.141 Hepatic recycling occurs after the liver dumps some of these toxins into the intestines with bile, but when these compounds make it to the small intestine, they are reabsorbed into the bloodstream and sent back to the liver. This recycling pattern is the main reason why such a minute amount of these toxins actually make it out of the body. Although RBF helps to break this recycling and gets more toxins to leave, wheat bran showed absolutely no benefit in this regard.142 A study using either spinach fiber or RBF in animals that had been exposed to PCBs showed that RBF increased fecal PCB excretion 6.6 times and spinach fiber 4.1 times.143 Another animal study showed that a 10% RBF diet increased the excretion of toxic furans 4.5 times that of placebo.144 A few studies were done on a fermented RBF product that is available as a food item in Japan. PCB-burdened patients who consumed 7 to 10 grams of it three times daily (after each meal) for a year had twice the amount of dioxin excretion as their counterparts who did not consume that much fiber.145
Chlorophyll has long been thought of as a blood purifier and recent studies have documented its effectiveness at helping to clear persistent chemical pollutants from the body. As previously mentioned, both spinach fiber and matcha green tea increased the excretion of chlorinated persistent pollutants. Both of these compounds have chlorophyll, which may be a part of their effectiveness. The seaweed nori, which also contains chlorophyll, was tested in rats to measure its power at helping to clear dioxins. Rats fed a diet of 10% nori had an increase in fecal excretion of two different dioxins at levels 5.5 and 6.0 times more than the control group.146 Chlorella, long a popular “detoxification” agent was also tried with dioxin-contaminated rats. The group of rats given chlorella had increased dioxin excretion that varied from 30% to over 300% higher than the control group.147 Postulating that it was the chlorophyll content of the chlorella that was the active ingredient, this group of researchers then set out to measure that hypothesis.
The effectiveness of chlorophyll alone on the excretion of dioxins and furans from rats was quickly established. The higher the content of chlorophyll in the diet, the greater the excretion of these fat-soluble persistent toxins in the feces. The ranges of chlorophyll went from a low of 0.1% to a high of 0.5% in the diet. A diet with 0.1% chlorophyll is roughly equivalent to consuming 10% of your diet as spinach or 20% as seaweed. In the 0.1% group, the fecal excretion of the various toxins ranged from 40% to 80% greater than the control group. At the end of the study, all of the animals that were given chlorophyll had a lower total body burden of these persistent toxins than their counterparts.148
Because chlorophyll turned out to be the active agent in binding some of these toxic pollutants and increasing their levels in the stool, the next step was to check how well chlorophyll-containing vegetables did in lowering toxic burden. In this study, rats were fed either a diet with or without 10% vegetables. As with the previous study, the higher the level of chlorophyll in the vegetables, the higher the rate of excretion of the toxins.149 The vegetables with the smallest increase in fecal dioxin excretion (60% to 300% increase) were Chinese cabbage, broccoli, onion, Welsh onion, cabbage, and celery. The vegetables with the next highest dioxin excretion (330 to 480% increase) were kale, Chinese chive, Shungiku, Chingensai, green lettuce, and sweet peppers. The group that topped the charts with an increased dioxin excretion of 760% to 1160% were: Komatsuna, mitsuba, spinach, and perilla. So, here again we have spinach topping the charts. However, because spinach is 1 of the top 12 most toxic vegetables, one would need to find organic spinach or use some other form of chlorophyll. The same can be said for seaweeds’ toxin mobilizing ability, which has been previously discussed. Seaweeds have been found to be highly contaminated with heavy metals and, therefore, are not a good addition to diet or health plans.
3. Nutritional supplementation. In cases of toxic overload, supplementation can be tricky, as some persons with severe chemical reactivity can react to many of the nutrients that are normally needed. In his four-volume treatise on Chemical Sensitivity, Rea stated that his chemically burdened patients were typically deficient in magnesium, selenium, and Vitamin B6 (whether or not they were taking oral supplements of these).5 Supplementation with high levels of antioxidants is typically recommended because all of these xenobiotics have been shown to cause oxidative damage.
4. Depuration (cleansing). The removal of impurities from the body is known as depuration. This is the preferred term for cleansing xenobiotics from the body. Besides all of the literature about the use of RBF and chlorophyll for depuration, two additional methods have been discussed in the scientific literature: fasting and sauna.
Most of the published literature is from one of the Health Med clinics associated with the Church of Scientology, which performs the “Hubbard Purification Rundown.” This protocol utilizes exercise, high temperature saunas, increasing doses of niacin, and electrolyte replacement. They published studies showing the benefit of this protocol for reducing levels of PCBs, polybrominated biphenyls (PBBs), and hexachlorobenzenes.150–152 Their studies, along with unpublished information from Environmental Health Center, Dallas (EHC-D), with William Rea, MD, showed that sauna therapy reduces xenobiotic levels in treated individuals.
The only published treatment besides sauna therapy that has shown benefit in treating poisoned individuals is fasting. This has been documented in a single study that examined individuals poisoned by PBB contaminated rice bran cooking oil in Taiwan.153 Although fasting reduced their symptoms, it increased the level of circulating xenobiotics in their serum. Presumably the elevation of circulating toxins was due to the increased rate of lipolysis in fasting individuals. Thus, the fat soluble PBBs were released from storage into the bloodstream in higher than normal rates. At that point it, would have been up to the liver to clear these out of the serum or they would have been redeposited into the adipose tissue. More research is obviously needed on the role of fasting in the treatment of environmental overload.
A comprehensive naturopathic protocol for treating environmentally poisoned individuals was developed by the author and has been in use for over 10 years. An outcome study on persons who underwent this protocol for a variety of chemically-induced ills revealed it to be surprisingly effective. Of all the various problems treated with the depuration protocol, 83% of the participants rated their results as good or great. The two conditions in which 100% of the participants reported great results were asthma (n = 3), and addiction recovery (n = 1). There were several problem (chief complaint) categories in which 100% of the participants rated their results as moderate/good or great. Those categories were autoimmune, dermatologic, and gastrointestinal, and/or liver. The categories with the next highest ratings of moderate/good and great were fatigue with 92% improvement, allergies with 85%, and chemical sensitivities with 84% improvement.154
The Crinnion Depuration Protocol
The Crinnion Depuration Protocol consists of the following components:
1. Daily exercise. Exercise usually consists of using an exercycle, rebounder, or brisk walking to begin lipolysis and diaphoresis.
2. Thermal chambers. Up to 36 minute “sauna” sessions are done with temperatures at a range of 120°F to 135°F with cool-down periods in between. Glass bottled spring water is given along with electrolyte replacement. Although the Hubbard clinics use higher temperatures, we found that individuals will put out more toxins (as evidenced by stronger chemical odors), and will have less adverse symptoms when lower temperatures are used. The thermal chambers will increase the rate of lipolysis in the adipose tissue throughout the body. When this occurs, the lipophilic xenobiotics will be released into the bloodstream. Those compounds in the subcutaneous fat pads will be mobilized through sweat as well as into the blood.
3. Constitutional hydrotherapy. This uses alternating hot and cold towels with sine wave stimulation as done by Drs. O.G. Carrol and Harold Dick. This therapy has been used for decades to stimulate the body’s own self-healing activity. We found that it also increased the amount of toxin-laden bile dumped from the liver into the intestines. Also assisting the choleretic and cholagogue action on the liver is an herbal capsule taken daily consisting of Chelidonium, Chionanthus, Taraxacum, Arctium lappa, Silybum mar., and Urtica dioca.
4. Colonic irrigation. Gravity fed machines are used to gently introduce triple-filtered water into the large intestines, providing an avenue for toxic bile to rapidly leave the body. Individuals will routinely have “liver dumps” of bile that range in color from yellow to red, with occasional gray or brown. The color of bile normally ranges from green to yellow to orange to red depending upon the amount of time of exposure to bacterial action in the bowel. However, in this situation we believe that it is dumped from the liver and rapidly passed through the small intestines, similar to what is seen in “gastric dumping” syndrome. We are therefore unable to account for the differences in color of this effluent. In some patients with heavy agricultural exposure, we have seen higher amounts of fluorescent yellow bile. Hence, the color of the bile may be more attributable to the chemical compounds in the bile than the bacterial action upon the bile. We have documented that chlorinated pesticides are present in the effluent, which we refer to as “bile dumps.”
5. Constitutional homeopathy. This has been used primarily as a stand-alone treatment with the use of any other supplemental and treatments prohibited. However, we have found it to be a valuable component of this protocol and completely compatible with all the other treatment methods involved. It appears most beneficial in those individuals who need a boost for their vital force to get them moving toward healing, and for those who are stuck in emotional issues that they have not been willing to look at.
6. Body therapies (massage, Shiatsu, craniosacral, visceral, chiropractic). These are done as needed for the individual to treat specific musculoskeletal problems and to assist in mobilizing toxins that are stored in the tissues.
7. Counseling. Mental and emotional toxins are as big a problem as physical and/or chemical toxins. When people are exposed to powerful emotional toxins (abuse, etc.) that they have no outlet for handling, they end up “stuffing” the emotional toxins. When this emotional stuffing occurs, any physical toxins that they are exposed to at that time are also stuffed (stored) rather than being eliminated. Because of this, when they start to mobilize the physical toxins, the old emotional issues will come back into consciousness. When individuals choose to again suppress the emotional issues (rather than facing them), their physical cleansing will also stop. This is evidenced by the observations that they will stop sweating in the thermal chambers, stop heating the cold towels in the hydrotherapy, and stop having good liver releases in the colonic therapy. When the emotional “toxins” are faced and released, then these cleansing parameters are returned to former levels. Assisting all of the individuals going through this depuration protocol with their emotional issues helps them to cleanse physically.
Summary
Exposure to many of the ubiquitous xenobiotic toxicants can be easily eliminated by simple lifestyle choices (Box 35-3), although the burden of fat-stored pollutants can be reduced by depuration techniques that often can be handled through dietary changes. The diagnosis of xenobiotic-induced damage can be elucidated by a comprehensive history, along with evidence of serum toxin levels and toxin-induced immune system damage.
BOX 35-3 Treatment
Avoiding toxic exposures is mostly in one’s control
1. Avoid the 12 most toxic fruits and vegetables (peaches, apples, bell peppers, celery, blueberries, kale, nectarines, strawberries, cherries, pears, imported grapes, spinach, lettuce, potatoes); use organic varieties of these instead.
2. Freely eat all of the 15 least toxic fruits and vegetables (onions, avocado, sweet corn, pineapples, mango, asparagus, sweet peas, kiwi fruit, cabbage, eggplant, cantaloupe, watermelon, grapefruit, sweet potato, honeydew melon).
3. Do not eat any farmed or Atlantic salmon
4. Freely eat Alaskan salmon (available fresh only from June until October); canned and frozen Alaskan Salmon available year round.
5. Avoid the fish with the highest mercury content (shark, swordfish, king mackerel, tuna, orange roughy, marlin, Chilean bass, lobster, halibut, snapper).
6. Freely eat the fish with the lowest mercury content (clam, Ocean perch, Alaskan salmon, tilapia, flounder, sole, catfish).
7. Avoid all sugar—sugar reduces the ability of the liver to clear toxic compounds out of the bloodstream.
8. Begin to reduce the toxicity of the air inside the home:
1. Consume broccoli and the other members of the brassica family daily.
3. Increase levels of green foods (green leafy veggies) daily.
4. Consume brown rice daily, or take a rice-fiber supplement.
1. Multivitamin/multimineral—take a quality product daily
2. Vitamin C—begin with 3000 mg/day, for cases of high toxicity, a total of at least 9000 mg/day may be needed (unless this causes diarrhea).
3. N-acetyl cysteine—1500 to 1800 mg/day. This nutrient helps to increase the amount of glutathione in the body.
4. Magnesium citrate—1 capsule (140 mg) up to three times daily.
6. Rice bran fiber—1 tablespoon in water or juice after each meal.
7. Whey protein powder—2 scoops daily in water or organic juice—high quality whey protein will help boost glutathione level and increase the ability of the liver to clear toxins out of the blood.
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* Three good books on this subject are Less Toxic Living by Carolyn P. Gorman, available from Environmental Health Center-Dallas (214) 368-4132; Success in the Clean Bedroom by Natalie Golos, Pinnacle Publishers, Rochester, NY; and Your Home, Your Health, Your Well-Being by David Rousseau, published by Hartley and Marks, Vancouver, BC, Canada.