ENVIRONMENTAL DISEASE

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[ CATS Home | About CATS | CATS Teaching Modules | Course Outline | Environmental Pathology | UVM Department of Pathology | Other Pathology Sites | UVM College of Medicine | UVM ]

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I. INTRODUCTION
II. CAUSE AND EFFECT ASSOCIATIONS
III. IONIZING & NON-IONIZING IRRADIATION
IV. UV LIGHT & SKIN CANCER
V. ELECTROMAGNETIC ENERGY
VI. AIR POLLUTION
VII. INDOOR AIR POLLUTION
VIII. CIGARETTE SMOKING
IX. CARDIOVASCULAR DISEASE
X. SMOKING AND PULMONARY DISEASE
XI. SMOKING AND URINARY TRACT CANCER
XII. SMOKING AND DISEASES OF THE FETUS AND NEONATE
XIII. OTHERS

I. INTRODUCTION

Up to the present time in your medical education, you have been accumulating basic information regarding the structure and function of cells and tissues, and the general features of disease as it occurs in humans. We have talked very little about causation. A substantial proportion of the various diseases experienced by humans are consequent to exposure to agents in our general environment, including the workplace. Many of these, of course, are infectious and you have a course in Microbiology which considers these causative agents in detail. Today, we will discuss an additional spectrum of environmental exposures that can result in disease.

Environmental toxicology is a relatively immature field of science and there are many imperfections in our understanding of cause and effect relationships. Thus, it is often difficult to causitively associate a specific disease process with an exposure to a specific environmental contaminant. While pollutants are often ubiquitous in the environment, the individual diseases occur with relative infrequency. For example:

• The UV rays of sunlight are the accepted cause of skin cancer, yet cancers of the skin occur relatively infrequently and usually in the elderly;
  
  
• Cigarette smoking is the major cause of lung cancer, yet only a small proportion (10 to 15%) of the men and women who smoke develop lung cancer (decades later);
  
  
• Benzene, a recognized cause of leukemia, is found at low concentrations almost everywhere in the air we breathe. Medical radiation with X-rays, another known cause of leukemia, has been experienced by us all. Yet, leukemia accounts for only 1% of adult deaths;
  
  
• Asbestos is ubiquitous in the human environment, yet the asbestos-related diseases occur infrequently.

What, then, is the explanation for these apparent discrepancies? Listed below and briefly discussed are some of the paramount considerations which environmental scientists must address in attempting to establish cause and effect relationships.

• DOSAGE EFFECTS (concentration and duration of exposure) are key considerations. At the outset, this seems obvious, but it is often difficult to know what dosage of an agent is required to cause disease, and what amounts can be tolerated by humans. These are critical considerations as society attempts to develop regulations to control environmental pollution. Some environmentalists argue that even a minute exposure can result in disease in a small proportion of the population. To what extent are they correct?
  
  
• LATENCY PERIODS (i.e., the interval from the time of exposure to the time clinical disease develops) are often long. For example, lung cancer rarely develops in smokers with less than 20 years of exposure. Mesothelioma often requires 30, 40 or 50 years to develop after exposure to asbestos. Because of these long latency periods, it is often difficult to establish cause and effect relationships, and usually, the research must be done retrospectively, decades after the exposure has ceased.
  
  
• People differ with regard to SUSCEPTIBILITY to environmental pollutants. For example, compelling scientific information now indicates that we differ one from another with regard to our ability to metabolize certain chemical carcinogens, such as those in industrial effluents and cigarette smoke. The skin of a black person, because of his or her skin pigmentation, is remarkably less susceptible to the adverse effects of UV radiation than is the skin of the fair- complected caucasian. Thus, skin cancer on the sun-exposed surfaces of the body almost invariably occurs in whites.

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II. CAUSE AND EFFECT ASSOCIATIONS

• Establishing cause and effect relationships are exceedingly difficult, for most of us have little or no knowledge or understanding as to what we have been exposed to in the past. In addition, humans change their residence and occupations frequently, thus compounding the problem. Environmental pollution is not static; while some pollutants have been eliminated from our environment, other new substances have appeared. For example, during World War II, many young men were exposed to asbestos during military service or in the construction industry. Later in life, they often work in trades in which asbestos exposure is minimal or nonexistent. Yet, some 50 years later, these men are now developing diseases consequent to their exposure to asbestos in earlier decades of life. Similarly, diagnostic radiation of infants and children sporadically has resulted in disease during adulthood.
  
  
• Animal experimentation and other forms of laboratory studies are imperfect means for predicting the toxicity of a substance for humans. Most foreign substances cause disease in animals at high concentrations, i.e., dosages far in excess of those to which humans are exposed. The National Toxicological Program, sponsored by the federal government, has found that a substantial proportion (i.e., 75%) of the industrial chemicals injected into animals in long-term experiments result in the development of liver cancer in the animals. Yet, liver cancer is an uncommon and increasingly infrequent cause of disease among residents of the highly industrialized United States. Moreover, epidemiological studies have failed to show that Americans develop liver cancer as a consequence of industrial exposures. Usually, it is a result of alcohol beverage consumption.
  
  
• Most cause and effect relationships are established by retrospective epidemiological analyses. Epidemiological approaches are imperfect. In order to establish statistically reliable results, they require the study of large populations of individuals with documented exposures to environmental pollutants. In addition, these studies can rarely address dosage considerations critically and they are not applicable to unique exposures to uncommon environmental pollutants that affect only small numbers of individuals.
  
  
• Many environmental diseases are multifactorial and several different foreign substances can contribute to their development. For example, in addition to cigarette smoking, radon, heavy metals and various chemicals can play a role in the causation of lung cancer. Alternatively, nutritional factors such as the consumption of vitamin A and its analogs have a protective effect. Since humans are exposed to a variety of carcinogenic substances over a period of time, and differ one from another with regard to nutrition, establishing a cause and effect relationship retrospectively is often extremely difficult.
  
  
• The basic science of most environmental pollutants is exceedingly complex. In addition to dosage considerations, the type and form of the material as well as the route of exposure are critical considerations. For example, 95% of the asbestos used in this country is of a type (chrysotile) that rarely, if ever, causes mesothelioma. Whereas, the infrequently used (amphibole) type is the major cause of this disease. If one does not pay specific attention to this point, establishment of a cause and effect relationship between mesothelioma and asbestos exposure would be extremely difficult task.

III. IONIZING & NON-IONIZING IRRADIATION

• Ionizing Irradiation
  
  
  • X-ray
  • alpha, beta, gamma particles
  • neutrons
  • radon gas- alpha particle emitter

  
  

• Non-Ionizing
  
  
  • UV light

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IV. UV LIGHT & SKIN CANCER

• ULTRAVIOLET RADIATION (UV) is ubiquitous because it is a component of terrestrial sunlight. UV radiation forms part of the spectrum of electromagnetic radiation, with wavelengths between x-rays and visible light. It has been arbitrarily divided into three components: ultraviolet A (UVA), ultraviolet B (UVB), and ultraviolet C (UVC). Only UVA (320 to 400 nm) and UVB (290 to 320 nm) reach the earth's surface. Of the total solar radiant energy that reaches the earth, approximately 3% to 5% is UV. Depending on the time of day and atmospheric conditions UVB composes 10% or less of the total. Stratospheric ozone is crucial for the protection of living organisms because it completely absorbs UVC (200 to 290nm), absorbing UVB to a lesser extent. Exposure to UVC occurs from artificial sources of radiation, such as germicidal lamps.
  
  
• Human skin is exposed to solar UV radiation during the course of everyday life. The degree of exposure varies greatly, with geography playing a large role in determining the extent of UV exposure. The closer the latitude to the equator, the greater the UV exposure. Altitude affects the amount of UV that reaches the earth's surface. Weather conditions, including cloud cover, humidity and urban SO2 "haze" also affect the amount of UV reaching the earth's surface. SO2
  
  
• Ozone in the stratosphere above the earth absorbs UVC radiation entirely and attenuates the amount of UVB reaching the earth.
  
  
• Certain occupations require a great deal of outdoor work. Farmers and fishermen, for example, have a greater exposure to sunlight. Also, many people spend a large part of their leisure time outdoors. In our cultures, the acquisition of a suntan is looked on with favor.
  
  
• Skin cancer is an extremely common form of malignancy. Nonmelanoma skin cancers make up more than one third of all cancers in the United States. It is estimated that more than 700,000 new cases of nonmelanoma skin cancer occur each year. From 1960 to 1986, the incidence of squamous cell carcinoma increased 2.6 times in men and 3.1 times in women. The incidence of melanoma rose 3.5- fold in men and 4.6-fold in women.
  
  
• UV exposure is strongly linked to the development of skin cancer. In white people, chronic UV exposure appears to be the major risk factor for both basal cell carcinoma and squamous cell carcinoma. It is generally agreed that solar UV radiation is the major environmental cause of melanoma. Because the epidemiology of this type of cancer, strange scientists believe intense UV exposure with skin burns in childhood may be cause, rather than repeated +/or continuous chronic exposure for many years.

V. ELECTROMAGNETIC ENERGY

The health effects of electromagnetic energy commands considerable attention in the media and to a lesser extent in the scientific press. Concerns are based on a fragmentary body of epidemiological evidence suggesting that various forms of electromagnetic energy are associated with an increased prevalence of cancer in the exposed population. For example, children living in proximity to high tension electrical conduits are said to have an increased likelihood for developing of leukemia and, some evidence suggests that breast cancer is produced by magnetic fields associated with household wiring. You only need to ponder these questions briefly to realize how complex a problem one confronts in attempting to determine whether or not the electromagnetic forces that we are exposed to on a daily basis cause a disease as complex as cancer. Experimental evidence in animals is not particularly helpful in this regard and does not provide a definitive answer. Electromagnetic forces are present everywhere in our environment. The cellular phones so many Americans use on a regular basis have been incriminated in the development of brain cancer. Electromagnetic energy forces are everywhere in our home, use of television, a computer or a microwave oven have also been implicated in diseases. As of November, 1996 the evidence fails to associate electromagnetic energy with disease in humans. If the health risks exist, they must be minimal or restricted to persons exposed in unique ways to high energies. It is currently unclear how this problem will be resolved.

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VI. AIR POLLUTION

• Air pollution is a product of the industrial revolution in urban areas of Europe and the United States were heavily polluted decades ago. After the second World War, several community catastrophes occurred; weather inversion caused the accumulation of enormous concentrations of air pollutants in localized geographical areas or cities. As a result, numerous persons with chronic respiratory disease and the elderly died, provoking an enormous public concern. As a result, air quality standards began to be developed and implemented and the concentrations of the major culprits have decreased gradually ever since.
  
  
• SO2 is a product of carbonaceous fuel incineration. Thus, it is found where coal and coke or crude oil are used as heat sources or in industry. Nitric oxide and its oxidation products and ozone are released when refined petroleum products are incinerated. Expansion in our societal use of the internal combustion engine compounded by heavy automotive traffic in major urban areas results in a release of these products. NO, through a complex series of reactions, produces the photo-oxidant haze now accumulates over many urban areas on a daily basis. O3 reaches high concentrations in urban areas when air flow is reduced, particularly during the heat of the summer. Photo-oxidant hazes in and of themselves do not cause health problems, but O3 induces bronchiolar constriction and, therefore, shortness of breath in citizens of all ages, particularly those with preexisting chronic respiratory illness.
  
  
• Particulates are a subject of continuing importance. The crude particles released into the general environment years ago have largely been cleaned up by regulations and technical improvements. Nonetheless, very fine particulates continue to be found in the air of urban and industrial areas. Their presence in air is strongly correlated with respiratory systems, specifically bronchospasm of the airways. During the past year, a medical report from Provo, Utah, documented a striking relationship between the number of emergency room admissions for respiratory illness and activity in the local steel mill. A strike occurred and the number of admissions dropped off substantially, but it returned to normal levels when labor peace evolved. Particulates in the air pose engineering problems for removal that have not yet been resolved.
  
  
• In developed countries, air pollution with the gases, SO2, NOx, CO2, CO and particulates have reached crisis proportions. Energy generation and automobile exhaust are the major sources, but heavy industry contributes a substantial amount in some urban areas. The topic of air pollutions technically exceedingly complex and beyond the scope of our expectations for you. In the lecture I will discuss the various facets of this field, but YOU WILL NOT BE EXPECTED TO KNOW THE DETAILS.
  
  
• In urban communities, weather inversion resulting in air pollution emergencies have been associated with increases in the number of residents with symptoms of rhinitis conjunctivitis and bronchospasm. Ozone, a product of complex interactions of NOx with the oxygen in air, and SO2 gases are major culprits, but increasingly , fine dust particulates are being shown to be important toxins for the respiratory airways. Asthma can be triggered by air pollution but the subject is controversial since high concentrations of pollutants do not consistently "trigger" asthmatic attacks. In adults with chronic pulmonary disease, pollutants provoke bronchospasm, compromising respiratory function further. Significant decreases in pulmonary function are detected in children and healthy young adults exposed to high concentrations of pollutants on "air pollution emergency days" such as frequently occur in Los Angeles, and other major urban areas.

Note: The term NOx may be confusing. Customarily NO is released into the atmosphere. It readily is converted to NO2 and NO4 etc. Thus, at anyone time a mixture of gases exists accounting for the designation NOx.

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VII. INDOOR AIR POLLUTION

• Most residents of developed countries spend a substantial proportion of their time indoors. The indoor air is a microenvironment that only partially reflects outdoor air conditions. This is particularly the case in modern, mechanically ventilated buildings in which for economic reasons, attempts are increasingly being made to reduce the exchange of outdoor air with indoor air. Approximately half of the workforce in developed countries are employed in offices. Indoor employment accounts for roughly 25% of the modern worker's day. The average adult spends roughly 60% of his or her time in the home environment; homemakers and children under school age generally spend much of their time in the house on a daily basis.
  
  
• Outbreaks of acute, nonspecific minor illnesses, primarily of the upper aerodigestive tract, the external eye, and central nervous system have been reported among indoor workers particularly those employed in offices. The relationship of the syndrome to the indoor environment appears to have been established because the symptoms seem to disappear when affected persons leave the building. Illness can be induced experimentally by manipulating the environment.
  
  
• Potential disease-causing indoor air pollutants can be classified into (1) biologicals, (2) volatile organic compounds, and (3) products of combustion.
  
  
• Most, if not all, homes and occupational settings are contaminated with a multiplicity of obscure organisms that give rise to potentially irritating or allergenic (or both) biological products. Rug mites are an inevitable inhabitant of buildings, where they feed on spilled food and animal products (hair and dander). Cockroaches and other vermin and microorganisms (including their spores) inhabit the nooks and crannies of most buildings, and pets are kept in more than half of U.S. homes. These diverse biota, their feces and urine proteins, carcasses and body parts, hair, and sloughed skin are the potential triggers of acute allergic reactions (asthma) in susceptible hosts. It is likely that they give rise to allergic complaints in many people, but specific documentation is lacking, and the mechanisms are not clearly defined.
  
  
• Volatile organic compounds are the constituents of insulation materials, carpets, draperies and other furnishings, paints, waxes, solvents, soaps, perfumes, detergents, and items found in the home and workplace. Of the many volatile indoor air pollutants, formaldehyde is one of the most ubiquitous because of its wide use in the synthetic chemical industry and more specifically in the manufacturing of insulation materials and various types of plywood, particle boards, and so forth.
  
  
• The relative importance of gaseous and particulate pollutants in the home and workplace is determined by architectural design and the potential for circulation of outside air. The increasingly popular use of woodstoves as a primary or supplementary source of heat has resulted in gas and particle accumulations not heretofore observed with the traditional home heating fuels, gas and oil. This is accompanied by the generation of substantial amounts of the potentially carcinogenic polycyclic aromatic hydrocarbons.
  
  
• Homes and office complexes with attached or basement garages exhibit special problems with regard to the potential for automotive exhaust to enter buildings directly or through air intake vents.

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VIII. CIGARETTE SMOKING

• The effects of cigarette smoking are catastrophic at all stages of life. Cigarette smoking synergizes with other constitutional and environmental factors in the causation of disease. It is the single most preventable cause of disease in our society. It contributes to approximately a half million deaths annually in the United States and 21.5% of all cancer deaths in women and 45% of all cancer deaths in men. The deaths per year caused by tobacco in the United States exceed by fourfold deaths caused by alcoholic beverages and also greatly exceed combined deaths caused by automobile accidents, hard drugs, suicide, homicide, airplane crashes, and the acquired immunodeficiency syndrome (AIDS).
  
  
• Cigarettes are made from blends of tobacco differing genetically and in the curing process. Cigarette tobacco is also sprayed with a mixture of humectants, sugars, and other flavorings. The economic advantage of using all of the tobacco purchased led to the development of reconstituted sheet tobacco. How the sheet is formulated can affect the final product in terms of the amount of particulates, nicotine and so forth, produced. The puff temperature of the burning tip of the cigarette may reach 900oC. The majority of the 4865 known constituents of smoke are formed in a pyrolysis-distillation zone just behind the heat- generating combustion zone. One cigarette yields approximately 400 to 500 mg of mainstream smoke made up to 400 to 500 gaseous components, of which nitrogen (58%), oxygen (12%), carbon dioxide (13%), and carbon monoxide (3.5%) are major components. The vapor phase also includes hydrogen, methane and other hydrocarbons, volatile aldehydes and ketones, nitrogen oxides, hydrogen cyanide, volatile nitriles, and several hundred other minor constituents. The particulate phase is operationally defined as particles of greater than 0.1 µm in diameter. The majority of genotoxic and cocarcinogenic substances in cigarette smoke as demonstrated by bioassay are present in the particulate phase. The particulate phase of cigarette smoke also contains a variety of insecticides and metals, including aluminum, cadmium, lead, mercury, nickel, and polonium-210. Compounds generated by reduction reactions are more common in sidestream smoke and include ammonia, aromatic amines, and volatile carcinogenic amines. Mainstream smoke also contains free radicals generated by the oxidation of nitric oxide (NO) to nitrous oxide (NO2).
  
  
• Tobacco use is addicting; nicotine is the active pharmacological agent that causes this addictive behavior. It is estimated that one third to two thirds of smokers become addicted to nicotine. Relapse rates are similar between tobacco, heroin, and alcohol in that 60% of people who quit smoking relapse in 3 months and 75% in 6 months. One year after surgery for lung cancer, 48% of patients had returned to their previous smoking habit.
  
  
• Nicotine inhaled in cigarette smoke is rapidly absorbed. It takes less than 19 seconds from the start of a puff to the delivery of nicotine to the brain. This rapid delivery enhances rapid behavioral reinforcement and allows the smoker to control the amount of nicotine absorbed. Nicotine readily crosses the blood-brain barrier and is distributed throughout the brain. The density of nicotinic receptors is increased in the brains of smokers as compared with nonsmokers.
  
  
• Nicotine appears to act presynaptically, leading to the release of acetylcholine, norepinephrine, dopamine, serotonin, vasopressin, growth hormone, and adrenocorticotropic hormone (ACTH). Smoking is also associated with an increase in beta-endorphin levels that increase in proportion to plasma nicotine levels. Tumorigenic substances in cigarette smoke include the following classes of compounds: polyaromatic hydrocarbons; aza-azarenes, N-nitrosamines; aromatic amines, including 4 aminobiphenyl; aldehydes; other organic compounds, including benzene; and inorganic compounds, including hydrazine and polonium-210. The basis of the tumorigenicity of many of these compounds is that they are or can become highly reactive electrophiles as a consequence of oxidation and form adducts with DNA, causing errors in transcription, replication, or repair, resulting in activation of oncogenes or inactivation of tumor suppressor genes. In addition, cigarette smoke contains a large number of substances, e.g., phenolics, that function as tumor promoters, resulting in expansion of susceptible cell populations. As you will recall tumor promoters are not in themselves carcinogenic or genotoxic but serve to stimulate cell replication directly or indirectly, in some instances.

IX. CARDIOVASCULAR DISEASE

Cardiovascular disease is the leading cause of death and disability in the United States. Approximately 1 million people died of various cardiovascular diseases in 1987, and it is estimated that 200,000 of these were directly related to cigarette smoking. For each 10 cigarettes smoked per day, there is an incremental increase in cardiovascular mortality in men (18%) and in women (31%). In the Nurses Health Study, smoking as few as one to four cigarettes/day was associated with a doubling of the risk for coronary heart disease. Smoking is by itself a major independent risk factor for coronary heart disease, equivalent to either hypercholesterolemia or hypertension, and it synergizes with these other major risk factors in induction and progression of vascular disease.

X. SMOKING AND PULMONARY DISEASE

• Smoking is the cause of the vast majority of lung cancers of all histological type occurring in this country today. It synergizes with alcoholic beverages to cause cancer of the mouth, pharynx, larynx and esophagus.
  
  
• Chronic obstructive pulmonary disease (COPD) accounts for approximately 62,000 deaths per year, of which 90% are related to cigarette smoking. It is part of a spectrum of change in the lung involving bronchitis and bronchiolitis at one extreme and emphysema at the other, both brought about as a consequence of inflammatory responses triggered by inhalation of cigarette smoke and, at some point recurrent or chronic infection.

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XI. SMOKING AND URINARY TRACT CANCER

The risk for developing cancer of the kidneys, ureters and urinary bladder is increased 2 to 4 fold in smokers.

XII. SMOKING AND DISEASES OF THE FETUS AND NEONATE

Approximately 31% of women smoke before pregnancy, and 25% smoke during pregnancy. Smoking is the most harmful known environmental exposure affecting pregnancy. The influence of smoking may begin at the time of conception. A strong association has been reported between maternal cigarette smoking and spontaneous abortion. Smoking is associated with an increased incidence of low birth weight. The mechanisms underlying this association are unknown but may be related to the effects of nicotine on energy consumption. Cigarette smoking also appears to be associated with the development of sudden infant death syndrome.

XIII. OTHERS

• Smoking has been associated epidemiologically with the earlier appearance of menopause and with osteoporosis.
  
  
• Smoking has been associated with toxic goiter in a number of studies over the last decade.
  
  
• Cigarette smoke benzo-a-pynene "adducts" have been found in the colorectal and cervical epithelium; they may contribute to the development of cancer at these sites. The incidence of these cancers increased in those who smoke.

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