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What Happened to the Mink?

In the early 1980s, reproductive complications were observed in mink (Aulerich & Ringer, 1977). Several dietary components were evaluated to determine whether they were the cause of this failure for mink to reproduce. Neither the Coho salmon, which made up the major component of their diet, nor other species of Great Lakes fish appeared to cause this response in experimental mink. Diets and carcasses were evaluated for mercury and chlorinated pesticides, and there was no correlation. Analysis of the pathological signs suggested that PCBs (polychlorinated biphenyls) might be the causative agent. However, no other species was presenting with these signs. With feeding of groups of mink on 30 ppm PCB diets or salmon from the Great Lakes, the signs were identical to those of wild mink. It turned out that mink are extremely sensitive to the reproductive effects of PCBs and there were enough PCBs in Great Lakes Coho salmon to induce the detrimental reproductive effects.

The next issue was to determine the source of the PCBs. It was determined that the major use of PCBs was as a heat transfer agent in electrical transformers (International Agency for Research on Cancer [IARC], 1978). At first glance, this use would not suggest an etiology for the high levels of PCBs that were observed in the mink and Coho salmon. However, PCBs are not metabolized to any large extent and, therefore, were stable in the environment. Because they were fat soluble and only marginally water soluble, the PCBs accumulated in the fat of the fish, which then accumulated in the fat of the mink. During the winter, as the mink lost their fat, their blood levels of PCBs would increase sharply. The PCBs caused increased drug metabolism that was reflected in alteration of circulating sex hormone levels that then adversely affected mink reproduction.

The science did not end here. It turned out that PCBs were contaminated with another chlorinated, environmentally stable hydrocarbon, TCDD (tetrachlorodibenzodioxin, more simply known as dioxin), which was three orders of magnitude more toxic than PCBs (Mandal, 2005). This substance was even more widely distributed and was found not only associated with PCBs but also in landfills associated with paper mills that chlorinated their waste at elevated temperatures. This discovery led to a change in the paper-making process in which chlorine dioxide—rather than chlorine—is used. Chlorine replacement due to environmental contamination will be a continuing theme in this chapter; it is a costly step that does not necessarily translate to developing countries.

Parenthetically, the PCB toxic response was replicated in humans when a Japanese family used PCBs for cooking instead of cooking oil; the signs of toxicity were the same. This chapter evaluates what makes one species more sensitive than another, how we characterize the toxicity of materials, and how we can extrapolate risk to environmental exposures. Although there was no human reproductive toxicity observed in these studies, the studies did cause a careful evaluation by regulatory agencies of the safety of Great Lakes fish, particularly to the Canadian aboriginal population, who consume large quantities of these animals.

What About the Cats in Japan?

In the 1950s, the domestic house cat population in Japan demonstrated a highly unusual central neurotoxicity characterized by staggered gait and other signs—a condition referred to as Minimata disease, after the Japanese seaside town where the phenomenon was observed (Takeuchi, D’Itri, Fischer, Annett, & Okabe, 1977). A chemical plant had initiated manufacture of acetaldehyde and dumped waste methyl mercury in Minimata Bay. Methyl mercury, being fat soluble and not metabolized by fish, accumulated in fish in the bay. The cats ate these fish exclusively in their diet. Subsequently, people living in Minimata began to show the same neurological signs, which also included tunnel vision and learning deficits.

Methyl mercury is a well-known neurotoxin that causes neuropathies in experimental animals and has been studied as a pesticide. In the 1960s, grain was shipped to Iraq for planting that was treated with methyl mercury as a pesticide (Rustam & Hamdi, 1994). This pesticide was purple in color, and it was not expected that people would eat the grain; rather, they were instructed to plant it. They prepared it as bread, however, and a clear dose-response was noted between bread consumption and tunnel vision, peripheral neuropathies, terata, and other forms of methyl mercury toxicity.

Methyl mercury is a component of sea water and accumulates in pelagic (oceangoing) fish. Considerable debate has arisen about the safety of pelagic fish due to methyl mercury contamination. Island populations consuming diets consisting almost exclusively of fish have been studied, but to date these results are inconclusive (Board on Environmental Science and Toxicology, 2000).

When methyl mercury is used as an herbicide, such as on golf courses, where the water is not free flowing like the ocean, its concentration can become excessive and the fish in the local waters can represent a source of toxicity.

Why do We Discuss Selenium?

The biological effects of selenium represent the best example of environmental health and toxicology. Selenium is a metal that is found in abundance in many parts of the world and concentrates in some plants. Most selenium is consumed as the sulfur amino acids methionine and cysteine, as the selenium can replace the sulfur in these compounds. There is a nutritional requirement for selenium in several biochemical pathways. In New Zealand, China, and Finland, for example, selenium deficiency has been a major public health problem; in these countries, selenium intake is less than 50 mcg/day. Selenium deficiency is characterized by cardiomyopathy and muscle pain (Dodig & Cepelak, 2004; Rederstorff, Krol, & Lescure, 2006). In contrast, in other areas of the world, selenium is present in excess (Dodig & Cepelak, 2004). In these areas, a characteristic neurotoxicity is observed when levels exceed 250 mcg/day. Consideration of selenium deficiency or excess in the absence of knowledge of the other biological properties might lead to other toxic effects.

Vitamin A

Vitamin A, α-tocopherol, is a necessary component of the human diet. Vitamin A, which is needed for vision, is a fat-soluble vitamin that becomes concentrated in the liver (Fishman, 2002; Russell, 1967). Vitamin A, like selenium, also has toxic properties when consumed in excess. This toxicity has been documented among arctic explorers and Eskimos who consume polar bear. Polar bears live on a diet rich in fish, which in turn are rich in vitamin A. When arctic explorers consumed polar bear liver, their dose of vitamin A was enormous. As this example demonstrates, a nutrient that receives little attention in the Western diet can be a serious toxin in other conditions. A deficiency of vitamin A is characterized by night blindness, which is then followed by development of connective tissue disorders. Chronic toxicity affects the skin, the mucous membranes, and the musculoskeletal and neurological systems. Vitamin A toxicity is not necessarily restricted to polar bear consumption, however, as megadose vitamins are becoming popular.

Lessons to Be Learned

All materials have toxicity when their exposure reaches high enough doses. In the case of methyl mercury and PCBs, those animals with the highest consumption of these materials were harbingers of human exposure. With selenium and vitamin A, toxicities arise from both deficiencies and excesses. As they demonstrate, just because a material is required as part of the human diet does not mean it has no toxicity.

PRINCIPLES OF ENVIRONMENTAL HEALTH

Definitions

For the purposes of this chapter, infectious agents are excluded from the discussion to the extent possible. Very frequently, there is a trade-off between infectious agents and chemicals: Examples include food preservatives and water purification, not to mention antibiotics and other pharmaceuticals and antiseptics. Due to the ability of microorganisms to reproduce, infectious disease almost always represents a greater public health concern than chemical contamination.

Assessment of environmental health is couched in technical terms that have clear definitions. Sometimes these definitions have connotations that public health professionals must ignore. For example, workplace exposure to toxic substances is different from environmental exposure. However, contamination of rivers with pharmaceutical agents is an environmental event. The use of estrogens as birth controls agents in women would not be considered environmental. These hormones are excreted in urine, however, and may end up in river water (Shore, Gurevitz, & Semesh, 1993). In one case, this phenomenon resulted in developmental and reproductive problems in striped bass that almost killed the species. Prior to delineating the impact of environmental chemicals on public health, it is important to clarify these terms.

Environment

The environment is defined as the air we breathe, the water we drink, and the food we eat. None of these environmental components is pure in the chemical sense. That is, there is no chemical definition of air, water, or food, as each is a mixture and has both major and minor components contributed by natural sources. For example, the air in the forest contains chemical substances (e.g., terpenes) that volatilize from trees in the forest. Although these substances are natural components of the forest air, they are intentional additives in cleaning products, and in some cases have pesticidal and biocidal activity. The same caveat applies to food. Although a synthetic diet can be constructed from purified starches, proteins, and fatty acids, no one consumes this diet. Therefore, a qualifier is usually appropriate with an environmental component, such as “forest air” or “Great Lakes water.”

Environmental Agent

An environmental agent is the chemical or infectious agent or radiation source that is alleged to induce an environmental health incident. Such an agent is associated with two critical characteristics.

First, the quality of data linking the agent with the effect is important. Although Koch’s postulates can be applied to infectious agents, it is more difficult to apply them directly to environmental health. Koch’s postulates are as follows:

1. The pathogen must be present in all hosts diagnosed with the disease.

2. The pathogen must be isolatable from the diseased host.

3. The pathogen must be purifiable.

4. The purified pathogen must cause the specific disease.

5. The pathogen must be isolated from the host used in step 4.

6. The pathogen in step 5 must be shown to be the same pathogen purified in step 3.

To do this, one would have to demonstrate that the environmental agent was present in the affected population, that the agent could cause the environmental outcome, and that it was present in sufficient quantities to account for the effects.

Second, there must exist an analytical technique for the agent in question. Of course, that requires a detailed definition of the environmental agent. For example, it is not sufficient to suggest that the neurological behavior observed in the cats at Minimata Bay was caused by methyl mercury. Instead, the neurological signs must be demonstrated in experimental animals following methyl mercury treatment. Methyl mercury had to be isolated from the cats at doses that would cause the disease. The first step in any environmental evaluation is always the development of an analytical method.

Adverse Health Effect

An adverse health effect is usually defined in preclinical toxicology as any significant deviation from the norm. In the human environment, applying this definition is not always easy. The best example of such difficulty in defining adverse health effects lies in the manufacture of hypnotics. These substances are safe and effective in people even when used in large doses. Sleep induction is a therapeutic response. However, in the manufacturing environment, they may cause workers to fall asleep on the job; this is an adverse outcome. As this example demonstrates, the definition of adverse health effect is subjective: It is the induction of an effect that the exposed population does not intend or want. This has already been demonstrated with environmental exposure to estrogens that can also inhibit reproduction in the environment.

Risk

Risk is the probability that an adverse outcome will occur. Individual risk is the probability that an individual will suffer from an adverse outcome. The opposite of individual risk is population risk—the expected number or percentage of adversely affected individuals in a population who will suffer an adverse outcome. Obviously, exposure of three people to a material that will cause one adverse event in a million is different from exposing 300 million people to that risk.

Risk has three components: exposure, causation, and dose-response. The calculation and interpretation of risk will be dealt with in great detail later.

Ecology

Receptors for adverse events are not restricted to humans but are also present in wildlife, including fish. Due to the varied spectrum of species and their different physiologies, a substantial difference in sensitivity has been observed. Subtle questions can be asked with regard to protection of the environment. For example, are environmental evaluations performed by protecting most of the species exposed or by protecting the total population?

Toxicology

Toxicology is the study of the adverse effects of materials, chemicals, or radiation on living organisms. Although not explicit in the definition, what makes a toxicologist different from other scientists is that a toxicologist relates dose and response rather than just studying response. The terms “adverse effects” and “toxicological effects” are used interchangeably in this chapter.

Physiologically or Toxicologically Significant Adverse Health Effects

Although the issue of what qualifies as a significant adverse effect might seem easily resolved, it is actually very difficult to state with clarity. For example, an environmental substance that causes weight loss at a specific dose is considered to be inducing an adverse effect. However, when that same substance is evaluated as a pharmaceutical for that purpose, it is considered therapeutic. Looking at the same situation in reverse, one can look at a material that can be used safely and effectively as a hypnotic. The dose at which it manifests the hypnotic response is not a toxic dose but rather a dose that produces a pharmacologically beneficial event. However, when this material is manufactured in the workplace and exposure takes place at a level sufficient to induce a hypnotic dose, the workers fall asleep, and there are substantial problems thereafter.

To put matters in perspective, one can consider how to evaluate additives for food that decrease calorie availability or promote weight loss. When a manufacturer evaluates an inert ingredient such as a nonmetabolizable starch for use in breads, cookies and cakes, the U.S. Food and Drug Administration (FDA) requires at least a 100-fold safety margin be maintained. Of course, adding 100 times the amount to be used in breads, cakes, and cookies will result in body weight loss, as the test animals do not eat enough food to compensate for the starch. It then appears that there is a toxic response characterized by weight loss. Because such components are food additives and not drugs, a margin of safety is required before they can be included in foods for the general public. Thus the definition of “adverse effect” is not always obvious.

Similarly, with large sample sizes or sensitive assays, small effects that have no physiological significance can be detected even while the response has no physiological significance. The terms “statistical significance” and “toxicological significance” relate to different findings: The former is dependent on characteristics of the assay and the sample size, while the latter deals with hazards. It is important to evaluate whether effects observed in populations around the world are real adverse health effects or just statistical anomalies caused by large sample sizes or sensitive assays.

Global Catastrophic Risk

There are a few risks whose consequences can be so significant that normal considerations of cost, benefit, weight of the evidence, and concentration dependency are not considered. The most obvious of these is global warming, which results from destruction of the ozone layer of the atmosphere and consequent warming of the surface of the earth by a few degrees Celsius. The postulate underlying the theory of global warming is that release of carbon dioxide or fully halogenated hydrocarbons (to be discussed later in this chapter) into the atmosphere can decrease the density and effectiveness of the stratospheric filter for radiation. Although the data are poor and the effects immeasurable, if true, this outcome would mean a global catastrophe. Therefore, the threat must be dealt with as if it were absolutely true. Such mega-events are not common, but when present require an entirely different way of thinking about risk. Treatment of drinking water, safety of vaccines, and contamination of foodstuffs all fit into this global catastrophic risk.

PRINCIPLES OF TOXICOLOGY

A detailed and comprehensive treatise on toxicology is beyond the scope of this chapter. However, there are some very critical concepts that can be covered here.

Intrinsic Activity

FIGURE 16-1 Comparison of Potency and Intrinsic Activity

Intrinsic activity can be defined as the maximum response that can be induced by a material. It can be seen in Figure 16-1, which is an idealized schematic. Of the four curves, two have the same intrinsic activity and two have the same potency. For intrinsic activity, the maximum response is 40 at both high and low potency, whereas the maximum at the low dose is 8. Intrinsic activity is a biological property of a substance. For example, the diuretic properties of a substance such as melamine and the porphyrin-modifying properties of lead and iron are intrinsic activities; they may be considered as a physical property of the substance. Such activities are generally determined in animal experiments or in vitro studies, but sometimes are identified in humans first as anecdotal observations, such as the observation that vinyl chloride was a human carcinogen. In the European Union, a classification system for intrinsic activity has been developed, where category 1 is an activity known to occur in humans, category 2 is an activity that will probably occur in humans, and category 3 is an activity that has been identified only in animals.

Intrinsic activity does have degrees of effectiveness associated with it. That is, the maximum effect of a substance can differ between two substances. For example, one substance may induce more chromosomal anomalies than another at the maximum dose tested.

One can compare the bladder cancer–inducing activity of chemicals as an example. Several materials such as melamine or cyclamate will precipitate in the bladder. This precipitate can irritate the walls of the bladder and cause tumors to be produced. Very seldom does the incidence of tumors produced by this mechanism exceed 15% even at doses such as 6000 ppm in the diet (Heck & Tyl, 1985; Melnick, Boorman, Haseman, Montali, & Huff, 1984). In contrast, some aromatic amines cause bladder cancer in rats in 50% of the animals (“Bioassay of 4,4′-Methylenebis-(N,N-dimethyl)benzeneamine,” 1979).

Potency

Potency relates to the dose at which an effect is observed. The units of expression of potency are either expressions of doses where no responses occur or expressions of doses where a 50% response occurs. In the case of the doses with no response, the “no observed adverse effect” level (NOAEL) is used; it depends on the dose spacing and sensitivity of the assay to detect responses. The NOAEL is the experimental dose at which no adverse effect has been observed, but this experimental point is highly dependent on the protocol, quality of data, experimental design, and sample size. The poorer the design, the lower the quality of the data, or the smaller the sample size, the higher the NOAEL.

In the case of measuring a 50% response, the ED50 (effective dose in 50% of the population), LD50 (lethal dose in 50% of the population), or benchmark dose (BMD; a curve-fitting exercise) is used (“Bioassay of 4,4′-methylenebis-(N,N-dimethyl)benzeneamine,” 1979). These metrics are the most reproducible experimental observations. Finally, a mathematical curve fitting can be used that will generate the best-fitting curve—that is, the curve that takes into account all of the data points. This mathematical expression can then be used to generate a theoretical 10% dose-response, which is the BMD. Because this is a mathematical curve fitting, virtually any dose can be used or the statistical bounds could also be used. In Figure 16-1, the ED50 for the higher-potency material is 4; for the lower-potency material, it is 6.

The concepts of potency and intrinsic activity underscore the inability to compare the adverse effects of substances. Either potency or intrinsic activity can be a variable.

LEGAL AND ETHICAL ISSUES

Laws and Regulations

Government of democratic nations is accomplished in two ways. First, laws are passed by an elected legislature that provides direction for governance. Second, within these laws is the delegation of responsibility to or establishment of an executive agency for implementation and enforcement of these laws.

The executive agencies deal with the details of management of nations. As an example, the U.S. Congress passed the Federal Insecticide, Pesticide and Rodenticide Act, which gave the U.S. Environmental Protection Agency (EPA) control over the labeling of pesticides and the FDA responsibility for establishing limits (tolerances) for pesticides in food. This separation of authority between legislative and executive branches is not unique to the United States, but rather is global in nature. Serious abuses in this system occur when there is no legislative branch to write the laws, such that the executive branch writes the laws, establishes the regulations, and performs the enforcement. This system typically leads to corruption and environmental deterioration.

Legal challenges to regulations, which make for interesting news, deal with whether the regulatory agency has the authority to perform a specific task as identified by legislation, or whether the regulatory agency has acted as described by law. Citizens may then challenge the regulatory enforcement on the basis that it was either not correctly carried out by law or that the law did not authorize the agency to act the way it did.

Perhaps the best example of the difference between regulation and legislation can be seen in the failed attempts of the FDA to regulate cigarette smoking. Clearly, the FDA is responsible for a major component of public health, and clearly cigarette smoking is detrimental to public health. However, there was no authorization in the Food, Drug, and Cosmetic Act that would allow the FDA to regulate smoking. Cigarette smoke is neither a food nor a food additive, and Congress chose not to change the legislation so as to authorize FDA regulation of tobacco products. Tobacco is also not considered a drug, as manufacturers do not make any health-related claims for cigarette smoke. It was only recently that the FDA embarked on regulating cigarette smoke by declaring cigarettes to be a drug delivery system, delivering nicotine as a drug (Centers for Disease Control and Prevention [CDC], 2007; FDA, 1995). This allegation brought cigarettes under the Food, Drug, and Cosmetics Act and, therefore, made them subject to FDA regulation. Otherwise, independent of the adverse health effects of cigarettes, the FDA was powerless to regulate tobacco smoke.

Regulation Versus Ethics

Ethics becomes an issue when there are no laws or regulations to be enforced. The critical issue associated with ethical decisions lies in the values involved. Values have many varied definitions, and can be parsed into moral values, ethical values, family values, religious values, and so on. Based on the soft and personal nature of values, interpreting them for environmental decision making is virtually impossible. Ethical considerations must either be converted to some form of regulation or cannot be major decision criteria for environmental issues.

An example of an ethical decision is Proposition 6 in California, a regulation to ban consumption of horse meat (CDC, 2007; Prohibition of Horse Slaughter, 1998). There was no public health issue involved in this proposition and no laws under which to regulate horse meat. Thus the state made a decision that it was unethical to slaughter horses for the purpose of human consumption.

WHAT IS THE ENVIRONMENT?

As noted earlier, the environment consists of the air we breathe, the water we drink, and the food we eat. Public health concerns about each of these aspects of the environment are very different.

Air Pollution

There are four major classes of air-polluting gases: irritating chemicals, asphyxiating chemicals, air toxics, and atmospheric reactants.

Irritants

Irritants damage the surface of the respiratory tract. Highly water-soluble irritants such as formaldehyde cause irritation of the upper respiratory tract, whereas less water-soluble irritants such as nitrogen oxides cause lower respiratory tract irritation.

Hydrogen chloride is very water soluble and is an upper respiratory tract irritant. Its inhalation causes effects in the nose, for example. As a response to contact with upper respiratory tract irritants, individuals will hold their breath or breathe more shallowly. The major chronic effect of upper respiratory tract irritants is loss of the sense of smell through toxicity to the olfactory epithelium. Sulfur dioxide is another example of an upper respiratory tract irritant.

Oxides of nitrogen such as nitrogen dioxide are lower respiratory tract irritants; exposure to these substances is accompanied by chest pains. The other major environmental irritant gases are ozone and chlorine, which oxidize in the lower respiratory tract. In each case, the result is fibrotic/scarring lesions in the irritated portion of the lung with an accompanying loss of function. Lower respiratory tract irritants can also cause emphysema and other typical pulmonary lesions.

It is extremely import to differentiate irritants from foul-smelling materials. Odor is not necessarily a characteristic of toxic vapors. Foul smells are designed to elicit an avoidance response.

Asphyxiates

Asphyxiates cause suffocation or lack of oxygen transport to the body. The major asphyxiate is carbon monoxide; overexposure to this gas leads to a chemical asphyxiation. Carbon dioxide induces a similar response but at markedly higher concentrations.

Toxics

The third class of pollutant gases comprises toxics—gases that are absorbed through the lungs and have adverse systemic effects. For example, hydrogen cyanide has direct effects on the blood, but not on the lungs. A wide variety of other materials, when inhaled, produce systemic toxicity. Anesthetic and neurotoxic gases, such as ether and toluene, are in this class. Virtually any material when inhaled can be absorbed into the lung to some extent.

High-molecular-weight polymers and water-insoluble chemicals are not absorbed into the bloodstream, but rather are deposited into the lungs and remain there. These materials may be removed by a system that moves them up the trachea for excretion or to be swallowed. The body defenses against these materials may have a side effect of irritating the adjacent lung tissue. Macrophages are designed to kill bacteria in the lungs by producing peroxide. An effect of some particulates is to kill the macrophages, thereby causing peroxide buildup in the lungs, which eventually proves toxic. Finally, exercise can accentuate lung toxicity through increase in the respiratory rate. With increased respiration, the dosage increases.

Atmospheric Reactants

Chemical reaction of pollutants with atmospheric constituents can induce serious environmental degradation. The two major classes of these air pollutants are smog and greenhouse gases.

Smog.

Photochemical smog is a concern in most major urban centers. Smog is caused by a reaction between sunlight and emissions, mainly from human activity such as automobile exhaust and fireplaces. Photochemical smog is the chemical reaction of sunlight, nitrogen oxides (NOx), and volatile organic compounds (VOCs) in the atmosphere, which leaves behind airborne particles (called particulate matter) and ground-level ozone. Nitrogen oxides are released in the exhaust of fossil fuel–burning engines in cars, trucks, coal power plants, and industrial manufacturing factories. VOCs are vapors released from gasoline, paints, solvents, pesticides, and other chemicals.

Greenhouse Gases.

Some organic substances—the most notable and avoidable being fully halogenated substances such as chlorofluorocarbons (CFCs)—decrease the atmospheric filter for sunshine. The greenhouse gases may interact with ozone, which filters sunlight and provides a stable temperature on Earth. Perhaps the most significant of these gases is carbon dioxide, which is produced by burning fossil fuels and by the setting of concrete. Methane is produced by livestock farming and rice paddies. Sunlight and other radiation turn methane and carbon dioxide into free radicals, which then interact with ozone.

Water Pollution

Pollution of drinking water can take the form of either chemical or microbial contamination. Microbial contamination is beyond the context of this chapter, except to note that it necessitates chemical treatment of water. In the absence of chemical treatment, epidemics of cholera and typhus can occur, as well as E. coli infection. On a global basis water contamination is a leading cause of death as an inducer of diarrhea.

Treatment of microbial contamination is not difficult, but it is costly. It generally involves killing the organisms with chlorine, chlorine dioxide, or ozone. The costly part is not only the treatment phase, but also the transport of the water to the site of use. In developing countries without water purification plants, boiling water is effective as a microbial decontamination measure. In general, chemical oxidants are added to the water to sterilize it. Historically the most popular of these compounds has been chlorine. Chlorine is an inexpensive and effective agent for this purpose. The downside of chlorine use is twofold: It is difficult and risky to transport, and the chemical reaction between chlorine and the biological agents in water results in the production of chloroform and other trihalomethanes that are carcinogens at high doses in experimental animals. Chemical reaction rate constants show that the bromine analogues—bromoforms—are also produced from this process. For this reason, newer water treatment facilities tend to use either peroxide or chloramine. Peroxide is very effective at eliminating other chlorination by-products such as TCDD, which is among the most toxic of all organic chemicals and is highly persistent in the environment. Paper mills, which may have a very high organic content waste, use the more costly peroxide process to avoid TCDD production. Chloramine is not without its disadvantages, however, as it appears to increase the level of nitrosamines in the water. Nitrosamines are highly carcinogenic chemicals more commonly found in nitrite-preserved meats.

The issues involved in the evaluation and trade-off of these treatment methods are closely analogous to the ethical decisions discussed previously. Possibly the worst alternative is microbiological contamination, but only peroxide is without a potentially toxic sequela. Yet the concentrations of halogenated contaminants are very low following water treatment, and the nitrosamine concentration resulting from this process amounts to less than 0.5% of dietary intake of these compounds. Regulatory risk assessment methods assume that there is no risk-free dose.

Radiation

Radiation represents an electromagnetic spectrum that covers many facets from visible light, to ultraviolet light, to infrared to radio waves, to microwaves, and so forth. From a health viewpoint, radiation can be condensed into three facets: ionizing, non-ionizing, and thermal radiation.

Ionizing Radiation

Ionizing radiation consists of high-energy radiation such as gamma rays, X-rays, and other high-energy particles. These forms of radiation penetrate the skin and are not stopped by most boundaries. Biologically, they ionize chemicals in the body, which has two effects. First, the ionization mutates DNA. Dividing cells with damaged DNA either will be repaired, will die, or will be transformed into cancer cells. Approximately 1 million DNA lesions per cell per day are produced as a result of background radiation. In the case of other cellular components, contact with ionizing radiation causes them to become oxidized. The resulting oxidative stress has many sequelae, such as aging and many diseases. The most significant lesion entails chromosome breakage, a nonrepairable phenomenon. However, it appears to be at least a second-order reaction; thus, at low levels of radiation, the risk of chromosome breakage is exponentially less than at high doses.

Non-ionizing Radiation

Non-ionizing radiation (UV radiation) is responsible for suntans and other dermal responses. It does not penetrate the skin to any great depth. While the chemical reaction resulting in tanning is not deleterious, non-ionizing radiation can cross-link dermal DNA, thereby inducing mutagenic reactions. This results in severe dermatological responses such sunburns and melanomas.

Thermal Radiation

Long-wave radiation such as microwave or radar causes water molecules to heat up and produce a thermal effect. This effect is usually not a concern in the environment.

PERSISTENT ORGANICS

Water contamination results in pollution from two sources. First and most obvious is drinking the water itself. Second, and not as obvious, is consumption of fish and seafood harvested from the water. The ability of materials to accumulate and persist in wildlife is a measurable characteristic of organic and inorganic chemicals. Some of the most recognizable of these persistent chemicals are DDT, PCBs, and TCDD. The environmental concern is not that these compounds are toxic at ambient concentrations, but rather that they can accumulate in biota to reach toxic levels as discussed earlier with methyl mercury. On a global basis, these persistent organic pollutants are being banned with the same aggressiveness as those that cause global warming.

Clearly, low-cost chlorination will continue to predominate in countries where the social costs of its elimination cannot be borne by the economy. In the Western world, one of the other water treatment methods will be selected.

Toxics

In the same way that there are toxic substances in the air, so there can also be toxic substances in water. Toxics are defined as materials in water that exert toxic effects through systemic absorption. Establishing an acceptable dose for materials in water is difficult. In addition, estimating consumption of water toxics is complicated. In the United States, individuals move frequently and their exposure to any particular drinking water source is, on average, limited to 10 years. Most individuals have an average consumption of 3 liters of water per day.

Toxics in drinking water may include pesticides, heavy metals, nitrosamines, halogenated materials from chlorination, and other pollutants, depending on the area, groundwater source, purification methods, and so on. There is currently no way to remove metals from drinking water, so these components represent a special problem. Symptomatology in a population exposed to chemically contaminated drinking water will not be restricted to a single individual, but rather will appear in large numbers of the overall population. For example, contamination of water with large amounts of iron salts will result in liver and blood problems in many people. If only a single individual is found to have a problem, the causative agent is not likely present in the community’s drinking water.

A special subset within the general population when it comes to water pollution is people who have wells. Because the well can be contaminated in its construction, use, or the water supply it accesses, a family deriving its water from that source can have toxic symptoms separate from the overall population. For example, one family in Japan lined its well with an acrylamide polymer that had not sufficiently polymerized to remove the acrylamide (Igisu, Glote, Kawamura, Kato, & Izumi, 1975). The entire family then came down with acrylamide neurotoxicity, while the rest of the population remained healthy.

Biological Oxygen Demand

When microorganisms in water metabolize pollutants to nontoxic carbon dioxide, they utilize oxygen in this process. As a side note, the degradability of an organic chemical is measured in terms of the demand it presents on oxygen. Such oxygen depletion can be disastrous to animals in the water that require oxygen, such as fish. Fish kills can be caused by adding to water various nutrients that microorganisms metabolize, thereby depleting the available oxygen. Another way to stimulate growth of oxygen-depleting organisms is to add a cofactor to the water that had previously been growth limiting. Runoff of phosphate from agricultural and suburban land, for example, provides much needed phosphate to algae, which then grow and deplete the oxygen in the water in which they live. This reaction is ruinous to many lakes and estuaries such as the Everglades. Globally, this problem has become more extensive as the equation for the value of conservation versus agricultural production has shifted to favor agricultural production in the developing world.

FOOD

The inclusion of food in this chapter is not meant to imply that food is toxic. However, food can serve as a source of pharmacologically active substances that must be considered in disease causation. These substances can arise through food storage, manufacture, or cooking, or they can be integral parts of the food being consumed. For example, some Guam inhabitants chew on cycad nuts (“The Cycad Story Extended,” 1970). As a result, these individuals may develop a disease similar to amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease).

There are two ways of looking at food contamination. Historically, epidemiologists have been primarily concerned with low levels of very potent contaminants. In reality, there may be an even higher risk associated with high levels of low-potency substances.

For example, the presence of nitrosamines in nitrite-preserved foodstuffs has been the subject of extensive research. These substances cause cancer at low doses in virtually every species tested, including humans. Nevertheless, their presence in foodstuffs appears so low that they do not represent a public health risk. Nitrosamines are generally the result of food preservation using nitrites or are produced by the conversion of nitrate to nitrite in the stomachs of neonates and subsequent in vivo nitrosation. They are found in low levels in drinking water as a result of chloramine purification as well.

In contrast, polyunsaturated fatty acids are another cancer risk, albeit one with very little animal data to support their carcinogenic role. These chemicals are present in very high levels in many foods, delivering very significant doses to people who consume these foodstuffs. Even though they appear to have low potency, they may represent a much greater risk than the much more potent nitrosamines, simply because of the volumes in which they are consumed.

The argument about “risk versus potency” of components in foods approaches absurdity when nitrosamines are compared with the use of salt. Salt represents a real public health problem, even though it is a naturally occurring substance (Hussein & Brasel, 2001).

Food Storage

Contamination of food during storage can be a major source of toxic substances. Peanuts provide a perfect example of this problem. Peanuts, being approximately 50% fat, are an excellent substrate for mold growth. The mold Aspergillus flavus has been particularly well studied (Hussein & Brasel, 2001). This mold produces a unique metabolite, aflatoxin, which is among the most carcinogenic substances known. In many areas of the world, such as central Africa, this mold growth results in a substantial increase in liver cancer cases. Some areas of China also exhibit the same increased cancer incidence from aflatoxin consumption. Peanuts are not the only aflatoxin substrate, however; Aspergillus can also grow on corn, wheat, and so on. The FDA monitors aflatoxin contamination very closely, and foodstuffs are carefully assayed for aflatoxin content.

Many storage molds produce very potent toxins (Howlett, 1996). A laundry list will not be provided here, as this list grows continually with the discovery of new molds.

Food Manufacture

Contamination of food and beverages by chemicals during manufacture is a heavily regulated issue in the developed world. Many developing nations follow FDA or European Union (EU) regulations for their internal food manufacture industries. The United States and the EU have different approaches to this issue, however (“Evaluation of Certain Food Contaminants,” 2006; Hattan & Kahl, 2002).

In the United States, industry must supply FDA not only with safety information that is correlated with expected exposure, but also with efficacy data in the case of direct food additives. Chemicals are evaluated on a single-use basis; that is, if a chemical is used in more than one process, each process is evaluated independently. Each chemical is also evaluated independent of the foodstuff. For example, the fortification of breakfast cereals does not consider the presence of these nutrients in the milk added to the cereal.

In contrast, the EU has developed a list of substances that are considered acceptable for food use. In addition, the EU has created a list of chemicals that are not allowed for use in foods. Efficacy is not an issue in the EU when it comes to food additives.

Consider the example of the addition of calcium to breakfast cereal. The FDA would consider the nutrient properties of calcium and set a standard for addition of calcium in breakfast cereal. It would not consider the calcium level in milk added to the breakfast cereal, arguing that cereal can be consumed without milk. In the EU, calcium salts are approved for use in foodstuffs, so calcium may be added to cereal or even milk by any food manufacturer.

Cooking

The most readily apparent cooking contaminants are associated with grilling food at high temperatures. The charred surfaces of meats and other grilled foodstuffs are rich in polynucleated aromatic hydrocarbons (PAHs). These materials are carcinogenic and mutagenic, and they induce reproductive disorders when present at elevated concentrations. The chemistry that produces PAHs occurs at elevated temperatures from all organics. For example, smoke from fires or automobile exhaust may contain high levels of these materials. Once highly significant air pollutants, PAHs are now tightly regulated in the developed world.

In contrast, heating amino acids—the major component of proteins—causes the production of heterocyclic amines (HCAs). The major source of these chemicals is cooking of muscle meat. Epidemiologists have linked this cooking process with cancer of the stomach. Frying, broiling, and barbequing cause much more HCA production than baking or microwaving, as they induce higher temperatures in the foodstuff.

In the same fashion as HCAs are produced by heating muscle meat at high temperatures, acrylamide is produced by heating starchy foods in excess of 230 °F. Acrylamide has long been established as a human neurotoxin due to its mishandling in industry. An industrial intermediate, it is used in the manufacture of polymers for water treatment, mining, paper manufacture, and sludge dewatering. Excessive heating of the amino acid asparagine in the presence of reducing sugars also produces acrylamide. In the mid-1980s, acrylamide was found to cause cancer in laboratory rats and to influence chromosomal segregation in male reproductive tissue. It is found in greatest quantities in those starchy foods cooked at the highest temperatures, such as potato chips. This elevated cooking process is used to drive out the water in the food product so that the temperature can exceed the boiling point of water. For example, acrylamide has been found in the crust of bread but not in the middle.

Saturated fatty acids have been found in low levels in meats. To increase their shelf life, some foodstuffs are treated with antioxidants to keep the unsaturated fatty acids from going rancid, which in turn elevates the saturated fatty acid content. Saturated fatty acids have been associated with many maladies, including memory loss and cancer.

Intrinsic Pharmacologically Active Chemicals

There is no end of naturally occurring chemicals in food that have pharmacological activity. For example, the puffer fish—considered a delicacy in Japan—is rich in tetrodotoxin, an extremely potent neurotoxin. Consequently, preparation of puffer fish must be done by a licensed individual who can remove the poisonous gland. Some mushrooms contain α-amanitin, which was developed into the anticancer drug amantadine. The existence of such potent agents has spawned an effort by the pharmaceutical industry to seek biological substances that occur naturally and develop them into commercial medications.

The presence of these substances in foodstuffs does not have a large impact on the Western world, where diets are relatively standard. In the developing world, however, it is a different story. As noted earlier, consumption of cycad nuts in Guam (and the Philippines) has resulted in amyotrophic lateral sclerosis. In the Western world, concern about foodstuffs focuses on those materials that are present in large amounts and have low potency, such as cholesterol. In the developing world, the more potent contaminants become more important. That is not to say that there is not also toxicity from low-potency chemicals. For example, iron toxicity is rampant in some areas of China and Africa as a result of cooking in rusty pots.

Food allergies are another area where intrinsic properties of food represent serious medical hazards. To some individuals, peanuts are extremely toxic. The incidence of this allergy is low, perhaps 1 person per million population. However, with 300 million inhabitants in America, it is questionable whether this risk can be economically regulated (Schoessler, 2005).

SUSTAINABLE DEVELOPMENT

According to the United Nations, sustainable development is the process of developing land, cities, business, communities, and so on, so that the result “meets the needs of the present without compromising the ability of future generations to meet their own needs” (“The Environment Becomes a Political Issue,” 1988). One of the factors that sustainable development must overcome is environmental degradation, but it must do so without foregoing the needs related to economic development, social equality, and justice. To accomplish this goal, a balance must be struck between industrial development, pollution control with an absence of environmental degradation, and attention to the needs for the future. We have discussed air pollution with its toxics and oxidants, water pollution with its toxics and persistent organic chemicals, and the protection of our food supply. An unsustainable situation occurs when natural capital (the sum total of nature’s resources) is used up faster than it can be replenished. Sustainability requires that human activity, at a minimum, use nature’s resources only at a rate at which they can be replenished naturally. Implicit in this concept is the idea that pollution prevention is as important or more important than pollution development.

STUDY QUESTIONS

1. Explain, with examples, why it is important to human health to pay attention to environmental incidents caused by chemicals, infectious agents, or radiations. How do these agents cause global environmental health incidents?

2. Relate the problems of selenium deficiency and excess. What are some contributing factors in the environment which can cause these abnormalities? What solutions can correct these abnormal conditions? What other substances also have potential problems with excess and deficiency?

3. What is meant by dose and potency?

4. Explain how food can be contaminated during storage. What are the health implications? What are the important factors to consider while protecting our food supply?

5. Discuss how some methods of cooking food can cause harm to the body.

6. Explain, compare, and contrast examples of sustainable and unsustainable developments.

CASE STUDY: MICRONUTRIENT: AFLATOXIN B1

In 1960, more than 100,000 young turkeys on poultry farms in England died from an apparently new liver disease that was termed “Turkey X disease.” It was soon found that ducklings and young pheasants were also affected, and heavy mortality among these fowl populations was experienced. This disease became associated with feed, particularly peanut meal from Brazil. Subsequently it was found that a potent toxin, aflatoxin B1, was present in the feed. Aflatoxin B1 was produced by a storage mold that grew on the peanuts because of the relative humidity on the surface of the peanuts. Visual selection of peanuts for human consumption could eliminate the aflatoxin contamination.

Chronic toxicology studies in rats revealed that aflatoxin B1 is among the most potent carcinogens known, causing liver cancer in rats (Figure 16-2). However, there are some geographic areas in the world where aflatoxin exposure causes no increase in liver cancer. Confounding environmental factors involved in aflatoxin-related liver cancer based on the global distribution of liver cancer and aflatoxin exposure can be present in some world locations, such as central Africa. Within central Africa, hemosiderosis, produced by iron toxicity from using rusty cooking utensils, causes liver cancer (Mandishona et al., 1998).

In China, there is a high rate of hepatitis B virus, which acts synergistically with aflatoxicosis. Knowledge of this phenomenon is enormously significant in preventing liver cancer. Specifically, the same techniques that are useful in Africa will not have utility in China. In both cases, hygienic food storage will be effective. In Africa, upgrading the cooking utensils will produce a sharp drop in liver cancer; in China, an upgrade in cooking utensils could prevent hepatitis B (Chen & Zhang, 2011; Yu & Yuan, 2004). An important lesson to be learned here is the same one that was presented with methyl mercury—namely, that domestic or wild animals can be a sentinel of human disease.

Case Study Questions

1. Earlier in this chapter, the presence of aflatoxin in peanuts was discussed. Are there any other foods that might be contaminated by aflatoxin?

2. As there may have been two factors required for the appearance of human cancer, is the risk from aflatoxin overestimated?

FIGURE 16-2 Correlation Between Populations with High Liver Cancer Rates and High Risk of Chronic Exposure to Aflatoxin Contamination

Source: National Institute of Environmental Health Sciences. Liver cancer data from the GLOBOCAN 2002 database (http://www-dep.iarc.fr/GLOBOCAN_frame.htm). Aflatoxin data from Williams et al. (2004). Human Aflatoxicosis in Developing Countries. American Journal of Clinical Nutrition, 80, 1106–1122.

CASE STUDY: BALKAN NEPHROPATHY

Balkan nephropathy is an interstitial nephropathy first identified in the 1920s in people living along the Danube River (Cosyns, 2003). It was not a typical nephropathy, from a morphological standpoint, and was restricted to adults—that is, no children presented with the disease. Chronic exposure to dietary aristocholic acid appears to be a major causative risk factor for this nephropathy. Aristocholic acid may come from Aristolochia clematitis, a plant native to the endemic region, and its seeds may comingle with wheat used for bread. According to the International Agency for Research on Cancer, several Aristolochia species have been used in traditional Chinese medicine as antirheumatics, as diuretics, and in the treatment of edema. Aristolochic acids are constituents of these plant species.

After the recognition of these acids’ role of Balkan nephropathy, the American Public Health Service tested aristocholic acid in rats and mice for chronic toxicity. This substance caused tumors at the site of application as well as kidney tumors in rats. Based on these toxicology studies, follow-up studies were done on individuals with nephropathy. High rates of urethral cancer, primarily of the upper urinary tract, among individuals with renal disease who had consumed botanical products containing aristocholic acids were found.

The human carcinogenicity of aristocholic acids was first identified in studies of Belgian patients with nephropathy (progressive interstitial renal fibrosis) related to the consumption of herbal medicines. More than 100 cases have been reported in Belgium and more than 170 cases in other locations, including the United States, the United Kingdom, Japan, Taiwan, and China. Clinical studies found significantly increased risks of transitional-cell carcinoma of the urinary bladder and upper urinary tract among Chinese renal-transplant or dialysis patients who had consumed Chinese herbs or drugs containing aristocholic acids, using non-exposed patients as the reference population. This is the first “known human carcinogen” that was first discovered in animals.

Case Study Questions

1. Should FDA regulate the import and use of herbal medicines? If so, how should the FDA do so?

2. How would you compare the risk and hazards from aristocholic acid and aflatoxin?

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