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8.2 Toxicology and environmental health: applications and interventions in public health

8.2 Toxicology and environmental health: applications and interventions in public health
Oxford Textbook of Public Health

8.2
Toxicology and environmental health: applications and interventions in public health

Bernard D. Goldstein and Michael Greenberg

Introduction
Laws of toxicology

The dose makes the poison

Specificity

Humans are animals
Human pathways of exogenous chemicals

Absorption

Distribution

Metabolism

Excretion
Susceptibility
The special problem of mixtures
The interface between toxicological science and public policy

The use of toxicology to test the safety of chemicals

The role of toxicological information in setting environmental health standards

Protection factors and weight of evidence
Criteria for evaluating environmental policies
Conclusion
Chapter References

Introduction
In recent decades we have witnessed a public outcry against pollution of the environment that parallels the force of the Sanitary Revolution of the mid-nineteenth century. New national and international governmental organizations reflect the political potency of this public concern. The chemical, electronics, and petroleum industries, whose previously steady growth had greatly accelerated following the Second World War, are now forced to consider factors other than utility and cost in the development of new products and the marketing of old ones. Substantial societal investments have been made in the developed countries to clean up old environmental pollution problems and to prevent new ones. Government departments that made and tested weapons of mass destruction now spend large portions of their budgets on cleaning up contamination and destroying their weapons. As with the Sanitary Revolution, part of the rationale has been a developing understanding of the relationship of a foul environment to human ill health; part is simply a human revulsion to dirty air, tainted water, and a blighted natural environment. Moreover, we have come to recognize that sustainable development of the Earth’s resources is not possible under the related threats of population growth and environmental degradation.
As we develop more understanding of the Earth, its ecosystems, and the pathways of chemical exposure, problems once thought to be limited to the natural environment have been shown to pose risks to human health, for example contamination of drinking water by hazardous waste dumps. The most substantial long-range threat to human health posed by environmental chemicals is the alteration of the Earth’s atmosphere. Chlorofluorocarbons (CFCs) and other compounds are producing a decrease in the levels of stratospheric ozone, which prevents shorter-range ultraviolet light rays from penetrating to the Earth’s surface, a protective mantle that has been present through much of evolution. The implications of climatic alterations, such as the greenhouse effect caused primarily by increased fossil fuel use and by agricultural practices, are potentially dire. Together, the secondary effects of the alteration of our global climate could be disastrous to human health, and could include major changes in the range and habitat of disease vectors, severe flooding, and famine from crop failure (McMichael 1994).
The global climate issue illustrates five points that are pertinent to this chapter.

1.
Understanding the effects of chemicals is crucial to environmental health.

2.
The system in which chemicals act, whether the human body or planet Earth, is a closed one with only limited response, repair, and regenerative potential.

3.
The effects of chemical and physical agents on health are often delayed and indirect, but nonetheless disastrous.

4.
Local, national, and international control efforts have tended to be most effective when dealing with a single pollutant in a single medium directly producing overt effects, and least effective when dealing with complex chemical mixtures, with pollutants that cross traditional air, water, soil, and food boundaries, and with effects that are delayed or indirect.

5.
A complex set of formal and informal policy processes need to be considered and employed to reduce the risk.
In this chapter we focus on the science of toxicology as it relates to environmental health. We also consider some of the interfaces between environmental health sciences and public policy. Toxicology is the science of poisons (Amdur et al. 1991). Knowledge about poisons extends back to the beginning of history as humans became aware of the toxicity of natural food components. The Bible contains injunctions concerning poisons, including how to avoid them. Greek and Roman history gives evidence of the use of poisons as an instrument of statecraft, an approach that was extended in the Middle Ages with such notable practitioners as the Borgias. Toxicologists tend to view Paracelcus, a seventeenth-century alchemist and a bit of a charlatan, as their ancestor, crediting him with the first law of toxicology—that the dose makes the poison (Gallo and Doull 1991). There are two other major maxims that underlie modern toxicology: that chemicals have specific biological effects, and that humans are members of the animal kingdom.
This chapter discusses ‘laws’ and general concepts of toxicology pertinent to understanding how a chemical or physical agent acts in a biological system. The focus is on the biological response, rather than on the intrinsic property of the agent, although the latter is briefly reviewed (Plaa 1991). This chapter is restricted to human health, although many of the concepts are applicable to ecological health as well.
Laws of toxicology
The dose makes the poison
Central to toxicology is the exploration of how dose is related to response. As a generalization, there are two types of dose–response curves (Fig. 1). One is an S-shaped curve that is characterized by having at lowest doses no observed effect and, as the dose increases, the gradual development of an increasing response. This is followed by a linear phase of increase in response in relation to dose and, eventually, a dose level at which no further increase in response is observed. Of particular pertinence to environmental toxicology is that this curve presumes that there is a threshold level below which no harm whatsoever is to be expected. There is an ample scientific base for the existence of thresholds for specific effects (Aldridge 1986). For example, if undiluted sulphuric acid is splashed on the skin it is capable of producing a severe burn. Yet one drop of pure sulphuric acid in a bathtub of water is sufficiently dilute to be entirely without effect. Thresholds for an adverse effect will differ among individuals based upon a variety of circumstances, some of which are genetically determined and others may represent stages of life or specific circumstances. In the example of sulphuric acid on the skin, there are genetically determined differences in susceptibility related to the protective presence of skin hair, babies will be more susceptible than adults, and skin that is already cut will be at particular risk. This S-type dose–response curve is assumed to fit all toxic effects except those that are produced by direct reaction with genetic material.

Fig. 1 Dose–response curves.

The second general type of dose–response curve has no apparent threshold dose. It covers those endpoints caused by persistent changes in the genes. This occurs in cancers, in which a so-called somatic mutation occurring in a single cell results in a clone of cancer cell progeny. Similarly, germ-like mutations can occur in the DNA of cells involved in reproduction. The genetic code can be considered as bits of information strung on a line in such a way that alteration of one single bit of information can have a profound effect on the overall meaning. It is believed that a single change in DNA can alter the genetic code in such a way to lead to a mutated cell. It therefore follows that any single molecule of a chemical compound, or packet of energy of a physical agent, such as ionizing radiation, that can alter DNA is theoretically capable of causing a persistent mutation. If the chemical adduct or other change in DNA is not repaired by cellular enzymes, each molecule or ionizing ray theoretically has the possibility of changing a normal cell to a cancerous cell. The resultant dose–response curve starts at a single molecule, that is, it has no threshold below which the risk is zero (Fig. 1). There is no absolutely safe dose. In this highly simplified scheme, the shape of the curve is linearly related to dose. The result is that the risk of two molecules of a DNA-altering chemical causing a mutation is twice that of one molecule. Eventually, the dose level is sufficiently high that it results in dead cells. As dead cells do not reproduce, they cannot be the basis for cancer or for inherited abnormalities. Note also that relatively few chemicals are capable of directly altering the DNA of a living cell. Further, the risk of any one molecule actually causing cancer is infinitesimally small—despite the immense number of carcinogenic molecules in the smoke of one cigarette, only a minority of cigarette smokers ever develop cancer. Yet the assumption that the risk is not zero has a major impact on communicating to the public about cancer risk from chemical and physical carcinogens. Industry has often claimed that a threshold exists for carcinogens and for a few chemical mechanistically based toxicological research has substantiated that claim. The prudent public health approach to known or potential human carcinogens places the burden of proof on an industry making such a claim (see Chapter 8.8).
Specificity
That chemical and physical agents have specific effects has been called the second law of toxicology. The concept is no different from recognizing that possession of a gun does not make one a murder suspect if the victim has been stabbed to death. This principle is well understood by the public in terms of medicine: aspirin will help with your headache but is useless for constipation, while laxatives have the opposite specificity. Nevertheless, various surveys suggest that the selectivity of effects of environmental chemicals is not well understood by the public; many believe that a chemical that can cause cancer in a particular organ can cause cancer and other diseases anywhere in the body.
The specificity of effects is due both to chemistry and to biology. Understanding the relationship between chemical structure and biological effect has been a central core of both pharmacology and toxicology. Structure–activity relationships (SAR) are often used to design a chemical with a specific effect that might be useful as a therapeutic agent. Also, SAR is used to predict whether a new chemical being readied for manufacture might be of potential harm. While SAR is a useful tool, the predictive value is too limited to be used without recourse to additional testing of a potentially toxic agent. For example, one methyl group separates toluene from benzene, only the latter causing bone marrow damage and leukaemia; ethanol from methanol, the latter causing acute acidosis and blindness; and h-hexane from either h-heptane or h-pentane, with only hexane being responsible for peripheral nerve damage. These differences reflect specificity in the formation of toxic metabolites and in interaction with biological receptors.
Chemical structure is also an important determinant of the specific characteristic of environmental persistence. There is substantial scientific and public concern about agents that accumulate in the human body or in the general environment. Many such compounds have already been banned or severely restricted (e.g. dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs)). There is a consensus that development or use of additional persistent and accumulative agents should be avoided, particularly as standard toxicological approaches cannot predict all untoward effects and it can be decades before reversal of the environmental effects of a persistent organic compound is possible. Sometimes, non-persistent compounds may be precursors of persistent agents, such as dioxins and dibenzofurans often produced in the incineration of chlorine containing wastes. The possibility that such compounds subtly alter oestrogenic hormone function has become a matter of intense interest (Colborn et al. 1993).
Specificity of effects is also conferred by the susceptibility of biological processes that lead certain cells to be more of a target to environmental agents. For example, haemoglobin, the iron-containing protein in red blood cells, is responsible for the delivery of oxygen to the tissues in the body. Significant toxicity can occur through several specific mechanisms. Oxidation of the reduced ferrous form to the ferric form of iron in the haemoglobin impairs the ability to carry and release oxygen in the tissues. Various chemical agents oxidize intracellular iron, including nitrites that are common contaminants of well water in agricultural communities. Carbon monoxide, an otherwise relatively inert gas, sufficiently resembles oxygen so that it can bind to the oxygen combining site of haemoglobin, thereby displacing oxygen. There are many other examples in which a normal body process is disrupted by an exogenous chemical through oxidation, covalent addition, or fitting into a niche designed through evolution to accommodate an internal chemical that it superficially resembles.
Humans are animals
That humans are animals is the third law of toxicology. The conceptual foundation for extrapolating findings in animals to expected effects in humans is a central facet of modern toxicology. The basic principles of cell and organ function are common to all of biology. All cells must obtain energy, build internal structures, and release waste. Specificity of toxic effects is relatively similar across mammals. In other words, a kidney poison in one species is likely to be a kidney poison in another, although there are exceptions. However, dose–response considerations often vary substantially, reflecting differences in adsorption, distribution, metabolism, excretion, function, and target organ susceptibility among species. Understanding the factors responsible for interspecies differences greatly facilitates extrapolation from animals to humans. Once elucidated, the role of different absorption rates, metabolism or other factors can be taken into account, often through a mathematical approximation called physiologically based pharmacokinetics (Frantz et al. 1994).
Human pathways of exogenous chemicals
A central focus of toxicological science is the assessment of the pathways taken by a chemical from its entrance into the body until its eventual excretion. This process is usually divided into four related processes of absorption, distribution, metabolism, and excretion (Gallo et al. 1987).
Absorption
Absorption of a chemical into the body occurs through the mouth, respiratory tract, and skin. Depending upon the specific chemical, the route of exposure can have major implications to absorption into the body and the resultant toxicity. For example, almost 100 per cent of inhaled lead particles are absorbed into the circulation as compared with a much smaller per cent of ingested lead. Internal factors can affect absorption, particularly from the gastrointestinal tract. For example, iron and calcium deficiencies, which are common in children in inner city areas where lead is prevalent, both produce an increase in absorption of ingested lead. The milieu of the exposure agent can also have an effect on its bioavailability. For example, the rate at which benzene in gasoline is absorbed through the skin is increased by the addition of oxygenated components to the gasoline mixture, and the extent to which dioxin in soil is absorbed through the gastrointestinal tract differs many hundred-fold depending upon the source of the contaminated soil (Umbreit et al. 1986).
Often, a single route of absorption is dominant. Nevertheless, in many instances more than one route is important. For example, exposure due to contamination of well water through a leaky underground storage tank is usually thought of solely in terms of water intake. However, depending upon the height of the water table there may be evaporation into the basement producing inhalation exposure, and during showering there is likely to be both inhalation and transdermal absorption.
Distribution
Distribution of the chemical, once inside the body, occurs through different pathways. In part this distribution depends upon the route of absorption. Most compounds absorbed in the gastrointestinal tract go directly to the liver and may go no farther, while inhaled agents first go to the lung or other parts of the respiratory tract. Distribution also depends upon the chemical and physical properties of the agents. Small particles tend to be distributed deep within the respiratory tract, while larger particles wind up in the nose or upper respiratory tract. Chemicals that are poorly soluble in water, for example oils, usually distribute within fatty tissues, and only certain types of compounds can penetrate from the blood to the brain. Distribution will often depend upon organ-specific factors. For example, the high levels of iodine in the thyroid are due to a specific thyroid pump for the uptake of iodine needed for the synthesis of thyroid hormones.
Metabolism
Metabolism in the narrowest sense of the term refers to alteration of chemicals by the body (Kato et al. 1989). The major metabolic function of the body is to alter food into energy or structural materials. Most foods and other exogenous chemicals are metabolized in the liver. All organs have metabolic capability, often related both to organ function and to susceptibility to toxic agents. Understanding the specifics of the enzyme and enzyme families responsible for metabolism within cell types is important to the question of why chemicals have specific effects in specific organs.
Metabolism is often divided into two phases. Phase I reactions usually involve oxidation, reduction, or hydrolysis and often result in converting exogenous chemicals into substances capable of being converted by phase II enzymes into conjugates that can be excreted from the body, or into building blocks useful for synthesis of body components. The major family of enzymes involved in phase I reactions are cytochrome P-450 containing mono-oxygenases, of which there are multiple forms with varying degrees of specificity.
Metabolism of foreign substances is often protective, converting unwanted absorbed materials into chemical forms that are readily excretable. Thus, a fat-soluble agent can be converted into more water-soluble agents capable of being excreted in the bile or the urine. At times, metabolism is central to toxicity through the conversion of relatively inactive compounds into harmful agents (Guengerich and Liebler 1985). A variety of compounds ranging from polycyclic organic hydrocarbon components of soot to the leukaemogen benzene require metabolic activation to become carcinogenic. In the case of benzene, about 50 per cent of the body burden is exhaled unmetabolized and about 50 per cent is metabolized into potentially toxic metabolites. Slowing benzene metabolism leads to an increase in the relative amount exhaled rather than metabolized and a decrease in bone marrow toxicity. In contrast, speeding up benzene metabolism increases its toxicity (Snyder et al. 1993). For example, alcohol induces an increase in the specific cytochrome P-450 responsible for benzene metabolism and has been shown to potentiate benzene toxicity.
Excretion
Excretion from the body can occur through a variety of routes. These include the gastrointestinal tract for unabsorbed ingested components, and the urine for water soluble agents of appropriate molecular weight and charge. The urinary excretion rate can be substantially affected by the state of body hydration. Agents metabolized in the liver are often excreted through the biliary tract. Significant loss of volatile compounds can occur through the respiratory tract, as noted above for benzene. Other routes of excretion include sweat and lactation, the latter unfortunately putting the infant at risk when mothers’ milk contains toxic agents.
Susceptibility
One of the more difficult problems in toxicology is to understand the basis for differences in human susceptibility to environmental insults (Grandjean 1995). In some individuals cigarette smoking will cause death at a relatively young age due to lung and other cancers, chronic lung disease, or cardiovascular disease, while other individuals with the same or greater smoking history will survive with relatively minimal damage until much older. A partial explanation is that certain environmental toxins act to speed up the effects of impacts that would have occurred later in life due to genetic or other environmental causes. For example, someone who would have died of a heart attack at age 70 due to an inherited tendency to cholesterol accumulation in their arteries coupled with a high cholesterol intake in the diet, may have a heart attack at age 55 because of the added insult of cigarette smoking. Increasing asthma rates among African-Americans has become a major public health issue in the United States, with many possible factors contributing to susceptibility currently under consideration. Understanding the interaction of genetic and environmental factors in human disease will be greatly abetted by current research on the human genome. While a genetic basis for most diseases will be discernible, it must be emphasized that the inherited factors will usually be necessary but not sufficient to lead to disease. Except for certain childhood disorders, environmental factors will usually determine whether and when the genetically determined disease will become manifest (see Chapter 2.4).
The known causes of increased human susceptibility to a specific level of a noxious environmental agent fit into four classes: increased uptake into the body increased delivery of the agent or its metabolite to the target organ increased susceptibility of the target organ to damage and increased susceptibility of the individual to a given level of target tissue damage. Increased absorption of an air pollutant may simply represent the difference between sitting on a park bench and jogging in the park. The tragic finding of two dead children in the back seat of a snowbound car with the motor left running, while the adults in the front seat are only unconscious, is due primarily to the greater respiratory rate per body size in the children, leading to a greater uptake of carbon monoxide (Plunkett et al. 1992). Genetically determined differences in certain enzymes are well known to affect the rate of metabolism of certain drugs and environmental agents significantly, both detoxification of a noxious compound and activation to a noxious form. For example, acetylation, a common metabolic process, occurs at a relatively fast or slow rate depending upon common variants of the responsible gene and enzyme. Other key metabolic enzymes can have their activity altered by dietary components, alcohol, therapeutic drugs, or previous exposure to the noxious agent. Target organs also may react differently to a given level of an environmental agent or its metabolite. As examples, one in seven black males in the United States has an inherited variant of the enzyme glucose-6-phosphate dehydrogenase that protects against malaria but leaves the red blood cells at particular risk to oxidizing drugs, and there are individuals who are at high risk of sunlight-induced skin cancer because they are lacking certain enzymes capable of repairing the DNA damage caused by ultraviolet light. Lastly, individuals may be more susceptible to harm from an environmental toxin not because their target organ response is greater, but because the effect of a loss of function is more deleterious. For example, cigarette smokers have no more, and perhaps even less, lung responsiveness to inhalation of the air pollutant ozone. This is presumably because the increased mucus in the airways of smokers acts to scrub out the ozone before it reaches the lung cell surface. Yet, because cigarette smokers have so much less overall respiratory capability than do non-smokers, a relatively small ozone-induced additional loss of respiratory capability may have more of an impact on the actual functioning of a smoker than of a non-smoker. Similarly, the loss of lung and other organ reserve with ageing will make an elderly individual more susceptible than a younger adult to an identical toxic effect in an organ.
The special problem of mixtures
Except in special circumstances, human exposure to potentially toxic chemical and physical agents occurs as part of a mixture. We are genetically well programmed to deal with mixtures—most foodstuffs contain an enormous variety of chemicals. However, the science of toxicology, and the regulation of chemicals, has generally focused on individual chemicals rather than the broad mix of agents that are present in contaminated air or water, or in such common consumer products as gasoline.
An example of the problem posed by this approach is the recent change in the automotive fuel mixture in the United States to include oxygenates such as methyl tert-butyl ether (MTBE). Many people are complaining about non-specific symptoms related to the addition of MTBE to gasoline. These clinical complaints are not well supported by the information in the toxicology database. However, the relevant toxicological database is almost totally restricted to studies of MTBE alone, rather than MTBE in gasoline.
The issue of how to predict the effect of mixtures is not confined solely to a single exposure matrix. As described above, ingestion of alcohol alters the level of metabolic enzymes responsible for the activation or inactivation of a variety of drugs and environmental chemicals. Many other food constituents have such effects, often in different directions from each other. An unexpected finding of the effect of alcohol consumption on the metabolism of a drug was traced to a natural component of grapefruit juice used to dilute the alcohol given to the study participants (Bailey et al. 1994).
Most studies of mixtures have found that the effects are additive in that they are predictable by summing up the effects of the individual components of the mixture. This is particularly true when agents have similar effects. At times, the interaction is synergistic. For example, the lung cancer incidence due to cigarette smoking plus occupational asbestos exposure is far greater than should be expected due to the sum of the risks (Selikoff et al. 1968). Antagonism also occurs; for example, exposure to toluene plus benzene leads to less benzene toxicity to the bone marrow than if the exposure were to benzene alone (Andrews et al. 1977). This is believed to be due to both agents being metabolized by the same metabolic machinery. Benzene is converted into a bone marrow toxin while toluene is converted into a harmless agent. If there is sufficient toluene available to tie up the metabolic machinery, benzene metabolism will be slowed and a less toxic metabolite will be formed. Note that no interaction between toluene and benzene occurs when exposure levels are relatively low as there is then sufficient metabolic machinery to handle both of these compounds independently. Potentiation also occurs when one agent (e.g. alcohol) that has no effect itself increases the effect of another agent.
In view of the almost infinite number of potential combinations of exogenous chemical and physical agents, studying them all is impossible. Two approaches have been developed to deal with this problem. One is to study those combinations to which humans are likely to be exposed, for example gasoline. The other is to focus on understanding the mechanism of toxicity of the individual components so as to predict interactive effects.
The interface between toxicological science and public policy
Toxicology is relied on as a way of protecting the public and the general environment. Toxicology has two important roles: detection of cause and effect relationships linking environmental chemical and physical agents to adverse effects to humans or the environment, and development of techniques capable of preventing these problems. Toxicologists usually approach questions of causation of disease by starting with the chemical or physical agent and studying its effects in laboratory animals or in test tube systems. One of the more exciting aspects of modern toxicology is the possibility of linking subtle biological markers indicative of exposure with biomarkers showing early effects, thereby providing epidemiologists with powerful early warning tools to evaluate cause and effect relationships between environmental exposure and human diseases (National Research Council 1989).
The use of toxicology to test the safety of chemicals
Assessment of the safety of chemicals has evolved into a relatively standardized approach, particularly when considering new chemicals being developed for the market. The starting assumption is that all chemicals have toxic effects. To protect the public and the worker it is necessary to know what specific effect occurs at what dose.
A relatively standardized battery of laboratory tests has been developed to assess chemical toxicity. Although varying greatly in effectiveness and cost, they are of value when used with judgement and with understanding of basic mechanisms of toxicity that govern the ability to predict effects. For certain types of endpoints, such as mutations, there are a variety of apparently effective testing procedures. For other endpoints, such as neurobehavioural effects, we are far less able to predict whether a new agent may have an adverse outcome in humans.
The Ames test for mutagenesis is an example of a short-term test designed specifically to screen for potentially cancer-causing chemicals. By using a bacterial test system that can readily show when a mutation occurs, and coupling that to an actively metabolizing fraction of rodent liver, compounds that are capable of producing mutations can usually be detected (Ames et al. 1975). Other short-term tests for mutagenesis depend upon mammalian cells in vitro or in vivo. The classic long-term test lasts almost 2 years, close to the lifetime of a rat or mouse. The dose chosen is one that is maximally tolerated by the laboratory animal in a 90-day trial. The use of a high dose, well beyond that of usual human exposure, has been controversial. Detractors point out that at high doses the toxicological response mechanisms may differ from that at usual doses, and that cell toxicity may lead to false positive findings, particularly of cancer. Supporters point out the effectiveness to date of detecting potential human carcinogens and the statistical impossibility of finding even a 1 in 1000 cancer risk using only at most a few hundred test animals exposed to usual environmental doses (National Research Council 1993).
Some of these useful animal tests are under attack by animal rights activists, although for most adverse endpoints there are no validated in vitro test procedures capable of protecting the public, or for that matter, capable of protecting pets, such as cats and dogs, that have benefited greatly from the development of chemical products that decrease their suffering and prolong their life.
In some cases, laws and governmental regulations specify the toxicological test information necessary, depending upon the type of product, for example pesticides or food additives. In all cases public concern and the activities of toxic tort plaintiffs’ lawyers have produced pressure on chemical industries to carry out careful screening of new compounds for adverse effects before they are released to the market. Perhaps 1500 new chemicals pass through the screening process and enter the market each year in the United States.
The role of toxicological information in setting environmental health standards
As discussed below, the setting of environmental health standards depends upon many factors, including legal requirements and political, economic, and social considerations. Certain laws, such as the United States Clean Air Act, require the Administrator of the Environmental Protection Agency to set ambient standards based upon the protection of sensitive populations, but with no consideration of the costs to achieve the standard. Other laws, such as the Toxic Substances Control Act in the United States, expressly attempt to balance the value to society of new chemical products against the potential risks to human health and the environment from use of these chemicals.
Not surprisingly, there are different levels of toxicological information required by these different laws. As a generalization, chemical agents developed for the marketplace can be considered under four headings: agents clearly intended to have a biological impact in humans, primarily therapeutic drugs or vitamins; agents with more limited biological effects in humans, such as cosmetics that alter skin moisture or food additives aimed at the taste bud; agents for which a biological impact is intended, but not in humans, such as pesticides or herbicides; and chemical agents for which no biological effect is desired, such as paints and window cleaners. Before a new drug can be marketed, the Food and Drug Administration requires extensive animal studies and then carefully controlled trials in humans. In contrast, in the United States premanufacturing notification for a new paint thinner requires little more than identifying the chemical structure and perhaps a few short-term test-tube assays. Usually, the chemical industry is sufficiently concerned about liability issues and the good name of the company so that it will more extensively test a new product before putting it on the market.
Protection factors and weight of evidence
Setting standards for exposure to chemicals has evolved from a rather straightforward arithmetic formulation based upon relatively minimal data in animals to the present day situation where there is often a large body of evidence, including information about humans. As a generalization, the toxicology of the past used a dose–response approach to establish a no observed effect level (NOEL) in laboratory animals. The NOEL is in essence the highest tested level below the threshold. Various protection factors, often mislabelled as safety factors (Goldstein 1990), were then applied, usually by dividing the NOEL by factors of 10 each for the greater variability in humans than in inbred laboratory animals, for the possibility that humans were more sensitive than the laboratory species under study, and even for the possibility that there were unobserved effects in the laboratory animals that were pertinent to humans. The resultant level, usually one-hundredth or one-thousandth of the NOEL, was then used to establish the standard. In the United States the new Food Quality Protection Act adds another factor of 10 for the protection of children.
Variants of this protective factor approach still exist, often in the more sophisticated form of a reference dose or benchmark dose. However, particularly in situations where there is a relatively mature database, a more formal approach to the weighing of evidence is often taken. For example, the United States Clean Air Act requires that the Environmental Protection Agency (EPA) Administrator sets an ambient standard for each of six major air pollutants: ozone, sulphur dioxide, particulates, nitrogen dioxide, carbon monoxide, and lead. The standard is required to protect sensitive populations from adverse effects with an adequate margin of safety. The law also sets up the Clean Air Scientific Advisory Committee, a seven-member panel that carefully reviews the evidence and makes recommendations to the EPA Administrator, including recommendations concerning the margin of safety. The standards are set without recourse to automatic factors of 10. Rather, the available toxicological and epidemiological evidence is carefully weighed as the basis for the recommendation. Recent recommendations have led to the EPA proposing changes in the ambient standards for ozone and for particulates.
The weight of evidence approach is increasingly used to come to judgement about complex issues. An important example is the classification of potential human carcinogens by the International Agency for Research on Cancer (IARC 1992).
Criteria for evaluating environmental policies
Environmental policies in the United States are neither knee-jerk reactions to mass media coverage of environmental risks, as some claim, nor, as many scientists wish, are they the product of carefully conceived analyses of all the factors that should be considered (Portney 1990; Carlisle and Chechile 1991). Eight criteria for policy formation are described below in the form of questions asked by decision-makers or analysts. The first two are always explicitly considered; the last three are often not considered.

1.
Health/safety/environmental protection. This is clearly the first criterion. What risks will the proposed policy decrease? Will it increase any risks? To what certainty are these risks known and predictable from toxicology and epidemiology? In other words, how much uncertainty is there? The greater the uncertainty, the greater the importance of the other seven criteria.

2.
Legal/political feasibility. Is the proposed policy consistent with existing legal mandates? Can it be implemented with existing legislative mandates and rules? Does it support national, state, and local political goals? For example, in the United States will the policy be consistent with a political trend toward less government, less interference with private enterprise, transfer of authority from the national government to state and local governments, from government to private enterprise?

3.
Reactions from stakeholders. What interest groups are likely to support the proposed policy, oppose the proposed policy? Will elected and agency officials support or oppose it? Can they be persuaded to support it? What will be voter and media reactions?

4.
Economic feasibility. Is the policy affordable? Can we prepare an implementation strategy that reaches the ultimate goal in divisible stages? Will the investment of a small amount of money in the initial stages accomplish most of the goals?

5.
Benefits/costs. Will the proposed policy yield economic, social, and health benefits that exceed the costs? Are there advantages of using the funds for this purpose rather than another environmental protection policy? Is the proposed approach the least costly or most cost-effective way to obtain the desired benefits?

6.
Ethical imperative. Does the proposed policy disproportionately benefit some groups (economic, ethnic, racial, generation, gender) while placing others at greater risk? How will the consent of the most seriously impacted groups be obtained? Does the policy increase the probability of damaging a unique national or cultural resource?

7.
Time pressure. What will happen if the policy is deferred for 1, 5, 10, 20, or more years?

8.
Flexibility. Is the policy adaptable to advances in science and engineering and changes in the political climate?
The clean-up of nuclear and chemical wastes at the major nuclear weapons sites that are the responsibility of the United States Department of Energy (DoE) is a widely publicized illustration of the complex interactions of these eight policy factors (Office of Environmental Management 1995a,b). We briefly summarize key points and pose an important policy question under each category. Regarding environmental health and safety a great deal is known about the toxicological properties of radio-active materials. The high level radio-active wastes and radiological hot spots at the DoE’s major sites in Colorado, Idaho, Tennessee, South Carolina, and Washington are clearly dangerous, and plumes of contaminated ground water are another concern. However, the public is buffered from these threats by engineering controls, security, and open space. A goal is to convert the most dangerous materials from liquid to solid forms so that they cannot migrate into the environment. A key policy question is whether every possible gram of radiological and chemical waste be removed even if that entails destroying natural ecological systems that have been undisturbed for decades.
The United States government has legal requirements and a political system that oblige it to prevent exposure to the legacy of 50 years of developing, manufacturing, and testing nuclear weapons. Only during the last decade has the security veil at these weapons sites been lifted to the point that other federal agencies, such as the EPA, tribal nations, and state governments, have a legal say in the clean-up and future uses of the sites. The DoE has signed legal agreements with the EPA and states that requires it to meet mandated clean-up objectives. In other words, it can no long act unilaterally. A key policy question is how much of a role other federal agencies, and especially state and local governments, should play in the future of the DoE sites.
Psychological studies show that the word ‘nuclear’ engenders great fear. Stakeholders do not want nuclear facilities, especially waste management facilities, near them. Highly publicized attempts to bury high-level waste in Yucca Mountain have been vehemently opposed by the government and the overwhelming majority of the residents of the State of Nevada. An important policy question is how responsive the federal government should be to these fears of human health effects and economic stigma when it makes location decisions.
The DoE has an environmental management budget of about $6 billion out of a total budget of $16 billion. This is the largest environmental management budget of any government agency in the world. Yet the economic feasibility of clean-up of sites to levels desired by the states and local governments is problematic because the DoE’s budget is under considerable pressure by the United States Congress and Executive branch. About 70 per cent of the DoE environmental management budget is spent at the five sites in Colorado, Idaho, Tennessee, South Carolina, and Washington. The communities surrounding these sites depend on the DoE to support their economies. In other words, the costs are to United States taxpayers as a whole whereas the benefits are geographically concentrated in a few locations. How much influence should the economic impact of DoE expenditures have on how the DoE’s funds should be spent?
The American government has a moral obligation, which is has acknowledged through the DoE, to remediate the nuclear waste sites. However, the issue is how much clean-up needs to occur. Economic analyses estimate costs ranging from $100 to $400 billion over 70 years. The lowest estimate translates into controlling dangerous materials, monitoring, and securing the sites. The most expensive approach requires the removal and/or destruction of nuclear materials and opening them up for public access. Should the American population as a whole commit hundreds of billions of dollars to remediate these sites back to levels that approach their precontamination levels?
Time pressure and flexibility are important policy drivers in the case of the DoE’s major weapons sites. Some of the radio-active materials will be dangerous for thousands of years. These sites require long-term stewardship. While dangerous material decay, scientists will be developing new methods of destroying and controlling nuclear waste. Should the DoE delay clean-up of radio-active materials while waiting for new technological developments?
Overall, the management of the legacy of nuclear weapons production in the United States illustrates both the important role of toxicology and its complex interactions with other factors that play in policy formation.
Environmental health issues are increasingly international. The ability of humans to affect our planet has increased both because of the increase in our number and the increase in our power to interact with the environment. Many closely connected feedback loops have been demonstrated between our biosphere and our planet, including its atmosphere, climate, and oceans. Destruction of forests in one part of the world can have an impact on the climate for much of the rest of the planet. The loss of the protective effects of stratospheric ozone due to the use of CFC refrigerants is just one example of inadvertent effects of human activities that alter planetary systems so as to adversely affect human health. Our increasing interconnectedness in telecommunications, transportation, and trade also is having a profound impact, both for good and bad. We are now more able to recognize and communicate potential global problems, but we also appear more willing to wrap economic trade issues in the green flag of environmental protectionism. The precautionary principle is an excellent example of a valuable formulation of a principle that is basic to public health, yet is at risk of being distorted for economic and nationalistic purposes.
Developing countries are particularly at risk. In their rush to become modern producers, these countries make economic decisions to produce industrial products cheaply without instituting costly environmental safeguards. In addition, hazardous waste from developed countries may be more cheaply disposed of in developing countries, thus hazardous jobs and hazardous chemicals may be exported by developed countries to developing countries that have less stringent and less costly environmental regulations. Sea-level rise and severe climate events will have greater impact on poorer more densely populated areas without the resources to prevent or respond to the impacts. The lack of environmental health infrastructure and expertise also puts developing nations at risk; at times due to the inability to recognize the hidden threats of policies imposed upon them by the international community. A case in point is the horrific results of arsenic poisoning of village water supplies in Bangladesh in which simple tube wells, used to replace contaminated surface drinking water sources, in many cases tapped into groundwater that was heavily contaminated with arsenic.
Conclusion
Toxicology occupies an important niche between science and public policy. Its major contribution has been to provide tools to policy-makers and the public that have prevented what would have been substantially greater environmental degradation, including adverse human health impacts. As society changes due to new technology and to the challenge of sustainable development in the face of increased human population, the role of toxicology in enlightened public policy will become even more important. However, while toxicological information is critical to decision-making, it is not the sole determinant of policy, particularly when uncertainty exists.
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