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TOXICOLOGY


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General Considerations

CONTENTS

Definition and Purpose of Toxicology

3
Scope and Subdisciplines 4
Early Developments 5
Recent Developments 6
Some Challenges and Successes 8
Toxicity vs. Other Considerations 9
Future Prospects 10
References 11
Appendix 1   U.S. Laws That Have a Basis in Toxicology 12
Appendix 2   Examples of Outbreaks of Mass Poisoning 13

People are exposed to a great variety of natural and man-made substances. Under certain conditions such exposures produce adverse health effects, ranging in sever- ity from subtle biologic changes to death. Society’s ever-increasing desire to iden- tify and prevent these effects has prompted the dramatic evolution of toxicology as a study of poisons to the present-day complex science.

DEFINITION AND PURPOSE OF TOXICOLOGY

To state it simply and concisely, toxicology is the study of the nature and mech- anisms underlying toxic effects exerted by substances on living organisms and other biologic systems. Toxicology also deals with quantitative assessment of the adverse effects in relation to the concentration or dosage, duration, and frequency of exposure of the organisms.The assessment of health hazards of industrial chemicals, environmental pollutants, and other substances represents an important element in the protection of the health of the workers and members of communities. In-depth studies of the nature and mechanism of the effects of toxicants are invaluable in the invention of specific antidotes and other ameliorative measures. Along with other sciences, toxicology contributes to the development of safer chemicals used as drugs, food additives, and pesticides, as well as of many useful industrial chemicals. Even the adverse effects per se are exploited in the pursuit of more effective insecticides, anthelmintics, antimicrobials, and agents used in chemical warfare.

SCOPE AND SUBDISCIPLINES

Toxicology has a broad scope. It deals with toxicity studies of chemicals used (1) in medicine for diagnostic, preventive, and therapeutic purposes; (2) in the food industry as direct and indirect additives; (3) in agriculture as pesticides, growth regulators, artificial pollinators, and animal feed additives; and (4) in the chemical industry as solvents, components, and intermediates of plastics and many other types of chemicals. It is also concerned with the health effects of metals (as in mines and smelters), petroleum products, paper and pulp, toxic plants, and animal toxins.

Because of its broad scope as well as the need to accomplish different goals, toxicology has a number of subdisciplines. For example, a person may be exposed, accidentally or otherwise, to excessive large amounts of a toxicant, and become severely intoxicated. If the identity of the toxicant is not known, analytical toxi- cology will be called upon to identify the toxicant through analysis of body fluids, stomach contents, suspected containers, etc. Those engaged in clinical toxicology administer antidotes, if available, to counter the specific toxicity, and take other measures to ameliorate the symptoms and signs and hasten the elimination of the toxicant from the body. There may also be legal implications, and that will be the task of forensic toxicology.

Intoxication may occur as a result of occupational exposure to toxicants. This may result in acute or chronic adverse effects. In either case, the problem is in the domain of occupational toxicology. The general public is exposed to a variety of toxicants, via air and water, contact with skin as well as from food as additives, pesticides, and contaminants, often at low levels that may be harmless acutely but may have long-term adverse effects. The sources of these substances, their transport, degradation, and bioconcentration in the environment, and their effects on humans are dealt with in environmental toxicology. Regulatory toxicology attempts to protect the public by setting laws, regulations, and standards to limit or suspend the use of very toxic chemicals as well as defines use conditions for others. Some of the relevant laws in the United States are listed in Appendix 1.

To set meaningful regulations and standards, extensive profiles of the toxic effects are essential. Such profiles can be established only with a great variety of relevant toxicological studies, which form the foundation of regulatory toxicology.


The basic part of such studies is referred to as conventional toxicology. In addi- tion, knowledge of the mechanism of action, provided by mechanistic toxicology, enhances the toxicological evaluation and provides a basis for other branches of toxicology. The knowledge gained is then utilized to assess the risk of adverse effects to the environment and humans and is termed as risk assessment. A health risk assessment constitutes a written document that is based upon all pertinent scientific information regarding toxicology, human experiences, environmental fate, and exposure. These data are subject to critique and interpretation. The aim of this assessment is to estimate the potential of an adverse effect that occurs in humans and wildlife ecological system posed by a specific amount of exposure to a chemical.Risk assessments include several elements such as (1) description of the potential adverse health effects based on an evaluation of results of epi- demiologic, clinical, toxicologic, and environmental research; (2) extrapolation from these results to predict the type and estimate the extent of health effects in humans under given conditions of exposure; (3) judgments as to the number and characteristics of individuals exposed at various intensities and durations; (4) and summary judgments on the existence and overall magnitude of the public health problem (Paustenbach, 2002). Risk characterization represents the final and the most critical step in the risk assessment process whereby data on the dose– response relationship of a chemical are integrated with estimates of the degree of exposure in a population to characterize the likelihood and severity of a health risk outcome (Williams and Paustenbach, 2002).

EARLY DEVELOPMENTS

The earliest human was well aware of the toxic effects of a number of substances, such as venoms of snakes, the poisonous plants hemlock and aconite, and the toxic mineral substances arsenic, lead, and antimony. Some of these were actu- ally used intentionally for their toxic effects to commit homicide and suicide. For centuries, homicides with toxic substances were common in Europe. To protect against poisoning, there were continual efforts directed toward the discovery and development of preventive and antidotal measures. However, a more critical eval- uation of these measures was only begun by Maimonides (1135–1204) with his famous medical work Poisons and Their Antidotes, published in 1198.

More significant contributions to the evolution of toxicology were made in the 16th century and later. Paracelsus stated: “No substance is a poison by itself. It is the dose (the amount of the exposure) that makes a substance a poison” and “the right dose differentiates a poison and a remedy.” These statements laid the foundation of the concept of the “dose–response relation” and the “therapeutic index” developed later. In addition, he described in his book Bergsucht (1533–

1534) the clinical manifestations of chronic arsenic and mercury poisoning as well as miner’s disease. He might be considered the forefather of occupational toxicology. Orfila wrote an important treatise (1814–1815) describing a systematic correlation between the chemical and biologic information on certain poisons.


He also devised methods for detecting poisons and pointed to the necessity for chemical analysis for legal proof of lethal intoxication. The introduction of this approach ushered in a specialty area of modern toxicology, namely, forensic toxicology.

RECENT DEVELOPMENTS

In the face of a growing population, modern society demands improvements in health and living conditions, including nutrition, clothing, dwelling, and trans- portation. To meet this goal, a great variety of chemicals, many of them in large quantities, must be manufactured and used. It has been estimated that tens of thousands of different chemicals are in commercial production in industrialized countries. In one way or another, these chemicals come in contact with various segments of the population: individuals are engaged in their manufacture, han- dling, use (e.g., painters, applicators of pesticides), consumption (e.g., drugs, food additives, natural food products or nutraceuticals), or misuse (e.g., suicide, acci- dental poisoning, environmental disasters). Furthermore, people may be exposed to the more persistent chemicals via various environmental media and be affected more insidiously. To illustrate the devastating effects of toxicants, some examples of massive acute and long-term poisonings are listed in Appendix 2. In some of these episodes, a considerable amount of sophisticated toxicological investigation was done before the etiology was ascertained.

These and other tragic outbreaks of massive chemical poisonings have resulted in intensified testing programs, which have revealed the great diversity of the nature and site of toxic effects. This revelation, in turn, has called for more studies using a greater number of animals, a greater number of indicators of toxi- city, biomonitoring of chemicals, etc. There is, therefore, a need to render the task of toxicologically assessing the vast number of chemicals by using increasingly more complex testing procedures more manageable. As an attempt to fulfill this need, criteria have been proposed and adopted for the selection of chemicals to be tested according to their priority. In addition, the “tier systems” allow decisions to be made at different stages of toxicologic testing, thus avoiding unnecessary studies. This procedure has been particularly useful in the testing for carcino- genicity, mutagenicity, reproductive capacity, and immunotoxicity because of the large expenses involved and the great multitude of test systems that are available (Chaps. 7, 8, 11, and 25).

Because of the large number of individuals exposed to these chemicals, society cannot defer appropriate control until serious injuries have appeared. The modern toxicologist, therefore, must attempt to identify, where possible, indicators of exposure, and early, reversible signs of health effects. These will permit the formulation of decisions at the right time to safeguard the health of individuals, either as occupational workers or in exposed communities. The achievements in these areas have assisted responsible personnel in instituting appropriate medical surveillance of occupational workers and other exposed populations. Notable examples are the use of cholinesterase inhibition as an indicator of exposure to organophosphorous pesticides and various biochemical parameters to monitor the exposure to lead. Such “biological markers” are intended to measure exposure to toxicants or their effects as well as to detect susceptible population groups (NRC,

1987); they are used for clinical diagnosis, monitoring of occupational workers, and facilitating safety/risk assessment (WHO, 1993).

Advances made in biochemical and toxicokinetic studies as well as those in genetic toxicology, immunotoxicology, reproductive toxicology, morphologic studies on a subcellular level, and biochemical studies on a molecular and genetic level have all contributed to a better understanding of the nature, site, and mecha- nisms of action of toxicants. For example, technological breakthroughs enabled in vitro studies to demonstrate that whether the hepatocytes or the nonparenchymal cells affected by a chemical carcinogen is related to differences in their abil- ity to repair the DNA damage induced by the chemical.Studies using isolated nephrons have provided insight on the site and mode of action of nephrotoxi- cants (Chap. 14). Various other types of in vitro studies have demonstrated the possibility of their use in screening toxicants for specific effects such as muta- genicity and dermal irritancy. Numerous studies have shown that the responses to toxicants are better correlated with the effective dose, that is, the concen- tration of the toxicant at the site of action, rather than the administered dose. Furthermore, where the effect results mainly or entirely from an active metabo- lite, the concentration of the metabolite rather than that of the parent chemical is important.

An important function of toxicology is to determine safe levels of expo- sure to natural and man-made chemicals (see Risk Assessment above), thereby preventing the adverse effects of exposures to toxicants. One of the earliest offi- cial actions in this field was taken by the U.S. Food and Drug Administration. It stipulated that a 100-fold margin was required for a food additive to be per- mitted for use. In other words, a chemical additive should not occur in the total human diet in a quantity greater than 1/100 of the amount that is the maximum safe dosage in long-term animal experiments (Lehman and Fitzhugh, 1954). For several reasons this approach was not practicable on an international level (see Chap. 25). While evaluating a number of food additives in 1961, WHO coined the term “acceptable daily intake” (WHO, 1962). Using ADI procedure, WHO has since convened annual meetings of experts on food additives, contaminants, residues of veterinary drugs, and pesticide residues. Assessment of these chemi- cals has resulted, where appropriate, in the assignment of ADIs (Chap. 25). The term “ADI” and the WHO evaluations have been adopted by regulatory agencies in many nations. The inception, evolution, and application of ADI have been outlined by Lu (1988). For toxicants in the occupational settings, quantitative assessments are provided in terms of “threshold limit values” (Federal Register, 1971).

These determinations involve comprehensive studies of the toxic prop- erties, demonstration of dosages that produce no observable adverse effects,establishment of dose–effect and dose–response relationships, and toxicokinetic and biotransformation studies.

The greatly increased scope and the multiplicity of subdisciplines as outlined above provide a vivid view of recent progress in toxicology.

SOME CHALLENGES AND SUCCESSES

The so-called aniline tumors were reported by Rehn (1895), a German surgeon, in the urinary bladders of three men who had worked in an aniline factory. The role of aniline and aniline dyes as etiologic agents was confirmed only some 40 years later, after much experimental investigation in animals (e.g., Hueper et al.,

1938), and extensive epidemiologic studies by Case et al. (1954) had been carried out. This discovery led to improved occupational standards and more stringent controls of food colors derived from coal tar.

In the late 1950s, thalidomide was widely used as a sedative. It has a very low acute toxicity and readily met the toxicity testing protocol prevailing at that time. However, a rare form of congenital malformation, phocomelia (the virtual absence of extremities), was observed among some offspring of mothers who had taken this drug during the first trimester (Lenz and Knapp, 1962). This tragedy led to the explosive development of teratology (developmental toxicology), an important specialty area of toxicology. The importance of modifying factors has been dramatized by the tragic effect of cobalt among heavy beer drinkers (see Chap. 5).

The once prevalent lead poisoning in certain areas of industrialized coun- tries has now largely disappeared. This great accomplishment in the field of public health has resulted from the implementation of control measures devised on the basis of the knowledge gained from the numerous toxicologic studies of lead. However, this has now raised new concerns. Lead has been replaced by the gaso- line additive methylcyclopentadienyl manganese tricarbonyl (MMT). Combustion of MMT-containing gasoline generates tailpipe emissions of manganese and stud- ies have shown that manganese produces central nervous system disturbances (Gwiadza et al., 2007). Thus, it should be borne in mind that removal of one chemical and replacement with another does not necessarily reduce the risk for development of adverse effects.

Many cases of serious illness that culminate in permanent paralysis and death have been reported in Minamata and Niigata in Japan in the 1950s and 1960s, respectively (Study Group of Minamata Disease, 1968; Tsubaki and Irukayama,

1977). The cause of the illness was eventually traced to methyl mercury in the fish caught locally. The fish were contaminated with this chemical, which had been discharged as such into the water by a factory, or the contaminant was derived from elemental mercury discharged by the factory and methylated through microorganisms in the mud. Measures to rehabilitate the surviving patients and legal control of the factories have been instituted.


On the other hand, the cause of another mysterious illness in Japan, known as itai-itai disease, remains unsolved, although cadmium apparently played a role. The patients had resided for many years in areas that were in the vicinity of mines and where the cadmium levels in rice and water were excessive.

A more solid foundation in the assessment of risks of chemical carcinogens resulted from recent advances in epidemiologic studies, long-term animal studies, short-term mutagenesis/carcinogenesis tests, and mechanistic studies, as well as the realization that carcinogens differ in their potency, latency, and mode of action (Chaps. 7 and 25).

TOXICITY VS. OTHER CONSIDERATIONS

In general, exposure to toxic substances is to be avoided. However, the severity of the effects varies greatly; some chemicals induce mild, transient, reversible effects, whereas those of others may be irreversible, serious, and even fatal. Exposure to the former type of substances might thus be acceptable, but, as a rule, not the latter. Examples of the exceptions: methyl mercury, which is extremely toxic, is present in many species of fish. Because of the nutritional value of fish, permissible levels of methyl mercury are established to minimize the risk, yet not deny this valuable source of nutrients. Aflatoxin B1   is one of the most potent carcinogens but is present in a variety of foods. Yet the contaminated food is not banned as long as the toxin does not exceed the permissible levels.

The complex nature of assessing the toxicity of a substance in light of its ben- efits is also exemplified by the toxicology seen in lactation and over-the-counter (OTC) products. The former involves weighing the benefits of breast-feeding ver- sus the toxicity of certain potential contaminants. OTC products, when improp- erly used, present toxicologic problems. However, the value of these products in general cannot be ignored. There is a growing debate of natural food prod- ucts (nutraceuticals) where the benefits are accepted by some, yet these products have not been assessed toxicologically and there are reports of adverse effects. The therapeutic value of these products is subject to debate and needs extensive study as the number of consumers is in the millions, but the toxicity remains unknown.

The perception of risk and the benefits to society are crucial. It is clearly documented that with the introduction of chemicals to control infectious diseases and diminished occupational exposure through the use of protective gear have increased the life expectancy (or benefit) for humans. However, to completely eliminate any risk at all requires excessively high costs. Hence, it may not be realistic to derive any benefits if society demands that all risk be removed no matter the cost. In essence, by completely removing all chemicals and potential risk, the life expectancy would decrease and mortality would rise. The concept of acceptable risk/benefit ratio needs to be borne in mind. The dilemmas involved in these topics are further described and discussed in other chapters.


FUTURE PROSPECTS

The need of new substances will undoubtedly continue. Some of them will treat or prevent a variety of diseases, which are currently untreatable or unpreventable. Others will render food more plentiful, tastier, and hopefully healthier. Still others will improve living conditions in various ways. At the same time, people are more conscious of subtle adverse effects on health and expect the new substances to be “absolutely safe.” Furthermore, the disposal of these substances and their by-products is expected to produce no environmental hazards, adversely affecting humans and the ecosystem.

To satisfy these seemingly irreconcilable societal demands, the toxicolo- gist must carry out a series of studies on each substance: is it readily absorbed, distributed to specific organs, stored, and/or readily excreted? Is it detoxicated or bioactivated? What kind of adverse effects does it induce and what are the host and environmental factors, termed confounding factors, which can alter these effects? How does it produce the effect on a cellular and molecular level? What type of “general toxicity” does it produce? What organs are its targets? What is its pre- dominant mechanism of action? How or can it be eliminated from the organism? Answers to these and other questions will provide a scientific basis for assessing its safety and risk for the intended use.

It is evident that the multitude of studies involved will place an increasing demand on the limited facilities for toxicologic testing and on the short supply of qualified personnel. It is of utmost importance therefore that toxicity data generated anywhere be accepted internationally. However, to ensure general acceptance, the data must meet certain standards. The “Good Laboratory Practice” promulgated by the U.S. Food and Drug Administration (FDA, 1980) and the Organization of Economic Cooperation and Development (OECD, 1982) should be adopted by all countries involved in toxicological testing.

To streamline the long and costly testing of each chemical separately, there have been schemes that test a representative chemical extensively and verify the results on other members of the group with minimal testing. This practice has been adopted successfully when the substances included in a group are essentially similar. A proposal to ban all chlorine compounds, however, appears to have gone too far in ignoring the great diversity of the toxic nature and potency of such a large group of substances (Karol, 1995). Similar calls for the ban of substances containing bromine, especially flame retardants present in furniture, computers, televisions, which are crucial for protection against hazards from fire damage, have been instituted by a segment of the population based on the adverse effects of these chemicals. It will be a major challenge to determine how diverse a variety of chemicals can be rationally grouped for toxicological testing and assessment purposes.

Other trends designed to simplify and hasten the testing include a reduction in the use of laboratory animals and supplement or supplant them with in vitro studies. This is done partly in response to a societal call on humane grounds.


Isolated organs, cultured tissues and cells, and lower forms of life will be increas- ingly used. Furthermore, such test systems will likely be faster and less expensive, and will augment the variety of studies, especially those related to the mechanism of toxicity. An understanding of the mechanism of action of a chemical is often valuable in providing a sounder basis for the assessment of its safety/risk. Other types of improvements of the testing procedure with respect to simplicity and reliability will continue to be made.

As noted earlier, to provide a basis for proper assessment of the safety/risk of a chemical and for a variety of other purposes, toxicology is increasingly becoming a multifaceted science. To facilitate the acquisition of a broad knowledge of toxicology, this book covers four major areas.

Part I describes general topics related to absorption, distribution, and excretion of toxicants, their transformation in the body, the various types of toxic effects they exert, and the host and environmental factors that modify these effects.

Procedures used in determining the general and specific effects are described in

Part II.

Part III describes the organ/system-specific toxicants and the procedures com- monly used to detect their effects.

Part IV discusses several major groups of toxicants such as food additives and con- taminants, pesticides, metals, over-the-counter preparations, various envi- ronmental pollutants, and toxicants in the workplace. The last chapter out- lines the widely adopted approaches to the assessment of safety/risk of noncarcinogenic and carcinogenic chemicals. In addition, two indices are appended listing chemicals and subjects, respectively, to assist the reader in retrieving relevant parts of the text.

REFERENCES

Case RAM, Hosker ME, McDonald DB, et al. (1954). Tumours of the urinary bladder in workmen engaged in the manufacture and use of certain dyestuff intermediates in the British chemical industry. Br J Ind Med 11, 75–104.

FDA (1980). Code of Federal Regulations, Title 21, Food and Drugs. Part 58. Washington, D. C.: U.S. Government Printing Office.

Federal Register (1971). Threshold Limit Values Adopted by the American Conference of Governmental Industrial Hygienists, 1968, vol. 36, no. 105, May 29. Washington, DC: U.S. Government Printing Office.

Gwiadza R, Lucchini R, Smith D (2008). Adequacy and consistency of animal  studies to evaluate the neurotoxicity of chronic low-level manganese exposure in humans. J Toxicol Environ Health A 70, 594–605.

Hueper WC, et al. (1938). Experimental production of bladder tumors in dogs by adminis- tration of beta-naphthylamine. J Ind Hyg Toxicol 20, 46.

Karol MH (1995). Toxicologic principles do not support the banning of chlorine: A Society of Toxicology position paper. Fundam Appl Toxicol 24, 1–2.


Lehman AJ, Fitzhugh OG (1954). 100-fold margin of safety. Q Bull Assoc Food Drug

Officials U.S. 18, 33–35.

Lenz W, Knapp K (1962). Thalidomide embryopathy. Arch Environ Health 5, 100–105. Lu FC (1988). Acceptable daily intakes: Inception, evolution and application. Regul Toxicol

Pharmacol 8, 45–60.

NRC Committee on Biological Markers (1987). Biological markers in environmental health research. Environ Health Perspect 74, 3–9.

OECD (1982). Good Laboratory Practice in the Testing of Chemicals. Paris Cedex, France: Organization of Economic Cooperation and Development.

Paustenbach DJ (2002). Human and Ecological Risk Assessment. Theory and Practice.

New York, NY: John Wiley and Sons, Inc.

Rehn L (1895). Blasengeschwulste bei Fuchsin-Arbeiten. Arch Klin Chir 50, 588.

Study Group of Minamata Disease (1968). Minamata Disease. Minamata, Japan: Minamata

University.

Tsubaki T, Irukayama K (1977). Minamata Disease: Methyl Mercury Poisoning in Mina- mata and Niigata, Japan. New York, NY: Elsevier Scientific.

WHO (1962). Sixth Report of the Joint FAD/WHO Expert Committee on Food Additives.

Geneva, Switzerland: World Health Organization.

WHO (1993). Biomarkers and Risk Assessment: Concepts and Principles. Environ Health

Criteria 155.

Williams PRD, Paustenbach DJ (2002). Risk characterization: Principles and  practice.

J Toxicol Environ Health B 5, 337–406.

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