Toxicology: Past, Present, and Future

ALEX A. PAPPAS MD+, NICOLE A. MASSOLL MD+, and DONALD J. CANNON++, PhD

+Department o f Pathology University o f Arkansas fo r Medical Sciences 4301 West Markham Street, #517 Little Rock, AR 72205-7199

++Quest Diagnostics Incorporated One Malcolm Avenue Teterboro, NJ 07608

ABSTRACT

Toxicology is the study of poisons and poisoning and has an ancient and venerable history. Although there have been numerous notorious poisonings throughout the ages and rather astute descriptions of toxic agents, the scientific study of toxicology did not commence until the 19th century. There was rapid development of analytical methods in the late 19th century and then an acceleration of both method and scientific development in the latter half of the 20th century. Toxicology today can be subdivided into clinical toxicology, forensic toxicology, industrial or occupational toxicology, environmental toxicology, pharmaceutical toxicology, experimental toxi cology, and workplace drug testing. The historical development of these overlapping areas of toxicology will be discussed, culminating in a prediction as to what the future may bring.

Toxicology can be defined as the scientific history. From the study of poisonings and poi study of poisons, their actions, their detection, sons, toxicology has gradually evolved. Each and the treatment of conditions produced by generation has had its own poisons and meth them. Perhaps the best definition of poisons is ods of administration, from the first poisoned that of Paracelsus, a 16th century physician, arrow tip to the current “weapons of mass “. . . all substances are poisons and only the destruction.” Toxicology had its prehistoric ori dose determines the effect.” Toxicology can gins when man first realized he could use natu currently be subdivided into various overlap rally occurring plant and animal toxins to ping subdisciplines of clinical toxicology, increase his hunting efficiency. The writings of forensic toxicology, and regulatory toxicology, the ancient Egyptians, Indians, and Greeks the latter includes industrial or occupational mention the toxic effects of minerals and natu toxicology, environmental toxicology, pharma rally occurring substances in plants, animals, ceutical toxicology, experimental toxicology, and foods.1’2 Epidemic poisoning was reported and workplace drug testing (table 1). as early as the 4th century BC in ancient Poisoning, whether intentional or acciden Rome. In 82 BC the Romans issued the Lex tal, has played a major role in the events of Cornelia, the first recorded law against poison- 253 0091-7370/9/0700-0253 $02.50 © Institute for Clinical Science, Inc. 254 PAPPAS, MASSOLL, AND CANNON

TABLE I familiar to chemists today. They were the first to use the word drug. The most famous Ara Various Sub-Disciplines of Toxicology bian physician, Aviceman, wrote a five volume Clinical Toxicology: The measurement of treatise, the Canon of Medicine of which Vol xenobiotics (drugs, poisons, etc/) in human ume 5 is a pharmacopoeia. biologic fluids for the purposes of patient care, In 14th century Italy, the Machiavellian Forensic Toxicology: The study and practice of school of diplomacy used poisoning as a com toxicology in a legal environment. mon weapon in political and social life. The Regulatory Toxicology: Testing of xenobiotics as Borgias were renowned in their use of poisons mandated by law. and political poisoning became a major busi Industrial Toxicology- Concerned with protecting the worker from hazardous ness enterprise. The ruling Venetian Council substances in the workplace. of Ten had a price scale for poisoning people, Environmental Toxicology-Concerned with the price depended upon the difficulty of protecting humans and other living access and the intended victim’s rank. organisms from toxins (pollutants) in air, During the sixteenth and seventeenth cen water, and ground. turies, poisoning became a serious menace in Workplace Drug Testing -T o protect us western Europe. Aqua Toffana, a cosmetic from ourselves and others. containing white phosphorus, was used in Italy by a Neapolitan woman name Toffana. Hei- ronyma Spara, a reputed sorceress, met with ing. Learned treatises and various notable young women in Rome to poison their hus events of these ancient “toxicologists” are bands. The incidence of young widowhood found in table 2.1,2 became noticeable, particularly in men who Poisoning holds a peculiar fascination for were allegedly unaccomodating to their wives. mankind. In Western Europe, during the For poisoning 600 people, Spara and twleve Middle Ages until the Renaissance, there women were hanged in 1719. was little in the advance of toxicology, but It is generally recognized that the founder of there were some rather notable poisoning the science of toxicology is the Spaniard, events. In the learning centers of the Middle Mateo J. B. Orfilia. Orfilia’s 1814 work Triate’ East, the Arabs translated the works of the de Toxicologie divides poisons into six classes: Greeks and then developed their own medical corrosives, astringents, acids, stupefying or system. The Arabs developed distillation, sub narcotics, acrids, and septics or putreficants. limation, crystallization, and other methods Orfilia administered known concentrations of

TABLE II

Ancient History of Toxicology (Poisoning)

People(s) Sources/Events Toxins

Prehistoric Unknown Animal venoms/plant poisons Egyptians Ebers Papyrus (1552BC) Hemlock, lead, opium, antimony Indians Charaka Sambita (600-1000BC) Greeks Plato (399BC) Hemlock, history of plants Death of Socrates Theophractus (300BC) King of Mithrus of Pontus Mithridatics (antidotes) Romans Lex Cornelia Death of Claudius Brittanicus (-100AD) A SURVEY OF TOXICOLOGY 255 drugs to animals, observed the physiologic From the late 1930s to the early 1960s reactions, and after death examined the organs methodological advances included the devel grossly and analyzed the tissues. Orfilia discov opment of a colorimetric method for barbitu ered that poisons were absorbed from the rates, better extraction methods for alkaloids stomach and would accumulate in certain and other drugs, ultraviolet (UV) and infrared organs, such as liver, brain, and kidney. Prior (IR) spectrophotometry, paper and gas chro to these scientific observations, a chemist not matography.3,4 In the past 20 to 30 years there finding a poison in the stomach would search have been refinements of these methods with no further. The analytical methods introduced automation; the introduction of thin-layer by Orfilia and many of his ideas in toxicology chromatography (TLC), which can rapidly remain valid today. Robert Christianson, who screen for many drugs; gas chromatography- studied under Orfilia, further advanced the mass spectrometry (GC-MS), which can pro field of toxicology with the publication of A vide positive identification from only a few Treatise on Poisons (1829). Qualitative meth nanograms of a substance; high pressure liquid ods for the detection of toxic substances were chromatography (HPLC), which can sensi developed during the 19th century, (table 3). tively and specifically identify many therapeu Such early qualitative methods were refined tic drugs; and anodal stripping voltametry and adapted to yield quantitative measures of (ASV), which can sensitively detect metals. toxins in organs, tissues, and foods.1'2 Various immunoassays: radioimmunoassay In 1877, the first medical examiner’s office (RIA), enzyme-multiplied immunoassay tech was established in Boston, Massachusetts, fol nique (EMIT), and fluorescent polarization lowed by the establishment of the New York immunoassay (FPIA) are exquisitely sensitive Medical Examiner’s Office in 1915. Dr. but often demonstrate poor specificity.5,6,7 Charles Norris was appointed as New York’s (table 4). first Chief Medical Examiner. A toxicology Specimen collection for postmortem toxico laboratory was established under Dr. Alex logic analysis is an important aspect of an ander Gettler, who would train some of the autopsy8 (table 5). In general, postmortem bio country’s most renowned toxicologists. logic specimens must be pretreated to remove

TABLE III

Development of Toxicology - The Nineteenth Century

Qualitative Methods Year Method Developer

1805 Isolation of morphine Sertürner 1836 Arsenic Marsh 1841 Arsenic Reinsch 1844 General test for poisons Fresenius and Von Babo 1851 Alkaloid extractions Stas-Otto 1868 Nonvolatile organic compound extraction Dragendoff

Qualitative Methods Year Method Developer 1879 Arsenic Gutzeit 1865-1889 Carbon monoxide Salokowki - alkali dilution Stoczanski - tanuic acid 256 PAPPAS, MASSOLL, AND CANNON

TABLE IV

Comparison of Analytical Techniques Used in Clinical Toxicology

Pretreatment Major Sensitivity Personnel Technique of Sample Instrumentation (Hg/mL) Experience

TLC Yes No (<$1000) 0.5 - 1.0 Moderate EMIT/FPIA No Yes ($25- 50,000) .02 - .05 Moderate HPLC Yes Yes ($25- 50,000) 0.02 -10.0 High GC Yes Yes ($25- 50,000) 0.01 -10.0 Moderate GC/MS Yes Yes ($75-125,000) 0.001 - 5.0 High ASV No Yes ($20- 30,000) 0.03 - 0.05 Moderate EAAS No Yes ($70-150,000) .0 0 5 - .020 High

TLC = Thin layer chromatography. EMIT = Enzyme multiplied immunoassay technique. FPIA = Fluorescence polarization immunoassay. HPLC = High performance liquid chromatography. GC = Gas chromatography. MS = Mass spectrometry. ASV = Anodal stripping voltametry. EAAS = Electrothermal atomic absorption spectrometry. interfering substances to permit analytical tion. In the forensic toxicology laboratory, the analysis. No single method of extraction or most frequently used extraction method is analysis is sufficient and the methods to be multistep liquid-liquid extraction, while gas used depend on the particular case in ques and liquid chromatography are the most preva-

TABLE V

Postmortem Forensic Toxicology Specimen Requirements

Specimen Volume Comments

Blood 50-100ml Ethanol by HS-GC drug analysis may need Heart, peripheral extensive “clean-up” extraction. subdural hematoma Vitreous humor All practical Clinical chemistry analysis, drugs. Protected from putrefaction, etc. Urine All present Easy specimen to analyze, drugs usually higher concentrations than blood. Bile All present Useful for narcotics, benzodiazepines. Liver -1 OOgr Tricyclic antidepressants, barbiturates, propoxyphene. Stomach contents All present Tablets, measure volume. Brain -1 OOgr Volatiles. Kidney -100gr Mercury. Spleen -1 OOgr Carbon dioxide. Adipose tissue -100gr Pesticides, lipophilic drugs. Fingernails/hair All practical Heavy metals. A SURVEY OF TOXICOLOGY 257 lent of the many forms of instrumentation cur unwholesome or lowers its nutritive or thera rently in use.3'4'8,9 peutic value), and misbranding (offering any Current advances in these analytical capa food or drug under false or misleading claims bilities are used in all subdivisions of toxicol as to its source, kind, quality, or amount) of ogy. Clinical toxicology is the treatment of foods and pharmaceuticals. The establishment human exposure. In children the toxin most of the FDA is credited with the pioneering often seen are common household items such work of Dr. Harvey Wiley, who was at that as cleaning products, analgesics, cosmetics, time Director of the Bureau of Chemistry, US plants, and cough or cold preparations. Com Department of Agriculture, and his “poison mon poisons that lead to deaths in all ages squad.” Subsequent amendments to the law include antidepressants, stimulants, street banned the sale of over-the-counter “danger drugs, cardiovascular drugs and sedative/ ous drugs,” and established tolerances for hypnotices. In general, the average individual residual deposits of pesticides in agricul will be accidentally poisoned by common tural products.18 household products, prescription medica With the dawning of the “Age of Aquarius” tions, over the counter medications, and by (circa 1966-1968) there was a mushrooming of drug interactions.10 illicit drug use, across all socioeconomic strata, Interpretation of forensic toxicologic exami in the United States. The Department of nation can be difficult whereas interpretation Defense (DOD), was the first to begin using in the realm of clinical toxicology and thera massive drug testing programs to combat illicit peutic drug monitoring is usually straight for drug use which had been prevalent during and ward.511,12’13 With the establishment of poison after the Vietnam War.19,20 Urine drug testing centers, education, improved analytical meth was then instituted for federal employees fol ods and various treatment facilities for the lowed by drug of abuse testing of various acutely toxic patient, the morbidity and mor employees in the civilian workplace.7,21 The tality from poisoning have decreased.14,15,16,17 National Institute on Drug Abuse (NIDA) Regulatory toxicology includes industrial established analytical, technical and quality and environmental toxicology and occupa assurance guidelines for drug of abuse testing tional medicine. This field is concerned with (table 6). Criteria for certification as a drug human exposures in the workplace and the abuse testing laboratory became well estab regulation thereof. Workplace drug testing is a lished and are quite stringent.22,6 These over highly regulated program to detect abused sight duties of NIDA have now been assumed drugs in the workplace. Environmental toxicol by the Substance Abuse and Mental Health ogy is concerned with the distribution of toxic Services Administration (SAMHSA). substances in the atmosphere, water, and soil. Approaches to workplace drug testing Regulatory toxicology can be traced back to a include pre-employment (most popular), decree by King James II of Scotland which probable (proof or suspicion of drug use or forbade the use of poisons. In the United intoxication during job or accident believed to States, the Pure Drug and Food Act was be due to drug use) cause, random on a gen passed in 1906 after the exposé of the food eral basis, and safety-sensitive (failure to meet industry by Upton Sinclair’s book The Jungle. performance may adversely affect the health The Harrison Narcotic Law, in 1914, con and lives of others) testing.23 trolled the use of opium, cocaine and their Drug testing has been viewed as successful derivatives. In 1937 the Marijuana Act regu in regimented situations such as the military or lated the use of marijuana and in 1938 the in highly focused pre-employment or probable Food, Drug, and Cosmetics Act, which estab cause testing.23,24 The most frequently found lished the Food and Drug Administration drugs in the workplace are marijuana, cocaine, (FDA) forbade the addition of adulterants (any and opiates.25 The prevalence of the particular substance which makes a food or drug drugs found depends on the test popula 258 PAPPAS, MASSOLL, AND CANNON

TABLE VI

Positive Decision Levels for Screening and Confirmation of Selected Drugs of Abuse in Urine

Screening Confirmatory Test Duration of Drug Test ng/mL ng/mL Detection

Marijuana 3 days to a month Metabolites 100 ---- depending on 9-Carboxy-THC ---- 15 chronicity Cocaine 2-3 days Metabolites 300 ---- Benzoylecgonine ---- 150 Opiates* 2-3 days Metabolites 300 ---- Morphine ---- 300 Phencyclidine 25 25 2-3 days Amphetamine® 1000 ---- 2-3 days Amphetamine ---- 500 Methamphetamine ---- 500

aFor Substance Abuse and Mental Health Service Administration, amphetamine must be at 200 ng/mL in order to report a positive methamphetamine. *The Substance Abuse and Mental Health Service Administration has mandated opiate screening and confirmation cutoffs of 2000 mg/ml for individuals subject to their regulations.

tion.26,27 With any drag testing program, the Industrial toxicology (hygiene) which is the positivity rate will decrease with time and for study of occupational diseases and hazards that reason drug testing may be considered dates back to Hippocrates, who in 400 BC efficacious in the workplace. The effects of described the symptoms of lead toxicity in workplace drug testing on job performance are mining operations. Only during the 20th cen difficult to document. The intent and efficacy tury, particularly after World War II, were of random urine drag testing remains conten public policies and strategies developed to tious and controversial.28,29,30 There appears control occupational hazards in the workplace. to be a financial benefit to pre-employment The Occupational Safety and Health Act in drag screening, but the key is the potential 1970 placed into the law the responsibility and cost of a major accident attributed to drug or accountability for the control of occupational alcohol use.31 hazards including chemicals and toxins. The The use of stimulant drugs and anabolic ste Occupational Safety and Health Administra roids to improve the mental and physical per tion (OSHA) promulgates regulations and con formance of athletes remains universal. Test ducts inspections of workplace facilities.10,32 ing for such “doping” substances began in 1968 The hazard associated with a substance is by the International Olympic Committee the likelihood of causing injury in a given envi (IOC) to detect the use of banned drugs, not ronment or situation. The hazard of a sub determine the degree of influence. In 47,000 stance depends on its toxicity, rate and route IOC samples, 2.5 percent were positive with of absorption, rate of metabolism, rate of the most frequently detected drugs being ana excretion, rapidity of action, presence of any bolic steroids (58 percent), pseudoephedrine warning factors, physical characterisics, and (13 percent), phenylpropanolamine (10 per manner of encounter in the workplace. In cent), and ephedrine (4 percent).24 the industrial setting, the most important route A SURVEY OF TOXICOLOGY 259 of chemical agents is inhalation (workplace with access to all available human evidence, asthma, pneumoconiosis) followed by physi coupled with other experimental and epide cal contact (dermatitis) and rarely by inges miological evidence, this agency strives to pro tion. Perhaps the most feared consequence vide an overall evaluation of risk. The qualita of industrial exposure is the development tive IARC classifications are as follows: Group otr cancer. 'i'i 1, carcinogenic to humans; Group 2A, prob In 1775, Percival Potts firmly established ably carcinogenic to humans; Group 2B, pos the occupational link between chimney sweeps sibly carcinogenic to humans; Group 3, not and scrotal cancer. There soon followed classifiable as to carcinogenicity to humans; descriptions of other benign and malignant Group 4, not carcinogenic to humans.35,36 cutaneous neoplasms with exposure to aro These IARC qualitative classifications may matic hydrocarbons in tar, paraffin (1875), have quantitative risk estimates by national or shale oil (1876), pitch, mineral oil (1892), and international committees or regulatory agen pitch dust (1912). In 1915, Yamagiwa induced cies such as OSHA.37 skin cancers in rabbits by painting their ears The discovery of occupational and environ with coal tar. In 1924, Kennaway identified the mental carcinogens have been the major force first carcinogenic hydrocarbon, 1,2,5,6- in the development of experimental toxicologic dibenzanthracene. The first description of research. The first era of experimental toxicol- bladder cancer and the relationship with the ogy, the “Era of Discovery” beginning about aromatic amine, fuschin, was reported by 70 years ago, was characterized by descriptive Rehn in 1895 and the linkage between aro analysis of many easily measured variables matic amines (naphthylamine, benzene) and such as; body weight gain, food intake, vital bladder cancer was confirmed by the epide signs, reproductive function, descriptive miological studies of Case in the 1950s. When pathomorphologic features, biochemical assays Roentgen discovered x-rays in 1898 and the of hormones, neurotransmitters, and meta Curies isolated radium, a powerful cancer- bolic products.38 It was soon recognized that it causing environmental agent was unleashed. was necessary to consider biologic mechanisms Early workers with ionizing radiation devel in the causation of toxic effects and thus the oped radiation-induced cutaneous carcinomas. “Era of Biomechanistic Investigation” began Madam Curie died of leukemia as did her circa 1940 and will continue into the 21st cen daughter. The inhalation of radioactive iso tury. By understanding the molecular mecha topes in mines and in laboratories was linked nism of toxic substances, explanations of such to excessive lung cancer deaths. In the 1930s, problems such as species differences, organ asbestos workers were found to have an 18 affinities, and chemical interaction will be percent frequency of lung cancer.34 forthcoming. The “Era of Individual Expres The establishment of threshold levels for sion” or genetic toxicology which delves into exposures to various substances in the work the genetic background of the exposed subject place and the environment have enormous began about 1970 and is now an “emerging impact on protecting humans, on the environ market.” Genetic traits that carry the liability ment, on the cost of manufacturing or process of higher susceptibility to chemical injury have ing of materials or foods and on legal liability been identified.39 and costs. Although the world-wide burden of Environmental toxicology is generally cancer is large and growing, the occupational restricted to substances in the atmosphere, factor is modest. Epidemiological studies are a water and soil that are toxic to humans and major component in identifying carcinogenic other living organisms.40,41 The EPA has been hazards. Since 1972, the International Agency regulating air quality, water quality, toxic for Research on Cancer (IARC) has developed waste, and pesticides since 1970. Since that a program to evaluate carcinogenic risks to time there have been decreases in all but one humans. By using an expert working group of six common air pollutants lead, -98 percent; 260 PAPPAS, MASSOLL, AND CANNON ozone, -23 percent; sulfur dioxide, -32 per frequently an expert is asked if a toxin or an cent; carbon monoxide, -23 percent; nitrogen action causes an injury. The foundation of the dioxide; +14 percent, and particulate matter, opinion is usually a straightforward interpreta -78 percent. The average blood lead level in tion of analytical results or explanation of the children decreased from 19 jjug/dl in 1978 standard of laboratory care or practice. Admis to 7 |Jig/dl currently. Since the early 1970s, sibility of evidence and the expert’s opinion in the EPA has banned or eliminated the clinical or forensic circumstances is not usually use of over 230 pesticides and 20,000 pesticide a problem. In the area of occupational or envi products42’43'44 ronmental toxicology, the question that has to As with occupational exposure, the greatest be answered is whether data supports a cause risks from environmental pollutants are respi and effect relation between a given chemical ratory compromise, increased infant mortality, and a disease process, such as cancer, and mental retardation and chronic ingestion whether the chemical at a particular dose will which can lead to premature death. The devel cause disease or cancer. Trial judges now have opment of cancer is the most feared and well important roles as “gatekeepers” in evaluating known consequence of chronic exposure to an expert’s opinion regarding the relevance environmental agents. The assessment of risk and reliability of scientific evidence. The court in the environmental setting is similar to that based admissibility of evidence, known as the in the occupational setting starting with clini Daubert balancing test, includes general cal case reports or an environmental disaster, acceptance by the scientific community, peer- epidemiologic studies, and animal studies.45’46 reviewed publication, known or potential rate More recently, the use of “biomarkers” in both of error and standards controlling the technical occupational and environmental toxicology are operation, and theory or technique tested with being utilized in epidemiology and in research. scientific methods. Thus admissibility of an A biomarker is a measurable event in a bio expert opinion may be problematic in these logical system that indicates that an early or types of cases.50 subclinical change has occurred that could The field of toxicology is ever evolving. Most lead to a related adverse effect when exposed of the difficulties in the field today are not to a toxic factor. Three specific types of bio analytical but political, psychological, and markers are identified; exposure biomarkers, sociological.45,51 In the area of clinical toxi effect biomarkers, and susceptibility biomark cology there will be the further development ers.47 Exposure biomarkers can be the toxic of immunoassay “dipsticks” for home or bed agent itself, a metabolite, a DNA adduct, or side monitoring of therapeutic drugs as well as hemoglobin adduct. Effect biomarkers may be drug screens for the overdosed patient or the an endogenous component or a measure of the worker who might want to check his urine functional capacity of the organ system, as before going to work. Proper quality control affected by the exposure. Susceptibility bio and assurance will not keep up with the pro markers, either inherited or induced, are an liferation of “point of care” technology and indicator of whether an individual is hypersen there will be unfortunate clinical and socio sitive to a particular agent. Susceptibility bio logic misadventures. Instrumentation will con markers include cholinesterase variants, p53 tinue to be miniaturized. Communications oncogenes, and HLA-MHC antigens.48 protocols will be developed so that analytical Inherent to the practice of toxicology, a results can be rapidly compiled into instanta clinical scientists may be called upon or com neous national databases. With these super all- pelled to give an expert opinion or further inclusive databases correlated with clinical and explanation of scientific evidence about the forensic findings, there will be a true validation risks and effects of toxic agents. A witness may of toxic levels and monitoring of regional drug be qualified as an expert by knowledge, skill, usage patterns in real time. With molecular experience, training, and education.49 Most methods, genotherapeutic drug monitoring A SURVEY OF TOXICOLOGY 261 will evolve where patient susceptibility and 10. Ellenhom M, Schonwald S, Ordog G, Wasserberger J. response to a medication will be determined Ellenhom medical toxicology. In: Cooke DB, Zinner SR, editors. Williams & Wilkins, Baltimore 1997;13- apriori and eventually with the use of DNA 46:1912-1925. microchip dipsticks. Industrial and environ 11. Pappas AA, Taylor EH, Ackerman B. Therapeutic mental toxicology will begin to use molecular drug monitoring. In: Howanitz JH, Howanitz PJ, edi tors. Laboratory medicine: test selection and interpre methods to identify toxic effects on a molecu tation. New York: Churchill Livingstone 1991:333- lar level, this coupled with the applications of 368. various biomarkers may indeed lead to the 12. McBay AJ. Toxicological findings in fatal poisonings. Clin Chem 1973;19/4:361-365. development of practical methods of risk 13. Baselt RC. Disposition of toxic drugs in man. Year assessment. Noninvasive and minimally inva Book Medical Publishers, Chicago, 4th edition 1995. sive devices to monitor various biomarkers in 14. Litovitz T, Manoguerra A. Comparison of pediatric poisoning hazards: An analysis of 3.8 million exposure at risk populations will be developed. incidents. A report from the american association of Workplace drug testing will continue to poison control centers. Pediatrics 1992;89(6 pt 1): remain “status quo” until society decides how 999-1006. 15. Pappas AA, Gadsden RH Sr, Taylor EH. Serum osmo to best handle the drug epidemic in this coun lality in acute intoxication: A prospective clinical try. Forensic toxicology which is currently study. Am J Clin Pathol 1985;85/1:74—79. using molecular methods for identification 16. Liang HK. Clinical evaluation of the poisoned patient purposes will further adapt the aforemen and toxic syndromes. Clin Chem 1996;42/8:1350- 1355. tioned trends and predictions in clinical and 17. Bayer MJ, McKay C. Advances in poison manage regulatory toxicology to meet its unique needs. ment. Clin Chem 1996;42/8:1361-1366. It is interesting that forensic toxicology which 18. DuBois KP, Geiling EMK. Alcohols and other indus trial solvents. In: DuBois KP, Geiling EMK, eds. Text is the “mother” of the other disciplines of toxi book of toxicology. New York: Oxford University Press cology will no longer take the lead but rather 1959:3-17. enjoy the fruits of her children. 19. Irving J. Drug testing in the military-technical and legal problems. Clin Chem 1988;34/3:637-640. 20. Finkle BS. Drug-analysis technology: Overview and state of the art. Clin Chem 1987;32(11 suppl):13B- R eferences 17B. 21. Snyder JW, Klees JE. Drug testing programs in gov 1. DuBois KP. Textbook of toxicology. New York: Oxford ernment agencies and private workplaces. Occup Med University Press 1959. 1996:11/1:87-101. 2. Niyogi SK. Historical overview of forensic toxicology. 22. Critical issues in urinalysis of abused substances: In: Cravey RH, Baselt RC, editors. Introduction to fo report of the substance abuse committee. Clin Chem rensic toxicology. Biomedical Publications 1981:7-21. 1988;34/3:605-632. 3. Clarke EGC. Isolation and identification of drugs in 23. Osterloh J. Drug testing in the workplace. Occup Med pharmaceuticals, body fluids, and post-mortem mate 1990:5/3:617-633. rial. Volume I, II. The Pharmaceutical Press, London 24. Christophersen AS, Morland J. Drug analysis for con 1978. trol purposes in forensic toxicology, workplace testing, 4. Methodology for analytical toxicology. In: I Sunshine, sports medicine, work and related areas. Pharmcol editor. CRC Press, Cleveland, OH 1975. Toxicol 1994;74/4-5:202-210. 5. Pappas AA, Taylor EH, Ackerman B. Toxicology and 25. Issac PC, Heatley M, Savoie J. Rates of drug detection drugs of abuse. In: Howanitz JH, Howanitz PJ, edi in urine samples from various populations. Clin in Lab tors. Laboratory medicine: Test selection and inter Med 1990:10/2:289-299. pretation. New York: Churchill Livingstone 1991:369- 26. Jones DW, Adams D, Martel PA, Rousseau RJ. Drug 398. population in one thousand geographically distributed 6. Council on Scientific Affairs. Scientific issues in drug urine specimens. J Anal Toxicol 1985;9/3:125-130. testing. JAMA 1987;257/22:3110-3114. 27. Rouse, BA. Epidemiology of illicit and abused drugs 7. McBay AJ. Drug-analysis technology-pitfalls and in the general population, emergency department problems of drug testing. Clin Chem 1987;33(11 drug-related episodes, and arrestees. Clin Chem SuppI):33B^0B. 1996:42/8:1330-1336. 8. Levine BS, Smith ML, Froede RC. Postmortem 28. Lundberg GD. Mandatory unindicated urine drug forensic toxicology. Clinics in Laboratory Medicine, screening: Still chemical McCarthyism. JAMA 1986; Clinical Toxicology II. WB Saunders, Philadelphia, PA 256/21:3003-3005. 1990;10/3:571-590. 29. Dougherty RJ. Controversies regarding urine testing. 9. Wallace JE, Hamilton HE. Analytical principles. In: J Subst Abuse Treat 1987;4/2:115-117. Cravey RH, Baselt RC, editors. Introduction to foren 30. Dupont RL, Griffin DW, Siskin BR, Shiraki S, Katze sic toxicology. Biomedical Publications 1981:87-109. E. Random Drug Tests at Work: The probability of 262 PAPPAS, MASSOLL, AND CANNON

identifying frequent and infrequent users of illicit 41. Silkworth JB, Brown JF. Evaluating the impact of drugs. J Addict Dis 1995;14/3:1—17. exposure to environmental contaminants on human 31. Peat MA. Financial viability of screening for drugs of health. Clin Chem 1996;42/8:1345-1349. abuse. Clin Chem 1994;41/5:805-808. 42. Council on Scientific Affairs. Cancer risk of pesticides 32. Http://www.osha.gov in agricultural workers. JAMA 1988;260:959-966. 33. Vemitt S. Occupational cancer, biological mecha nisms. In: Raffle PB, Adams PH, Baxter PH, Lee WR, 43. Http://www.epa.gov editors. Hunter’s diseases of occupations, 8 th ed. Lon 44. Dich J, Zahm SH, Hanberg A, Adami HO. Pesticides don: Edward Arnold Publishers 1994:623-653. and cancer. Cancer Causes Control 1997;8/3:420-443. 34. Harring JM, Saracci R. Occupational cancer, clinical and epidemiological aspects. In: Raffle PB, Adams 45. Chenoweth MB. Perspectives in toxicology. Ann Rev PH, Baxter PH, Lee WR, editors. Hunter’s diseases of Pharmacol Toxicol 1985;25:33^0 occupations, 8 th ed. London: Edward Arnold Publish 46. Ames BN, Gold LS. The causes and prevention of ers 1994;7/22:654-688. cancer: the role of environment. Biotherapy 1998;ll/2— 35. International Agency for Research. Evaluation of car 3:205-220. cinogenic risk to humans, international agency for 47. Grandjean P. Biomarkers in epidemiology. Clin Chem research on cancer. In: Raffle PB, Adams PH, Baxter 1995;41/12B:1800-1803. PH, Lee WR, editors. Hunter’s diseases of occupa tions, 8 th ed. London: Edward Arnold Publishers 48. Cullen MR, Redlich CA. Significance of individual 1994:743-748. sensitivity to chemicals; elucidation of host suscepti 36. Http://www.iarc.fr/ bility by use of biomarkers in environmental health 37. Ward EM, Burnett CA, Ruder A, Davis-King K. research. Clin Chem 1995;41(12B):1809-1813. Industries and cancer. Cancer causes control 1997; 49. Chamberlain RT. Role of the clinical toxicologist in 8/3:356-370. court. Clin Chem 1996;42(8 pt 2):1337-1341. 38. Zbinden G. Three eras of research in experimental toxicology. TiPS 1992;13:221-223. 50. Rodricks JV, Rieth SH. Toxicological risk assessment 39. Kramer PJ. Genetic Toxicology. J Pharm Pharmacol in the courtroom: are available methodologies suitable 1998;50/4:395-405. for evaluating toxic tort and product liability claims? 40. White PA. The genotoxic hazards of domestic wastes Regal Toxicol Pharmacol 1998;27(1 Pt 1):21-31. in surface waters. Mutation Research 1998;410:223- 51. Lundberg GD. New winds blowing for american drug 236. policies. JAMA 1997;278/ll:946-947.