Dictionary of Toxicology

Dictionary of Toxicology

Third Edition

Editors

Ernest Hodgson, Ph.D.

North Carolina Agromedicine Institute and Toxicology Program, Department of Applied Ecology, North Carolina State University, Raleigh, NC, USA

R. Michael Roe, Ph.D.

Department of Entomology and Toxicology Program, North Carolina State University, Raleigh, NC, USA

Richard B. Mailman, Ph.D.

Department of Pharmacology Pennsylvania State College of Medicine, Pennsylvania State University, Hershey, PA, USA

Janice E. Chambers, Ph.D.

Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA

Table of Contents

Cover image

Title page

Copyright

About the Editors

Contributors to the Third Edition

Contributors to the First and Second Editions

Preface

Introduction

Abstract and Keywords

A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Q

R

S

T

U

V

W

X

Y

Z

Copyright

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About the Editors

Ernest Hodgson, distinguished professor emeritus, North Carolina State University and executive director, Foundation for Toxicology and Agromedicine was educated at King’s College of the University of Durham (now the University of Newcastle), Oregon State University, and the University of Wisconsin. At North Carolina State University, since 1961, he was a William Neal Reynolds Professor and head of the newly formed department of toxicology. He was also one of the founders of the three university (East Carolina University, North Carolina State University, and North Carolina A&T University) program in agromedicine, an organization which led to the formation of the North Carolina Agromedicine Institute.

He has conducted research on xenobiotic biochemistry for several decades, has authored c. 400 peer-reviewed papers in this area, and is editor and part author of several monographs. Most recently, his research has focused on human studies utilizing human hepatocytes and subcellular preparations. He is currently involved as a collaborator with Michael Roe in RNAseq studies of genome-wide effects of environmental chemicals. From 1961 until his retirement he was supported by extramural funding, primarily from NIH (NIEHS) and the US Army.

He is also an editor and contributing author of toxicology textbooks (Textbook of Modern Toxicology and Molecular and Biochemical Toxicology, both currently in their fourth editions) and is a lexicographer (Dictionary of Toxicology and a Dictionary of Agromedicine, being created for the NC Agromedicine Institute). He is well recognized for his role as a teacher of toxicology. In addition to his role as editor and part author of textbooks he has trained some 40 graduate students and 20 postdoctoral research associates.

His service on federal study sections and other federal panels has been extensive and includes the following agencies: NIH, NASA, US Army, and others. He has been recognized by awards from the Society of Toxicology, the American Chemical Society, the International Society for the Study of Xenobiotics, the Consolidated University of North Carolina, and North Carolina State University. He is a past president of the International Society for the Study of Xenobiotics.

R. Michael Roe, PhD, is a William Neal Reynolds Distinguished Professor in the department of entomology and the department of environmental and molecular toxicology at North Carolina State University (NCSU) in Raleigh, NC, and was elected as fellow in 2012. He is internationally recognized for his research in insect and acarine physiology, biochemistry, genomics, and toxicology, and the use of fundamental research in chemistry, nuclear science and biology to solve practical problems and develop new commercial technologies.

He was born in Plaquemine, LA, in 1952 where he graduated high school in 1970. He obtained his BS degree with a minor in chemistry from Louisiana State University (LSU) in Baton Rouge in 1974. He continued his graduate education at LSU obtaining a MS degree in physiology with a minor in biochemistry in 1976 and a PhD in entomology and a minor in nuclear science in 1981. He was an NIH fellow in Cellular and Molecular Biology in the department of entomology at the University of California at Davis from 1981–1984 and in 1984 accepted a position as assistant professor in entomology at North Carolina State University, Raleigh.

His laboratory focuses on understanding how insect and acarine systems function at the molecular level, the use of synthetic organic chemistry to understand structure-activity, and applications in bioassay, chemistry, molecular biology, and physics to solve practical pest problems in the context of integrated pest management. He is also interested on the impact of environmental chemicals on human health, focusing on global gene expression and epigenetics using primary human cells, risk assessment, and mechanisms of action. His lab is especially active in technology transfer and product development. Some of his greatest successes include a USEPA registered insect and tick repellent more effective than DEET and a fast acting, natural broad spectrum herbicide, among many others. He has been at NCSU for more than 30 years and is a prolific author with more than 250 published papers, 8 books, 36 patents, and 10 licensed technologies. He has been an invited speaker for more than 40 scientific events throughout the world and was the organizer of several national and international scientific meetings. He is the president of the company, InTox Biotech, in Middlesex, NC, and has served or is serving on the advisory boards for several companies and nonprofit organizations in the United States. He is also a founding member of the interdepartmental Biotechnology Program at NCSU which provides hands-on courses in molecular techniques and a minor in biotechnology and has developed new courses at NCSU in physiology, insect morphology, molecular entomology, toxicology, and professional development.

He has received several awards for his accomplishments. However, he considers his greatest professional successes and greatest joy in the more than 50 graduate students that he has trained as the committee advisor with MS and PhDs in chemistry, biochemistry, nuclear engineering, physiology, toxicology, biology, textile science, and entomology at NCSU. He has also trained over 20 postdoctoral researchers. His graduates and postdocs have gone on to successful careers in academia, industry, and government in the United States and throughout most of the world. He is married to Janet (Richard) Roe and has a son, Jonathan, and a daughter, Jennifer. His hobbies include work on his farm east of Raleigh, repairs on his MG, camping, and surf fishing on islands off the coast of NC.

Janice Chambers is a William L. Giles Distinguished Professor and Director of the Center for Environmental Health Sciences in the College of Veterinary Medicine at Mississippi State University. She is originally from Berkeley, CA, and she received her BS in biology from the University of San Francisco and her PhD in animal physiology from Mississippi State University. She has experience in pesticide toxicology with major emphases on: the effects of pesticides on the nervous and endocrine systems; the metabolism of pesticides; developments of neuroprotectants for organophosphate anticholinesterases; mechanisms by which pesticides cause toxicity; the levels of exposure of people to pesticides; and predicting the effects of mixtures of pesticides. Her current research activities involve: health disparities/minority health and the association of legacy pesticides with the prevalence of type 2 diabetes; characterization of biomarkers of risk of chronic disease; and the development of novel antidotes to nerve agents. She has received board certification in toxicology through both the American Board of Toxicology and the Academy of Toxicological Sciences. She has received the Education Award from the Society of Toxicology and the American Chemical Society International Award for Research in Agrochemicals. She has served on the executive boards and committees of several scientific organizations and the two toxicology certification organizations. She has also served on several advisory and review panels, including study sections for the National Institutes of Health and the Scientific Advisory Panel for the Federal Insecticide, Fungicide and Rodenticide Act for the US Environmental Protection Agency and the Human Studies Review Board for the USEPA. She has been the principal investigator of over US$25 million in federally funded competitive grants primarily from the National Institutes of Health, the Department of Defense/Defense Threat Reduction Agency and the US Environmental Protection Agency, and she has published over 125 articles in scientific journals, edited books, and book chapters, and over 300 abstracts from conference proceedings. She is actively engaged in graduate education.

Richard Mailman is Professor and College of Medicine Distinguished Senior Scholar of Pharmacology and Neurology at the Penn State University College of Medicine. He earned his PhD. in physiology/toxicology from North Carolina State University working with Dr. Ernest Hodgson where his major contribution was the first demonstration of multiple forms of cytochrome P450 in chemically-untreated animals. After post-doctoral training, he joined the faculty at the University of North Carolina School of Medicine where he rose to the rank of Professor and Director of the Division of Basic Psychobiology. In 2008, he was recruited to his current position at the Penn State College of Medicine. His research has focused on the pharmacology and toxicology of brain dopamine systems, and on mechanisms of ligand-receptor interactions.

Dr. Mailman is the author of more than 250 research papers, two books, six patents, and numerous pending patent applications. He has been a consultant for large and small pharma, several foundations, and has served continuously for several decades on Federal review groups, most recently as a member of the DDNS study section of the National Institutes of Health and as Chair of the Neurobiology E study section of the Veterans Administration. He currently serves on several editorial boards and as a regular peer reviewer for more than two-dozen journals. He is a Fellow of the American College of Neuropsychopharmacology, and has received several awards including the Burroughs-Wellcome Fund Scholar in Toxicology, and the Hargraves Award in Mental Health Research. He also has received teaching awards both at the University of North Carolina and at Penn State.

Contributors to the Third Edition

Lauren Aleksunes,     Rutgers University

Ronald L. Baynes,     North Carolina State University

Hari K. Bhat,     University of Missouri, Kansas City

Janice E. Chambers,     Mississippi State University

Michael R. Franklin,     University of Utah

Ernest Hodgson,     North Carolina State University

M. Elizabeth Hodgson,     Social and Scientific Systems

David A. Lawrence,     New York State Department of Health

Marce Lorenzen,     North Carolina State University

Richard B. Mailman,     Pennsylvania State University College of Medicine

Sharon A. Meyer,     University of Louisiana at Monroe

Loganathan Ponnusamy,     North Carolina State University

R. Michael Roe,     North Carolina State University

Carol L. Sabourin,     Battelle, USA

Patrick J. Sabourin,     Battelle, USA

John Seubert,     University of Alberta, Canada

Andrew D. Wallace,     Catalent Pharma Solutions

Contributors to the First and Second Editions

Due to the long elapsed time since the second edition, many of these contributors are no longer active or involved in the Dictionary of Toxicology. Some are deceased, some are retired from toxicology, and others are involved in different activities at different locations. It seemed appropriate, however, to record the names and institutions at the time of the contribution. Our thanks go to those below who helped initiate this work, now entering its third edition.

Earl G. Alley,     Mississippi State University

William H. Benson,     University of Mississippi

William O. Berndt,     University of Nebraska Medical Center

Thomas W. Bouldin,     University of North Carolina School of Medicine

Alan Brimfield,     United States Army Medical Research Institute of Chemical Defense

Leslee D. Brown,     Murfreesboro, TN

Lewis R. Brown,     Mississippi State University

Jerry Browne,     University of North Carolina School of Medicine

Philip Carl,     University of North Carolina School of Medicine

Franklin R. Champlin,     Mississippi State University

Howard Chambers,     Mississippi State University

Janice E. Chambers,     Mississippi State University

Lorris G. Cockerham,     SITEK Research Laboratories

Robert K. Collins,     Mississippi State University

Sue Conly-Danehower,     Glaxo Wellcome, Inc.

Jon C. Cook,     Dupont Haskell Laboratory

Nancy M. Cox,     Mississippi State University

Kevin M. Crofton,     U.S. Environmental Protection Agency

Walter C. Dauterman,     North Carolina State University

Walter J. Diehl,     Mississippi State University

Donald N. Downer,     Mississippi State University

Laurence Fishbein,     Environ Corporation

Joyce E. Goldstein,     National Institute of Environmental Health Sciences

Frank E. Guthrie,     North Carolina State University

Doyle Graham,     Vanderbilt University Medical Center

Raymond E. Grissom,     Agency for Toxic Substances and Disease Registry

John E. Harkness,     Mississippi State University

Ernest Hodgson,     North Carolina State University

Mary E. Hodgson,     University of North Carolina, Chapel Hill

Clinton D. Kilts,     Emory University Medical Center

Renate D. Kimbrough,     Institute for Evaluating Health Risks

Steven Kinsler,     Agency for Toxic Substances and Disease Registry

John S. Kizer,     University of North Carolina School of Medicine

Cindy P. Lawler,     University of North Carolina School of Medicine

Ross B. Leidy,     North Carolina State University

Ann T. Lemley,     Cornell University

Patricia E. Levi,     North Carolina State University

Margaret Lewandowski,     BASF

Mark H. Lewis,     University of Florida Health Science Center

Kim E. Light,     University of Arkansas for Medical Sciences

Morris A. Lipton,     University of North Carolina School of Medicine

Richard B. Mailman,     University of North Carolina School of Medicine

Beth Mileson,     International Life Sciences Institute

Pierre Morell,     University of North Carolina School of Medicine

Toshio Narahashi,     Northwestern University Medical School

David E. Nichols,     Purdue University

Deborah L. Novicki,     Chiron Corporation

Jerome J. Perry,     North Carolina State University

Mario Perez-Reyes,     University of North Carolina School of Medicine

Gary Peterson,     University of North Carolina

Stephen B. Pruett,     Louisiana State University Medical Center

T. Wayne Schultz,     University of Tennessee

Tony M. Shih,     US Army Medical Research Institute of Chemical Defense

Ivin S. Silver,     Glaxo Wellcome, Inc.

Gary Smith,     University of North Carolina School of Medicine

Ronald E. Tynes,     Sandoz Biotechnology

Mary Vore,     University of Kentucky College of Medicine

Charles A. Waggoner,     Mississippi State University

Quentin D. Walker,     Duke University Medical Center

William Wargin,     Glaxo Wellcome Research Center

Charles L. Wax,     Mississippi State University

John H. Weisburger,     American Health Foundation

Christopher F. Wilkinson,     Jellinek, Schwartz and Connolly, Inc.

Gary M. Williams,     American Health Foundation

Dwayne A. Wise,     Mississippi State University

John F. Young,     National Center for Toxicological Research

Preface

Ernest Hodgson, R. Michael Roe, Richard B. Mailman and Janice E. Chambers

Many factors were considered in the decision to publish a third edition of the Dictionary of Toxicology. It is a fact that many sources of information, usually web-based, are available and that experts in any narrowly focused aspect of toxicology are not likely to need to look up the meaning of terms in their area of expertise. However, toxicology includes not only fundamental studies in molecular, biochemical, and cellular science but applied fields such as risk analysis, risk communication, and legal and regulatory aspects of risk management among many others. Thus a real need exists to provide meaning for those in fundamental toxicology wishing to extend the scope of their activities and also those in all the areas that toxicology impacts to understand the terms they need to carry out their tasks. Finally, it must always be remembered that many, if not most, web-based sources contain material that is not peer reviewed.

To bring out a print version of a dictionary, monograph, or journal at a time of transition to electronic versions of all of these is, perhaps, foolhardy but to anticipate the inevitable the publisher will have a dedicated Dictionary of Toxicology web site for additions, revisions, and corrections.

Compiling or revising a dictionary is work intensive and not only requires dedication from the editors but also from many others willing to help. It is with pleasure we thank all of those mentioned in the lists of contributors as well as many at Academic Press/Elsevier who made it all possible. Our special thanks to Molly McLaughlin without whose expertise, good humor, and always available help we would not have brought this project to completion.

June 2014

Introduction

See: immediately after the entry, indicates that while there is no definition at that point, there is another synonymous but more appropriate entry name.

See also: after the note on sources, refers to other entries useful for further information or comparisons. Finally, Reference(s): will list references to sources when appropriate.

Abstract and Keywords

Abstract

The Dictionary of Toxicology published by Academic Press and edited by Drs. Ernest Hodgson and Michael Roe from North Carolina State University, Dr. Richard Mailman from Pennsylvania State University, and Dr. Janice Chambers from Mississippi State University provides succinct definitions to the terms associated with the general field of toxicology. The list of terms and the definitions are provided by named experts in the field with illustrations, cross-references, and citations as needed. The terms and definitions also include associated areas of risk assessment, communication, legal and regulatory aspects, metabolism, molecular toxicology, quantitative toxicology, nanotoxicology, and related fields of physiology, genetics, chemistry, biochemistry, genomics, microbiomics, and bioinformatics as they apply to toxicology. The aim of the dictionary is to provide a reliable, to-the-point, explanation of toxicology terms, but the dictionary will also serve as a reliable reference to almost all areas of science associated with the environment and its biota.

Keywords: Dictionary, Definitions, Toxicology, Risk Assessment, Environment, Chemistry, Biochemistry, Genomics, Microbiomics, Bioinformatics

A

AAALAC See: Association for Assessment and Accreditation of Laboratory Animal Care International.

AAAS See: American Association for the Advancement of Science.

AACT See: American Academy of Clinical Toxicology.

AAFS See: American Academy of Forensic Sciences.

AAG See: α1-acid glycoprotein.

AAPCC See: American Association of Poison Control Centers.

AAS See: spectrometry, atomic absorption.

Abakabi disease See: tricothecenes.

ABCW extrapolation (Obsolete) A method formerly used for extrapolating germ cell mutation tests from species to species. The name is derived from the authors of the initial paper (Abrahamson, Bender, Conger & Wolf, Nature 245, 461, 1973). Based on the results of published studies on the effects of ionizing radiation, the extrapolation was performed by normalizing the mutation rate to the amount of DNA in the haploid genome of the species in question. Attempts to extend the ABCW hypothesis to chemical mutagens were less successful, and the original hypothesis has been challenged even with regard to ionizing radiation. This extrapolation is of historical importance but has been superseded by other techniques. See also: extrapolation; extrapolation, to man; species extrapolation.

ABFT See: American Board of Forensic Toxicology.

abiotic Nonliving; in toxicology used primarily for the nonliving parts of ecosystems.

ABMT See: American Board of Medical Toxicology.

abnormal base analogs Exogenous (xenobiotic) analogs of the bases normally found in DNA, similar enough to substitute for the normal base and give rise to abnormal base pairing. As a result they are potent mutagens. 5-Bromouracil, 5-fluorouridine, 2-aminopurine, and 6-mercaptopurine are examples of mutagenic abnormal base analogs. Incorporation into DNA results in mispairing during the next replication cycle, giving rise to altered (mutant) DNA. Since these chemicals are mutagens and carcinogens, the toxic hazard attendant upon their use is high. See also: carcinogenesis; DNA; 6-mercaptopurine; mutation; therapeutic index. See Figure A1.

Figure A1

abnormal development, consequences Death, malformation, growth retardation, or functional disorders can occur as consequences of abnormal development. The embryo is not usually damaged by most agents prior to differentiation; however, a sufficiently high dose may result in death of the embryo. The time of organogenesis is the most sensitive time for induction of specific malformations, whereas structural defects at the tissue level, growth retardation, or functional deficits are most likely to occur from damage during the fetal period. Structural defects are the main criteria used in estimating teratological risks since they are more obvious. However, functional disorders may be as incapacitating and result in as great a mortality rate among offspring as morphological abnormalities. See also: teratogenesis, critical periods.

ABP See: androgen-binding protein.

ABPI See: Association of the British Pharmaceutical Industry.

abrin (toxalbumin) A lectin composed of two polypeptide chains connected by a disulfide bridge. It is nearly identical to the toxin produced by the castor bean (Ricinus communis). Abrin is found in the seed of the rosary pea (Abrus precatorius), a common vine of the tropics. The LD50 in mice is 0.02 mg/kg, i.p. Ingestion of one chewed or broken seed can be fatal. It is a gastrointestinal toxin; one of the polypeptide chains binds to the intestinal cell membrane, allowing the other chain to enter the cytoplasm. Ribosomal protein synthesis is inhibited, resulting in cell death. Diarrhea associated with bloody mucus may begin as late as 3 days following ingestion of seeds with broken seed coats. Death may occur from loss of intestinal function and consequent alterations in plasma composition leading to secondary cerebral edema and cardiac arrhythmia. Therapy for acute poisoning is to correct hypovolemia and electrolyte balance. See also: castor beans; lectins; ricin.

absinthe A distilled alcoholic drink manufactured from wormwood (Artemisia absinthum), absinthe was widely popular in the late nineteenth and early twentieth centuries especially in France. Although containing minor amounts of neurotoxic materials from the wormwood, it was no more hazardous to human health than other distilled alcoholic drinks. Due to its (probably mistaken) reputation as an addictive drug, by 1915 it was widely banned throughout the western world, including the United States. By the late twentieth century it was no longer prohibited and was once again produced and sold, today enjoying some popularity.

ABVT See: American Board of Veterinary Toxicology.

acaricides Pesticides with specificity for mites, the term being used primarily for phytophagous mites in contrast to parasitic mites, although drugs used for treatment of the latter could be referred to as acaricides. A number of insecticides display acaricidal as well as insecticidal activity. The acaricides include a diverse array of chemical structures. Common examples are dicofol and chlorobenzilate. See also: dicofol.

Acarin See: dicofol.

acceptable daily intake (ADI) The estimated amount of a chemical (usually restricted to pesticides and food additives) that can be ingested daily, by humans, for an entire lifetime without causing appreciable adverse effects; it is expressed in mg/kg body weight/day. The ADI is obtained by dividing the no observed adverse effect level (NOAEL) by an uncertainty factor (e.g. , 10, 100, or 1000) that is intended to make allowance for possible differences in sensitivity between the animal test species and humans, as well as for interindividual variations within the human population. The term ADI was first used by the Joint FAO/WHO Expert Committee on Food Additives in 1961 and subsequently was adopted by the Joint FAO/WHO Expert Committee on Pesticide Residues (1962). The ADI constitutes a useful regulatory benchmark that is employed by international (e.g., FAO/WHO) and national (e.g., EPA, UK Advisory Committee on Pesticides and Other Toxic Chemicals) agencies for establishing tolerances for pesticide residues in raw agricultural and other commodities and for developing health advisory guidelines for such residues in potable water. For regulatory purposes, however, it is being replaced by the USEPA with the reference dose (RfD), also derived from the NOAEL adjusted by uncertainty factors and modifying factors. See also: modifying factor; no observed effect level; reference dose (RfD); uncertainty factor.

acetaminophen (N-(4-hydroxyphenyl)acetamide; paracetamol; tylenol). CAS number 103-90-2 An analgesic and antipyretic drug. It is also been used in the manufacture of azo dyes and photographic chemicals. The oral LD50 in mice is 338 mg/kg and the i.p. LD50 is 500 mg/kg. Acetaminophen is a hepatotoxicant at high doses and, in some developed countries is the leading cause of acute liver failure, primarily as a result of deliberate (suicidal) overdose. Toxicity is due to the metabolism of acetaminophen to a toxic intermediate, N-acetyl-p-benzoquinonimine (NAPQI) by cytochrome P450. Following an overdose, detoxication of NAPQI by glutathione conjugation is saturated, leading to an increase in the concentration of the toxic metabolite that, in turn, binds to various hepatocellular constituents. Within hours sweating, anorexia, nausea, and vomiting develop. In 3–5 days, jaundice, coagulation defects, hypoglycemia, renal failure, and myocardiopathy may occur. If given within 12 h of ingestion of an acetaminophen overdose, N-acetylcysteine appears to be effective in blocking the covalent binding of the toxic metabolite and the prevention of hepatotoxicity. See Figure A2.

Reference: Hinson, J. A. et al. Drug Metabol Rev. 36, 805–822, 2004.

Figure A2

acetazolamide ((N-(5-)aminosulfonyl)-1,3,4-thiadiazole-1,2-yl) acetamide; 5-acetamido-1,3,4-thiadiazole-2-sulfonamide; Diamox). CAS number 59-66-5 Acetazolamide is a carbonic anhydrase inhibitor used as a diuretic, including use in the treatment of lithium overdose and toxicity, and in the treatment of glaucoma. It is known to be teratogenic in mice and the effect is believed to be mediated via elevated maternal plasma CO2 tension. See Figure A3.

Figure A3

acetone. CAS number 67-64-1 A metabolic intermediate formed during the degradation of fats as well as a widely manufactured solvent and chemical intermediate. Acetone can be exhaled or further metabolized to acetate and, subsequently, to glucose. While acetone has a variety of irritant or chronic effects at high doses, it does not appear to represent a serious chronic hazard. It has not been reported to be carcinogenic. Acetone is an inducer of cytochrome P450 2E1 (CYP 2E1) in the liver of rodents regardless of the route of exposure. The mechanism is not well understood but appears to involve both increased protein synthesis and inhibition of protein kinase C. See Figure A4.

Figure A4

acetonylacetone See: 2,5-hexanedione.

N-2-acetylaminofluorene. CAS number 53-96-3 Because of its effect as a potent bladder carcinogen, N-2-acetylaminofluorene is of importance as a model compound that has been studied with regard to metabolic activation as a carcinogen and hepatotoxicant and the role of its metabolites in the subsequent processes of carcinogenesis. The primary metabolism of N-2-acetylaminofluorene is monooxygenation catalyzed by cytochrome P450. The reactions involved are either aromatic hydroxylation (a detoxication reaction) or N-hydroxylation (an activation). Interspecies variations in the cytochrome P450 isozymes catalyzing these reactions are held to explain interspecies differences in carcinogenic susceptibility. Subsequent phase II reactions, sulfate ester formation, acetylation, and glucuronidation can also yield reactive metabolites that can react with nucleophilic substituents on nucleic acids and proteins. Adducts of N-2-acetylaminofluorene metabolites with DNA bases have been identified. See also: phase I reactions; phase II reactions. See Figure A5.

Figure A5

acetylation Acetylation is the introduction of an acetyl group into a chemical. It may be non-enzymatic or enzymatic, the latter being important both in normal metabolism and in the biotransformation of toxicants. Many enzymes or other proteins may be acetylated, including histones, tubulin, and p53. Acetylated derivatives of exogenous amines are formed by N-acetyltransferase (NAT), an enzyme that utilizes acetyl CoA as the acetyl donor. This cytosolic enzyme has been purified from rat liver, but is known to occur in several organs, probably as multiple isoforms. Although a variety of groups on endogenous substrates may be acetylated, in xenobiotics primarily amino groups appear to function as acetyl group acceptors. Newborn mammals generally have low levels of the transferase activity, whereas genetically determined fast and slow acetylators occur in both rabbit and human populations. Slow acetylators are more susceptible to the effects of compounds detoxified by acetylation. The N-acetyltransferase(s) responsible for the acetylation of S-substituted cysteines, the last step in mercapturic acid formation, is found in the microsomes of kidney and liver. It is specific for acetyl CoA as the acetyl donor and is distinguished from other N-acetyltransferases by substrate specificity and subcellular location. See also: acylation; fast and slow acetylators; polymorphisms.

acetylator phenotype Variation in the expression of N-acetyltransferase (NAT) isoforms in humans gives rise to two groups with different phenotypes within any given population, fast and slow acetylators. Slow acetylators are more susceptible to the toxic effects of drugs that are detoxified by acetylation. See also: acetylation, fast and slow acetylators; polymorphisms.

acetylethyltetramethyltetralin (AETT; polycyclic musk; musk tetralin; Versalide; Musk 36A; 1,1,4,4-tetramethyl-6-ethyl-7-acetyl-1,2,3,4-tetrahydronaphthalene). CAS number 83-29-9 Primarily of historic interest, AETT was originally used in fragrance preparations but was withdrawn from commercial use due to a number of behavioral and morphological neurotoxic effects. See Figure A6.

Figure A6

accessory cells of immune system See: immune system; macrophages/monocytes.

accessory cells of testis See: Sertoli cells.

accreditation, in toxicology Certification of the expertise of individuals in toxicology or in various toxicological specialties. Accreditation is done by several organizations who establish standards and accredit on the basis of education, experience, accomplishments, and/or successful completion of a written examination. See also: American Board of Forensic Toxicology; American Board of Medical Toxicology; American Board of Toxicology; American Board of Veterinary Toxicology; American College of Toxicology.

acesulphane K (Sumet) See: sweetening agents.

acetaldehyde (ethanal; ethylaldehyde; acetic aldehyde, CH3CHO). CAS number 75-07-0 An organic compound used in the manufacture of paraldehyde, acetic acid, butanol, aniline dyes, synthetic rubber, and in the silvering of mirrors. It is also used in trace quantities in artificial flavors. The principle importance of acetaldehyde in toxicology is as the toxic product of the oxidation of ethanol by alcohol dehydrogenase and it further oxidation by aldehyde dehydrogenase. Acetaldehyde is also produced metabolically by plants and occurs in significant quantities in ripe fruit. It is believed to be the cause of hangovers caused by excessive consumption of ethanol and is produced physiologically in significant quantities in individuals taking disulfiram who have also ingested ethanol. The oral LD50 in rats is 1930 mg/kg and the inhalation LD50 in rats is 4000 ppm/4 h. The primary toxic action is irritancy. Acetaldehyde interferes with mitochondrial oxygen consumption and energy production in rat liver. After inhalation, it causes irritation, nausea, and vomiting. Skin and eye contact results in a burning sensation and severe irritation. The therapy after inhalation is to remove the victim to fresh air and give artificial respiration if breathing has stopped. Following eye contact, the eyes should be flushed with water; following skin contact, the skin should be washed with soap and water. See also: alcohol dehydrogenase; aldehyde dehydrogenase; disulfiram.

acetylcholine (ACh). CAS number of chloride 60-31-1, of bromide 66-23-9 The choline ester of acetic acid. ACh is released in vertebrates as the neurotransmitter for cholinergic neurons in the CNS, as well as at several peripheral locations: somatic neurons innervating skeletal muscle (neuromuscular junctions); preganglionic neurons in both divisions of the autonomic nervous system; parasympathetic postganglionic neurons; and a few sympathetic postganglionic neurons. ACh is synthesized from choline and acetyl CoA by the mitochondrial enzyme choline acetyltransferase. Cholinergic receptors (cholinoceptors), that mediate the effects of ACh, are generally classified as nicotinic or muscarinic, based on their binding preferences for nicotine and muscarine, respectively. ACh is hydrolyzed to choline and acetate by acetylcholinesterase, that is an important target for a variety of toxic and therapeutic anticholinesterases, such as the nerve agents, carbamate, and organophosphorus insecticides. See also: acetylcholine receptors, muscarinic and nicotinic; acetylcholinesterase; anticholinesterases; choline acetyltranstranase; organophosphorus insecticides. See Figure A7.

Figure A7

acetylcholine receptors, muscarinic and nicotinic (cholinergic receptors; cholinoceptors) The receptors for the neurotransmitter acetylcholine (ACh) are classified into two major groups—muscarinic and nicotinic. The muscarinic receptors occur at autonomic effector cells and are stimulated by the alkaloid muscarine derived from certain mushrooms; these receptors mediate the effects of postganglionic parasympathetic neurons. Some muscarinic receptors also occur in autonomic ganglia and in cortical and subcortical neurons in the brain. Cholinergic agonists for muscarinic receptors include bethanechol and methacholine; the belladonna alkaloid atropine is an effective antagonist. Muscarinic receptors are subdivided into subtypes, such as M1 and M2 receptors, based on selective agonist/antagonist activities or binding affinities. The nicotinic receptors occur at autonomic ganglia and at the endplates of skeletal muscle and are stimulated by the alkaloid nicotine. Cholinergic agonists for nicotinic receptors include nicotine, and antagonists include D-tubocurarine, hexamethonium, and some snake toxins. See also: muscarine; nicotine.

acetylcholine release Acetylcholine (ACh) is released from the nerve terminals of cholinergic neurons in response to an action potential in the neuron (excitation–secretion coupling). Agents that enhance ACh release cause hyperexcitability of cholinergic pathways. Two natural toxins possessing this activity are black widow spider venom and β-bungarotoxin. See also: black widow spider venom; β-bungarotoxin.

acetylcholinesterase (AChE; acetylcholine acetylhydrolase; cholinesterase; EC 3.1.1.7) An enzyme that hydrolyzes the neurotransmitter acetylcholine (ACh) to choline and acetate, and thus terminates the action of ACh. It is found extensively throughout the nervous system, as well as in many non-nervous tissues. The enzyme contains two binding sites for ACh: an anionic site and an esteratic site, containing a serine residue that is the target for numerous organophosphorus and carbamate inhibitors. The inhibition of AChE by these anticholinesterases leads to an accumulation of endogenous ACh, and thus results in hyperactivation of cholinergic receptors. Signs of acute poisoning can include irritability, tremors, convulsions, and predominately parasympathetic effects, with death usually the result of respiratory failure. Since AChE is contained in erythrocytes, the assay of erythrocyte AChE activity can be used as a diagnostic tool to assess exposure to organophosphorus anticholinesterases. See also: acetylcholinesterase, aging; anticholinesterases; acetylcholine receptors, muscarinic and nicotinic; carbamate insecticides; carbamate poisoning, symptoms and therapy; nerve agents; nerve gases; organophosphate poisoning, symptoms and therapy; organophosphorus insecticides.

acetylcholinesterase, aging An event that occurs subsequent to the inhibition of acetylcholinesterase (AChE) by certain organic phosphates and phosphonates. Although the precise mechanism involved has not been established, it is apparently a simple hydrolysis of an alkoxy group on the phosphorus atom. Cleavage of the P-O-alkyl, rather than the P-O-AChE, bond yields an inhibited enzyme with a spontaneous recovery rate near zero and that is refractory to reactivation by oximes. Fortunately, the methoxy and ethoxy groups prevalent in commercial insecticides age rather slowly. The isopropoxy group (e.g., DFP and sarin) ages within 1–2 h, and the 1,2,2-trimethylpropoxy group (e.g., soman) ages within minutes. See also: acetylcholinesterase.

acetylcholinesterase, in chronic toxicity testing See: chronic toxicity testing.

acetylcholinesterase, inhibitors See: anticholinesterases.

acetylcholinesterase, reactivation Acetylcholinesterase (AChE) that has been inhibited by a carbamate or organophosphorus (OP) anticholinesterase can be restored to normal functional capacity if hydrolysis removes the moiety carbamylating or phosphorylating the enzyme. This reactivation occurs spontaneously for both groups of anticholinesterases, with the reactivation of carbamates occurring much more rapidly than that of the OP compounds. The reactivation of OP-inhibited AChE can be enhanced by the use of oxime reactivators, such as N-methylpyridinium-2-aldoxime (2-PAM), provided that aging of the phosphorylated AChE has not occurred. See also: acetylcholinesterase, aging; anticholinesterases; N-methylpyridinium-2-aldoxime.

N-acetylcysteine conjugates See: mercapturic acids.

acetylene dichloride See: 1,2-dichloroethene.

acetylesterases See: hydrolysis.

3-acetylpyridine (methyl pyridyl ketone). CAS number 350-03-8 Used in the fragrance industry and as an intermediate in the synthesis of a number of clinical drugs, including Imatinib, Mesylate, Metyrapone, Telithromycin, and Ridogrel. An analog of nicotinamide that competes for incorporation into NAD. It has been used to chemically lesion the inferior olive nucleus, thereby eliminating climbing fibers within the cerebellar cortex. The loss of contacts to the Purkinje cells of the cerebellum from climbing fibers can seriously impair locomotor activity. In addition to the inferior olive, 3-acetylpyridine also induces neuropathological changes in areas CA3 and CA4 of the hippocampus, the lateral geniculate nucleus, pars compacta of the substantia nigra, supraoptic nucleus of the hypothalamus, and the nucleus dorsalis of the raphe. Toxic effects of 3-acetylpyridine are thought to result from abnormal nucleotide synthesis following replacement of pyridine by 3-acetylpyridine. The compound has had particular utility in neurotoxicological studies (e.g., in which the climbing fibers were thought to be altered by toxicants). See Figure A8.

Figure A8

acetylsalicylic acid See: aspirin.

N-acetyltransferase See: acetylation.

ACGIH See: American Conference of Governmental and Industrial Hygienists.

ACh See: acetylcholine.

AChE See: acetylcholinesterase.

acid activating enzyme See: amino acid conjugation.

acid/base balance The ratio of acidic to basic ions in a solution. In vivo ), the bicarbonate ion being formed in the red blood cell by carbonic anhydrase. The Henderson–Hasselbalch equation illustrates the role of bicarbonate in maintaining blood pH at 7.4.

Thus disturbances in acid/base balance affect blood pH, giving rise to acidosis or alkalosis. See also: acidosis, metabolic; acidosis, respiratory; alkalosis, metabolic; alkalosis, respiratory.

acid deposition The wet and dry air pollutants that lower the pH of deposition and subsequently of the environment. Acid rain refers to the wet components. Acid rain has a pH of 4 or lower, compared with normal rain that has a pH of about 5.6. Sulfuric and nitric acids, from sulfur and nitrogen oxides, respectively, are the major contributors arising primarily from burning fossil fuels. High-sulfur content coal is responsible for much of the sulfuric acid. In regions where the buffering capacity of substrates is limited, the lakes have become acidic enough to kill fish and are unable to support fish populations. Contributing to this toxicity in fish is the fact that the acidic conditions concurrently release toxic metals (e.g., aluminum) into the water. In terrestrial ecosystems the acids also leach nutrients (e.g., sodium, potassium, calcium, magnesium) from the soil, resulting in a detrimental effect on tree growth.

α1-acid glycoprotein (AAG; acute-phase reactant protein; orosomucoid) A low-molecular-weight (Mr=40,000), anionic (pI=2.7–3.5), polymorphic protein produced primarily by the liver and regulated by two polymorphic genes. Approximately 45% of AAG is carbohydrate, consisting of hexose, hexosamine, and sialic acid in equal proportions. Normal plasma concentration of AAG is 50–150 ng/mL, with a plasma half-life of 5 days. The physiological function of AAG is unknown but it serves to transport basic and neutrally charged drugs (cf, albumin, a carrier of acidic drugs). AAG is an acute-phase reactant, and plasma levels may be elevated as a consequence of acute physiological stress or from chronic inflammation. Decreases in AAG may occur secondary to severe malnutrition, severe hepatic damage, and severe protein-losing gastroenteropathies. Although AAG binds a number of basic drugs through electrostatic interactions, changes in its plasma concentration appear to have little pharmacological effect. See also: protein binding; plasma proteins.

acid mine drainage Drainage from pyritic coal mines that is frequently acidic as a result of the chemical and bacterial oxidation of reduced iron and sulfur to ferric hydroxide precipitates and sulfuric acid, respectively. Acid mine drainage has killed fish and lowered the quality of drinking water. It also has potential for leaching heavy metals into the water supply.

acid phosphatase A lysosomal acid hydrolase that hydrolyzes phosphoric acid esters and is important in the absorption and metabolism of carbohydrates, nucleotides, and phospholipids. Serum levels of acid phosphatase become elevated in cases of metastatic prostatic carcinoma, benign prostatic hypertrophy, prostatitis, Paget’s disease, and metastases to bone and liver from breast carcinoma.

acid rain See: acid deposition.

acid soot (acid smut) Particles of carbon held together by water made acidic due to combination with sulfur trioxide. The carbon particles are emitted during combustion, with the soot particles being roughly 1–3 mm in diameter. Where oil-burning installations have metal chimneys, acid soot can acquire iron sulfate that produces brown stains on materials and damages paintwork.

acidosis A condition in which the pH of the blood is acidic beyond the normal range. Although acidosis can occur for reasons unrelated to toxic compounds, it may also result from the generation of an acidic metabolite (e.g., formic acid from methanol) by loss of base or by carbon dioxide retention. Therapeutically acidosis is treated by maintaining an adequate airway, artificial respiration to prevent carbon dioxide retention or by administering sodium bicarbonate, either i.v. or orally. See also: acidosis, metabolic; acidosis, respiratory; alkalosis; maintenance therapy; maintenance therapy, respiration; maintenance therapy, water and electrolyte balance.

acidosis, metabolic A form of acidosis resulting from the generation of excess acid and the resultant disturbance of the acid/base balance. It occurs not only in diabetes and renal disease, but also following acid salt poisoning, methanol poisoning, etc. Characteristic signs are a decrease in blood bicarbonate and increased respiratory rate. See also: acidosis.

acidosis, respiratory A form of acidosis resulting from failure to expire carbon dioxide. It can occur in pneumonia, emphysema, and congestive heart failure, but also with poisons causing lung edema and with narcotic depressants. It involves an increase in blood bicarbonate concentration. See also: acidosis.

acinus A number of secretory cells in an exocrine gland that secrete into a cavity; the smallest unit in a gland.

aclacinomycins A family of antineoplastic antibiotics isolated from Streptomyces galilaeus. The major components (aclamycin A and aclamycin B) have LD50 in mice of 22.6 and 13.7 mg/kg, i.p., respectively. See Figure A9.

Figure A9

ACM See: Contaminants Advisory Committee on Mutagenesis (ACM) (Formerly Advisory Committee on Mutagenesis).

ACNFP See: Advisory Committee on Novel Food and Processes.

aconitase Aconitase is the enzyme that reversibly interconverts citric acid, cis-aconitic acid, and isocitric acid in the tricarboxylic acid cycle (TCA) (formerly known as the citric acid or Krebs cycle) by dehydration and hydration reactions. Aconitase is the target for fluoroacetate, a potent rodenticide, that condenses with oxaloacetate to yield an aconitase inhibitor (fluorocitric acid), with resultant accumulation of citric acid and thus blockage of the TCA cycle, leading to an inhibition of aerobic energy production. See also: lethal synthesis.

aconitine (16-ethyl-1,16,19-trimethoxy-4-(methoxymethyl)aconitane-3,8,10,11,18-pentol 8-acetate 10-benzoate; Monkshood). CAS number 302-27-2 Aconitine is one of several toxic alkaloids produced by Aconitum species. It causes reflex bradycardia, induces arrhythmias, and causes nausea, vomiting, and weakness. A tingling burning feeling on the lips, mouth, gums, and throat is the first sign following ingestion. Aconitine acts on nerve axons by opening voltage-dependent sodium ion channels, as well as by inhibiting complete repolarization of the membrane of myocardial tissue, causing repetitive firing. It is sometimes used to produce cardiac arrhythmias in experimental animals. It also has an antipyretic action. The oral LD50 in mammals is 1 mg/kg or less, depending on species, and can be as low as 0.025 mg/kg. Procaine may be useful in reversing the toxic effects of aconitine. See Figure A10.

Figure A10

Aconitum species A genus of the family Ranunculaceae, A. napellus is the cultivated aconite, A. columbianum is a native of moist woodlands in Western North America, A reclinatum and A. uncinatum are native to the eastern United States, while A. japonicum and A. carmichaelii are oriental species that are used in oriental medicine. Aconitum species contain several C19 diterpenoid ester alkaloids that are potent poisons, including aconitine, mesaconitine, and jesaconitine. Historically aconite root has been used for homicides, as an arrow poison, and in medicine.

ACOP Approved Code of Practice under UK’s COSHH Regulation. See: COSHH.

acoustic startle response See: auditory startle; neurobehavioral toxicology.

ACP See: Advisory Committee on Pesticides.

acquired immune deficiency syndrome (AIDS) A condition in humans in which the immune system suffers a progressive failure, leaving the victim susceptible to opportunistic infections. It is caused by the human immunodeficiency virus (HIV), a slow-acting retrovirus that invades and kills T4 helper cells that are integral to the immune system. AIDS is believed to have occurred first in the late 1950s and was identified as a distinct medical condition in the early 1980s. It is believed to have originated in Africa, probably by several mutations of a virus transmitted from green monkeys to humans in an area where green monkeys are eaten; within a few years further mutations produced a number of distinct viral strains. Estimates of the number of infected persons who will develop the full range of symptoms vary widely. While there is neither cure nor vaccine continuing treatment with antiretroviral drugs can increase life expectancy, in some cases to the extent that it is unimpaired. HAART (Highly Active Antiretroviral Therapy) represents aggressive treatment to prevent viral replication and progression of the disease. A typical drug combination used would consist of at least three medications from at least two classes.

Reference: www.nim.nih.gov/medlineplus/hivaids.html.

ACT See: American College of Toxicology.

acridine (10-azaanthracene; dibenzo[b,e]pyridine). CAS number 260-94-6 A compound occurring in coal tar that has been used in the manufacture of dyes and intermediates. Derivatives are used as antiseptics (e.g., proflavine). Acridine is a strong irritant to mucous membranes and skin, and it causes sneezing on inhalation. Acridine is a mutagen that functions through additions and deletions of base pairs (frame shift mutations), especially in plasmids and other extra-chromosomal DNA. It is a known human carcinogen. The oral LD50 to rats is 2.0 g/kg and to mice is 0.5 g/kg. Acridine is also used as a general term for chemicals containing the C¹³N tricycle structure. See Figure A11.

Figure A11

acridine orange (3,6-bis(dimethylamino)acridine). CAS number 494-348-2 A dye used to stain nucleic acids. It fluoresces at 530 nm when intercalated into double stranded DNA, or at 640 nm when ionically bound to single stranded DNA. It produces mutations, some involving reading frame shifts, other deletions or insertions and is carcinogenic. It is also known to be a dermal phototoxicant. See also: acridine; aminoacridines.

acrolein (acraldehyde; acrylaldehyde; acrylic aldehyde; aqualin; 2-propenal; allyl aldehyde; NSC 8819). CAS number 79-06-1 A chemical intermediate in the manufacture of methionine, glycerin, acrylic acid esters, glutaraldehyde, and cycloaliphatic epoxy resins. It is used as an aquatic herbicide, biocide, and slimicide. Acrolein is formed during partial combustion of organic material (e.g., in forest fires, urban fires, exhaust emissions, and tobacco smoke). The oral LD50 in rats is 46 mg/kg and in mice is 28 mg/kg. The irritation threshold is 0.1 ppm, the TLV-TWA 0.1 ppm, TLV-STEL 0.3 ppm, and IDLH 5 ppm. Acrolein reacts with critical sulfhydryl groups in lungs, heart, eyes, skin, and the respiratory tract, and causes disruption of intermediary metabolism, impairment of DNA replication, inhibition of protein synthesis and mitochondrial respiration, hepatic periportal necrosis, and destruction of NADPH-cytochrome c reductase. In humans, it causes intense irritation of eye and mucous membranes of the respiratory tract. Direct contact leads to skin or eye necrosis, pulmonary edema, bronchitis, tracheobronchitis, severe gastrointestinal distress, and/or lachrymation. Inhalation can lead to pneumonia and nephritis, degeneration of the bronchial epithelium leading to emphysema and focal calcification of the renal tubular epithelium. After acute poisoning, the subject should be removed from the contaminated area and should be administered oxygen with subsequent corticosteroid treatment for pulmonary inflammation. If acrolein is ingested, gastric lavage, saline cathartics, and demulcents should be used. See Figure A12.

Reference: ATSDR-ToxFAQs™: Acrolein.

Figure A12

acrylaldehyde See: acrolein.

acrylamide (acrylamide monomer; acrylic acid amide; propenamide; vinylformic acid). CAS number 79-06-1 Humans exposed to acrylamide monomer, but not its polymers, are vulnerable to neurotoxic injury. Although acute high doses of the monomer can result in an encephalopathy that is apparently reversible, repeated smaller doses are cumulative and result in a distal sensorimotor axonopathy. The earliest signs are difficulty in walking and clumsiness of the hands. Distal deep tendon reflexes are lost, and sensory disturbances, such as numbness in feet and fingers are accompanied by objective loss of vibration sensation without objective changes in superficial sensation. Excessive sweating and contact dermatitis are common. Neurofilament-filled axonal swellings are less common than in γ-diketone or carbon disulfide intoxication. Degeneration of distal axons follows, especially in the long, large-diameter axons in the peripheral nervous system. Neurofilament-filled axonal swellings and axonal degeneration are seen to a lesser degree in the CNS. The oral LD50 is 150–180 mg/kg in rats, guinea pigs, and rabbits. The mechanism of action is unknown, but suspected to be related to the reaction of the vinyl group with nucleophiles, such as thiols and amino groups. There is no therapy except removal from exposure. Although high doses cause cancer in rats there is, to date, no convincing evidence for human carcinogenicity. Acrylamide is polymerized and the polyacrylamide used in wastewater treatment, the manufacture of paper and cardboard, as a grouting agent and in modern biochemistry laboratories for polyacrylamide electrophoresis. See Figure A13.

Figure A13

acrylonitrile (vinyl cyanide; cyanoethylene; propene nitrile). CAS number 107-13-1 A designated possible carcinogen (IARC, class 2B), hazardous substance (EPA), hazardous waste (EPA), and priority toxic pollutant (EPA). Acrylonitrile is a slightly acrid, colorless liquid that is both explosive and flammable. Acrylonitrile is used as an intermediate in the manufacture of synthetic fibers, plastics, nitrile rubber, and adhesives. The common routes of entry are inhalation and percutaneous absorption. Local effects of acrylonitrile include irritation of the eyes, and prolonged exposure may cause skin irritation. The effects of systemic exposure include nausea, vomiting, headache, etc., whereas exposure to high concentrations may cause weakness, asphyxia, and death. See Figure A14.

Figure A14

ACTH (adrenocorticotropic hormone; adrenocorticotropin) A hormone secreted by the adenohypophysis in response to hypothalamic corticotropin-releasing hormone (CRH). ACTH stimulates the secretion of glucocorticoids and androgens from the zona fasciculata and the zona reticularis of the adrenal cortex, respectively, but does not stimulate the secretion of mineralocorticoids from the zona glomerulosa. ACTH secretion is increased in stress situations.

actinomycin D (Dactinomycin; Meractinomycin; Cosmegen) An antibiotic and antineoplastic produced by Streptomyces parvullus. The LD50 in mice is 2.0–2.4 mg/kg, i.p. Actinomycin D is a carcinogen that inhibits DNA-dependent RNA synthesis and DNA synthesis. It produces chromosomal breaks and translocations, by intercalation in double-stranded DNA between deoxyguanine residues with the peptide side chains in the minor groove. In humans, it produces bone marrow suppression, gastrointestinal toxicity, and the possibility of anaphalaxis. See Figure A15.

Figure A15

activated charcoal Charcoal that, after pyrolysis during manufacture, has been subjected to steam or air at high temperature, thus making it an efficacious absorber of substances. It is used as an oral absorbent in treating oral intoxication from many substances.

activation (bioactivation) In toxicology, any metabolic reaction of a xenobiotic in which the product is more toxic than the substrate. Such reactions are most commonly monooxygenations, the products of which are electrophiles that, if not detoxified by phase II (conjugation) reactions, may react with nucleophilic groups on cellular macromolecules such as protein and DNA. See also: phase I reactions; phase II reactions; reactive intermediates.

activation energy The energy required, in addition to the change in free energy, to convert chemical reactants to products. Enzymes catalyze reactions by lowering the activation energy and thereby allow reactants (substrates) to be converted to products more quickly.

active avoidance See: conditioned avoidance.

active oxygen (singlet oxygen) ) formation. The divalent reduction of O2 results in H2O2 formation. Trivalent reduction of oxygen yields the highly reactive hydroxyl radical (OH·). This extremely strong oxidant can also be formed in a metal-catalyzed Fenton-type reaction between O2 and H2O2. Reactions of these compounds with organics could yield organic peroxy and alkoxy radicals that are also often considered active forms of oxygen. Upon spin inversion of one of the electrons in the π-orbital, singlet oxygen is produced. See also: superoxide.

active site, of enzymes Part of an enzyme that (1) specifically binds the substrate(s) and (2) catalyzes product formation. The active site consists of two or more often overlapping regions that recognize and bind the substrate(s) and then catalyze the ensuing reactions. The amino acids of each of these regions are not necessarily adjacent in the linear polypeptide(s), but may be brought together by the protein folding. The active site, whether occurring on the surface of the enzyme or buried in a cleft, usually occupies only a small percentage of the total surface of the enzyme molecule. The initial binding of the substrate involves the formation of non-covalent bonds (e.g., hydrogen bonds, ionic bonds, hydrophobic interactions) with chemical groups at the active site. During catalysis, covalent bonds may be formed, and then broken, as part of the reaction mechanism. Catalysis generally involves one or more of the following: optimal spatial alignment of the substrate(s) on the protein surface; distortion of bond angles and stretching of bond lengths or transfer of protons or electrons (acid/base catalysis). The chemical groups involved in catalysis include the chemically reactive side chains of the amino acids histidine, lysine, arginine, serine, threonine, tyrosine, cysteine, glutamic acid, and aspartic acid, and for some enzymes a coenzyme or cofactor. The active sites of many enzymes are targets for a number of toxicants. See also: covalent binding; enzyme; hydrogen bonding; hydrophobic bonding; van der Waals forces.

active transport The energy-dependent process of moving of chemicals across biological membranes. In toxicology, active transport is important as a mechanism for the absorption of chemicals in the gastrointestinal tract and for the excretion of toxicants and their metabolic products from the liver or the kidney or to restrict access to protected tissues such as brain and testes, active transport can mediate the uptake and/or efflux of chemicals. Although entry (uptake) of toxicants usually results from passive diffusion of lipophilic molecules some toxicants are absorbed by active transport because of their close similarity to either nutrients or endogenous metabolites (e.g., 5-fluorouracil is transported by the pyrimidine transport system, MPPT is transported by the dopamine transport system). Active transport systems have several properties in common: they require metabolic energy; they can be inhibited by chemicals that affect energy metabolism; they are selective in terms of the molecules transported; they are saturable; and they can transport chemicals against a concentration gradient. The energy required for active transport can be obtained from the hydrolysis of ATP or coupling of carriers to ion channels. See also: absorption of toxicants; entry mechanisms, special transport; excretion, alimentary; excretion hepatic; excretion renal; facilitated transport.

acute exposure See: exposure, acute.

acute-phase reactant protein See: α1-acid glycoprotein.

acute toxicity Toxicity manifested within a relatively short time interval after toxicant exposure (i.e., as short as a few minutes to as long as several days). Such toxicity is usually caused by a single exposure to the toxicant. See also: acute toxicity, clinical signs; acute toxicity testing.

acute toxicity, clinical signs The signs of intoxication displayed by the person or animal that has been exposed to a toxicant. These signs will include levels of activity such as restlessness, irritability, hyperreflexia, confusion, delirium, mania, self-injury, convulsions, coma, or circulatory collapse; they will also include autonomic signs such as diarrhea, altered pupil size, gooseflesh, hyperactive bowel sounds, hypertension or hypotension, tachycardia or bradycardia, and lacrimation. Other signs can include insomnia, muscle cramps, and yawning. See also: acute toxicity.

acute toxicity testing In the past, such tests were usually concerned with lethality estimated by the LD50 or LC50 tests. At present acute tests include those for eye and skin irritation and sensitization and changes in autonomic and cardiovascular function. More comprehensive acute toxicity tests also include gathering data on cause of death (where applicable), symptomatology, specific organ effects, metabolism and mode of toxic action, as well as forming the basis for subsequent subchronic studies. See also: acute toxicity testing, factors affecting; dermal irritation tests; dermal sensitization tests; eye irritation tests; LC50; LD50; phototoxicity tests; testing variables, biological; testing variables, non-biological; toxicity testing, factors affecting.

acute toxicity testing, alternate approaches See: LD50.

acute toxicity testing, factors affecting Biological variables including: species, strain, sex, stage of reproductive cycle, age, diet, disease, and stress that can affect the results of acute toxicity tests. Non-biological variables include: environmental conditions (temperature, humidity, light cycle); housing (cage design, bedding, population density, and composition); hygiene; statistical design and randomization. The two classes of variables are related since many of the non-biological variables directly affect such biological variables as stress and disease. These variables also affect subchronic and chronic tests and must be carefully controlled to ensure reproducibility. See also: acute toxicity testing; LD50; testing variables, biological; testing variables, non-biological; toxicity testing, factors affecting.

acycloguanosine See: acyclovir.

acyclovir (2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one; acycloguanosine; Zovirax). CAS number 277-89-3 A synthetic acyclic nucleoside with inhibitory activity toward herpes viruses. In mice its oral LD50 is greater than 10,000 mg/kg and its i.p. LD50 is about 1000 mg/kg. Topical application may cause irritation, and i.v. administration may cause transient renal dysfunction. Acyclovir is phosphorylated by herpes-specific thymidine kinases, resulting in the formation of acyclo-GTP that inhibits viral DNA polymerase 10–30 times more efficiently than it does cellular DNA polymerase. Acyclo-GTP is incorporated into viral DNA causing termination of strand synthesis. See Figure A16.

Figure A16

acylation Important phase II reactions of two general types: (1) acetylation by an activated conjugation agent, CoA; (2) a process consisting first of the activation of the foreign compound and the subsequent acylation of an amino acid to yield the amino acid conjugate. This type of conjugation is characteristic of exogenous carboxylic acids and amides. See also: acetylation; N,O-acyltransferase; amino acid conjugation; phase II reactions.

acyl CoA:amino acid N-acyltransferase See: amino acid conjugation.

acyl CoA synthetase See: amino acid conjugation.

N,O-acyltransferase This enzyme is believed to be important in the activation of arylamines, many of which are carcinogenic. Arylamines are first N-oxidized and then, in some species, N-acetylated to arylhydroxamic acids. The N-acyl group of the hydroxamic acid is first removed by the N,O-acyltransacetylase and then transferred either to an amine to yield a stable amide or to the oxygen of the hydroxylamine to yield a reactive N-acyloxyarylamine. These highly reactive compounds form adducts with proteins and nucleic acids. N,O-Acyltransferase that has been purified from the cytosolic fraction of rat liver increases the mutagenicity of compounds such as N-hydroxy-2-acetylaminofluorene when added to the medium in the Ames test.

ADAM See: MDMA.

adaptation to toxicants The ability of an organism to show either insensitivity, or decreased sensitivity, to a chemical that normally causes deleterious effects. The terms resistance and tolerance are closely related and have sometimes been used interchangeably. The present consensus is that resistance refers to the situation in which a change in the genetic constitution of a population in response to selection by the stressor chemical enables a greater number of individuals to resist the toxic action than were able to resist it in the unselected population. Thus, an essential feature of resistance is its inheritance by subsequent generations. In microorganisms this frequently involves mutations and induction of enzymes by the toxicant; in higher organisms it usually involves selection for genes already present in the population at low frequency. Tolerance is reserved for those situations in which individual organisms acquire the ability to resist the effect of a toxicant, usually as a result of prior exposure. Tolerance may also be used for populations that have the genes for resistance at a high frequency before exposure. More often, however, this is known as natural resistance, in contrast to acquired resistance, derived by selection as described above. See also: cross-resistance.

ADCC See: antibody-dependent cellular cytotoxicity.

addiction The overwhelming desire or need to continue the use