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AN INTRODUCTION TO INTERDISCIPLINARY
TOXICOLOGY
AN INTRODUCTION TO
INTERDISCIPLINARY
TOXICOLOGY
FROM MOLECULES TO MAN

Edited by

Carey N. Pope
Regents Professor, Physiological Sciences, College of Veterinary Medicine, Interdisciplinary Toxicology Program,
Oklahoma State University, Stillwater, OK, United States

Jing Liu
Senior Research Scientist, Charles River Laboratories, Reno, Nevada, United States
Academic Press is an imprint of Elsevier
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 Contents

List of contributors xiii II

Foreword xvii
RESPONSES TO CHEMICAL
Preface xix
TOXICANTS

I 4. Toxicant interactions with

GENERAL CONCEPTS macromolecular targets
RUDY J. RICHARDSON

1. History and basic concepts of 4.1 Toxicokinetics and toxicodynamics 45

toxicology 4.2 Toxicokinetics 45
CAREY N. POPE, DANIEL SCHLENK AND
4.3 Toxicodynamics 46
FRÉDÉRIC J. BAUD 4.4 AChE and OP insecticide mechanism and mode of
action 47
1.1 A brief history of toxicology 3 4.5 Mechanism and mode of action of OP inhibitors of
1.2 Important concepts in toxicology 6 AChE 47
References 14 4.6 Toxicodynamic factors for inhibition of AChE by
OP compounds 49
2. Absorption, distribution, and excretion 4.7 Kinetic and equilibrium constants 49
4.8 Determining ki under pseudo-first-order
in complex organisms conditions 50
LARA MAXWELL 4.9 The IC50 and pIC50 51
4.10 Determining the Kd and k2 components of ki 53
2.1 Introduction to xenobiotic disposition 17
4.11 Determining Kd and k2 in the presence of
2.2 Absorption of xenobiotics 22
substrate 53
2.3 Distribution of xenobiotics 24
4.12 Postinhibitory reactions: reactivation and
2.4 Elimination: metabolism and excretion of
aging 54
xenobiotics 26
4.13 Mutant AChE produces insecticide resistance in
References 29
mosquitoes 55
4.14 Conclusion 56
3. Xenobiotic metabolism and References 56
disposition
GUANGPING CHEN 5. Cellular responses to toxicants
LIN LIU
3.1 Introduction 31
3.2 Phase I drug-metabolizing enzymes 32 5.1 Introduction 59
3.3 Phase II drug-metabolizing enzymes 37 5.2 Cell adaptation, injury, and death 59
3.4 Phase III drug transporters 40 5.3 Oxidative stress and cellular protection system 64
3.5 Conclusions 42 5.4 Cellular techniques 66
References 42 Further reading 67

v
vi Contents

6. Disruption of extracellular References 109

signaling Further reading 110
CAREY N. POPE AND KIRSTIN HESTER
9. Epigenetics
6.1 Overview of extracellular signaling 69 JOSEPH PAUL BRESSLER, RICHARD S. LEE AND JAIRUS
6.2 Disruption of extracellular signaling in the PULCZINSKI
expression of toxicity 72
6.3 Conclusions 78 9.1 Historical perspective 111
References 78 9.2 Chromatin remodeling 112
9.3 DNA methylation 112
9.4 Histone modifications 113
7. Disruption of intracellular
9.5 Toxicology and epigenetics 114
signaling 9.6 Cancer as an epigenetic disease 122
ANUMANTHA KANTHASAMY, JIE LUO, 9.7 Pitfalls in epigenetics research 123
DHARMIN ROKAD AND ADHITHIYA CHARLI
References 124
Further reading 124
7.1 Overview of intracellular signaling 81
7.2 Mitochondria-targeted pesticides and mitochondrial
dysfunction 82 10. Microbiome in toxicity and its
7.3 Neuroinflammation 85 modulation
7.4 Oxidative stress 87 KATHLEEN AHLES AND GERWALD KOEHLER
7.5 Concluding remarks and future directions 89
Acknowledgments 90 10.1 Introduction 127
References 90 10.2 Ingested toxicants and the microbiome 129
10.3 Pesticides and the microbiome 132
8. Carcinogenesis 10.4 Environmental toxicants and the
microbiome 133
JAMES E. KLAUNIG
10.5 Toxic metals and the microbiome 134
8.1 Background 97 10.6 Concluding remarks 135
8.2 Definitions 97 References 136
8.3 Mechanisms of chemical carcinogens 99
8.4 Genotoxic/DNA-reactive compounds 100
8.5 Mutation 101 III
8.6 DNA repair 102 ORGAN SYSTEM EFFECTS
8.7 Nongenotoxic carcinogens 102
8.8 Cytotoxicity 103
8.9 Receptor mediated 104 11. Dermal toxicity
8.10 DNA methylation 104 MICHAEL F. HUGHES
8.11 Immunosuppression 104
8.12 Oxidative stress 105 11.1 Introduction 141
8.13 Gap junctional intercellular communication 105 11.2 Histology of skin 142
8.14 Polymorphisms in carcinogen metabolism and 11.3 Dermal absorption of xenobiotics 144
DNA repair 105 11.4 Metabolism 146
8.15 Proto-oncogenes and tumor-suppressor genes 105 11.5 Contact dermatitis 147
8.16 Multistage carcinogenesis 106 11.6 Photosensitivity 147
8.17 Evaluating chemicals for carcinogenicity 108 11.7 Disorders and diseases of skin 148
8.18 Determining human carcinogenic risk 108 11.8 Tattoos 150
 Contents vii
11.9 Conclusions 150 15.3 Classical cardiovascular toxicants and their
References 150 mechanisms of action 201
References 204
12. Hepatic toxicology
ATRAYEE BANERJEE AND SHASHI K. RAMAIAH 16. Introduction to reproductive and
developmental toxicology
12.1 Introduction 153
VICKI SUTHERLAND
12.2 Hepatic structural and functional
organization 153
16.1 Introduction 207
12.3 Cellular components and functions 154
16.2 Hypothalamus and hormones 208
12.4 Mechanism of bile formation and function 154
16.3 Male reproductive system 210
12.5 Types of liver injury 155
16.4 Female reproductive system 212
12.6 Additional mechanisms 160
16.5 Pregnancy and embryo/fetal development 216
12.7 Current state of serum biomarkers to assess liver
16.6 Toxicants 217
damage 160
References 220
12.8 Conclusions 161
Further reading 220
References 161

13. Renal toxicology 17. Organ system effects: endocrine

HYUNG SIK KIM toxicology
NANCY D. DENSLOW AND CHRISTOPHER J. MARTYNIUK
13.1 Structure and function of kidney 163
13.2 Adaptation and susceptibility of kidneys to 17.1 Introduction to hormone systems and endocrine
toxicants 165 toxicology 221
13.3 Site-selective kidney toxicity 167 17.2 General overview of hormone signaling 222
13.4 Evaluation of renal function 170 17.3 Hormone axis and chemical perturbation 223
13.5 Classification of nephrotoxic substances 172 17.4 Comparative endocrinology: insight into endocrine
References 176 toxicology 229
17.5 New directions for the study of endocrine
14. Respiratory toxicology 229
KEVIN N. BAER
Abbreviations 229
References 230
14.1 Introduction 179
14.2 Toxicants affecting the lung following 18. Immunotoxicology
inhalation 181 RANDLE GALLUCCI, LERIN LUCKETT-CHASTAIN AND
14.3 Systemic lung toxicants 185 BERRAN YUCESOY
14.4 Reactive airway dysfunction syndrome 186
References 187 18.1 Introduction 233
18.2 Types of immunotoxicity 233
15. Cardiovascular 18.3 Metals 236
TAMMY R. DUGAS AND KURT J. VARNER 18.4 Pesticides 237
18.5 Polycyclic aromatic hydrocarbons 237
15.1 Overview of cardiovascular physiology 191 18.6 Pulmonary immunotoxicants 238
15.2 Mechanisms of toxicity and disease 18.7 Smoking, alcohol, and drugs of abuse 240
pathogenesis 196 References 241
viii Contents

19. Sensory function 22.5 Conclusion 307

WILLIAM K. BOYES, BENOÎT POUYATOS AND JORDI References 307
LLORENS

19.1 Introduction 245 V

19.2 Vision 245
19.3 Audition 247 TOXICOLOGY AT HOME AND
19.4 Vestibular 252 THE WORKPLACE
19.5 Somatosensory 254
19.6 Olfactory/chemosensory perception 257
19.7 Sensory perception in nonmammalian 23. Toxicology in the home
systems 258 MARION EHRICH
19.8 Conclusion 259
Acknowledgments 259 23.1 Introduction 315
References 259 23.2 Nonprescription drugs 315
23.3 Common prescription drugs 318
20. Nervous system 23.4 Household chemicals 320
Acknowledgments 324
DAVID R. WALLACE AND ALEKSANDRA BUHA
DJORDJEVIC
References 324

20.1 Introduction 261 24. Toxicology in the workplace 327

20.2 Mechanisms and types of neurotoxicity 262 MARIE FORTIN AND MARIE CAPDEVIELLE
20.3 Selected neurotoxicants 265
References 276 24.1 Introduction 327
24.2 Case studies 328
24.3 Managing exposures and protecting workers 334
IV 24.4 Conclusion 336
References 336
MODULATION OF TOXICITY

21. Intrinsic and extrinsic factors that can VI

modify toxicity TOXICOLOGY IN THE
JING LIU AND CAREY N. POPE COMMUNITY
21.1 Intrinsic modifying factors 285
21.2 Extrinsic modifying factors 289 25. Love canal: a classic case study of a
References 291 contaminated community
DUANE A. GILL AND TAMARA L. MIX
22. Influence of dietary factors and
nutritional status on toxicity response to 25.1 Framework and concepts: contamination in the
environmental pollutants context of natural and technological disasters 341
BRENDA J. SMITH AND EDRALIN A. LUCAS
25.2 Love Canal: a historical case study 342
25.3 Sociocultural and psychosocial effects of residing in
22.1 Introduction 295 a contaminated community 347
22.2 Macronutrients 295 25.4 Implications and connections 349
22.3 Micronutrients 300 25.5 Critical connections 350
22.4 Protective effects 306 References 351
 Contents ix
26. “Dear People of Flint”: environmental 28.5 Examples of modes of action of special relevance
justice in a community context, the case of to ecotoxicology 384
28.6 Relating effects from molecular to community
water contamination in Flint, Michigan
levels 384
TAMARA L. MIX AND DUANE A. GILL
28.7 Understanding and measuring exposure in
ecotoxicology 386
26.1 Concepts: environmental inequality and
28.8 Bioconcentration, bioaccumulation, and
justice 353
biomagnification 388
26.2 The case in context: water contamination in Flint,
28.9 Approaches for evaluating the presence of or
Michigan 355
potential for an environmental impact 389
26.3 Environmental inequality and justice intersected:
28.10 Toxicity of mixtures and multiple stressors 391
outcomes in Flint, Michigan 358
28.11 Conclusion 392
26.4 Conclusion 359
References 392
Critical connections 360
References 360
IX
VII NANOTOXICOLOGY
ENVIRONMENTAL EXPOSURES
29. Selected aspects of nanotoxicology
D.B. WARHEIT AND S.C. BROWN
27. Hazardous release: point source
dispersion modeling 29.1 Introduction 397
JOSHUA D. RAMSEY 29.2 Hazard versus risk and regulatory distinctions 399
29.3 Relevant routes of exposure to nanoscale
27.1 Introduction 365 particulate materials—a brief review 400
27.2 Exposure limits 366 29.4 Oral or ingestion exposures 400
27.3 Factors that affect dispersion 368 29.5 Dermal exposures 401
27.4 Dispersion modeling 369 29.6 Toward a future understanding of
27.5 Example problems 374 nanomaterials 404
27.6 Pasquill Gifford dispersion model 29.7 Evaluating the risks associated with nanomaterial
limitations 377 exposures: the NanoRisk Framework 405
27.7 Conclusions 377 29.8 Subchronic inhalation toxicity study in rats with
References 377 carbon nanofibers 407
29.9 Conclusions 407
References 408
VIII
ECOTOXICOLOGY X
CLINICAL TOXICOLOGY
28. Introduction to ecotoxicology
JASON BELDEN
30. Introduction to clinical
28.1 Defining ecotoxicology 381 toxicology
28.2 Goals and challenges of ecotoxicology as FRÉDÉRIC J. BAUD AND PASCAL HOUZÉ
compared to human toxicology 381
28.3 Variability of toxicity between species 382 30.1 The pharmacological basis of clinical
28.4 Toxicity testing using surrogate species 382 toxicology 413
x Contents

30.2 What clinical toxicology actually is? 421

30.3 What does a clinical toxicologist do
XIII
every day? 422 REGULATORY TOXICOLOGY
30.4 Research in clinical toxicology 425
References 428
33. Mammalian cell culture models
THERESA M. FREUDENRICH AND TIMOTHY J. SHAFER
XI 33.1 Basic cell culture laboratory and terminology 463
VETERINARY TOXICOLOGY 33.2 Good cell culture practices 464
33.3 Types of cultures 465
33.4 Use of mammalian cell models for regulatory
31. Introduction to veterinary toxicology 468
toxicology 33.5 Summary 471
RAMESH C. GUPTA Acknowledgments 472
References 472
31.1 Introduction 431
31.2 Classification of poisons 431 34. Toxicity testing: in vitro models in
31.3 Types of poisoning 431 ecotoxicology
31.4 Factors affecting poisoning 432
JUSTIN SCOTT AND MATTEO MINGHETTI
31.5 Diagnostic criteria in animal
poisonings 432 34.1 Overview of the use of animals in toxicology 477
31.6 Toxicology of specific poisons 432 34.2 Alternative methods in regulatory
31.7 Concluding remarks 440 ecotoxicology 479
Acknowledgment 440 34.3 Conclusion 484
References 440 Acknowledgments 485
References 485

XII 35. Toxicology testing: in vivo mammalian

FORENSIC TOXICOLOGY models
K. OLIVIER AND S. KARANTH

32. Introduction to forensic 35.1 Mouse 489

toxicology 35.2 Rat 491
JARRAD R. WAGNER
35.3 Rabbit 495
35.4 Dog 498
32.1 Introduction 445 35.5 Nonhuman primates 499
32.2 History of forensic toxicology 445 References 505
32.3 Human performance testing 446
32.4 Postmortem toxicology 447 36. In vivo ecotoxicology models
32.5 Forensic/workplace drug testing 447 JOSEPH R. BIDWELL
32.6 Fundamental principles of forensic
toxicology 447 36.1 Introduction 507
32.7 Analytical techniques in forensic 36.2 Basic methods for regulatory ecotoxicology
toxicology 449 testing 507
32.8 Quality assurance in forensic 36.3 Alternatives to animal models in ecotoxicity
toxicology 458 testing 520
32.9 Conclusion 458 36.4 Summary 520
Further reading 459 References 521
 Contents xi
37. The zebrafish (Danio rerio) model in 40.4 Future considerations and applications 563
toxicity testing 40.5 Conclusions 566
References 566
STEPHANIE PADILLA AND SCOTT GLABERMAN

37.1 Introduction 525 41. Adverse outcome pathways in

37.2 Using zebrafish for human toxicity ecotoxicology
characterization 526 DANIEL SCHLENK
37.3 Zebrafish in ecotoxicology 527
37.4 Emerging novel technologies 530 41.1 Introduction 569
References 530 41.2 Adverse outcome pathway overview 571
41.3 Examples of adverse outcome pathways in
38. Caenorhabitidis elegans as an animal ecotoxicology 572
model in toxicological studies 41.4 Additional directions for adverse outcome
pathways 576
MARINA LOPES MACHADO, DANIELE CORADINI
ZAMBERLAN, LETICIA PRISCILLA ARANTES, MICHAEL 41.5 Conclusions 577
ASCHNER AND FÉLIX ALEXANDRE ANTUNES SOARES References 578

38.1 Introduction 533

38.2 Neurotoxicology applications 534 XIV
38.3 Heavy metal toxicity 536
38.4 Radiation damage 537 REFERENCE MATERIALS AND
38.5 Pesticide toxicity 539 WEBSITES
38.6 Final remarks—perspectives for C. elegans use in
toxicology 540
Acknowledgments 541 42. Toxicology literature, databases, and
References 541 other online resources
PHILIP WEXLER
39. Principles of risk assessment
ROBINAN GENTRY, ALLISON FRANZEN AND TRACY
42.1 Introduction 583
GREENE 42.2 Books (often available in paper, online, and for e-
readers; check with publisher or Amazon) 583
39.1 Brief historical perspective 545 42.3 Journals (a sampling) 585
39.2 The risk assessment paradigm 546 42.4 Professional societies 586
39.3 Conclusions 557 42.5 US government organizations and laws 587
References 557 42.6 Other organizations 589
42.7 Online databases and other digital tools 590
40. Tox21 and adverse outcome pathways 42.8 The international legal and regulatory
COURTNEY ROPER AND ROBYN LEIGH TANGUAY framework 593
42.9 Social media and blogs 594
40.1 Overview of Tox21 559 42.10 A note about cost of access 595
40.2 Tox21 phases 560
40.3 Data analysis and dissemination 562 Index 597
 List of contributors
Kathleen Ahles Department of Biochemistry and
Microbiology, Oklahoma State University Center
for Health Sciences, Tulsa, OK, United States;
Present address: Tarrant County College, Hurst,
TX, United States
Leticia Priscilla Arantes Department of
Biochemistry and Molecular Biology, CCNE,
UFSM, Santa Maria, Brazil
Michael Aschner Department of Molecular
Pharmacology, Albert Einstein College of
Medicine Bronx, New York, NY, United States
Kevin N. Baer School of Basic Pharmaceutical and
Toxicological Sciences, Waste Management
Endowed Professorship in Toxicology, College of
Pharmacy, University of Louisiana at Monroe,
Monroe, LA, United States
Atrayee Banerjee Reckitt and Benckiser, Montvale,
United States
Frédéric J. Baud Medical and Toxicological Critical
Care Department, Assistance Publique—
Hôpitaux de Paris, Necker Hospital, Paris,
France; University Paris Diderot, Paris, France;
EA7323 Evaluation of therapeutics and pharma-
cology in perinatality and pediatrics—University
Hospital Cochin—Broca—Hôtel Dieu, Site
Tarnier, University Paris Descartes, Paris, France
Jason Belden Department of Integrative Biology,
Oklahoma State University, Stillwater, OK,
United States
Joseph R. Bidwell Department of Biological
Sciences, East Tennessee State University,
Johnson City, TN, United States
William K. Boyes Office of Research and
Development, U.S. Environmental Protection
Agency, NC, United States
xiii
Joseph Paul Bressler Department of
Environmental Health and Engineering, Kennedy
Krieger Institute, Bloomberg School of Public
Health, Johns Hopkins University, Baltimore,
MD, United States
S.C. Brown The Chemours Company, Wilmington,
DE, United States
Marie Capdevielle MCD Toxicology Consulting,
LLC., Middletown, NJ, United States
Adhithiya Charli Parkinson’s Disorder Research
Laboratory, Iowa Center for Advanced
Neurotoxicology, Department of Biomedical
Sciences, Iowa State University, Ames, IA, United
States
Guangping Chen Department of Physiological
Sciences, Oklahoma State University, Stillwater,
OK, United States
Nancy D. Denslow University of Florida,
Gainesville, FL, United States
Aleksandra Buha Djordjevic Department of
Toxicology ‘Akademik Danilo Soldatović’,
Faculty of Pharmacy, University of Belgrade,
Belgrade, Serbia
Tammy R. Dugas Comparative Biomedical
Sciences, LSU School of Veterinary Medicine,
Baton Rouge, LA, United States
Marion Ehrich Department of Biomedical Sciences
& Pathobiology, Virginia Maryland College of
Veterinary Medicine, Virginia Tech, Blacksburg,
VA, United States
Marie Fortin Early Development Department,
Jazz Pharmaceuticals, Philadelphia, PA, United
States; Rutgers University, Department of
Pharmacology and Toxicology, Piscataway, NJ,
United States
xiv List of contributors

Allison Franzen Ramboll US Corporation, S. Karanth Neuraly, Inc., Germantown, MD,

Monroe, LA, United States United States
Theresa M. Freudenrich Biomolecular and Hyung Sik Kim School of Pharmacy,
Computational Toxicology Division, Center for Sungkyunkwan University, Suwon, Republic of
Computational Toxicology and Exposure (CCTE), Korea
U.S. Environmental Protection Agency, Research James E. Klaunig School of Public Health, Indiana
Triangle Park, NC, United States University, Bloomington, IN, United States
Randle Gallucci Department of Pharmaceutical Gerwald Koehler Department of Biochemistry and
Science, University of Oklahoma Health Science Microbiology, Oklahoma State University Center
Center, Oklahoma City, OK, United States for Health Sciences, Tulsa, OK, United States
Robinan Gentry Ramboll US Corporation, Richard S. Lee Department of Psychiatry and
Monroe, LA, United States Behavioral Sciences, Johns Hopkins University
Duane A. Gill Department of Sociology, School of Medicine, Baltimore, MD, United States
Oklahoma State University, Stillwater, OK, Jing Liu Charles River Laboratories, Reno,
United States Nevada, United States
Scott Glaberman Department of Environmental Lin Liu Department of Physiological Sciences,
Science and Policy, George Mason University, Oklahoma State University, Stillwater, OK,
Fairfax, VA, United States United States
Tracy Greene Ramboll US Corporation, Monroe, Jordi Llorens Department of Physiological
LA, United States Sciences and Institute of Neurosciences, Faculty
Ramesh C. Gupta Toxicology Department, of Medicine and Health Sciences, Universitat de
Breathitt Veterinary Center, Murray State Barcelona, Barcelona, Spain
University, Hopkinsville, KY, United States
Edralin A. Lucas Department of Nutritional
Kirstin Hester Department of Physiological Sciences, Oklahoma State University, Stillwater,
Sciences, College of Veterinary Medicine, OK, United States
Interdisciplinary Toxicology Program, Oklahoma
Lerin Luckett-Chastain Department of
State University, Stillwater, OK, United States
Pharmaceutical Science, University of Oklahoma
Pascal Houzé Laboratory of Biochemistry, Health Science Center, Oklahoma City, OK,
Assistance Publique—Hôpitaux de Paris, United States
Necker Hospital, Paris, France; Laboratory of
Jie Luo Parkinson’s Disorder Research Laboratory,
Analytical Chemistry, Faculty of Pharmacy,
Iowa Center for Advanced Neurotoxicology,
University Paris Descartes, Paris, France;
Department of Biomedical Sciences, Iowa State
Chemical and Biological Technologies for Health
University, Ames, IA, United States
Unit, Paris 5-CNRS UMR8258 Inserm U1022,
Faculty of Pharmacy, University Paris Descartes, Marina Lopes Machado Department of
Paris, France Biochemistry and Molecular Biology, CCNE,
UFSM, Santa Maria, Brazil
Michael F. Hughes U.S. Environmental Protection
Agency, Office of Research and Development, Christopher J. Martyniuk University of Florida,
National Health and Environmental Effects Gainesville, FL, United States
Research Laboratory, Research Triangle Park, Lara Maxwell Department of Physiological
NC, United States Sciences, College of Veterinary Medicine,
Anumantha Kanthasamy Parkinson’s Disorder Oklahoma State University, Stillwater, OK,
Research Laboratory, Iowa Center for Advanced United States
Neurotoxicology, Department of Biomedical Matteo Minghetti Department of Integrative
Sciences, Iowa State University, Ames, IA, United Biology, Oklahoma State University, Stillwater,
States OK, United States
 List of contributors
Tamara L. Mix Department of Sociology,
Oklahoma State University, Stillwater, OK,
United States
K. Olivier Olivier KOnsulting LLC, Boston, MA,
United States
Stephanie Padilla Biomolecular and
Computational Toxicology Division, Center for
Computational Toxicology and Exposure, U.S.
Environmental Protection Agency, Research
Triangle Park, NC, United States
Carey N. Pope Department of Physiological
Sciences, College of Veterinary Medicine,
Interdisciplinary Toxicology Program, Oklahoma
State University, Stillwater, OK, United States
Benoı̂t Pouyatos Ototoxicity & Neurotoxicity
Laboratory, National Research and Safety
Institute for the Prevention of Occupational
Accidents and Diseases (INRS), Vandœuvre,
France
Jairus Pulczinski Department of Environmental
Health and Engineering, Kennedy Krieger
Institute, Bloomberg School of Public Health,
Johns Hopkins University, Baltimore, MD,
United States
Shashi K Ramaiah Pfizer Inc., New York, NY,
United States
Joshua D. Ramsey School of Chemical
Engineering, Oklahoma State University,
Stillwater, OK, United States
Rudy J. Richardson Computational Toxicology
Laboratory, University of Michigan, Ann Arbor,
MI, United States
Dharmin Rokad Parkinson’s Disorder Research
Laboratory, Iowa Center for Advanced
Neurotoxicology, Department of Biomedical
Sciences, Iowa State University, Ames, IA, United
States
Courtney Roper Sinnhuber Aquatic Research
Laboratory, Oregon State University, Corvallis,
OR, United States
Daniel Schlenk Department of Environmental
Sciences, University of California, Riverside, CA,
United States
Justin Scott Department of Integrative Biology,
Oklahoma State University, Stillwater, OK,
United States
xv
Timothy J. Shafer Biomolecular and
Computational Toxicology Division, Center for
Computational Toxicology and Exposure (CCTE),
U.S. Environmental Protection Agency, Research
Triangle Park, NC, United States
Brenda J. Smith Department of Nutritional
Sciences, Oklahoma State University, Stillwater,
OK, United States
Félix Alexandre Antunes Soares Department of
Biochemistry and Molecular Biology, CCNE,
UFSM, Santa Maria, Brazil; Department of
Molecular Pharmacology, Albert Einstein College
of Medicine Bronx, New York, NY, United States
Vicki Sutherland Division of the National
Toxicology Program, National Institute of
Environmental Health Sciences, Research
Triangle Park, NC, United States
Robyn Leigh Tanguay Sinnhuber Aquatic
Research Laboratory, Oregon State University,
Corvallis, OR, United States
Kurt J. Varner Pharmacology and Experimental
Therapeutics, LSU Health Sciences Center, New
Orleans, LA, United States
Jarrad R. Wagner School of Forensic Sciences,
Oklahoma State University Center for Health
Sciences, Tulsa, OK, United States
David R. Wallace Department of Pharmacology,
School of Biomedical Science, Oklahoma State
University Center for Health Sciences, Tulsa, OK,
United States; Interdisciplinary Toxicology
Program, Oklahoma State University, Stillwater,
OK, United States
D.B. Warheit Warheit Scientific LLC, Wilmington,
DE, United States
Philip Wexler Retired, National Library of
Medicine, Bethesda, MD, United States
Berran Yucesoy Department of Pharmaceutical
Science, University of Oklahoma Health Science
Center, Oklahoma City, OK, United States
Daniele Coradini Zamberlan Department of
Biochemistry and Molecular Biology, CCNE,
UFSM, Santa Maria, Brazil
 Foreword
Toxicological risk can be defined by the sim-
ple risk equation: RISK 5 INTRINSIC
TOXICITY 3 EXPOSURE. As will be seen in
this volume, this equation encapsulates all
aspects of toxicology, from fundamental defini-
tions of toxicology to its many subdisciplines.
Through its comprehensive coverage of this
broad field, this work provides a useful and
logical description of toxicology in a meaning-
ful and impactful manner. Spanning molecular
toxicology, organ systems and organismal toxi-
cology, ecotoxicology, and ultimately popula-
tion impact, An Introduction to Interdisciplinary
Toxicology covers the waterfront of the disci-
pline of toxicology.
Chemical exposure is widely explored in
this text because of its central role in defining
toxicity. From absorption, distribution, metabo-
lism, and elimination of a chemical in an
organism to environmental and occupational
exposures, the general principles of chemical
exposure are systematically examined. The
roles of competing pathways of metabolism,
including the opportunity for induction of met-
abolic enzymes with overall effects to magnify
or lessen the toxicity, are described.
Pathways to toxicity, including receptor
interaction, intracellular signaling pathways,
and covalent binding, are thoroughly dis-
cussed in pharmacological and molecular
terms. In many cases, the mechanistic basis for
a chemical’s toxicity is the disruption of an
endogenous biological pathway. Outcomes of
such disruption may be cancer or reproductive
toxicity, yet other mechanisms such as DNA
xvii
covalent binding or nongenomic alterations,
including epigenetic mechanisms, may play a
pivotal role.
At the organ system level, the impacts of
toxicants on the hepatic, renal, respiratory, and
cardiovascular systems are extensively exam-
ined. The sensitivity of these systems, includ-
ing the immune and reproductive systems, is
appraised. Distribution of receptor systems,
metabolic capability, enzymatic pathways, and
signaling pathways are examined as modula-
tors of potential toxicity.
Potentially toxic chemicals can be found
almost anywhere, including homes, work-
places, and communities. Exposure to potential
toxicants may vary widely in these different
environments, but knowledge of exposure sce-
narios and routes of exposure may provide
protective strategies for adults and children.
The principles of ecotoxicology are exam-
ined along with environmental impact of expo-
sures to chemicals. The concept of
environmental justice is thoroughly examined
and forces that control it are discussed.
Because wildlife and plant life can be affected,
the entire ecosystem must be considered. Even
the smallest of physico-chemical entities (i.e.,
nanoparticles) are evaluated for their relative
toxicity profiles compared with more tradi-
tional forms of those same chemicals.
The toxicological world has several branches
that are firmly attached to the major trunk of
the toxicology world. Among those examined
are clinical, veterinary, forensic, and regulatory
toxicology, each with its own focus of interest
xviii
but all firmly related to general toxicological
principles.
Finally, model systems and various risk
assessment approaches and tools are presented
to strengthen and reinforce the principles of
toxicology. These approaches allow prediction
and a quantitative definition of the risk associ-
ated with toxicant exposure. This comprehen-
sive and all-encompassing treatise on
Foreword
toxicology provides the basis for understand-
ing the importance of the principles of
toxicology.
William Slikker
National Center for Toxicological Research,
U.S. Food and Drug Administration
2020 Published by Elsevier Inc.
 Preface
The Interdisciplinary Toxicology Program
(ITP) was established at Oklahoma State
University (OSU) in 2012, with the recognition
that complex environmental issues of our time
surrounding chemical contamination will
require the efforts of investigators across disci-
plines and the cross-training of their students
to be effective investigators. Faculty and stu-
dents in our program come from 12 different
departments, 6 colleges, and 2 campuses. Our
earlier experience with an undergraduate toxi-
cology program at the University of Louisiana
at Monroe emphasized the value of starting
simple in developing and transferring knowl-
edge in toxicology through coursework and
laboratory experiences, highlighting important
concepts and skills in easy-to-understand
approaches. This same concept of education
and training applies to graduate students in an
interdisciplinary program, with students com-
ing from diverse multiple disciplines and
sometimes very different experiences.
This book is modeled after one of the
courses in the OSU ITP, Toxicology: from mole-
cules to ecosystems. The course begins with prin-
ciples and goes on to cover from toxicant-
target interactions to proteotoxicity, cellular
responses, toxicokinetics, organ systems, eco-
toxicology, forensics, population effects, the
sociology of chemical contamination episodes,
and other topics, matching the strengths of the
xix
participating faculty and the interests of their
students. While covering the subject matter can
be a challenge for both the students and the
instructors, most agree that synergy can
develop when bringing different emphasis
areas, concepts, and approaches together.
Active participation between the students and
instructors is an important part of the course
and facilitates an understanding among all for
their specific interests and experiences.
One advantage for putting this book
together was a necessary emphasis on what we
were teaching and how it could be made more
succinct and clear, in addition to having the
opportunity to recruit other OSU faculty for
coverage of new areas of emphasis. Expert
authors from other institutions contributed
chapters as well, and a number of those have
already visited or will visit OSU as part of our
annual ITP symposium. We are indebted to the
efforts of all of the chapter contributors with-
out which completion of the book could not
have happened. We hope that our book pro-
vides an easy-to-understand survey of timely
topics in toxicology suitable for graduate stu-
dents across disciplines entering into this excit-
ing area of investigation.
Carey N. Pope and Jing Liu
September 2019
 C H A P T E R

1
History and basic concepts of toxicology
Carey N. Pope1, Daniel Schlenk2 and Frédéric J. Baud3,4,5
1
Department of Physiological Sciences, College of Veterinary Medicine, Interdisciplinary Toxicology
Program, Oklahoma State University, Stillwater, OK, United States 2Department of Environmental
Sciences, University of California, Riverside, CA, United States 3Medical and Toxicological Critical
Care Department, Assistance Publique—Hôpitaux de Paris, Necker Hospital, Paris, France 4University
Paris Diderot, Paris, France 5EA7323 Evaluation of therapeutics and pharmacology in perinatality and
pediatrics—University Hospital Cochin—Broca—Hôtel Dieu, Site Tarnier, University Paris
Descartes, Paris, France

1.1 A brief history of toxicology
There is substantial evidence indicating that
humans have been aware of, and in some cases
utilized, the toxicity of various substances since
antiquity. While there is little evidence of poi-
sonings in the Paleolithic and Neolithic periods
in Europe, around 18,000 years ago Maasai
hunters in Kenya used arrow and dart poisons
(likely cardiac glycosides of Strophanthus spe-
cies) to increase the effectiveness of their weap-
ons. Indeed the term toxicology is derived from
the Greek terms toxikos (bow) and toxicon (poi-
son into which arrowheads are dipped).1
In the bronze (3000 1000 years BCE) and
iron ages (800 100 years BCE), people started
to communicate with writing, providing last-
ing documentation of accidental and inten-
tional intoxications and the use of toxic
substances in executions. During the Bronze
Age, metal alloys were first developed using
tin, aluminum, lead, manganese, and other
trace elements. During the Iron Age, the devel-
opment of iron and steel industries was instru-
mental in the maintenance of power and order
by European monarchies and feudal overlords.
One can assume that human exposure to heavy
metals was a constant threat due to the smelt-
ing, iron casting, and other activities such as
painting and tanning.
In the past, medical toxicology concerned nat-
ural substances including metals, plants, fungi
such as mushrooms and mycotoxins (ergot-
ism), bacterial exotoxin (botulism), and venom-
ous animals as well as carbon oxides produced
by combustion of carbonaceous materials. The
Eber’s papyrus, an ancient Egyptian text writ-
ten around 1500 BCE, is among the earliest of
medical texts, describing a variety of ancient
poisons including aconite, antimony, arsenic,
cyanogenic glycosides, hemlock, lead, man-
drake, opium, and wormwood.
The basis of pharmacology was clearly
stated in Phaedo by Plato (428 348 BCE), and

An Introduction to Interdisciplinary Toxicology

DOI: https://doi.org/10.1016/B978-0-12-813602-7.00001-6 3 © 2020 Elsevier Inc. All rights reserved.
4 1. History and basic concepts of toxicology
further developed by Aristotle (384 322 BCE).
At this time, the toxicity of plants and venom-
ous animals was well known as illustrated by
the modus operandi for Socrates’ sanctioned
execution by self-ingestion of hemlock
(470 399 BCE), while much later the Egyptian
queen Cleopatra died from a self-inflicted fatal
snake bite (51 30 BCE). The Roman empire
followed by the Middle Age and Renaissance
inaugurated a long period during which mur-
der using poisonous substances was a common
practice, using knowledge held by “wizards”
and alchemists. The Greek physician Galen
(c. CE 129 200) described Mithridates’ experi-
ences in a series of books on Antidotes.
Chemical warfare and infectious agents were
commonly used during sieges. A number of
historians suggested a relationship between the
large use of lead for the numerous pipelines
supplying Rome’s drinking water and chronic
lead poisoning of the Roman population lead-
ing to the twilight and eventual fall of the
Roman Empire in the mid-5th century CE.
The bean of the Calabar plant (Physostigma
venonosum) and seeds of a variety of other
plants were used in Africa and Madagascar for
likely hundreds of years as “ordeal poisons” to
determine guilt of someone accused of a crime.
While the substance and methods for using an
ordeal poison varied, the suspect was typically
forced to eat or drink the substance and the
reaction was observed. If the material was
expelled by vomiting, he or she was assumed
to be innocent. If the individual did not elimi-
nate the poison, toxicity would follow shortly
and the accused would be considered guilty by
the negative outcome.1,2
The term “poison” appeared first in the
English literature around CE 1225 to describe a
potion that was prepared with deadly ingredi-
ents. Since the Middle Age, members of aristoc-
racy used “tasters” to shield themselves from
potential poisoners by having them first sample
their beverages and meals before consuming
themselves. Interestingly, the concept of making
a “toast” arose from a common fear of
I. General concepts
FIGURE 1.1 Commemorative to Paracelsus, University
of Ferrara, Italy. In this University, the great scientist
Theophrastus Bombastus von Hohenheim Paracelsus
obtained a degree in Medicine. Initiator of a new system in
therapeutics. Master of the modern medical sciences.
Naturalist philosopher of Europe. Pioneer of Toxicology.
poisoning. It was believed that if all present
would drink from the same container at the
same time, it would likely be devoid of any
deadly poison. Obviously, a martyr (person
who will die for a cause) could make this strat-
egy less protective.
During the Italian Renaissance, Paracelsus
(1493 1541) at the University of Ferrara in Italy
described a number of principles of human toxi-
cology (see Fig. 1.1). The most well known is
the prominent role of the dose of the substance
in toxicity, reported as No substances are safe, all
substances are poisonous. The major parameter of
toxicity is the dose. However, Paracelsus’ ideol-
ogy should not be restricted to this major princi-
ple. His work led to the description of some
types of toxicants as xenobiotics (toxic sub-
stances originating from outside of the human
body) and to the field of organ toxicology.
In the mid-17th century, Bernardino
Ramazzini (1633 1714) first developed the
area of occupational medicine. In 1700 he wrote
De Morbis Artificum Diatriba (diseases of work-
ers), the first comprehensive text discussing
the relationship between disease and work-
place hazards. Ramazzini described diseases
associated with 54 occupations, including sol-
vent poisoning in painters, mercury poisoning
 1.1 A brief history of toxicology
in mirror makers, and pulmonary diseases in
miners. Around 1775, Sir Percivall Pott uncov-
ered the association between workplace expo-
sures and cancer, when he reported a high
incidence of scrotal cancer in English chimney
sweeps, whose occupation was associated with
direct and chronic exposure to incomplete
combustion products such as complex polycy-
clic aromatic hydrocarbons.
About one century later, the French physician
Bonaventure Orfila (1787 1853) highlighted the
role of toxicology as a distinct discipline sepa-
rated from clinical medicine and pharmacology.
His treatise Traité des Poisons (1814) is regarded
as the foundation of experimental and forensic toxi-
cology, promoting the use of chemical analysis
and autopsy for medicolegal purposes. The
French physician Claude Bernard (1813 78) was
instrumental in discovering the mechanism of
toxicity of carbon monoxide through its binding
to hemoglobin. He also provided the first com-
pelling evidence for a synapse between a motor
neuron and the muscle cell with which it com-
municates. Interestingly, much of Bernard’s
work in this context relied on the effects of one
of the arrow poisons, curare. He promoted
experimental studies in physiology to assess the
accuracy of hypotheses regarding mechanism of
toxicity and advised the use of poisons to study
organ function, summarized in his aphorism:
“The poison is for the physiologist like the scal-
pel is for the surgeon.”
While one can identify through literature
when chemicals were first being used for poi-
sonings, it is more difficult to determine a time
when people first started using substances for
recreational purposes. It is known however that
marijuana (Cannabis sp.) has been used for mil-
lennia. Many natural plants, herbs, and seeds
contain psychoactive substances which have
been used in traditional medicines. Written
communication did not start in China until the
1700s, but it is suggested that the Chinese have
been using herbal medicines for likely thou-
sands of years. In Europe in the 16th century,
Paracelsus was promoting the medical use of
I. General concepts
5
opium. In the 17th century, the English physi-
cian Thomas Sydenham proposed a formulation
of opium tincture for various purposes.
Alice Hamilton (1869 1970) was first to
highlight occupational toxicology. By living and
working in a working class neighborhood in
Chicago, she identified “dangerous trades”
including those working with rubber, dyes,
lead, enamelware, copper, mercury, and explo-
sives, documenting the different types of disor-
ders. Her work on lead intoxication was one of
the first that focused on gender differences in
response to toxicants.
The awareness of toxicological hazards to
which the general population may be exposed
is a relatively recent phenomenon. The estab-
lishment of regulatory authorities appeared
only very recently. Interestingly, in France, a
progressive and continuing decrease in
attempted murders using poisonous sub-
stances was associated with increasing legal
freedom to divorce starting in the late 18th
century. The US Pure Food and Drug Act of
1906 was the first federal legislative antipoi-
soning regulatory initiative.1 The Federal
Caustic Poison Act of 1927 was the first fed-
eral legislation to specifically address house-
hold poisonings. In fact, the US Food and
Drug Administration was born out of a major
drug-related poisoning disaster. In the ear-
ly mid 1930s, sulfamides were developed as
potent antimicrobial agents. Unfortunately,
the antimicrobials were given intravenously
in a diethylene glycol solvent, leading to the
deaths of hundreds of patients from acute
renal failure. After this tragedy, the policies
that required safety testing of new drugs
before marketing were developed and imple-
mented. Nowadays, in addition to therapeu-
tics and drugs of abuse, environmental
contaminants, and ecotoxicology are major
concerns, and governmental agencies are
addressing to change large-scale activities.
The development of Poison Control Centers in
the mid-20th century was also a major step
worldwide for vigilant tracking of human
6 1. History and basic concepts of toxicology
responses to xenobiotics, determining toxic
relationships between exposure to newly
released or currently marketed drugs and
environmental contaminants.
1.2 Important concepts in toxicology
Chemical contamination episodes occur rel-
atively often and can be found in reports by
various news outlets. The public’s perception of
these events plays a major role in how commu-
nities deal with such episodes and how those
communities, interest groups, and local, state,
federal, and international governments may
respond. A basic understanding of the princi-
ples of toxicology is important for communi-
cating the relative nature of chemical hazards
and informing public perception.
1.2.1 The dose response relationship
A key factor for placing in context any intoxi-
cation or chemical contamination event, and a
hallmark of toxicology as a scientific field, is the
concept of the dose response relationship, that is,
the relationship between the incidence or mag-
nitude of a toxic response and the extent of the
chemical exposure. As noted in Section 1.1, the
Swiss physician Theophrastus von Hohenheim
(1493 1541), who took the name Paracelsus
later in life, was an early proponent of the
application of chemistry in medicine and
medical education.3 In the 16th century,
Paracelsus was the first to propose that a
predictable relationship exists between the
extent of exposure to a substance and its relative
therapeutic or toxic effect. His quote dosis sola
facit venenum (dose alone makes the poison) is
widely paraphrased. Because of the paramount
importance of the dose response relationship
in chemical toxicity, Paracelsus is commonly
recognized as the father of toxicology.4
Toxicity can be defined as the inherent capac-
ity of a chemical to do harm to a living
I. General concepts
organism. Hazard is defined as the probability
or practical certainty that an adverse effect
(harm) will occur when a chemical is used under
stated conditions (amount, dose, concentration,
exposure, duration of exposure, use of personal
protective equipment, etc.). In contrast, safety is
the practical certainty that toxicity will not occur
when a chemical is used under defined condi-
tions. The hazard/safety associated with the
use of any chemical therefore depends not only
on its inherent chemical properties, but also on
the likelihood (and if so the extent) of exposure
when the chemical is used under defined con-
ditions. An important corollary of Paracelsus’
centuries-old concept is that while all chemicals
can elicit toxicity, any chemical can be used
safely if its toxic potential is recognized and the
exposures are effectively controlled.
Exposures can be considered in a number of
ways. They can be based on the amount of
chemical in the ambient environment, on the
amount of chemical absorbed into the organ-
ism, or most importantly on the amount of
chemical that reaches receptors within an
organism that initiate a toxic response. While it
is appreciated that the magnitude of a toxic
response is related to the concentration or dose
of the toxicant, what is critical is the concentra-
tion of the chemical at the receptor site, with
the toxicant receptor interaction constituting a
molecular initiating event that progresses
through key events to an ultimate toxic
response. In essence, a toxicant must interact
with a receptor on/in a cell or tissue to initiate
toxicity. Theoretical and practical implications
of the toxicant receptor interactions continue
to impact how chemicals are evaluated and
regulated for protecting public health and the
environment.4 The frequency and duration,
when repeated exposures occur, are also vital
in the expression of dose-related toxicity.
All chemicals have the capacity to elicit toxic
responses. It is therefore important to consider
a chemical’s toxicity in context with other sub-
stances. The most recognized endpoint in toxi-
cology for comparing substances is historically

the lethal dose 50 (LD50), that is, a statistically
determined dose of a chemical that leads to
death in 50% of a group/population of
exposed organisms. The standard LD50
approach has been progressively replaced in
many areas by assessment with other methods
such as estimating maximum tolerated dose
(MTD) approaches generally requiring less ani-
mals to derive an estimate of acute lethality.
In ecological studies, the environmental
medium is typically used for exposure, with
those exposures being quantified by the sub-
stance concentration within the medium. Thus
toxicity is often expressed as the concentration in
the medium that kills 50% of the exposed popu-
lation, that is, the LC50. It is important to differ-
entiate between concentration and dose, since
the former does not measure internal (target/
receptor site) content of the chemical but only
measures the chemical’s concentration in the
medium. Concentration is also generally used to
characterize in vitro and other exposures, for
example, in inhalation toxicity studies.
Knowledge of doses or concentrations of a
chemical that either do or do not elicit toxicity
is essential in characterizing that chemical’s rel-
ative potency. There are two major types of
dose response or concentration response
relationships, that is, those which exhibit a
threshold and those which do not. Fig. 1.2 pro-
vides examples of both (data in these
100
(A) Threshold
Percent response
80
60
40
Chem X
20
0
0.01 0.1 1 10
Dose (mg/kg/day)
FIGURE 1.2 Basic types of dose response relationships. A threshold (A) and no threshold (B) dose response rela-
tionship is shown. The threshold dose response relationship has been the cornerstone for regulating noncarcinogens while
the no threshold dose response relationship is generally considered in estimating risk for genotoxic carcinogens.
1.2 Important concepts in toxicology 7
figures are not from any real study but are
merely for example purposes). In Fig. 1.2A,
both chemical X and chemical Y elicit a dose-
related increase in toxicity. With lower expo-
sures (0.03 mg/kg/day for chemical X and
0.03 2 1 mg/kg/day for chemical Y), no inci-
dence of the response is noted. As the dose
increases, however, the percent of individuals
showing toxicity also increases. Note that the
dose or concentration in dose response rela-
tionships is typically shown on a semilog scale
and dose response relationships often show
an “S-shaped” curve similar to chemical X in
Fig. 1.2A. The data portrayed in Fig. 1.2A pro-
vide an example of a threshold dose response
relationship. In essence, while lower doses do
not elicit toxicity, at some “threshold” level of
exposure, a toxic response is noted (in this case
in a proportion of individuals) which then
increases in incidence with higher doses (or
increases in magnitude when the degree or
extent of a response is measured). The concept
that a threshold exists in exposures below
which no toxic response occurs has been the
foundation for chemical risk assessments and
regulatory decision-making for decades. It is
assumed that if levels of exposure below the
threshold do not elicit toxicity, then regulat-
ing/managing chemicals such that exposures
fall below the threshold will maintain public
safety and environmental health.
20
(B) No threshold
15
Chem Y
10
5
0
0.01 0.1 1 10
Dose (mg/kg/day)
I. General concepts
8 1. History and basic concepts of toxicology
Several conclusions can be extracted from
threshold dose response data. First, when
comparing chemicals X and Y (Fig. 1.2A), one
can see that chemical X is more potent, that is,
it elicits toxicity at lower levels of exposure. If
you draw a line at the 50% response level, you
can graphically estimate the dose of chemical X
that would elicit toxicity in 50% of the indivi-
duals (around 1 mg/kg/day). Similarly, the
dose of chemical Y that elicits toxicity in 50%
of the individuals can be estimated at about
10 mg/kg/day. Thus you can consider based
on the toxic response being measured that
chemical X is roughly 10 times more potent
than Chemical Y. Second, both chemicals can
elicit the toxic response in essentially all of the
individuals exposed, as long as the dose is
high enough. Third, these types of data allow
you to operationally define a “no effect” or no
observed adverse effect level (NOAEL). For a
given dataset (in the case of Fig. 1.2A, doses of
0.01, 0.03, 0.1, 0.3, 1, and 3 mg/kg/day), the
highest dose in the study associated with no
toxicity is defined as the NOAEL. For chemical
X, the NOAEL would thus be defined as
0.03 mg/kg/day, while the NOAEL for chemi-
cal Y would be 1 mg/kg/day. Chemical-
specific NOAEL values derived primarily from
experimental studies on chemicals that exhibit
threshold dose response relationships, along
with considerations of uncertainty based on
extrapolating results from animal studies to
humans, and variability among different peo-
ple, have historically been essential in estimat-
ing safe levels of exposures and protecting
public health.
In contrast, Fig. 1.2B shows the second major
type of dose response relationship, that is, one
in which no apparent threshold is exhibited. In
this case, as before, increasing dose leads to an
increased proportion of individuals exhibiting
toxicity, but there is no clear-cut “break”
between exposures that do or do not elicit tox-
icity. Genotoxic carcinogens often exhibit non-
threshold dose response relationships. Even
I. General concepts
very low exposures may elicit some incidence
of toxicity. The process for evaluating risk of
chemicals that do not show a threshold is con-
ducted by a different paradigm compared to
those that show thresholds, based at least
partly on the uncertainty of responses at very
low levels of exposure, which are very difficult
to study in experimental models for a variety
of reasons.
Two substances with exceedingly different
toxic potencies can be used to illustrate how
both the chemical’s inherent properties and the
type of exposure interact to influence whether
or not toxicity occurs. Let us first consider bot-
ulinum toxins. These toxins exist as a family of
eight distinct polypeptides (referred to as types
A H) that are produced by the bacterium,
Clostridium botulinum and/or related microor-
ganisms. Severe muscle paralysis is a poten-
tially lethal response to botulinum toxin
exposure. Nerve cells in complex organisms
communicate with other neurons (and other
cell types, e.g., muscle cells) by releasing spe-
cific neurotransmitters which interact directly
with the target cell (see Chapter 6: Disruption
of extracellular signaling and Chapter 20:
Nervous system). All subtypes of botulinum
toxin act by binding to specific proteins within
the nerve terminal to block neurotransmitter
release and thereby disrupt cellular communi-
cation.5 Neurons that supply or innervate skele-
tal muscles release the neurotransmitter
acetylcholine to cause that muscle cell to con-
tract. A botulinum toxin acting on those neu-
rons will therefore block acetylcholine release,
leading to reduced muscle contractions and
potentially paralysis of the affected muscles.
Botulinum toxin A is considered the most
toxic substance known to man, with reported
LD50 values in the low ng/kg range (i.e., an
amount approximately 100 trillion-fold lower
than the weight of a human).6 It would there-
fore make inherent sense to avoid any exposure
to these exceptionally toxic substances. As is
well known however, botulinum toxins have
 1.2 Important concepts in toxicology
been developed as therapeutic agents to reduce
muscle contractions in disorders that are asso-
ciated with excessive muscle contractions.
Moreover, therapeutic applications for botuli-
num toxins to treat other medical conditions
continue to be pursued.7 Thus the most potent
toxic substances in the world can be used effec-
tively and safely, but only by understanding
their inherent toxic potential and by strictly
controlling exposure.
On the other end of the spectrum from botu-
linum toxins is water, an absolutely essential
substance for all living organisms on Earth.
One would assume that any hazard associated
with systemic water exposure would be mini-
mal, and that is in fact, generally the case.
Water is not without an inherent capacity to do
harm, however. A reduction in blood sodium
levels (hyponatremia) by excess water con-
sumption can increase fluid uptake due to dis-
ruption of the sodium concentration gradient
between blood and the organs/tissues. If
excess fluid accumulates in the brain, swelling
of the tissue will lead to increased pressure
(due to the rigid, bony skull) and damaged/
dead cells within the brain, potentially leading
to severe effects including seizures, uncon-
sciousness, respiratory arrest, and death.
Excessive water consumption has been
reported in attempts to dilute a person’s urine
before a drug test, leading to serious complica-
tions.8 Although infrequent, cases of child
abuse have been reported involving forced
water consumption and subsequent water
intoxication.9 Some case studies report exces-
sive water intake and water intoxication in
marathon runners after a race. What is clear
from these examples is that although water is
absolutely essential for all living organisms,
excessive intake (as with any substance) can
lead to toxicity. Botulinum toxins and water
therefore provide evidence that on the one
hand all chemicals are toxic, and on the other
even the most toxic substances can be used
safely.
I. General concepts
9
100
U-shaped
80
60
40
20
0
0.1 1 10
Dose (g/kg/day)
FIGURE 1.3 A U-shaped dose response relationship.
This type of relationship is exhibited by essential
substances.
The extreme case of water intoxication pro-
vides the opportunity to consider a third type
of dose response relationship, one that is
exhibited by substances which are essential for
the organism. Fig. 1.3 shows a hypothetical
dose response relationship for water intoxica-
tion. Very low water is associated with dehy-
dration, with fluid levels insufficient to
maintain homeostasis, tissue hydration, ionic
balances, and sufficient blood volume, leading
to some form(s) of toxicity. Within a certain
range of higher exposures, fluid homeostasis is
maintained and no adverse effects are noted.
With excessive (much higher) exposures how-
ever, adverse effects occur which can be life-
threatening.
Other types of dose response relationships
can be observed. For example, some endo-
crine disrupting chemicals (see Chapter 17:
Organ system effects: endocrine toxicology)
have been reported to elicit toxicity at low
levels of exposure, but not at higher levels.
Some chemicals can elicit beneficial effects
at low levels of exposure, but adverse effects
with higher exposures. These other nonmono-
tonic dose response relationships may be
based on adaptive changes (e.g., receptor
upregulation or downregulation) or feedback
loops that occur at one end of the dosing spec-
trum, but not at the other.
10 1. History and basic concepts of toxicology
Botulinum toxin(s) as an acute toxicant is in
a class of its own based on acute lethality (LD50
approximately 1 ng/kg). Ethyl alcohol (etha-
nol) is a common substance that is well known
for its adverse effects with acute and long-term
exposures. The adverse health effects of
chronic alcohol consumption take a huge toll
on many individuals, families, and society in
general. Although it is possible to elicit severe
toxicity with high acute ethanol exposures
(and reports of hazing-related deaths from
alcohol-related toxicity continue as evidence),
its potency as an acute toxicant is actually very
low (LD50 on the order of 5 10 g/kg, or over
a billion times less potent than botulinum
toxin). Table 1.1 shows a categorical ranking of
acute lethality that can be used as a framework
for comparing relative acute potencies. Note
that botulinum toxin would be an outlier in
this table, needing its own category (e.g.,
super-super toxic).
Testing for toxicity is an essential component
in the process of developing new drugs. Any
new drug candidate must have its potential tox-
icity fully characterized before it is approved
and introduced into the market. In preclinical
or nonclinical drug testing, a number of meth-
ods are used to measure the desirable drug
effects (i.e., its efficacy) as well as identify types
of toxic responses that may occur with its use.
The LD50, MTD, or NOAEL for a drug candi-
date can all be quantitative indicators for its rel-
ative potential to cause harm. When compared
TABLE 1.1 Relative categories for
comparing acute lethality among chemicals.
LD50 Category
. 5 g/kg Essentially nontoxic
0.5 5 g/kg Slightly toxic
50 500 mg/kg Moderately toxic
5 50 mg/kg Very toxic
, 5 mg/kg Extremely toxic
I. General concepts
to a quantitative measure of its efficacy, the
drug’s potency at causing desirable versus
undesirable effects can be estimated as some
form of a therapeutic index (TI). A common way
to calculate TI is to divide the chemical’s LD50
by the dose of the drug that elicits a therapeutic
response in 50% of the population, that is, the
effective dose 50 (ED50): TI 5 LD50/ED50.
If we consider hypothetical dose-related
data generated in a drug testing laboratory, we
can further clarify the concepts of potency and
efficacy. Dose-related studies to evaluate rela-
tive toxicity and efficacy can provide drug
candidate-specific information important in
selecting candidates for further development.
One can see that high TI values for a given
drug candidate would be advantageous over
other candidates with lower TI values.
A relatively high acute LD50 or other indica-
tors of acute toxicity means that the chemical
in question has relatively low potency at eliciting
acute toxicity. It must be stressed however that
low toxicity with acute exposures does not
mean that the chemical would be relatively
safe with long-term exposures. Vinyl chloride,
one of the highest production volume chemi-
cals in the world, is extensively used in the
production of polyvinylchloride-based plastics.
In animal studies, vinyl chloride is slightly
toxic based on the general acute toxicity scale
shown in Table 1.1 (i.e., it has an LD50 in rats
with oral dosing of about 4 g/kg). With long-
term exposures, however vinyl chloride can
elicit liver cancer in animals and humans.10 In
a similar situation, toxic responses in ecological
settings are rarely acute and tend to be charac-
terized as reductions in growth, reproduction,
and development. Consequently, such suble-
thal responses with environmental contamina-
tion tend to have more ecological relevance
with regard to population changes than with
the fate of individual organisms.
Another example of a chemical with low
acute toxicity but which elicits chronic toxicity is
the organophosphorus chemical, tri-ortho-cresyl
 1.2 Important concepts in toxicology
phosphate (TOCP). TOCP is one isomer of a mix-
ture of tri-cresyl phosphate (TCP), used for dec-
ades as a lubricant and plasticizer. The acute
LD50 for TOCP is .1 g/kg. This “slightly toxic”
chemical based on acute lethality can lead how-
ever to irreversible damage in the nervous sys-
tem. Interestingly, the other two isomers (meta
and para) in the TCP mixture also have low
acute toxicity potential, but they cannot elicit the
long-term neurological changes associated with
exposure to the ortho isomer. Moreover, in con-
trast to vinyl chloride where repeated, long-
term exposures are necessary to elicit chronic
toxicity (liver cancer), the chronic effects of
TOCP can occur following a single exposure.
Fortunately, the ortho isomer is now removed
from TCP in use today. It should be noted that
some studies suggest that TCP (free of the ortho
isomer) may contribute to another condition
referred as “aerotoxic syndrome.” As a lubricant
component in jet engines, TCP can leach into the
aircraft cabin when an engine seal is defective,
thereby exposing travelers and flight personnel
to TCP vapors. A causal relationship between
TCP and any “aerotoxic” syndrome has not
been firmly established however.
1.2.2 Time as a factor in the expression
of toxicity
The amount of time between exposure to a
chemical and a toxic response is important in
characterizing chemical toxicity. In acute poi-
soning, the interaction between time of expo-
sure and dose on toxic outcome was studied
by Fritz Haber, who was awarded the Nobel
Prize for inventing the method to synthesize
ammonia from nitrogen in ambient air. Haber
was also the scientific adviser of the German
Kaiser during World War I (WWI). Haber
showed that the cumulative lethal effect of a
toxic gas depended on the atmospheric concen-
tration multiplied by the duration of exposure.
I. General concepts
11
These results were unfortunately used in the
proposal to use chlorine gas as a chemical
weapon in WWI. The study of the relationship
between concentration and exposure time with
acute toxicity of gases continues today.
Basic categories of toxic responses relative to
the time of exposure include acute versus
chronic toxicity, and immediate versus delayed
toxicity. Acute toxicity is generally character-
ized by a rapid course of overt signs, generally
occurring soon after the time of exposure. The
harm from this type of toxic response is gener-
ally reversible, if the exposure is low enough
for survival. Acute toxicity is also generally
much easier to associate with a specific toxi-
cant due to the relatively short amount of time
for other factors to confound the interpretation
of cause-and-effect.
An example of an acute intoxication would
be the expression of neurological, muscular,
and respiratory effects that occur shortly after
acute exposure to an organophosphorus nerve
agent such as sarin. Unfortunately, there are
recent real-world examples of the type of acute
toxicity that can be elicited by organophospho-
rus nerve agents.11 13 The signs and symptoms
of nerve agent intoxication, along with verifica-
tion of chemical residues in environmental
media or biomarkers of exposure in affected
individuals in these cases, helped confirm a
cause effect relationship.
In contrast, chronic toxicity, either from an
acute intoxication or from repeated lower level
exposures, is often associated with an accumu-
lation of damage over time. Chronic toxicity is
generally more insidious in nature than acute
toxicity, being more difficult to associate with a
particular substance, and often characterized
by irreversible damage. For example, the asso-
ciation between long-term exposure to tobacco
smoke and chronic health consequences was
only firmly established after decades of
research (and unfortunately, facilitated by the
large number of individuals affected).
12 1. History and basic concepts of toxicology
1.2.3 Time as a factor in exposures
As stressed earlier, hazard is a product of
both the intrinsic properties of a substance and
the degree or extent of exposure(s). As with
the role of time in the expression of toxicity,
time is also important in characterizing expo-
sures. In mammalian toxicity testing, acute
exposures are either single or a few multiple
exposures, all occurring within a short time
period (up to 24 hours). Acute oral toxicity is
most often based on studies with only single
exposures. In some cases, for example, studies
related to pesticide exposures in the diet, acute
exposures can be throughout a given day (such
as to model three meals). Subacute exposures
are repeated exposures that occur roughly
within a month. In mammalian toxicity testing,
subacute exposures are often daily exposures
occurring for 14 continuous days. Subchronic
exposures are generally repeated, daily expo-
sures occurring for 1 3 months. A subchronic
dosing study in rodents typically lasts for 90
days. Finally, chronic exposures are repeated
exposures that occur for more than 3 months,
typically 6 24 months. Keep in mind that a
chemical may elicit very different responses
when lower exposures occur over longer peri-
ods, compared to responses following higher,
short-term exposures. In the ecological testing
context, acute exposures are generally
48 96 hours in duration, and chronic expo-
sures cover an entire life or reproductive cycle.
For example, chronic invertebrate bioassays
can be as short as 10 days, but tests in fish can
last up to 28 days, depending on the species.
1.2.4 Local versus systemic toxicity
The site of a toxic response is also an impor-
tant characteristic in defining toxic potential.
Local toxicity, that is a toxic response that
occurs at the site of chemical contact, is very
important in occupational settings. The major-
ity of intoxications in the workplace involve
I. General concepts
dermal reactions, occurring at the site of chem-
ical exposure on the skin. For example, acid
spills can lead to caustic damage to the affected
area of the skin, with relatively few systemic
effects. Similarly, strong bases such as cationic
detergents can damage the skin, buccal cavity,
esophagus, or other areas of the gastrointesti-
nal tract with relatively little systemic toxicity.
Locally acting toxicants harm the tissues that
are in direct contact (see Chapter 23:
Toxicology in the home, and Chapter 24:
Toxicology in the workplace).
While localized responses can be life-
threatening, most severe intoxications involve
absorption and systemic toxicity. Chemicals
which are absorbed into the circulation can
have far-reaching effects in tissues distant from
the site of chemical contact. Organisms within
aquatic ecosystems can undergo local toxicity
at the site of absorption (i.e., gills), but gener-
ally systemic exposure is largely dependent on
the solubility of the chemical in the water.
Chemicals which are poorly soluble in water
can still undergo uptake through dietary expo-
sures, potentially leading to bioaccumulation.
Depending on the physical nature of the
chemical, it may gain access into the circulation
by which it can be distributed throughout the
body. Once absorbed, a chemical can be modi-
fied by biotransformation reactions that alter
the structure of the toxicant. Either the “par-
ent” compound or a metabolite may interact
with target macromolecules within the body to
initiate a toxic response. Ultimately, the parent
compound and/or its metabolites are elimi-
nated by excretory pathways. If a chemical is
poorly metabolized and accumulates within an
organism, the likelihood of adverse effects is
enhanced, as is the ecological transfer to preda-
tory organisms that feed upon the contami-
nated organism. This process is referred to as
biomagnification and occurs for several well-
known persistent environmental contaminants
including DDT (dichlorodiphenyltrichlor-
oethane) and methyl mercury.
 1.2 Important concepts in toxicology 13

1.2.5 Interactions of 4, then one could conclude additivity. A sim-

The great majority of information known
about chemical toxicity has been derived from
experimental studies of individual chemicals.
In contrast, individuals and communities/
populations of individuals are typically
exposed to a mixture of chemicals at any given
time. These chemicals can come from the ambi-
ent environment or from dietary, occupational,
or pharmaceutical sources. Understanding the
toxicity of any chemical is complex and
requires extensive investigation: the study of
mixtures of chemicals can be markedly more
complex. While a considerable amount of
information on the mechanism of toxicity, toxi-
cokinetics, biotransformation, etc., is known for
a relatively large number of chemicals, much
less is known about the toxicity of mixtures of
chemicals.
A starting point for studying mixtures is
with the interaction between two chemicals.14
Fig. 1.4 shows four basic types of interactions
that can occur between two chemicals: additiv-
ity, antagonism, synergism, and potentiation. To
illustrate these types of interactions, let us con-
sider two chemicals referred to as A and B. For
measuring toxicity, we will use a ranked grad-
ing scale for recording the severity of response
from 0 (i.e., no signs of toxicity) to 6 (lethality).
If chemical A alone elicits an average response
of 2 and chemical B also elicits a score of 2, and
when given together they yield a median score
ple description of additivity is:
ToxicityBoth 5 ToxicityA 1 ToxicityB
With antagonism, the toxicity of one chemical
is reduced or eliminated by the other. To use
our earlier example of toxicity ranking, if
chemical A elicits a median response of 5 while
chemical B elicits no response (i.e., median
score 0), but both chemicals given together
yield a median score of 1, then one can con-
clude that chemical B was an antagonist of
chemical A. A simple mathematical description
for antagonism is:
ToxicityBoth , ToxicityA 1 ToxicityB
Synergism occurs when two chemicals elicit
some degree of a toxic response but when
given together, the response is much greater
than expected based on the toxicity of the indi-
vidual compounds. For example, if both chemi-
cal A and chemical B elicit a median response
of 1 but when given together they elicit a
median score of 6, synergism has occurred.
Potentiation is similar to synergism in that the
toxic response to a chemical is amplified by
another, but in this case, the amplifying chemi-
cal does not elicit the toxic response when
given alone. Based on our scale, this would be
exemplified by a median score of 3 for chemi-
cal A, a median score of 0 for chemical B, but a
score of 6 when the two chemicals are given in

6 FIGURE 1.4 Basic types of toxicological interactions

between two chemicals. Interactions leading to additiv-
ity, antagonism, synergism, and potentiation are
Toxicity score

illustrated.
4

A
2
B
A+B
0
Additivity Antagonism Synergism Potentiation

I. General concepts
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 ŒUFS AU PLAT.

A pewter or any other metal plate or dish which will bear the fire,
must be used for these. Just melt a slice of butter in it, then put in
some very fresh eggs broken as for poaching; strew a little pepper
and salt on the top of each, and place them over a gentle fire until
the whites are quite set, but keep them free from colour.
This is a very common mode of preparing eggs on the continent;
but there is generally a slight rawness of the surface of the yolks
which is in a measure removed by ladling the boiling butter over
them with a spoon as they are cooking, though a salamander held
above them for a minute would have a better effect. Four or five
minutes will dress them.
Obs.—We hope for an opportunity of inserting further receipts for
dishes of eggs at the end of this volume.
 MILK AND CREAM.

Without possessing a dairy, it is quite possible for families to have

always a sufficient provision of milk and cream for their consumption,
provided there be a clean cool larder or pantry where it can be kept.
It should be taken from persons who can be depended on for
supplying it pure, and if it can be obtained from a dairy near at hand
it will be an advantage, as in the summer it is less easy to preserve it
sweet when it has been conveyed from a distance. It should be
poured at once into well-scalded pans or basins kept exclusively for
it, and placed on a very clean and airy shelf, apart from all the other
contents of the larder. The fresh milk as it comes in should be set at
one end of the shelf, and that for use should be taken from the other,
so that none may become stale from being misplaced or overlooked.
The cream should be removed with a perforated skimmer (or
skimming-dish as it is called in dairy-counties) which has been
dipped into cold water to prevent the cream, when thick, from
adhering to it. Twelve hours in summer, and twenty-four in winter, will
be sufficient time for the milk to stand for “creaming,” though it may
often be kept longer with advantage. Between two and three pints of
really good milk will produce about a quarter of a pint of cream. In
frosty weather the pans for it should be warmed before it is poured
in. If boiled when first brought in, it will remain sweet much longer
than it otherwise would; but it will then be unfit to serve with tea;
though it may be heated afresh and sent to table with coffee; and
used also for puddings, and all other varieties of milk-diet.
 DEVONSHIRE, OR CLOTTED CREAM.

From the mode adopted in Devonshire, and in some other

counties, of scalding the milk in the following manner, the cream
becomes very rich and thick, and is easily converted into excellent
butter. It is strained into large shallow metal pans as soon as it is
brought into the dairy and left for twelve hours at least in summer,
and thirty-six in cold weather. It is then gently carried to a hot plate—
heated by a fire from below—and brought slowly to a quite scalding
heat but without being allowed to boil or even to simmer. When it is
ready to be removed, distinct rings appear on the surface, and small
bubbles of air. It must then be carried carefully back to the dairy, and
may be skimmed in twelve hours afterwards. The cream should be
well drained from the milk—which will be very poor—as this is done.
It may then be converted into excellent butter, merely by beating it
with the hand in a shallow wooden tub, which is, we are informed,
the usual manner of making it in small Devonshire dairies.
 DU LAIT A MADAME.

Boil a quart of new milk, and let it cool sufficiently to allow the
cream to be taken off; then rinse an earthen jar well in every part
with buttermilk, and while the boiled milk is still rather warm, pour it
in and add the cream gently on the top. Let it remain twenty-four
hours, turn it into a deep dish, mix it with pounded sugar, and it will
be ready to serve. This preparation is much eaten abroad during the
summer, and is considered very wholesome. The milk, by the
foregoing process, becomes a very soft curd, slightly, but not at all
unpleasantly, acid in flavour. A cover, or thick folded cloth, should be
placed on the jar after the milk is poured in, and it should be kept in a
moderately warm place. In very sultry weather less time may be
allowed for the milk to stand.
Obs.—We give this and the following receipt from an unpublished
work which we have in progress, being always desirous to make
such information as we possess generally useful as far as we can.
 CURDS AND WHEY.

Rennet is generally prepared for dairy-use by butchers, and kept

in farmhouses hung in the chimney corners, where it will remain
good a long time. It is the inner stomach of the calf, from which the
curd is removed, and which is salted and stretched out to dry on
splinters of wood, or strong wooden skewers. It should be preserved
from dust and smoke (by a paper-bag or other means), and portions
of it cut off as wanted. Soak a small bit in half a teacupful of warm
water, and let it remain in it for an hour or two; then pour into a quart
of warm new milk a dessertspoonful of the rennet-liquor, and keep it
in a warm place until the whey appears separated from the curd, and
looks clear. The smaller the proportion of rennet used, the more soft
and delicate will be the curd. We write these directions from
recollection, having often had the dish thus prepared, but having no
memorandum at this moment of the precise proportions used. Less
than an inch square of the rennet would be sufficient, we think, for a
gallon of milk, if some hours were allowed for it to turn. When rennet-
whey, which is a most valuable beverage in many cases of illness, is
required for an invalid to drink, a bit of the rennet, after being quickly
and slightly rinsed, may be stirred at once into the warm milk, as the
curd becoming hard is then of no consequence. It must be kept
warm until the whey appears and is clear. It may then be strained,
and given to the patient to drink, or allowed to become cold before it
is taken. In feverish complaints it has often the most benign effect.
Devonshire junket is merely a dish or bowl of sweetened curds
and whey, covered with the thick cream of scalded milk, for which
see page 451.
 CHAPTER XXIII.

Sweet Dishes, or Entremets.

Jelly of two colours, with macedoire of fruit.

 TO PREPARE CALF’S FEET STOCK.

The feet are usually sent in from

the butcher’s ready to be
dressed, but as they are sold at
a very much cheaper rate when
the hair has not been cleared
from them, and as they may
then be depended on for
supplying the utmost amount of
nutriment which they contain, it
is often desirable to have them
White and Rose-coloured Jelly.
altogether prepared by the cook.
In former editions of this work
we directed that they should be “dipped into cold water, and
sprinkled with resin in fine powder; then covered with boiling water
and left for a minute or two untouched before they were scraped;”
and this method we had followed with entire success for a long time,
but we afterwards discovered that the resin was not necessary, and
that the feet could be quite as well prepared by mere scalding, or
being laid into water at the point of boiling, and kept in it for a few
minutes by the side of the fire. The hair, as we have already stated in
the first pages of Chapter IX. (Veal), must be very closely scraped
from them with a blunt-edged knife; and the hoofs must be removed
by being struck sharply down against the edge of a strong table or
sink, the leg-bone being held tightly in the hand. The feet must be
afterwards washed delicately clean before they are further used.
When this has been done, divide them at the joint, split the claws,
and take away the fat that is between them. Should the feet be large,
put a gallon of cold water to the four, but from a pint to a quart less if
they be of moderate size or small. Boil them gently down until the
flesh has parted entirely from the bones, and the liquor is reduced
nearly or quite half; strain, and let it stand until cold; remove every
particle of fat from the top before it is used, and be careful not to take
the sediment.
Calf’s feet (large), 4; water, 1 gallon: 6 to 7 hours.
 TO CLARIFY CALF’S FEET STOCK.

Break up a quart of the stock, put it into a clean stewpan with the
whites of five large or of six small eggs, two ounces of sugar, and the
strained juice of a small lemon; place it over a gentle fire, and do not
stir it after the scum begins to form; when it has boiled five or six
minutes, if the liquid part be clear, turn it into a jelly-bag, and pass it
through a second time should it not be perfectly transparent the first.
To consumptive patients, and others requiring restoratives, but
forbidden to take stimulants, the jelly thus prepared is often very
acceptable, and may be taken with impunity, when it would be highly
injurious made with wine. More white of egg is required to clarify it
than when sugar and acid are used in larger quantities, as both of
these assist the process. For blanc-mange omit the lemon-juice, and
mix with the clarified stock an equal proportion of cream (for an
invalid, new milk), with the usual flavouring, and weight of sugar; or
pour the boiling stock very gradually to some finely pounded
almonds, and express it from them as directed for Quince Blamange,
allowing from six to eight ounces to the pint.
Stock, 1 quart; whites of eggs, 5; sugar, 2 oz.; juice, 1 small
lemon: 5 to 8 minutes.
 TO CLARIFY ISINGLASS.

The finely-cut purified isinglass, which is now in general use,

requires no clarifying except for clear jellies: for all other dishes it is
sufficient to dissolve, skim, and pass it through a muslin strainer.
When two ounces are required for a dish, put two and a half into a
delicately clean pan, and pour on it a pint of spring water which has
been gradually mixed with a teaspoonful of beaten white of egg; stir
these thoroughly together, and let them heat slowly by the side of a
gentle fire, but do not allow the isinglass to stick to the pan. When
the scum is well risen, which it will be after two or three minutes’
simmering, clear it off, and continue the skimming until no more
appears; then, should the quantity of liquid be more than is needed,
reduce it by quick boiling to the proper point, strain it through a thin
muslin, and set it by for use: it will be perfectly transparent, and may
be mixed lukewarm with the clear and ready sweetened juice of
various fruits, or used with the necessary proportion of syrup, for
jellies flavoured with choice liqueurs. As the clarifying reduces the
strength of the isinglass—or rather as a portion of it is taken up by
the white of egg—an additional quarter to each ounce must be
allowed for this: if the scum be laid to drain on the back of a fine
sieve which has been wetted with hot water, a little very strong jelly
will drip from it.
Isinglass, 2-1/2 oz.; water, 1 pint; beaten white of egg, 1
teaspoonful.
Obs.—At many Italian warehouses a preparation is now sold
under the name of isinglass, which appears to us to be highly
purified gelatine of some other kind. It is converted without trouble
into a very transparent jelly, is free from flavour, and is less
expensive than the genuine Russian isinglass; but when taken for
any length of time as a restorative, its different nature becomes
perceptible. It answers well for the table occasionally; but it is not
suited to invalids.
 SPINACH GREEN, FOR COLOURING SWEET DISHES,
CONFECTIONARY, OR SOUPS.

Pound quite to a pulp, in a marble or Wedgwood mortar, a handful

or two of young freshly-gathered spinach, then throw it into a hair
sieve, and press through all the juice which can be obtained from it;
pour this into a clean white jar, and place it in a pan of water that is
at the point of boiling, and which must be allowed only to just simmer
afterwards; in three or four minutes the juice will be poached or set:
take it then gently with a spoon, and lay it upon the back of a fine
sieve to drain. If wanted for immediate use, merely mix it in the
mortar with some finely-powdered sugar;[158] but if to be kept as a
store, pound it with as much as will render the whole tolerably dry,
boil it to candy-height over a very clear fire, pour it out in cakes, and
keep them in a tin box or canister. For this last preparation consult
the receipt for orange-flower candy.
158. For soup, dilute it first with a little of the boiling stock, and stir it to the
remainder.
 PREPARED APPLE OR QUINCE JUICE.

Pour into a clean earthen pan two quarts of spring water, and
throw into it as quickly as they can be pared, quartered, and
weighed, four pounds of nonsuches, pearmains, Ripstone pippins, or
any other good boiling apples of fine flavour. When all are done,
stew them gently until they are well broken, but not reduced quite to
pulp; turn them into a jelly-bag, or strain the juice from them without
pressure through a closely-woven cloth, which should be gathered
over the fruit, and tied, and suspended above a deep pan until the
juice ceases to drop from it: this, if not very clear, must be rendered
so before it is used for syrup or jelly, but for all other purposes once
straining it will be sufficient. Quinces are prepared in the same way,
and with the same proportions of fruit and water, but they must not
be too long boiled, or the juice will become red. We have found it
answer well to have them simmered until they are perfectly tender,
and then to leave them with their liquor in a bowl until the following
day, when the juice will be rich and clear. They should be thrown into
the water very quickly after they are pared and weighed, as the air
will soon discolour them. The juice will form a jelly much more easily
if the cores and pips be left in the fruit.
Water, 2 quarts; apples or quinces, 4 lbs.
 COCOA-NUT FLAVOURED MILK.

(For sweet dishes, &c.)

Pare the dark outer rind from a very fresh nut, and grate it on a
fine and exceedingly clean grater, to every three ounces pour a quart
of new milk, and simmer them very softly for three quarters of an
hour, or more, that a full flavour of the nut may be imparted to the
milk without its being much reduced: strain it through a fine sieve, or
cloth, with sufficient pressure to leave the nut almost dry: it may then
be used for blanc-mange, custards, rice, and other puddings, light
cakes and bread.
To each quart new milk, 3 oz. grated cocoa-nut: 3/4 to 1 hour.
Obs.—The milk of the nut when perfectly sweet and good, may be
added to the other with advantage. To obtain it, bore one end of the
shell with a gimlet, and catch the liquid in a cup; and to extricate the
kernel, break the shell with a hammer; this is better than sawing it
asunder.
 COMPÔTES OF FRUIT.

(Or Fruit stewed in Syrup.)

We would especially recommend these delicate and very
agreeable preparations for trial to such of our readers as may be
unacquainted with them, as well as to those who may have a
distaste to the common “stewed fruit” of English cookery. If well
made they are peculiarly delicious and refreshing, preserving the
pure flavour of the fruit of which they are composed; while its acidity
is much softened by the small quantity of water added to form the
syrup in which it is boiled. They are also more economical than tarts
or puddings, and infinitely more wholesome. In the second course
pastry-crust can always be served with them, if desired, in the form
of ready baked leaves, round cakes, or any more fanciful shapes; or
a border of these may be fastened with a little white of egg and flour
round the edge of the dish in which the compôte is served; but rice,
or macaroni simply boiled, or a very plain pudding is a more usual
accompaniment.
Compôtes will remain good for two or three days in a cool store-
room, or somewhat longer, if gently boiled up for an instant a second
time; but they contain generally too small a proportion of sugar to
preserve them from mould or fermentation for many days. The syrup
should be enriched with a larger quantity when they are intended for
the desserts of formal dinners, as it will increase the transparency of
the fruit: the juice is always beautifully clear when the compôtes are
carefully prepared. They should be served in glass dishes, or in
compôtiers, which are of a form adapted to them.
Compôte of spring fruit.—(Rhubarb). Take a pound of the stalks
after they are pared, and cut them into short lengths; have ready a
quarter of a pint of water boiled gently for ten minutes with five
ounces of sugar, or with six should the fruit be very acid; put it in,
and simmer it for about ten minutes. Some kinds will be tender in
rather less time, some will require more.
 Obs.—Good sugar in lumps should be used for these dishes.
Lisbon sugar will answer for them very well on ordinary occasions,
but that which is refined will render them much more delicate.
Compôte of green currants.—Spring water, half-pint; sugar, five
ounces; boiled together ten minutes. One pint of green currants
stripped from the stalks; simmered five minutes.
Compôte of green gooseberries.—This is an excellent compôte if
made with fine sugar, and very good with any kind. Break five
ounces into small lumps and pour on them half a pint of water; boil
these gently for ten minutes, and clear off all the scum; then add to
them a pint of fresh gooseberries freed from the tops and stalks,
washed, and well drained. Simmer them gently from eight to ten
minutes, and serve them hot or cold. Increase the quantity for a large
dish.
Compôte of green apricots.—Wipe the down from a pound of quite
young apricots, and stew them very gently for nearly twenty minutes
in syrup made with eight ounces of sugar and three-quarters of a pint
of water, boiled together the usual time.
Compôte of red currants.—A quarter of a pint of water and five
ounces of sugar: ten minutes. One pint of currants freed from the
stalks to be just simmered in the syrup from five to seven minutes.
This receipt will serve equally for raspberries, or for a compôte of the
two fruits mixed together. Either of them will be found an admirable
accompaniment to a pudding of batter, custard, bread, or ground
rice, and also to various other kinds of puddings, as well as to whole
rice plainly boiled.
Compôte of Kentish or Flemish cherries.—Simmer five ounces of
sugar with half a pint of water for ten minutes; throw into the syrup a
pound of cherries weighed after they are stalked, and let them stew
gently for twenty minutes: it is a great improvement to stone the fruit,
but a larger quantity will then be required for a dish.
Compôte of Morella cherries.—Boil together for fifteen minutes, six
ounces of sugar with half a pint of water; add a pound and a quarter
of ripe Morella cherries, and simmer them very softly from five to
seven minutes: this is a delicious compôte. A larger proportion of
sugar will often be required for it, as the fruit is very acid in some
seasons, and when it is not fully ripe.
Compôte of damsons.—Four ounces of sugar and half a pint of
water to be boiled for ten minutes; one pound of damsons to be
added, and simmered gently from ten to twelve minutes.
Compôte of the green magnum-bonum or Mogul plum.—The
green Mogul plums are often brought abundantly into the market
when the fruit is thinned from the trees, and they make admirable
tarts or compôtes, possessing the fine slight bitter flavour of the
unripe apricot, to which they are quite equal. Measure a pint of the
plums without their stalks, and wash them very clean; then throw
them into a syrup made with seven ounces of sugar in lumps, and
half a pint of water, boiled together for eight or ten minutes. Give the
plums one quick boil, and then let them stew quite softly for about
five minutes, or until they are tender, which occasionally will be in
less time even. Take off the scum, and serve the compôte hot or
cold.
Compôte of the magnum-bonum, or other large plums.—Boil six
ounces of sugar with half a pint of water the usual time; take the
stalks from a pound of plums, and simmer them very softly for twenty
minutes. Increase the proportion of sugar if needed, and regulate the
time as may be necessary for the different varieties of fruit.
Compôte of bullaces.—The large, or shepherds’ bullace, is very
good stewed, but will require a considerable portion of sugar to
render it palatable, unless it be quite ripe. Make a syrup with half a
pound of sugar, and three-quarters of a pint of water, and boil in it
gently from fifteen to twenty minutes, a pint and a half of the bullaces
freed from their stalks.
Compôte of Siberian crabs.—To three-quarters of a pint of water
add six ounces of fine sugar, boil them for ten or twelve minutes, and
skim them well. Add a pound and a half of Siberian crabs without
their stalks, and keep them just at the point of boiling for twenty
minutes; they will then become tender without bursting. A few strips
of lemon-rind and a little of the juice are sometimes added to this
compôte.
 Obs.—In a dry warm summer, when fruit ripens freely, and is rich
in quality, the proportion of sugar directed for these compôtes would
generally be found sufficient; but in a cold or wet season it would
certainly, in many instances, require to be increased. The present
slight difference in the cost of sugars, renders it a poor economy to
use the raw for dishes of this class, instead of that which is well
refined. To make a clear syrup it should be broken into lumps, not
crushed to powder. Almost every kind of fruit may be converted into
a good compôte.
 COMPÔTE OF PEACHES.

Pare half a dozen ripe peaches, and stew them very softly from
eighteen to twenty minutes, keeping them often turned in a light
syrup, made with five ounces of sugar, and half a pint of water boiled
together for ten minutes. Dish the fruit; reduce the syrup by quick
boiling, pour it over the peaches, and serve them hot for a second-
course dish, or cold for rice-crust. They should be quite ripe, and will
be found delicious dressed thus. A little lemon-juice may be added to
the syrup, and the blanched kernels of two or three peach or apricot
stones.
Sugar, 5 oz.; water, 1/2 pint: 10 minutes. Peaches, 6: 18 to 20
minutes.
Obs.—Nectarines, without being pared, may be dressed in the
same way, but will require to be stewed somewhat longer, unless
they be quite ripe.
 ANOTHER RECEIPT FOR STEWED PEACHES.

Should the fruit be not perfectly ripe, throw it into boiling water and
keep it just simmering, until the skin can be easily stripped off. Have
ready half a pound of fine sugar boiled to a light syrup with three-
quarters of a pint of water; throw in the peaches, let them stew softly
until quite tender, and turn them often that they may be equally done;
after they are dished, add a little strained lemon-juice to the syrup,
and reduce it by a few minutes’ very quick boiling. The fruit is
sometimes pared, divided, and stoned, then gently stewed until it is
tender.
Sugar, 8 oz.; water, 3/4 pint: 10 to 12 minutes. Peaches, 6 or 7;
lemon-juice, 1 large teaspoonful.