A Practical Guide to Toxicology and Human Health Risk Assessment

By Laura Robinson

Toxicology – the study of the adverse effects of chemicals on living organisms is the cornerstone to all aspects of chemical safety and knowledge of the subject is needed in a wide spectrum of fields from the chemical industry to medicine, emergency services, forensics, and regulatory science. Toxicology involves the study of symptoms, mechanisms, treatments and detection of poisoning ... especially the poisoning of people.

The many problems arising from a poor understanding of toxicology and its applications in hazard communication and chemical safety motivated the author's training courses and webinars, leading to this valuable book.

Providing a practical and accessible guide, A Practical Guide to Toxicology and Human Health Risk Assessment enables readers to quickly build up knowledge and understanding of toxicology and its use in hazard identification, which is a fundamental part of chemical risk assessment. The book also covers current toxicological testing strategies and the use of physicochemical test data in hazard identification and exposure assessment.

Examples are provided throughout the book to highlight important issues along with a summary of the key points that have been covered in each of the respective chapters. The book concludes with a listing of online resources on toxicology and risk assessment.

• Language: English
• Publisher: Wiley
• Release date: Nov 5, 2018
• ISBN: 9781118881903

Book preview

Table of Contents

Cover

Foreword

Preface

1 Welcome to the World of Toxicology

1.1 Chemicals – They Are All Around Us

1.2 Synthetic or Naturally Occurring Chemicals – Which Are Safer?

1.3 Chemical Control Regulations

1.4 Perception of Chemical Risk

1.5 Why Is Toxicology Important?

1.6 Summary

References

2 Basic Toxicological Terminology

Introduction

2.1 The Cell

2.2 Homeostasis

2.3 Adaptation and Cell Injury

2.4 Cellular Responses to Injury

2.5 Mode of Action and Mechanism of Action

2.6 Adverse Effects

2.7 Biological and Statistical Significance

2.8 Local and Systemic Effects

2.9 How Chemicals Cause Harm

2.10 Acute and Chronic Exposures

2.11 Chemical Interactions in Mixtures

2.12 Summary

References

3 The Dose Makes the Poison

Introduction

3.1 Dose–Response and Dose–Effect Relationships

3.2 Internal and External/Exposure Dose

3.3 The Dose Makes the Poison: Dose–Response/Effect Curves

3.4 No Observed Adverse Effect Level (NOAEL)

3.5 Lowest Observed Adverse Effect Level (LOAEL)

3.6 What Affects the NOAEL and LOAEL?

3.7 No Observed Effect Level (NOEL)

3.8 Summary

References

4 Toxicokinetics

Introduction

4.1 Why Is Toxicokinetics So Useful?

4.2 ADME: Absorption, Distribution, Metabolism, and Excretion

4.3 Biotransformation (Metabolism)

4.4 Bioavailability and Area Under the Curve (AUC)

4.5 Assessment Approaches

4.6 Summary

References

5 Factors That Modify Toxicity

Introduction

5.1 Lifestyle Factors – Alcohol and Tobacco

5.2 Influence of Age

5.3 Health Status

5.4 Nutritional Status – Diet

5.5 Sex

5.6 Adaptation

5.7 Genetic Variability

5.8 Summary

References

6 Local Effects

Introduction

6.1 Irritants and Corrosives

6.2 Skin Structure

6.3 Irritant Contact Dermatitis

6.4 Chemical Corrosives

6.5 The Skin as a Target Organ – Severity of Effect

6.6 Chemical Irritants and Other Exposure Routes

6.7 Summary

References

7 Systemic Effects

7.1 Chemical Allergies

Introduction

7.1.1 Hypersensitivity

7.1.2 Allergies

7.1.3 Autoimmunity

7.1.4 Allergens, Hapten, Antigens, and Atopy

7.1.5 How an Allergy Develops

7.1.6 Allergic Contact Dermatitis

7.1.7 Respiratory Allergy

7.1.8 Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis)

7.1.9 Can Skin Sensitizers Cause Respiratory Allergy and Vice Versa?

7.1.10 Summary

References

7.2 Genetic Toxicology

Introduction

7.2.1 Genotoxicity and Mutagenicity

7.2.2 The Dose Makes the Poison?

7.2.3 How Mutations Occur

7.2.4 Cellular Replication

7.2.5 How Chemicals Cause Harm – Mutations

7.2.6 Other Types of DNA Damage

7.2.7 DNA‐Repair Mechanisms

7.2.8 Carcinogens and Mutagens

7.2.9 Summary

References

7.3 Carcinogenicity

Introduction

7.3.1 What Is Cancer?

7.3.2 Chemical Carcinogenesis

7.3.3 Categories of Carcinogens

7.3.4 Benign and Malignant Tumors

7.3.5 Dose–Response Relationships

7.3.6 Causes of Cancer

7.3.7 Summary

References

7.4 Reproductive and Developmental Toxicology

Introduction

7.4.1 The Female Reproductive System

7.4.2 The Menstrual Cycle

7.4.3 The Male Reproductive System

7.4.4 Production of Sperm (Spermatogenesis)

7.4.5 The Reproductive Process and Fertilization

7.4.6 Organogenesis

7.4.7 The Endocrine System and Its Involvement in the Reproductive Process

7.4.8 Sexual Reproduction and the Implications of Chemical Exposure

7.4.9 Effects on the Developing Organism – Developmental Toxicology

7.4.10 Maternal Mediated Toxicity

7.4.11 Summary

References

8 Target Organ Toxicity

8.1 The Liver

Introduction

8.1.1 Histology of the Liver

8.1.2 Functions of the Liver

8.1.3 The Liver and the Thyroid Gland

8.1.4 The Liver as a Target Organ

8.1.5 Peroxisome Proliferation

8.1.6 Common Indicators of Liver Injury

8.1.7 Summary

References

8.2 The Kidney

8.2.1 Structure and Function of the Kidney

8.2.2 The Nephron

8.2.3 Filtration

8.2.4 Reabsorption and Secretion

8.2.5 Metabolic Ability of the Kidneys

8.2.6 Kidneys and Hormones

8.2.7 Why Are the Kidneys A Target Organ for Toxicity?

8.2.8 How Chemicals Cause Harm

8.2.9 Common Indicators of Renal Injury

8.2.10 Summary

References

8.3 The Immune System

Introduction

8.3.1 Innate and Adaptive Immunity

8.3.2 The Organs of the Immune System

8.3.3 Cells of the Immune System

8.3.4 The Immune System as a Target Organ

8.3.5 Testing Methodology

8.3.6 Developmental Immunotoxicity (DIT)

8.3.7 Summary

References

8.4 Hematopoietic System and Blood

8.4.1 Blood

8.4.2 Blood Formation

8.4.3 How Chemicals Cause Harm

8.4.4 How to Detect Effects on the Bone Marrow and Blood

8.4.5 Summary

References

8.5 The Nervous System

8.5.1 Introduction to the Nervous System

8.5.2 The Central Nervous System

8.5.3 The Peripheral Nervous System

8.5.4 The Cells of the Nervous System

8.5.5 Transmission of Information

8.5.6 The Nervous System as a Target Organ

8.5.7 Assessment of Neurotoxicity

8.5.8 Developmental Neurotoxicity

8.5.9 Summary

References

Additional Resources

8.6 The Respiratory Tract

Introduction

8.6.1 Function and Structure

8.6.2 Defense Mechanisms

8.6.3 What Can Be Inhaled?

8.6.4 Deposition within the Respiratory System

8.6.5 Respiratory Tract as a Target Organ

8.6.6 Chemical Pneumonitis and Aspiration Pneumonia

8.6.7 Toxicity to the Lungs – by Other Exposure Routes

8.6.8 Local Effects (to the Respiratory Tract)

8.6.9 Systemic Effects

8.6.10 Summary

References

8.7 The Endocrine System

Introduction

8.7.1 Hormones – Our Chemical Messengers

8.7.2 The Hypothalamus

8.7.3 The Endocrine Axis

8.7.4 What Can Go Wrong?

8.7.5 Timing Is Everything

8.7.6 Assessment for Endocrine Disruption

8.7.7 Summary

References

9 Assessment Methods

9.1 Assessment of Irritation and Corrosive Effects

Introduction

9.1.1 Assessment Approaches

9.1.2 Physicochemical Properties

9.1.3 Human Data

9.1.4 QSAR and Read Across

9.1.5 In Vitro Testing

9.1.6 In Vivo Testing

9.1.7 Respiratory Irritation

9.1.8 Summary

References

9.2 Assessment of Acute Toxicity

Introduction

9.2.1 Nontesting Approaches

9.2.2 Summary

References

Additional Resources

9.3 Repeated Dose Toxicity Testing

9.3.1 The Objectives of Repeated Dose Toxicity Testing

9.3.2 Limitations of Repeated Dose Toxicity Studies

9.3.3 Summary

References

9.4 Assessment of Carcinogenicity

Introduction

9.4.1 How to Identify Potential Carcinogens

9.4.2 Alternative Methods – (Q)SAR and Read Across

9.4.3 How Useful Are These Alternative Methods for the Assessment of Carcinogenicity?

9.4.4 In Vivo Testing – Repeated Dose Toxicity Studies

9.4.5 Summary

References

Additional Resources

9.5 Assessment of Genetic Toxicity

Introduction

9.5.1 Approach to Testing

9.5.2 In Vitro Studies

9.5.3 Gene Mutation Effects

9.5.4 In Vivo Testing

9.5.5 Germ‐Cell Tests

9.5.6 Summary

References

9.6 Assessment of Reproductive and Developmental Effects

Introduction

9.6.1 Sources of Data

9.6.2 In Vivo Data

9.6.3 Developmental Toxicity

9.6.4 Endocrine Disruption

9.6.5 Summary

References

9.7 Assessment of Skin and Respiratory Sensitization

Introduction

9.7.1 (Q)SAR and Read Across

9.7.2 Human Evidence

9.7.3 In Vitro Studies

9.7.4 In Vivo Studies

9.7.5 Assessment of Potency

9.7.6 Respiratory Sensitizers

9.7.7 Summary

References

10 Alternative Methods to Animal Testing

10.1 The Drive for Alternative Methods

10.2 Alternative Methods and the 3Rs

10.3 In Vitro and Ex Vivo Methods

10.4 Twenty‐First Century Toxicity Testing

10.5 Physicochemical Data and Their Use in Hazard Identification and Exposure Assessment

10.6 Summary

References

Additional Reading/Resources

11 Human Health Risk Assessment

Introduction

11.1 Human Health Risk Assessments – Prospective and Retrospective

11.2 Risk, Hazard, and Exposure

11.3 Chemical Risk Assessments

11.4 Linear Dose Response – Nonthresholded Effects

11.5 Exposure Assessment

11.6 Risk Characterization – Do We Have a Problem?

11.7 Summary

References

Glossary

Index

End User License Agreement

List of Tables

Chapter 02

Table 2.1 Common adaptive responses at the cellular level.

Table 2.2 How chemicals cause harm.

Table 2.3 Categories of chemical exposure in relation to duration.

Chapter 04

Table 4.1 Examples of apparent volumes of distribution.

Chapter 06

Table 6.1 Intrinsic and extrinsic factors that influence the development of irritant contact dermatitis.

Chapter 10

Table 10.1 Examples of tests where one or more of the 3R approach can be demonstrated.

Table 10.2 Examples of known structural alerts implicated with respiratory sensitization.

Chapter 11

Table 11.1 Default assessment factor values.

Table 11.2 Worked example 1 for the derivation of the DNEL (dermal, systemic, worker).

Table 11.3 Default safety/uncertainty factors.

Chapter 7.1

Table 7.1.1 The Gell and Coombs classification of hypersensitivity effect.

Table 7.1.2 Some of the common substances known to be respiratory sensitizers.

Chapter 7.2

Table 7.2.1 Types of gene mutations.

Chapter 7.3

Table 7.3.1 The multistage process of carcinogenesis.

Table 7.3.2 Hallmarks of cancer.

Chapter 7.4

Table 7.4.1 Summary of the hormones involved in the reproductive process.

Table 7.4.2 Male‐specific endpoints and interpretation.

Table 7.4.3 Female‐specific endpoints and interpretation.

Table 7.4.4 Wilson’s six principles of teratology.

Chapter 8.1

Table 8.1.1 How the liver responds to chemical injury.

Chapter 8.2

Table 8.2.1 Some of the common functions of the kidneys.

Table 8.2.2 Chemicals known to cause acute tubular necrosis.

Table 8.2.3 Common blood and urine tests to assess renal function.

Chapter 8.3

Table 8.3.1 The differences between the innate immune system and the adaptive immune system.

Table 8.3.2 Some of the key cytokines involved in the immune response.

Table 8.3.3 Summary of the different antibody classes, their location in the body, and their function.

Table 8.3.4 Outline of tests that are used for detecting immune alterations following chemical or drug exposure in rodents.

Chapter 8.4

Table 8.4.1 Types of white blood cells.

Table 8.4.2 Common symptoms resulting from a reduction in cell type.

Table 8.4.3 A summary of common blood investigative work that is undertaken and its purpose.

Chapter 8.5

Table 8.5.1 Neuroglial cells and function within the CNS.

Table 8.5.2 Neuroglial cells and function within the PNS.

Table 8.5.3 Categorization of adverse effects in the nervous system.

Table 8.5.4 Contributions from clinical observations in standard general toxicity studies.

Table 8.5.5 Methods for investigation of neurotoxicity.

Table 8.5.6 Indicators of neurotoxicity.

Chapter 8.7

Table 8.7.1 Some of the hormone classes based on their molecular structure.

Table 8.7.2 Outline of the endocrine glands and their associated hormones.

Table 8.7.3 Assays included in the Tier 1 Screening Battery.

Table 8.7.4 The levels within the OECD conceptual.

Chapter 9.1

Table 9.1.1 Test methods currently available for the assessment of skin corrosivity.

Table 9.1.2 Test methods currently available for the assessment of serious eye damage/eye irritation.

Chapter 9.3

Table 9.3.1 Repeated dose toxicity studies.

Table 9.3.2 Typical rat group sizes in OECD repeated dose toxicity and carcinogenicity studies.

Table 9.3.3 General observations that can be used during toxicity testing.

Table 9.3.4 Outline of common hematological tests.

Table 9.3.5 List of commonly used clinical chemistry determinations that are useful as a screen for toxicity.

Table 9.3.6 General observations, clinical laboratory tests, and pathology assessments that may be used in subchronic toxicity tests.

Chapter 9.6

Table 9.6.1 Endpoints of maternal toxicity.

Table 9.6.2 Developmental endpoints that are sensitive to endocrine disruption.

Chapter 9.7

Table 9.7.1 Skin sensitizer classification criteria using animal test results for Subcategories 1A and 1B.

List of Illustrations

Chapter 01

Figure 1.1 Chemicals are all around us.

Figure 1.2 Would you like a glass of wine?

Chapter 02

Figure 2.1 Cell structure.

Figure 2.2 Different cell types.

Figure 2.3 Image showing normal cells, hyperplasia, hypertrophy, and a combination of both.

Chapter 03

Figure 3.1 The dose makes the poison.

Figure 3.2 The dose–response curve showing the turning point/threshold dose.

Figure 3.3 Shape of the dose–response curve (thresholded effects). Chemical X has a steeper curve than Chemical Y and is therefore more potent. Chemical Y has a lower threshold, meaning that a lower dose would result in adverse effects compared to Chemical X.

Figure 3.4 Nonthresholded effects – Substance W is biologically active at all doses.

Chapter 04

Figure 4.1 The external (environmental) dose of a chemical contaminant will not be the same as the internal (tissue) dose.

Figure 4.2 Comparison of toxicokinetics and toxicodynamics.

Figure 4.3 The cell membrane is a phospholipid bilayer.

Figure 4.4 Types of transport across cell membranes. Passive and facilitated/active transport.

Figure 4.5 The pH varies widely within the digestive system.

Figure 4.6 The skin is a multilayered organ.

Figure 4.7 Mechanisms of elimination – metabolism (biotransformation) and excretion.

Figure 4.8 Area under the curve (AUC).

Chapter 05

Figure 5.1 Alcohol and tobacco can have significant impact on the toxicity of some chemicals.

Figure 5.2 Diet deficiencies can modify the susceptibility to chemical exposure.

Chapter 06

Figure 6.1 Many cleaning products are irritants and corrosives.

Figure 6.2 A spray application produces an airborne mist and the potential for exposure by other routes.

Figure 6.3 The skin is a multilayered organ.

Figure 6.4 The dermis is rich in blood vessels and nerve endings.

Figure 6.5 Chemicals with very high or very low pH are generally assumed to be corrosive.

Figure 6.6 The front (or anterior) part of the eye will be most affected, that is, the iris, cornea, and conjunctiva, and therefore, these are assessed in eye irritation/corrosion toxicity studies.

Figure 6.7 Eye irritation may arise from direct or indirect contact to the eyes.

Chapter 10

Figure 10.1 "In vitro is Latin for in glass."

Figure 10.2 High‐throughput screening assays.

Figure 10.3 pH Scale ranges from 1 (acidic) to 14 (alkaline).

Chapter 11

Figure 11.1 For there to be a risk of harm, there needs to be a hazard and exposure to it.

Figure 11.2 The four stages to risk assessment.

Figure 11.3 The dose–response assessment.

Figure 11.4 Linear and nonlinear dose response.

Figure 11.5 Use of the benchmark dose approach in risk assessment. In the figure, the BMD corresponds to a 5% change in response relative to background (BMR = 5%). The fitted curve yields an estimated background response of 8.7, and a 5% increase of that equals 9.14 (=8.7 + 0.05 × 8.7). Thus, the BMD05 of 21.50 is obtained from the intersection of the horizontal line, at a response of 9.14, with the fitted dose–response model. In this example, the BMDL05 has a value of 18.

Figure 11.6 Linear dose extrapolation and derivation of the cancer slope factor.

Chapter 7.1

Figure 7.1.1 Geraniol has to be metabolized to its active forms.

Figure 7.1.2 Lymphocytes with the correct receptor is selected by the antigen and activated to divide and then differentiate.

Figure 7.1.3 Symptoms of allergic contact dermatitis.

Figure 7.1.4 The relationship between work‐related asthma, occupational asthma, and work‐aggravated asthma.

Chapter 7.2

Figure 7.2.1 Genetic toxicology covers mutagenicity and other types of damage to the genetic material.

Figure 7.2.2 The nucleus of the cell is where the genetic material is stored.

Figure 7.2.3 The double helix structure of DNA.

Figure 7.2.4 Mitosis occurs in somatic cells.

Figure 7.2.5 A comparison of mitosis and meiosis.

Figure 7.2.6 The shortening of the telomere each time the cell divides eventually results in replicative senescence.

Figure 7.2.7 Down’s syndrome also called Down syndrome or trisomy 21.

Figure 7.2.8 Aflatoxin is produced by Aspergillus flavus and Aspergillus parasiticus. They are genotoxic and carcinogenic.

Chapter 7.3

Figure 7.3.1 A malignant tumor will spread to other parts of the body.

Figure 7.3.2 Saccharin.

Chapter 7.4

Figure 7.4.1 Sexual reproduction transmits genetic material to the offspring.

Figure 7.4.2 The female reproductive system.

Figure 7.4.3 The menstrual cycle showing the follicular and luteal phase together with the hormonal involvement.

Figure 7.4.4 The male reproductive system showing the key structures.

Figure 7.4.5 The stages of spermatogenesis.

Figure 7.4.6 The structure of sperm.

Figure 7.4.7 Fertilization where two sets of chromosomes from the male and female gametes combine to form the diploid zygote.

Figure 7.4.8 The stages following ovulation to the formation of the blastocyst.

Figure 7.4.9 HPG axis in males showing the negative feedback loops.

Figure 7.4.10 The reproductive cycle.

Figure 7.4.11 Other species can also have cleft palate.

Chapter 8.1

Figure 8.1.1 Human liver anatomy showing the blood supply.

Figure 8.1.2 Liver lobule showing the portal triad.

Figure 8.1.3 Thyroid gland and associated hormones.

Figure 8.1.4 Comparison of a normal liver and a fibrotic liver.

Figure 8.1.5 The metabolic pathways for paracetamol following ingestion of paracetamol for (i) within the therapeutic range and (ii) outside the therapeutic range.

Chapter 8.2

Figure 8.2.1 Anatomy of kidney.

Figure 8.2.2 The nephron showing the renal tubule and Bowman’s capsule.

Figure 8.2.3 Bowman’s capsule.

Figure 8.2.4 The kangaroo rat.

Figure 8.2.5 Stages in urine formation.

Chapter 8.3

Figure 8.3.1 Organs of the immune system.

Figure 8.3.2 The different types of white blood cells.

Figure 8.3.3 The immune response.

Figure 8.3.4 Cytokines play an important role as molecular mediators of the immune and inflammatory response.

Figure 8.3.5 Once activated, B cells undergo clonal expansion.

Figure 8.3.6 Structure of the immunoglobulin.

Figure 8.3.7 Antibody classification.

Figure 8.3.8 Interaction of the antigen with lymphocytes results in clonal expansion.

Chapter 8.4

Figure 8.4.1 The composition of blood.

Figure 8.4.2 Antarctic Icefish.

Figure 8.4.3 Heme structure showing the iron atom to which oxygen binds.

Figure 8.4.4 Hematopoiesis.

Figure 8.4.5 A blood test is only ever a snap shot in time.

Chapter 8.5

Figure 8.5.1 Anatomy of the brain.

Figure 8.5.2 The reflex arc.

Figure 8.5.3 The neuron is the functional cell of the nervous system.

Figure 8.5.4 Generation of the action potential.

Figure 8.5.5 The synapse showing the release of neurotransmitters.

Figure 8.5.6 Black widow spider venom is neurotoxic.

Figure 8.5.7 Puffer fish.

Figure 8.5.8 Carbamate functional group is a structural alert for neurotoxicity. (Note: R = alkyl, aryl, or H.)

Figure 8.5.9 Organophosphate structural alert for neurotoxicity.

Chapter 8.6

Figure 8.6.1 The respiratory tract is part of the respiratory system.

Figure 8.6.2 The alveolus has a very thin membrane and large surface area, which makes it perfect for gaseous exchange.

Figure 8.6.3 Aerosol spray from a can.

Figure 8.6.4 Image showing the anatomical effects of bronchitis.

Figure 8.6.5 Image showing the effects on the alveoli.

Figure 8.6.6 Chemical structure of paraquat, a contact herbicide.

Figure 8.6.7 Assessment methods following inhalation exposure.

Chapter 8.7

Figure 8.7.1 The endocrine system.

Figure 8.7.2 HPG axis in males, showing the negative feedback loops.

Figure 8.7.3 Hormonal control of ovulation in females.

Chapter 9.1

Figure 9.1.1 Top‐down approach to classification – skin effects.

Figure 9.1.2 Bottom‐up approach to classification – skin effects.

Chapter 9.3

Figure 9.3.1 Urinalysis is a useful noninvasive indication of kidney function.

Chapter 9.4

Figure 9.4.1 Structural alerts for carcinogenic activity.

Chapter 9.6

Figure 9.6.1 The reproductive cycle.

Chapter 9.7

Figure 9.7.1 Human skin patch testing for the identification of skin sensitizers.

Figure 9.7.2 Summary of the AOP for skin sensitization.

A Practical Guide to Toxicology and Human Health Risk Assessment

Laura Robinson

Toxicology Consulting Ltd, Brighton, UK

Wiley Logo

This edition first published 2019

© 2019 John Wiley & Sons, Inc.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Laura Robinson to be identified as the author of this work has been asserted in accordance with law.

Registered Office

John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA

Editorial Office

111 River Street, Hoboken, NJ 07030, USA

For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com.

Wiley also publishes its books in a variety of electronic formats and by print‐on‐demand. Some content that appears in standard print versions of this book may not be available in other formats.

Limit of Liability/Disclaimer of Warranty

In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

Library of Congress Cataloging‐in‐Publication Data

Names: Robinson, Laura, 1965– author.

Title: A practical guide to toxicology and human health risk assessment / Laura Robinson.

Description: First edition. | Hoboken, NJ : John Wiley & Sons, Inc, 2018. |

Includes bibliographical references and index. | Description based on print version record and CIP data provided by publisher; resource not viewed.

Identifiers: LCCN 2018019553 (print) | LCCN 2018044443 (ebook) | ISBN 9781118882078 (Adobe PDF) | ISBN 9781118881903 (ePub) | ISBN 9781118882023 (pbk.)

Subjects: LCSH: Toxicology. | Hazardous substances–Risk assessment. | Health risk assessment. | Environmental risk assessment.

Classification: LCC RA1211 (ebook) | LCC RA1211 .R634 2018 (print) | DDC 363.17/63–dc23

LC record available at https://lccn.loc.gov/2018019553

Cover design by Wiley

Cover image: © ALFRED PASIEKA/SCIENCE PHOTO LIBRARY/Getty Images

To my husband Andrew T. Austin and Nai‐Ling

Foreword

In 2015 a patient told me of how his life was saved in 1969 by the prompt action of his site foreman, following a mining accident when he was accidentally exposed to cyanide gas. Still here to tell the dramatic tale, 46 years later, of nitrates, oxygen, and then hospitalization, it really emphasized the need for an understanding of how we could reduce the harmful impact of chemicals.

As Laura writes in her first chapter, we live in a chemical environment, and therefore, we need to be aware of the ways in which chemicals can cause harm. This book allows us to do just that. Having distilled the spirit of each topic into readily comprehensible principles, which can then be used to address wider matters, the chapters are well organized and broken down into clear parts. At the back of each chapter, there are references that are useful for further study.

Anyone for whom toxicology has any relevance, e.g. nurses, doctors, paramedics, allied health professionals, pharmacists, environmentalists, chemists, pathologists, industrialists, and also toxicologists, in training and in practice, will find this book invaluable.

Dr Susan Elton, MBBS, MRCGP, DOccMed, Postgraduate Certificate in Law

Preface

Toxicology is the cornerstone to all aspects of chemical safety. Knowledge of the subject is needed in a wide variety of disciplines, not just the chemical industry but also other areas, including medicine, the emergency services, and forensics.

Many problems arise from the understanding of toxicology and its application in hazard communication and chemical safety. This has been highlighted by the numerous online webinars and face‐to‐face toxicology training sessions that have been delivered by Toxicology Consulting Ltd over the past five years.

The overall goal of this book is therefore to provide a very practical and easy‐to‐use guide that will enable the reader to quickly build up his or her knowledge and understanding (in terms of its application) of toxicology.

Acknowledgment

I would like to thank Dr Susan Elton for her careful review of the chapters from an occupational medicine/toxicology perspective.

1

Welcome to the World of Toxicology

1.1 Chemicals – They Are All Around Us

For many people the word chemical has many negative connotations, which include death, injury, and cancer. However, we encounter them daily – not only in our workplace but also in our home in the form of detergents, fragrances, personal care products, medicines, etc. They come in many different forms, which include solids, liquids, gases, aerosols, and mists. They can be synthetic or naturally occurring, and they are all around us (Figure 1.1).

Photo displaying ball-and-stick models and skeletal formulas of compounds.

Figure 1.1 Chemicals are all around us.

Source: E.Artem/Shutterstock.com.

We live in a chemical environment, and therefore, we need to be aware of the ways in which chemicals can cause harm. In other words, we need to understand toxicology, which is the study of the adverse effects of chemicals on living organisms. By doing this we can then put in measures to minimize the risk of any harm.

Chemicals are not new to humans. Their use, often for nefarious purposes, can be traced as far back as ancient civilizations where, instead of being called chemicals, they were referred to and used as poisons. Since then, and particularly following the industrial revolution, the use of chemicals in other applications, such as textiles and fertilizers, has dramatically increased (Rowe 1998).

This book is therefore about the ways in which chemicals can cause harm and how we can assess the likelihood of this occurring.

1.2 Synthetic or Naturally Occurring Chemicals – Which Are Safer?

Ask a group of people whether synthetic chemicals are more harmful than those that come from mother nature, i.e. naturally occurring, and it is likely that you will receive very divided opinions. However, this kind of question and others like it were investigated as far back as the early sixteenth century by a Swiss physician called Philippus Aureolus Theophrastus Bombastis von Hohenheim, or more commonly known as Paracelsus. From his work he concluded that in sufficient quantities everything had the potential to cause harm, and the only thing that differentiated something from being harmful or not was the dose. In other words, it is the dose which makes the poison. This means that irrespective of the source of the chemical, i.e. synthetically made in the laboratory or from a woodland plant, all have the potential to cause harm should the dose be sufficient. This dose–response relationship that Paracelsus discovered is a key theme in toxicology and will be covered in more detail in Chapter 3 of this book.

1.3 Chemical Control Regulations

Chemicals are an essential part of our daily lives, not just in the workplace but also in the home. However, there are often risks associated with their use, and therefore, chemical control regulations have been implemented in most countries. These ensure that hazardous chemicals are identified, which is where knowledge of toxicology is needed, and any likely exposure is minimized. Where necessary, these regulations can restrict or ban access to particularly hazardous chemicals. For example, under Article 57 of the EU REACH Regulation, a substance of very high concern (SVHC) is one that has been proposed to be subject to authorization for use within Europe. These substances are typically Category 1 carcinogens, mutagens, or toxic for reproduction (CMR) and are likely to have extensive human exposure (ECHA 2014). Furthermore, classification and labeling of hazardous substances and mixtures is also a requirement (GHS 2017), the results of which are communicated in the form of a safety data sheet and/or product label. Finally, chemical control regulations also ensure that appropriate risk assessments are undertaken. This is covered in more detail in Chapter 11.

Chemical control regulations cover the whole chemical life cycle. This includes their manufacture, use, transport, storage, and disposal.

1.4 Perception of Chemical Risk

With news stories sensationalizing the harmful effects of chemicals, it is no surprise that many people are suspicious of chemicals and see no benefit to society at all. Although there may be times when this is not without due reason, it can lead to the banning of chemicals whose benefits far outweigh any perceived drawbacks in their use. Conversely, despite well‐documented scientific evidence, which proves the adverse health effects associated with their use, people continue to smoke tobacco and drink alcohol (Box 1.1).

Box 1.1 A recent report by the World Health Organisation

Globally, alcohol results in approximately 3.3 million deaths each year, and this number has already been adjusted to take into account the beneficial impact of low risk patterns of its use on some diseases. Of all deaths worldwide, 5.9% are attributable to the use of alcohol; this is greater than, for example, the proportion of deaths from HIV/AIDS (2.8%), violence (0.9%) or tuberculosis (1.7%). The highest numbers of deaths are from cardiovascular diseases, followed by injuries (especially unintentional injuries), gastrointestinal diseases (mainly liver cirrhosis), and cancers (Figure 1.2).

Source: Reproduced with permission from WHO (2014).

Photo displaying wine spilling out from a transparent glass.

Figure 1.2 Would you like a glass of wine?

Source: MariyanaM/Shutterstock.com.

1.5 Why Is Toxicology Important?

Toxicology is the cornerstone in all aspects of chemical safety. Knowledge of the subject is needed in a wide variety of disciplines, not just the chemical industry but also other areas, including medicine, the emergency services, and forensic science. Many problems arise from a lack of understanding of toxicology and exposure considerations, both of which are explored in subsequent chapters of this book.

1.6 Summary

Chemicals comprise atoms or ions of different elements, and most chemicals we encounter are synthetic rather than naturally occurring.

Toxicology is the study of the adverse effects of chemicals on living organisms.

Work by Paracelsus in the early sixteenth century concluded that it is the dose which makes the poison. This dose–response relationship is a key theme in toxicology.

Chemical control regulations cover the whole chemical life cycle. This includes their manufacture, use, transport, storage, and disposal.

References

ECHA (2014). Prioritisation of Substances of Very High Concern (SVHCs) for Inclusion in the Authorisation List (Annex XIV) [Online]. https://echa.europa.eu/documents/10162/13640/gen_approach_svhc_prior_in_recommendations_en.pdf (accessed 2 February 2018).

GHS (2017). Globally Harmonized System of Classification and Labelling of Chemicals 7 [Online]. UNECE. https://www.unece.org/trans/danger/publi/ghs/ghs_rev07/07files_e0.html#c61353 (accessed 1 February 2018).

Rowe, D. J. M. (1998). History of the Chemical Industry 1750 to 1930 – An Outline [Online]. http://www.rsc.org/learn‐chemistry/resources/business‐skills‐and‐commercial‐awareness‐for‐chemists/docs/Rowe%20Chemical%20Industry.pdf (accessed 2 February 2018).

The World Health Organisation (2014). Global Status Report on Alcohol and Health [Online]. http://www.who.int/substance_abuse/publications/global_alcohol_report/en/ (accessed 2 February 2018).

2

Basic Toxicological Terminology

Introduction

This chapter explores some of the common toxicological terminology that is useful to understand prior to reading the other chapters of this book.

2.1 The Cell

The cell is the basic building block of all living organisms, and in mammals, the cells typically have a nucleus and cytoplasm, which contains various cellular organelles and a cell membrane (Figure 2.1). They can, however, differ in terms of shape, size, and function. For example, epithelial cells line both internal and external surfaces and are generally cuboidal in shape, whereas nerve cells (neurons) are long structures that transmit messages by means of an electrical impulse (Figure 2.2).

Cell structure with lines marking the intermediate filament, ribosomes, rough endoplasmic reticulum, nucleus, nucleolus, chromatin, Golgi apparatus, Golgi vesicle, peroxisome, secretory vesicle, etc.

Figure 2.1 Cell structure.

Source: © Vladmir Ischuk/Shutterstock.com.

Illustration displaying blood cells, surface skin cells, bone cell, columnar epithelial and goblet cells, cardiac muscle cell, skeletal muscle cells, neuron, and smooth muscle cells.

Figure 2.2 Different cell types.

Source: © Alila Media Medical/Shutterstock.com.

2.1.1 Stem Cells, Somatic Cells, and Germ Cells

As will be seen in later chapters, cells can be categorized as stem cells, somatic cells, and germ cells. Stem cells are nondifferentiated cells that can proliferate to produce more stem cells or differentiate into specific cell types. For example, the stem cells present in the bone marrow can differentiate into different blood‐cell types. Somatic cells are all the nonreproductive cells of the body; they include the epithelial and nerve cells mentioned earlier. Germ cells or gametes are the sex cells, and in males these are sperm, and in females the ovum or egg. Tissues are groups of similar cells, all with a specialized function and structure. There are four main types of tissue: muscular, epithelial, nervous, and connective tissue. Different types of tissue make up organs, which have a common function and shape. Examples include the liver, kidneys, and the heart. Toxicologists are particularly interested in chemically induced harm to different organs or organ systems. This is known as target organ toxicity and is covered in more detail in Chapter 8.

2.2 Homeostasis

The internal environment of the body is constantly changing not only in response to the external environment but also because of changes in activity. However, the maintenance of a stable internal environment is essential for all the cells of the body to ensure that they can maintain both function and viability. For example, changes in body temperature can have a significant impact on the functioning of enzymes, which are needed for metabolism. Also, concentrations of blood glucose, pH, and specific ions need to be maintained within a narrow range of physiological parameters (Tortora and Grabowski 1996). This process of maintaining optimum conditions and making the relevant adjustments by means of feedback loops is called homeostasis. As will be seen in Chapter 8, both the nervous system and endocrine system are closely involved in homeostasis, albeit in different ways.

2.3 Adaptation and Cell Injury

Homeostasis occurs because of the cells and tissues of the body being able to continually adapt to their ever‐changing environment, which enables them to maintain both function and viability.

An adaptive response is a reversible process by which the organism manages an increase in demand or compensates for injury or disease. Once the increased demand or injury has resolved, everything usually returns to normal. For example, in the absence of any hepatocellular injury, chemical induced liver enlargement, which is commonly observed in repeated dose toxicity studies, is generally considered to be an adaptive response. However, if the capacity for an adaptive response is exceeded, this may result in cell injury. At the cellular level, the main adaptive responses are hypertrophy, atrophy, hyperplasia (Figure 2.3), and metaplasia, all of which are summarized in Table 2.1.

Image described by caption.

Figure 2.3 Image showing normal cells, hyperplasia, hypertrophy, and a combination of both.

Source: © Designua/Shutterstock.com.

Table 2.1 Common adaptive responses at the cellular level.

Source: Adapted from Malarkey et