General, applied and system toxicology

4355 Pages·2014·58.265 MB·English

by  editors, Bryan Ballantyne, Timothy C. Marrs, Tore Syversen, Daniel A. Casciano and Saura C. Sahu.

Basic Elements of Toxicology
Bryan Ballantyne, Timothy C. Marrs and Tore Syversen
C O N T E N T S
1 Introduction
2 Historical Development of Toxicology
3 Definition and Scope of Toxicology
4 Descriptive Terminology of Toxic Effects
5 Morphologicaland Functional Nature of Toxic Effects
5.1 Genotoxicity
5.2 Reproductive and Developmental Toxic Effects
5.3 Pharmacological Effects
6 Dosage–ResponseRelationships
6.1 General Considerations
6.2 Expression of Dosage–ResponseRelationships
6.3 Applications of Dosage–ResponseInformation
6.4 Dosage–ResponseConsiderationsfor Acute Lethal Toxicity
7 Factors Influencing Toxicity
7.1 Species and Strain
7.2 Age
7.3 Nutritional Status
7.4 Time of Dosing
7.5 Environmental Factors
7.6 Dosing Characteristics
7.7 Formulation and Presentation
7.8 Miscellaneous
8 Biohandlingas a Determinant of Systemic Toxicity
8.1 Absorption
8.2 Biodistribution
8.3 Biotransformation
8.4 Excretion
8.5 BiohandlingInteractions
9 Routes of Exposure
9.1 Peroral
9.2 Cutaneous Contact and Percutaneous Absorption
9.3 Inhalation
9.4 Eye
10 Exposure to Mixtures of Chemicals
11 Toxicologyof Drugs
11.1 Undesirable Effects
11.2 Factors InfluencingDrug Toxicity
12 Nature, Design and Conductof ToxicologyStudies
12.1 General Considerations
12.2 General ToxicologyStudies
12.3 Specific Toxicology Studies
13 Reviewof Toxicology Studies
14 Hazard Evaluation and RiskAssessment
15 SpecialConsiderations in Human Hazard Evaluation
2 General, Applied and Systems Toxicology
15.1 Personal Habits
15.2 CoexistingDisease
15.3 Genetically SusceptibleSubpopulations
16 Professional and Ethical Issues
16.1 General Commentsand Principles
16.2 Conductof Laboratory Studies
16.3 Animal Welfare
16.4 Regulatory Activity
16.5 Publications
16.6 General Legal–Ethical–Professional–Employer Interfaces
References
Further Reading
1 INTRODUCTION protective measures are needed for safe use. Indeed with
drugs, pesticides, industrial chemicals, food additive
and cosmetic/personal care preparations, mandatory
Toxicology,essentiallyaddressingthepotentiallyharmful
toxicology testing and regulations exist. In the UK,
effects of chemicals to living organisms, is now a
safety evaluation toxicology has been closely associated
universally recognized scientific and medical discipline
with pathology and experimental pathology, but in many
devoted to a large and widespread number of basic and
other countries, including the USA, toxicology has been
applied issues. Although only generally accepted as a
regarded as a component or branch of pharmacology.
specific and defined area of knowledge and investiga-
However, with the growth of toxicology it has become a
tion since the early part of the twentieth century, its
major multidisciplinary science with significant overlap
principles and implication have been appreciated for
into other health-related science.
aeons. Thus, the harmful and lethal effects of certain
substances, plants, fruits, insect bites, animal venoms
and minerals, have been known since prehistoric times.
2 HISTORICAL DEVELOPMENT OF
Indeed, the Greek, Roman and subsequent civiliza-
tions knowingly used certain substances and extracts TOXICOLOGY
for lethality in hunting, protection, warfare, suicide and
homicide. Currently, activities in toxicology are mainly As noted in Section 1 above, toxicology in formal
centred around, though not exclusively, determining the terms has been regarded as a relatively young science.
potential for chemicals, both naturally occurring and However, the origins of toxicology are ancient, and it is
synthetic, to produce adverse effects, and as a conse- likely that man, unknowingly, undertook the first experi-
quence to assess hazard and risk from such chemi- ments in toxicology in searchesfor anacceptablediet on
cals to humans and lower animal forms, thus allowing movingoutofthehabitatinwhichheevolved.Itislikely
the development of appropriate precautionary, protec- that many of these early excursions had an unfortunate
tive, restrictive and therapeutic measures. For example, outcome. In Greek and Roman periods, poisons, gener-
substances used, or of potential use, in commerce, the ally of plant origin, were used for murder and suicide,
home,theenvironmentandmedicalpracticemaypresent whilst the potential danger of medicinal products and
variable types of harmful effects, whose nature is deter- their adulterants has been recognized since Babylonian
minedbymanyfactors,includingparticularlythephysic- times. Poisoning for nefarious purposes has remained
ochemical characteristics of the material, its potential to a problem ever since, and much of the earlier impetus
interactwithbiologicalmaterialsandthepatternofexpo- to the development of toxicology had been primarily
sure. forensic.Anothermotivationforthedevelopmentoftoxi-
Toxicology investigations can have far-reaching cologywasthecarefuldescriptionofadversereactionsto
implications for health-related issues in the workplace, medicinalproductsthatbegantoappearintheeighteenth
commerce, home and general environment. For century.ThusWilliamWitheringdescribeddigitalistoxi-
man-made and man-used materials, a balanced critical city in 1785, and around 1790 Hahnemann, the founder
approach may be necessary in order to assess the ofhomoeopathy,carriedouttoxicologicalexperimentson
risk–benefit ratio for their employment in specific himself and his healthy friends with therapeutic agents
circumstances, and to determine what precautionary and of his time, including cinchona, aconite, belladonna,
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BasicElements of Toxicology 3
ipecacuanha and mercury. The introduction of anaes- health, and for the adverse environmental impact of
thesia was followed by formal enquiries into sudden xenobiotics, increased. Additionally, the growth of
deathsduringchloroformanaesthesiaintheclosingyears toxicology has been fuelled by a series of disasters
of the nineteenth century. such as Seveso, Bhopal, tri-ortho-cresyl phosphate
During World War I, a variety of poisonous chem- (TOCP) poisoning incidents, methyl mercury incidents
icals were used in the battlefields of northern France and the thalidomide tragedy, which threw up lacunae in
and Belgium. This was the stimulus for much work knowledge concerning the toxic effects of substances,
on mechanisms of toxicity, as well as medical counter- as well as the inadequacy of testing procedures. One
measures to poisoning, In fact war, or the prospect of of the earliest of such disasters occurred in the USA in
war, played as great a part in the development of toxi- 1937 and resulted in the deaths of 105 individuals from
cology as of many other sciences. Much of the basic poisoning by an elixir of sulfanilamide containing the
work on organophosphates (OPs) was stimulated by the solvent diethylene glycol (DEG) (Calvery and Klumpp,
discovery of these compounds by the Germans in the 1939). This led to the passing of legislation in the
1930s. Although defence considerations stimulated this form of the US Federal Food, Drug and Cosmetic Act,
work, much of it, particularly related to treatment, is forbidding the marketing of new drugs until cleared for
applicable to the use in industry and agriculture of OP safety by the US Food and Drug Administration (FDA).
pesticides. Similarly, chelation therapy, initially studied Regulationshavebeenelaboratedatnational,continental
in relation to organic arsenicals,is now usedin the treat- (European Union (EU) and North Atlantic Free Trade
ment of poisoning by many metals. Area (NAFTA) and international levels. It is therefore
Occupational toxicology (see Occupational disappointing and frustrating to note that contamination
Toxicology and Occupational Toxicology and Occu- of medicinal formulations with DEG and resultant
pational Hygiene within the European Union (EU) large-scale outbreaks of poisoning with acute renal
Chemicals Regulation) originated in the late 1600s and failure, often with mortalities, has occurred on several
early 1700s with the writings of Bernardino Ramazzini, occasions up to the present time, since the original
a professor of medicine in the Universities of Modena poisoning outbreak in 1937. Most of these have been
and Padua, and referred to as the father of occupational recorded in children from countries having generally
medicine. It gained impetus in the nineteenth century lower standards of human care, and have included
as a product of the industrial revolution, with early the following: Cape Town, 1969 (seven deaths from
descriptions of occupational diseases induced by DEG-contaminated sedative formulations; Bowie and
chemicals, such as cancer of the scrotum in chimney McKenzie, 1972); Bombay, India, 1986 (14 deaths from
sweeps. Although in theory, but much less in practice, DEG-contaminated glycerine: Pandya, 1988); Nigeria,
affected workers in the past had some remedies at law, 1990 (47 deaths from DEG-adulterated paracetamol
major advances in the control of occupationally related (acetaminophen) syrup: Okuonghae etal., 1992); Dhaka,
diseases of chemical origin came in the period after Bangladesh, 1990–1992 (236 deaths of 339 children
1960 with the setting of threshed limit values (TLVs) having acute renal failure from DEG-containing parac-
and occupational exposure limits (OELs). Additionally, etamol (acetaminophen) elixir: Hanif etal., 1995); Haiti,
in Western countries the increasing wealth of workers 1996 (85 deaths in a follow-up group of 87 cases of
and the activities of their Unions have enabled them acute renal failure from DEG-contaminated paracetamol
to make use of existing legal remedies and make (acetaminophen) syrup: O’Brien et al., 1998); Gurgaon,
representation in respect of needed improvements in India 1998 (acute renal failure with 33 deaths from
occupational litigation. This has resulted in many contaminated cough expectorant: Singh et al., 2001);
companies having to take care of their workers and New Delhi, India (encephalopathy and renal failure in
devote greater resources to industrial hygiene and 11 children from DEG-contaminated paracetamol elixir;
occupational medicine. However, there are still clear Hari etal., 2006). In Argentina, during 1992, there were
needs for improvement in underdeveloped countries and 15 deaths of 29 victims of poisoning from the use of
with a few employers in Western countries. DEG-containing propolis syrup (for upper respiratory
Regulatory toxicology (see Regulatory Toxicology) infection) (Ferrari and Giannuzzi, 2005). A series of 64
has its origins in the development of the chemical Chineseadultpatients(GuangdongProvince)withsevere
and pharmaceutical industries in the nineteenth and liver disease received intravenous (iv) Armillarisin-A
twentieth centuries. The first toxicology regulation is (3-acetyl-5-hydroxylmethyl-7-hydroxycoumarin) that
often said to be the Alkali Act of 1863 (UK, 1863), contained DEG as solvent. Of these, 15 had confirmed
which was intended to control pollution by heavy DEG poisoning, of whom 12 died; findings in the
industry. Regulatory toxicology now accounts for poisoned patients included metabolic acidosis, acute
a very large majority of expenditure on toxicology renal failure and acute renal tubular necrosis with
testing and administration. Toxicology has only come interstitial nephritis on renal biopsy (Lin et al., 2008).
of age as a defined scientific discipline over the past Subsequently five employees of the Qiqihar No. 2
few decades, as concern for worker and consumer PharmaceuticalCompanyof Heilongjiang Province,who
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4 General, Applied and Systems Toxicology
were responsible for allowing DEG to be used in the was the publication by Rachel Carson of Silent Spring
production of Armillarisin A, were jailed for between (Carson, 1962).
fourandsevenyears(EAASM,2008).Withrespecttoall The past decades have seen a gradual shift in the
these cases of lethal human DEG poisoning the lessons emphasis of toxicology from its origins in acute toxicity,
are clearly there for all, but unfortunately unlearned particularly human, to long-term and nontarget species
by many. In some cases the DEG contamination was toxicity. More or less in parallel, stress has changed
accidental, but in others was financially driven. DEG, from studies of natural, usually plant, compounds to
an inexpensive solvent, was more profitable to use products of chemical synthesis. Additionally, in recent
than the more expensive propylene glycol or glycerine. years considerable resources have gone into testing for
Stricter pharmaceutical manufacturing oversight and carcinogenic potential, whilst there have been extensive
enforcement is required on a worldwide basis (Wax, and intensive investigations into in vitro alternatives to
1996). animal toxicology testing.
The main international organizations currently regu- Clinical toxicology, concerned with the causation,
lating chemicals are the Codex Alimentarious Commis- diagnosis and management of poisoning was origi-
sion (CAC), and its committees, for food standards, nally under the control of general physicians in general
and the Organization for Economic Cooperation and hospitals. Much of the impetus for the subsequent devel-
Development (OECD) for the standardization of test opment of clinical toxicology came from the activi-
methods. The International Conferences on Harmoniza- ties of government defence research establishments. For
tion (ICH) and the Veterinary International Conferences example, chelation therapy for heavy-metal poisoning
on Harmonization (VICH) have attempted to harmo- was discovered during searches for a method to treat
nize test requirements for pharmaceuticals, both human organic arsenical poisoning during World War II, while
and veterinary. Because of the tendency for new test oximes for OP poisoning were developed during the
methodstobeintroduced,oftenwithouteliminatingolder ‘cold war’ in the 1950s and 1960s (see above). As a
tests, regulations have been inclined to become ever distinct specialization, clinical toxicology is relatively
more complex, with the result that the cost of labora- new domain, having developed as a consequence of the
tory toxicology testing has become a significantly large fact that general physicians may not necessarily have
administrative and economic segment of product devel- access to the information required to treat their patients.
opment.However,morerecentlyintroducedtestmethods Currently clinical toxicology has its own certification
do not always imply added costs; thus the introduction requirements, specialized societies and journals specifi-
of in vitro genotoxicity studies may permit the avoid- cally devoted to the specialization. Poison information
ance of costly and time-consuming long-term in vivo services developed during the 1950s in the USA and
carcinogenicity bioassays. However, the complexity of UK, and the concept has since spread throughout the
toxicologicalregulationsmayimply,notonlyaneffecton world. Thus poisons information centres, which have
theprofitsofcompaniesdevelopingthechemicalordrug, access to information on thousands of drugs and chemi-
but also loss of potentially useful substances. In some cals that people may become accidentally or deliberately
cases this has led to sufficient disquiet for legislative poisoned with, are to be found in major cities in most
actiontobetaken.Examplesofthisarethe‘orphandrug’ developed countries. In many cases, units exist, not only
procedure in the USA, and the clinical trials exemption to back up clinicians with information and to act as a
intheUK.Industrialeffectsoftheincreasingcomplexity general advisory service to the general population, but
of regulatory activity have been the need to establish also to carry out hands-on management of poisoning
regulatory departments within chemical and pharmaceu- (see also Susceptibility of Children to Environmental
tical organizations for the interpretation of, adherence Xenobiotics; Ethical, Legal, Social and Professional
to, and oversight of regulations, and to establish discus- Issues in Toxicology).
sion channels with appropriate government departments A recent development was the recognition that
on safety issues related to company products. Also, for differing toxicology requirements may be a barrier to
reasons of size and costs, many companies have chosen free trade. Within major trading blocks such as NAFTA
not to develop their own toxicology testing facilities, and the EU it has been necessary to elaborate common
or abandon or significantly reduce their own ‘in-house’ toxicological requirements for clearance of materials,
facilities. This has resulted in the significant growth of while the agreement on the application of sanitary and
the contract toxicology testing industry. phytosanitary methods (‘SPS agreement’, WTO, 1994),
Organochlorine insecticides probably averted an achieved after tortuous negotiations in 1994, requires
epidemic of typhus at the end of World War II, but that, in most circumstances, CAC maximum residue
it was the persistence of these compounds in the levels (MRLs) for food additives, contaminants and
environment that was probably the greatest stimulus pesticides, be accepted for world trade purposes. This
to the evolution of environmental toxicology. A major inevitably raised the profile of the international expert
landmark in the evolution of this branch of toxicology committees,suchastheJointExpertCommitteeonFood
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BasicElements of Toxicology 5
Table1 Majordrivingforcesforthedevelopmentandincreasingspecializationofthescientificbasisand
applicationsoftoxicology
(cid:1) Exponentialincreaseinthenumberofsyntheticallyproducedindustrialanddomesticchemicals
(cid:1) Major increase in the numbers and nature of new drugs, pharmaceutical preparations, tissue-implantable
materialsandmedicaldevices
(cid:1) Increaseinthenumberandnatureofpesticidesandrelatedproducts
(cid:1) Growingconcernaboutthenumberoffood-additivematerials
(cid:1) Increasing concern that environmental agents, including pesticides, chemical pollutants and naturally
occurringtoxins,arecontributingtothecausationandpathogenesisofdiseases,inparticularcardiovascular,
neurological,pulmonaryandneoplastic.
(cid:1) Mandatorytestingandregulationofchemicalsanddrugsusedcommercially,domesticallyandmedicinally
(cid:1) Enhanced public awareness of the potential for adverse effects from xenobiotics and naturally occurring
chemicalstoman,animalsandthegeneralenvironment
(cid:1) Thepotentialforinteractionsbetweenoccupational,domesticandenvironmentalexposuresanditsinfluence
onadverseeffects
(cid:1) Litigation,principallyasaconsequenceofoccupationallyrelatedillness,unrecognizedorpoorlydocumented
product safety concerns and environmental harm. Recently, certain lawyers (of the ambulance-chasing type)
areinsertingadvertisementsontelevisiontodrawattentionofthegeneralpublictoadversedrugeffectsand
offering their services for litigation against companies and prescribers (a practice that will have detrimental
implicationsforfuturedrugdevelopment)
(cid:1) Activitiesofpublicawarenessand‘watchdog’groups
Additives (JECFA) and the Joint Meeting on Pesticide to the component elements. Most toxicology consider-
Residues (JMPR). ations, and hence definitions, are concerned with the
Major, extensive and rapid developments in the scien- effects from natural or synthetic (man-made) substances,
tific basis of toxicology and its practical applications including biological toxins and a wide range of commer-
have beenobvious since the early1950s. Thesedevelop- cial and domestic chemicals. Thus, many definitions
ments have been a consequence of a variety of reasons, hinge around chemical toxicology. The central consider-
the major elements of which are listed in Table 1. ation in toxicology is the potential for the agent(s) under
Reflecting these developments has been a major prolif- investigation to cause adverse (harmful) effects. Thus,
eration in the number of textbooks and journals devoted in definitions of toxicology, adverse effects imply those
to general and special aspects of toxicology; a prolifera-
thataredetrimentaltothe survivalornormalfunctioning
tionofabstractingandinformationservices;theprovision
of living organisms (Ballantyne, 1989). In view of this,
of undergraduate and graduate courses and of certifi-
some authorities and organizations have suggested that
cation requirements in general and applied toxicology;
an overall definition should include ‘catch all’ causative
and the establishment of an industry devoted to toxi-
agents that may produce adverse effects in biological
cology testing and consultation. Along with these has
materials. This has led to the inclusion of biological and
been an increase in the number of professional organi-
physical agents in some overview definitions. The core
zations and certification boards specifically devoted to
of chemical toxicology is that of a discipline concerned
toxicology. As a consequence of the markedly expanded
withinvestigatingthepotentialofchemicals,ormixtures
scopeoftoxicology,anumberofcircumscribeddiffering
of them, to produce harmful effects in living organ-
subdisciplines have emerged, and several major areas of
ismsanddeterminingtheimplicationsoftheseeffects;in
subspecialization have been defined (Table 2).
this chemical-limited concept, chemicals cover naturally
An excellent informative demonstration on milestones
occurring substances (from plants, animals and microor-
in the history of toxicology has been prepared by Dr.
ganisms) and synthetic (man-made) materials, the latter
Steven W. Gilbert and Dr. Antoinette Hayes, and is
often being referred to as xenobiotics. One overview
reproduced with their kind permission in Figure 1.
definition covering the various elements of toxicology
is as follows: ‘Toxicology is a study of the interac-
tion between chemical, biological and physical agents
3 DEFINITION AND SCOPE OF
in biological organisms in order to quantitatively deter-
TOXICOLOGY
mine the potential for these agents to produce morpho-
logical and/or functional injury that results in adverse
Definitions of toxicology vary according to the relative effects in living organisms, and to investigate the nature,
importance that the defining author or authority ascribe incidence, mechanism of production, factors influencing
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6 General, Applied and Systems Toxicology
Table2 Majorsubspecialtiesoftoxicology
Specialty Majorfunctionalcomponents
Laboratory Designandconductofinvivoandinvitrotoxicologytestingprogrammes
Regulatory Administrativefunctionconcernedwiththedevelopmentandinterpretationofmandatorytoxicology
testingprogrammes,andwithparticularreferencetoensuringthesafeuse,handlingand
transportationofsubstancesusedcommercially,domesticallyandtherapeutically,andwiththe
developmentofproduct-safetyliteratureandlabels
Clinical Thecausation,diagnosisandmanagementofpoisoninginhumans
Veterinary Thecausation,diagnosisandmanagementofpoisoningindomesticandwildanimals
Forensic Establishingthecausefordeathorintoxicationinhumans,byanalyticalprocedures,andwithparticular
referencetolegalprocesses
Occupational Determiningthepotentialforadverseeffectsfromchemicalsandotheragentsintheoccupational
environmentandthedevelopmentofappropriatescreeningproceduresandprecautionaryand
protectivemeasures
Product Assessingthepotentialforadverseeffectsfromcommerciallyproducedchemicalsandformulations,
anddevelopmentofrecommendationsonsafepatterns,protectiveandprecautionarymeasures,and
developmentofrelevantliteratureforusers
Pharmacological Assessingthetoxicityoftherapeuticagents
Aquatic Assessingthetoxicitytoaquaticorganismsofchemicalsdischargedintomarineandfreshwaters
Environmental Determiningtheadverseeffectsoftoxicpollutants,usuallyatlowconcentrations,releasedfrom
commercial,industrial,domesticandnaturalsourcesintotheimmediateenvironmentand
subsequentlywidelydistributedbyairandwatercurrentandbydiffusionthroughsoil.Itdiffersfrom
ecotoxicology(seebelow)infocussingontheeffectsonindividuals
Ecotoxicology Determiningadverseeffectsandimpactfromsyntheticornaturalpollutantsonpopulations,
communities,andterrestrial,freshwaterandmarineanimal,vegetableandmicrobialecosystems.If
differsfromenvironmentaltoxicology(seeabove)inthattheaimistointegratetheeffectsatalllevels
ofbiologicalorganizationfrommoleculartowholecommunities,andthereforeisabroaderdiscipline.
Toxicology Determiningthetoxicityofsubstancesofbiologicalorigin,includingplants,animalsandpathogenic
microorganisms
their development, and reversibility of such adverse 4. Toxicological investigations should ideally permit
effects’. the following characterization of toxicity to be eval-
Within the scope of this definition, adverse effects are uated:
those that are detrimental to either the survival or the (a) The basic structural, functional or biochemical
normal functioning of a living organism. Inherent in this injury produced
definition are the following key elements in toxicology, (b) The dose–response relationships
particularly with respect to chemical toxicology: (c) The mechanism(s) of toxicity, that is, the funda-
mental chemical and biological interactions and
1. Chemicals,ortheirconversionproducts,arerequired resultant aberrations that are responsible for the
to come into close structural and/or functional genesis and maintenance of the toxic response
contactwithtissue(s)ororgan(s)forwhichtheyhave (d) Thefactorsthatmayinfluencethetoxic response,
a potential to cause injury. for example, route of exposure, species, gender,
2. Whenpossible,theobservedtoxicity(oranendpoint age, formulation of test chemical and environ-
reflecting it) should be quantitatively related to the mental conditions
degree of exposure to the chemical (the exposure (e) The development of approaches and methods for
dose). Ideally, the influence of differing exposure the recognition of specific toxic responses
dosesonthemagnitudeand/orincidenceofthetoxic (f) The reversibility of toxic effects, either sponta-
effect(s)shouldbeinvestigated.Suchdose–response neously or with treatment procedures.
relationships are of prime importance in confirming
acausalrelationshipbetweenchemicalexposureand The word ‘toxicity’ is used to imply the induction of
toxic effect, in assessing relevance of the observed adverse effects and to describe the nature of adverse
toxicitytopractical(in-use)exposureconditions,and effects produced and the conditions necessary for their
to allow hazard evaluations and risk assessment. induction, that is, toxicity is the potential for a material
3. The primary aim of most toxicology studies is to to produce injury in biological systems. In some related
determine the potential for harmful effects in the or subdisciples of toxicology, specific terminology may
intact living organism, in many cases (and often by be used to describe adverse effects; for example, with
extrapolation) to man. pharmacologicallyactiveandtherapeuticagents(‘drugs’)
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BasicElements of Toxicology 7
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Mount VesuviusthErupted August 2479 CECity of Pompeii &Herculaneumdestroyed and buriedby ash. Pliny the Eldersuffocated by volcanic gases. Rodrigo &Cesare Borgia(1400-1500)Poisoned many people in Italyfor political and monetary gain.Used arsenic in a concoctioncalled “La Cantrella”. King Louis XIV1682Passed royal decreeforbidding apothecariesto sell arsenic or poisonoussubstances except to personsknown to them. Mateu J.B. Orfila(1787-1853)Considered the fatherof modern toxicology.In 1813 he publishedTraite des Poisons,which described the symptoms ofpoisons. Constantine FahlbergSaccharin - 1879Constantine Fahlbergdiscovered saccharinwhile working in thelaboratory of IraRemsen (right)in 1879. Marijuana Tax Act1937Federal criminaloffense to possess,produce, or dispensehemp. Non-medicaluse prohibited in California (1915)and Texas (1919). U.S. EPA1970Established toconsolidate federal research, onmonitoring, standard-settingand enforcement activities toensure human & environmentalprotection. Vioxx (1999-2004)A nonsteroidal anti-inflammatory,COX-2 selective inhibitor fortreatment of osteoarthritis,produced by Merck & Co.and voluntarilywithdrawn becauseof risk of heartattack & stroke. dDr.AntoinettofNeurotoxicol
12Steven G. Gilbert and Antoinette Hayes21Institute of Neurotoxicology and Neurological Disorders and Northeastern UniversityContact information: Steven G. Gilbert at [email protected] – For more information, its interactive (clickable) at www.asmalldoseof.org – 2006 Steven G. Gilbert L. Cornelius SullaGula 1400 BCEMithridates VIHippocratesSocratesPedaniusCleopatraHomerShen NungEbers Papyrus82 BCE(131-63 BCE)(460-377 BCE)(470-399 BCE)Dioscorides(69-30 BCE)850 BCE2696 BCE1500 BCEAntiquityGreek physician,(40-90 CE)Tested antidotesCharged withLex Cornelia deWrote of theExperimentedEgyptain recordsThe Father ofobservationalto poisons onreligious heresysicariis etuse of arrowswith strychninecontains 110Chinese000 BCE – 90 CEGreekSumerian texts refer to aapproach to human diseasehimself and used prisonersand corrupting the morals – lawveneficispoisoned with venom in theand other poisons onpages on anatomymedicine, notedpharmacologist andfemale deity, Gula. Thisand treatment, founder ofas guinea pigs. Createdof local youth. Death byagainst poisoning people orThe Odysseyepic tale of prisoners and poor.and physiology, toxicology,for tasting 365 herbs andDe Materiaphysician, wrote mythological figure wasmodern medicine, namedmixtures of substancesHemlock - active chemicalprisoners; could not buy,and The Iliad. From GreekCommitted suicide withspells, and treatment,said to have died of a toxic basis for theMedicaassociated with charms,cancer after creeping crab.leading to term mithridatic.alkaloid coniine.sell or possess poisons.toxikon arrow poison.Egyptian Asp.recorded on papyrus.overdose.modern pharmacopeia.spells and poisons. Venetian Council ofMoses MaimonidesRaymundus LulliusPetrus de AbanoZhou ManGreek FireAlbertus MagnusKnights TemplarsErgot OutbreakThe Black DeathTen - 1419(1135-1204)1275(1250-1315)1423673 CE(1193-1280)(1118-1307)994 CE(1347-1351)Middle AgesEther discovered40,000 diedItalian scholarChristian militaryBubonic &Dominican friarChinese explorerGroup ofJewishAncientby Spanishfrom eatingtranslatedorder alleged topneumonicwrote extensivelylost 1000s of crewpeople whophilosopher &“napalm” described by the476 CE – 1453chemist andcontaminated wheat/ryeHippocrates andbe experts withplague ravaged Europeon compatibilitymembers from uraniumcarried outphysician wrote:Crusaders as consisting oflater calledcaused gangrene - known asGalen to Latin. Wrote bookpoisons. They searched forleaving the highest numberreligion and science andexposure while mining leadmurders with poison for aTreatise on Poisons andnaptha, quicklime, sulphur,“sweet vitriol”.St. Anthony’s Fire.on poisons: De Venenis.the “Elixir of Life”.of casualties in history.isolated arsenic in 1250.in Jabiru Australia.fee..Their Antidotes& saltpeter. Catherine MonvoisinPope Clement VIICatherine MediciGuilia TophaniaShakespeareGeorgius AgricolaHieronyma SparaWilliam PisoLeonardo de VinciParacelsusRenaissance(LaVoisin)(1478-1534)(1519-1589)(1635-1719)(1564-1616)(1494-1555)~16591640(1452-1519)(1493-1541)(1640-1680)“All substancesWrote De ReExperimented withIn Brazil,Italian woman whoQueen of France,Roman women &From Romeo &Died (possibly14th–16thare poisons: publishedMetallicabioaccumulation ofstudied effectssupplied poison (arsenic) toexpert assassin,fortune tellerJuliet - act 5murdered) afterAccused sorcererthere is none which is not a1556. The mostpoisons in animalsCephaelisof wives looking to murderCenturiestested poisonsorganized wealthy wives and“Here’s to my love! O trueamanitaeating and convictedpoison. The right dosecomprehensive book onand called the procedure,Ipecacuanhatheir husbands. Lateron the poor andsold them a arsenic elixir toapothecary! Thy drugs are, (death cap)Phalloidespoisoner in France.differentiates a poison from amining and metallurgy.“passages”.an emetic; treat dysentery.executed by strangulation.the sick.murder their husbands.quick. Thus with a kiss I die.”mushroom.She was burned at the stake.remedy.” Francoise MagendiePercivall PottFowler’s SolutionPierre OrdinaireDevonshire ColicJohn JonesFelice FontanaFreidrich SerturnerCarl WilhelmRichard Meade(1783-1855)(1714-1788)1786-19361797-19151700’s17011767(1783-1841)Scheele (1742-176)(1673-1754)Discovered emetine1700sBritish physicianSwedish apothecaryCreated elixirPotassium arseniteItalian chemist andDevonshire,In 1702, wrote AIsolated an alkaloidEnglish doctor wroteand studied effectswho recognizedand chemist,using absinthesolution prescribedphysiologist whoFrom opium poppyEngland. HighMechanicalThe Mysteries of Opiumof strychnine &coal-tar causeddiscovered oxygen,popularized and sold by Henryas a general tonicwas the first to studyin 1803. He namedincidence of leadAccount of Poisons described manyReveal’dcyanide. Calledcancer of the scrotum inbarium, chlorine,Pernod. Absinthe was used byand used from aboutvenomous snakes. Discoveredit Morphine after Morpheus, thecolic drinkingdedicated to poisons snakes,treatments of opium, but alsothe father ofchimney sweeps. Chimneymanganese, andVincent Van Gogh; banned in1786 to 1936. Usedthat viper venom affects blood.Greek god of dreams.contaminated cider.animals and plants.withdrawal and addiction.experimental pharmacology.Sweepers Act of 1788.hydrogen cyanide.1915, subject of Degas.by Charles Darwin? Louis LewinArsenic Act 1851James MarshAscanio SobreroEmil FischerThomas de QuinceyClaude BernardRobert ChristisonJoseph Caventou &Theodore G. Wormley(1854-1929)Required arsenic to be colored(1794-1846)(1812-1888)1852-1919(1785-1859)(1813-1878)(1797-1882)Pierre Pelletier(1826-1897)with soot or indigo to prevent1800sGerman1820English writerChemist developedFrenchToxicologist atWrote the firstItalian chemist, in“accidental” poisoning.pharmacologistbecame addictedand perfected the Marsh test forphysiologistUniversity ofAmerican book1847 discoveredFriedrich Gaedcketo opium in earlyarsenic. The improved Marshstudied the effectsstudied and classifiedEdinburgh wrote Treatise ondedicated tonitroglycerin, a18551800’s andtest was used forensically forof carbon monoxide andPoisons in 1829; inventedpoisons in 1869powerful explosivehallucinogenic plants, IsolatedFrench pharmacists isolatedpublished Confessions of anthe first time in 1840 during thecurare. Influenced bypoison harpoon for whalingentitled: Microchemistry ofand vasodilator. Alfredcocaine fromalcohols and otherIsolated the stimulant caffeinequinine from bark of CinchonaOpium Eater in 1821.trial of Marie Lafarge.Francoise Magendie.that contained prussic acid.Poisons.Nobel was his student.Erythroxylon coca.psychoactive compounds.from plant extracts in 1895.tree in back of their pharmacy. Elixir SulfanilamideAlbert HofmannGeneva ProtocolChemical Warfare AUpton SinclairPure Food andU.S. ProhibitionGinger Jake 1929Hawk’s NestGerhard Schrader19371938Alcoholic tonic produced1925Reality 1915(1878-1968)Drugs Act - 19061919-1933Incident 1927-1935(1903-1990)illegally during prohibition1900-1930sHarvey WashingtonFood Drug &Law that madeHundreds of blackLysergic acidGermanGerman ChemistBanned use ofPublishedadulterated with TOCPWiley, M.D. (1844-workers die from(LSD) synthesizedchemist Fritzaccidentallychemical weapons.The Junglethe productionCosmetic Act1930). Law preventsproduced OPIDNacute silicosis whilein the SandozHaber (1868-1934)made nerve agents; sarin, tabun,Updated in 1993in 1905.and sale of1938production or traffickingdigging tunnel for aLaboratory (nowdeveloped blistering agentssoman, and cyclosarin while(Jake Leg),as the “Chemical WeaponsChronicled the unsanitaryalcoholic beveragesof mislabeled, adulterated100 die, diethylenehydroelectric projectNovartis). In 1943 Hoffmanused in WWI; chlorine anddeveloping insecticides 1938;Convention” to includeconditions in meat packingaffecting 50,000or poisonous foods, drugs,illegal but very profitable.glycol as a vehicle.for Union Carbidetested LSD on himself.cyanide gases.agents used in WWII.banning production.industry in Chicago.adults.medicines, and liquors. Thalidomide2,4-D – 1946Poison ControlRachel CarsonDDT – 1939Alice HamiltonMinimata JapanJournal of Tox. &Society of ToxicologyOccupational Safety(1959-1960’s)Centers 1953(1907-1964)Developed during(1869-1970)(1950’s)App. Pharmacology1961& Health Act 1970Recognized asWW II at Britishinsecticide by the Swiss1940-1960sDrug prescribed1959First, ChicagoFoundedMinimata BayPathologist andScientist leadAct passed on DecemberRothamstedscientist Paul Hermannto pregnant women for1953, secondcontaminatedfirst female facultyMarch 4, 1961,crusade against the use ofAdopted by29, 1970 to ensure everyExperimentalmorning sickness inducedMüller, who was awardedwith mercury by chemicalmember at Harvarddichlorodiphenyltrichloroethaneat Dukefirst formalSOT until 1981worker a safe and healthfulbirth defects.Station, by J.H. Quastelathe 1948 Nobelindustry. Thousands adultsMedical School. Associated(DDT) a pesticide andUniversity,meeting held April 15, 1962when SOTworkplace.Frances Kelseyand children were poisonedand sold commercially inworksite chemical hazardspersistent organic pollutant.Prize in PhysiologyNC in 1954, and third(9 founders, 183founded Fundamentals ofof FDA blockedfrom eating fish contaminatedwith disease. Studied effectsCarson several books including1946. Used to controland Medicine.opened in Boston 1955.charter members)..Applied Toxicologyapproval in U.S.with methyl mercury.of lead & rubber on workers.Silent Spring published 1962.broadleaf plants.Banned in 1972. Iraq – MercuryBangladeshi 1970sChernobyl AccidentMr. YukIUTOX 1980Bhopal DisasterTimes Beach 1983Tokyo Subway SarinLove Canal DisasterFirst Modern1971Arsenic poisoningApril 26, 19861971Dec. 3, 1984Gas Attack 19951978ToxicologyInternational Union ofDangerous levels of dioxinToxicologydiscovered in Times Beach,1970-2006August 7, 1978The ChernobylAccidental releaseTextbookPink-Members of religious groupTubewells,Symbol adoptedAmerican BoardMO. EPA ordersUS Presidentnuclear power plant40 metric tons ofAumby the Pittsburgh Poisoncoloreddrilled to1975the townof Toxicology (ABT)Jimmy Carteraccident produced amethyl isocyanateShinrikyoCenter at The Children’sseed grain coated with aprovide cleanevacuation andLouis J. Casarett1979 -declared Love Canal a federalplume of radioactivefrom a Union First exam Aug. 1980released sarinHospital in 1971. Used tomercury fungicide wasdrinking water, aremakes it aemergency. 42 million poundsdebris over theCarbide Indian pesticide plant& John Doull edited,gas in 5 placesAcademy ofeducate children and parentstragically consumed bycontaminated by arsenicsuperfund site.of over 200 chemicalsUkraine, Easternin heart of city resulted in thein Tokyo subway, killingToxicologicalabout poisons and to preventToxicology: The BasicIraqis tragically affectingresulting in millions ofAll residents gonecontaminated Love Canal,Europe, Scandinavia, UK andkilling thousands, and injured12 and injuring 6,000.Sciences (ATS)accidental poisonings., in 1975.Science of Poisonsover 40,000 people.people harmed.by 1985.disrupting many lives.eastern USA.100s of thousands.1981 MilestonesofToxicology.PreparedbyDr.StevenW.Gilbert(InstituteofNeurotoxicologyandNeurologicalDisorders,SeattleanernUniversity).OriginallypublishedinToxipedia(www.asmalldoseof.org).(ReproducedwithpermissionfromGilbert,InstitutealDisorders.)
3 1astgic
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8 General, Applied and Systems Toxicology
description of adverse or nondesired effects is most and chronic (entire lifespan or the major portion of it).
appropriately undertaken using certain specific terms, as Examplesoftoxic effectsclassifiedaccordingtolocation
discussed in Section 11. and to number of exposures are given in Table 3.
Toxicity (i.e. the potential to injure) investigations Additional descriptions of toxicity are by the time to
require clear differentiation from the process of hazard development and the duration of induced effects. Thus
evaluation, which determines the likelihood that a given they may be described as temporary (reversible or tran-
material will exhibit its known toxicity under particular sient) or permanent (persistent). Latent (delayed-onset)
conditions of use. toxicity exists when there is a period free from signs
following (usually) an acute exposure. Latent toxicity
is of particular importance in clinical toxicology since
4 DESCRIPTIVE TERMINOLOGY OF TOXIC individuals exposed to chemicals of known latency in
toxicity should be kept under review in order that any
EFFECTS
delayed adverse effects may be both promptly recog-
nized and treated. Cumulative toxicity involves progres-
Precision in communication depends on a clear under- siveinjuryproducedbysummationofincrementalinjury
standing of the definitions of technical and scientific resultingfromsuccessiveexposures.Examplesoftoxicity
terms in the context of their intended use. This section according to the timescale for development and dura-
discusses the derivationandmeaningsof frequentlyused tion of effect are given in Table 4. Effects may also be
expressions in toxicology. A schematic representation of classified, and described, according to the primary tissue
the basis for the general classification of toxic effects or organ forming the target for toxicity, for example,
is given in Figure 2. Before toxicity can develop, a hepatotoxic,nephrotoxic,neurotoxic,genotoxic,ototoxic,
substance must come into contact with a body surface, immunologic. A description of toxicity from a material
such as skin, eye or mucosa of the alimentary or respira- requires inclusion of the following: if effects are local,
tory tract; these are, respectively, the cutaneous, ocular, systemic or mixed; their nature and (if known) mecha-
peroral (po) and inhalation routes of exposure. Other nismoftoxicity;organsandtissuesaffectedandcondition
routesofexposure,notablyinexperimentalortherapeutic ofexposureresultingintoxicity (includingspecies,route
situations, are subcutaneous (sc), iv, intramuscular (im) and number or magnitude of exposure).
and intraperitoneal (ip). Harmful effectsthat occur at the
sites where a substance comes into initial contact with
the body are referred to as local effects. If substances
5 MORPHOLOGICAL AND FUNCTIONAL
are absorbed from the sites of contact, they, or prod-
NATURE OF TOXIC EFFECTS
ucts of their bioconversion, may produce toxic effects in
cells, tissues or organs remote from the site of exposure;
theseremoteresponsesarereferredtoassystemiceffects. The nature and magnitude of a toxic effect depend on
Many substances may produce both local and systemic many factors, amongst which are the physicochemical
toxicity. Also, since the nature and probability of toxi-
properties of the substance, its bioconversion, the condi-
citydevelopingdependsonthenumberofexposures,this
tions of exposure, and the presence of bioprotective
forms an additional general means for classifying toxic
mechanisms.Thelastfactorincludesphysiologicalmech-
effects into those developing after a single (acute) expo-
anisms, such as adaptive enzyme induction, DNA repair
sureormultiple(repeated)exposures.Repeatedexposure
mechanisms and phagocytosis. Some of the frequently
toxicitycancoverawidetimespan;however,itisdescrip-
encountered types of morphological and biochemical
tivelyconvenienttorefertoshort-termrepeated(notmore
injuryconstitutingatoxicresponsearelistedbelow.They
than 5% of lifespan), subchronic (5–20% of lifespan)
may take the form of tissue pathology, aberrant growth
processes, altered or aberrant biochemical pathways, or
extreme physiological responses.
Route of
Absorption
exposure
Inflammation: This is a frequent local response to
irritant chemicals or may be a component of systemic
tissue injury. The inflammatory response may be acute
Toxic Skin or Cell tissue
substance mucosae organ withirritantortissue-damagingmaterials,orchronicwith
repetitiveexposuretoirritantsorthepresenceofinsoluble
particulate material.
Local Systemic Fibrosis: This production and accumulation of fibrous
toxicity toxicity connective tissue may occur as a consequence of the
inflammatory process.
Figure 2 Schematic basis for the general classification of Necrosis: Pathologically used to describe circumscribed
toxiceffects. death of tissues or cells, necrosis may result from
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BasicElements of Toxicology 9
Table3 Examplesoftoxiceffectsclassifiedaccordingtotimescaleandlocation
Exposuretime Location Effect Substance
Acute Local Skincorrosion Methylamine
Lunginjury Hydrogenchloride
Systemic Kidneyinjury Phenacetin
Haemolysis Arsine
Mixed Lunginjuryandmethaemoglobinaemia Oxidesofnitrogen
Short-term Local Skinsensitization Ethylenediamine
Repeated Local Lungsensitization Toluenedi-isocyanate
Nasalseptumulceration Chromates
Systemic Neurotoxicity Acrylamide
Liverinjury Arsenic
Mixed Respiratoryirritationandneurobehavioural Pyridine
Chronic Local Bronchitis Sulphurdioxide
Laryngealcarcinoma Nitrogenmustard
Systemic Leukaemia Benzene
Angiosarcoma(liver) Vinylchloride
Mixed Emphysemaandkidneyinjury Cadmium
Pneumonitisandneurotoxicity Manganese
Table4 Examplesoftoxiceffectsclassifiedaccordingto Enzyme inhibition: This may decrease biological
thetimefordevelopmentordurationofthelesion activity in biologically vital pathways, producing
impairmentofnormalfunction.Theinductionoftoxicity
Timescale Effect Substance
from enzyme inhibition may be due to accumulation
Persistent Testicularinjury Dibromochloropropane of substrate or to deficiency of product or function.
Scarring Corrosives For example, OP anticholinesterases produce toxicity
(skin/eye) by accumulation of acetylcholine at cholinergic
Pleural Asbestos
synapses and neuromuscular junctions (Ellenhorn
mesothe-
and Barceloux, 1988). Cyanide inhibits cytochrome
lioma
oxidase and interferes with mitochondrial oxygen
Transient Narcosis Organicsolvents
transport, producing cytotoxic hypoxia (Ballantyne,
Sensory Acetaldehyde
1987).
irritation
Cumulative Squamous Formaldehyde Biochemical uncoupling: Agents capable of biochem-
metaplasia ical uncoupling interfere with the synthesis of high-
Liverfibrosis Ethanol energy phosphate molecules, but electron trans-
port continues resulting in excess liberation of
Latent Pulmonary Phosgene
oedema energy as heat. Thus, uncoupling produces increased
Peripheral Anticholinesterase oxygen consumption and hyperthermia. Examples of
neuropathy organophosphates uncoupling agents are dinitrophenol and pentachloro-
Pulmonary Paraquat phenol (Williams, 1982; Kurt etal., 1988).
fibrosis Lethal synthesis: This occurs when foreign substances
of close structural similarity to normal biological
substrates become incorporated into biochemical
pathways and are then metabolized to a toxic product.
a variety of pathological processes induced by chem- A classical example is that of fluoroacetate, which
ical injury, for example, corrosion, severe hypoxia, becomes incorporated in the Krebs cycle as fluoroacetyl
membrane damage, reactive metabolite binding, inhibi- coenzyme A, which combines with oxaloacetate to
tion of protein synthesis and chromosome injury. With form fluorocitrate. The latter inhibits aconitase, blocking
certain substances, differing patterns of zonal necrosis the tricarboxylic acid cycle and results, particularly,
may be seen. In the liver, for example, galactosamine in cardiac and nervous system toxicity (Albert,
produces diffuse necrosis of the lobules (Mehendale, 1979).
1987), acetaminophen (paracetamol) mainly centrilob- Lipid peroxidation: In biological membranes free
ular necrosis (Goldfrank etal., 1990) and certainorganic radicals start a chain of events causing cellular dysfunc-
arsenicalsperipherallobular necrosis(Ballantyne, 1978). tion and death. The complex series of events includes
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10 General, Applied and Systems Toxicology
oxidation of fatty acids to lipid hydroperoxides which of the response by the local lymph node proliferation
undergo degradation to various products, including assay (Gerberick et al., 2000; Hilton et al., 1998;
toxic aldehydes. The generation of organic radicals Kimber et al., 1994; 2001; Ryan et al., 2008), and
during peroxidation results in a self-propagating reaction where considered necessary confirmed by the human
(Horton and Fairhurst, 1987). Carbon tetrachloride, repeat insult patch test. Recently, various changes in
for example, is activated by a hepatic cytochrome epidermal Langerhans cells have been suggested as
P450-dependent mono-oxygenase system to the possibly forming the basis for the development of in
trichloromethyl and trichloromethyl peroxy radicals; vitro assays for assessing skin sensitization potential
the former radical probably covalently binds with (Ryan et al., 2005). Respiratory sensitization, mediated
macromolecules and the latter initiates the process by IgE- and Th2-cell responses, cannot be predicted by
of lipid peroxidation leading to hepatic centrilobular conventional repeated inhalation exposure studies, but
necrosis. The zonal necrosis is possibly related to high can addressed by studies such as the mouse IgE test and
cytochrome P450 activity in centrilobular hepatocytes
cytokine fingerprinting (Dearman and Kimber, 2001;
(Albano etal., 1982).
Dearman et al., 2003; Kimber et al., 2002; Holsapple
Covalent binding: Electrophilic reactive metabolites
etal., 2006).
covalently binding to nucleophilic macromolecules may
Immunosuppression: Suppression of the immune
have a role in certain genotoxic, carcinogenic, terato-
system by xenobiotics may have important reper-
genic and immunosuppressive events. Important cellular
cussions with respect to increased susceptibility to
defence mechanisms exist to moderate these reactions,
infective agents and certain aspects of tumorigen-
and toxicity may not be initiated until these mechanisms
esis.
are saturated.
Neoplasia: Agents stimulating neoplasia cause an aber-
Oxidative stress: Oxidative stress induces injury to
ration of tissue growth and control mechanisms of
cells by excessive production of reactive oxygen species
cell division, and result in abnormal proliferation and
(ROS) having high reactivity against DNA, lipids and
growth. This is a major consideration in repeated
proteins (Pe´rez etal., 2006).
exposure to xenobiotics. The terms tumorigenesis and
Receptor interaction: Occurs at a cellular or macro-
oncogenesis are general expressions used to describe
molecular level andinvolves specificchemicalstructures
overallthe developmentof neoplasms; the wordcarcino-
modifying the normal biological effect mediated by the
genesis should be restricted specifically to malignant
receptor;thesemaybeexcitatoryorinhibitory.Animpor-
tant example is effects on Ca2+ channels (Braunwald, neoplasms. In experimental and epidemiological situ-
ations, oncogenesis may be exhibited as an increase
1982).
in the total number of neoplasms, an increase in
Endocrine disruption: A number of xenobiotics found
specific types of neoplasm, the occurrence of ‘rare’ or
in both human community and wildlife environments
‘unique’ neoplasms or a decreased latency to detection
havebeenshowntohaveapotentialtodisruptendocrine
of neoplasms.
functions.Endocrinedisruptingeffectsofchemicalshave
a potential to cause reproductive problems and increase
theriskfordevelopmentofendocrine-dependentcancers.
Chemical carcinogenesis is a multistage process.
Interference with steroid biosynthesis may have adverse
Simplistically, the first, and critical, stage is a genotoxic
effectsonsexualdifferentiation,growthanddevelopment
event followed by other processes leading to the
(Sanderson, 2006). Additionally, there have been studies
pathological, functional and clinical expression of
on the interactions between xenobiotics and hormone
neoplasia. One multistep model that has received much
receptors, particularly thyroid hormone, oestrogen and
attention is the initiator–promoter scheme (Figure 3).
androgen receptors.
The first stage, that of initiation, requires a brief
Immune-mediated hypersensitivity: Such reactions
exposure to a genotoxically active material which results
stimulated by antigenic materials are particularly
in binding of the initiator or reactive metabolite to
important considerations for skin and lung resulting in
cellular DNA; there is a low, or no, threshold for this
allergic contact dermatitis, respiratory sensitization and
initiation stage. The second stage, that of promotion,
asthma (Cronin, 1980; Brooks, 1983; Bardana et al.,
permits the expression of the carcinogenic potential of
1992; Isola etal., 2008; see also Cytogenetics; Allergic
Asthma and Rhinitis: Toxicological Considerations; the initiated cell. Promoting agents have the following
Assessing Impacts of Environmental Contaminants characteristics:
on Wildlife). Skin-sensitizing potential, a Type VI
hypersensitivity reaction, can be investigated by
standard in vivo studies in laboratory animals, such as (cid:1) They need not be genotoxic
occluded patch tests (Buehler, 1965) and the guinea-pig (cid:1) Pepeated exposure is required after initiation
maximization procedure (Magnusson and Kligman, (cid:1) They show some evidence for reversibility
1969; Magnusson and Kligman, 1970), and by induction (cid:1) They may have a threshold for promoting activity.
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