PHRM310 Ch1 General Toxicology 9703

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Chapter-1: GENERAL TOXICOLOGY

ont nts

1. INTRODUCTION TO TOXICOLOGY

1.1. Basic defiiti!s ad ter"i!#!$%

1.&. D!se-resp!se re#ati!ship1.&.1. D!se Resp!se

1.&.&. The Basic C!"p!ets !f Tests Geerati$ D!se'Resp!se Data

1.&.(. D!se Esti"ates !f T!)ic Effects

1.&.*. Therape+tic Ide)

1.&.,. NOAEL ad LOAEL

1.&.. act!rs if#+eci$ D!se'Resp!se c+r/es

1.(. T!)icit%

1.(.1. act!rs If#+eci$ T!)icit%

1.*. 0%ste"ic t!)ic effects

1.,. Or$a 0pecific T!)ic Effects

1.. Ai"a# Testi$ f!r T!)icit%1..1. echais" !f ac+te t!)icit%

1.2. I"p!rtace !f t!)icit% st+d%

&. Discip#ies !f T!)ic!#!$%

1. INTRODUCTION TO TOXICOLOGY

1.1. BA0IC DEINITION0 AND TERINOLOGY

The literal meaning of the term toxicology is “the study of poisons.” The root word toxic entered

the English language around 1655 from the Late Latin word toxicus (which meant poisonous!

itself deri"ed from toxi#$n! an ancient %ree# term for poisons into which arrows were dipped.

The early history of toxicology focused on the understanding and uses of different poisons! and

e"en today most people tend to thin# of poisons as a deadly potion that when ingested causes

almost immediate harm or death. &s toxicology has e"ol"ed into a modern science! howe"er! it

has expanded to encompass all forms of ad"erse health effects that su'stances might produce!

not ust acutely harmful or lethal effects.

The following definitions reflect this expanded scope of the science of toxicology)

• T!)ic *ha"ing the characteristic of producing an undesira'le or ad"erse health effect.

• T!)icit% *any toxic (ad"erse effect that a chemical or physical agent might produce

within a li"ing organism.

• T!)ic!#!$% *the science that deals with the study of the ad"erse effects (toxicities

chemicals or physical agents may produce in li"ing organisms under specific conditions

PHRM310; Chapter-1: General Toxicology



of exposure. +t is a science that attempts to ,ualitati"ely identify all the ha-ards (i.e.!

organ toxicities associated with a su'stance! as well as to ,uantitati"ely determine the

exposure conditions under which those ha-ardstoxicities are induced. Toxicology is the

science that experimentally in"estigates the nature! incidence! mechanism! and ris#

factors for the ad"erse effects of toxic su'stances. The potential ad"erse effects of interest

may range from something relati"ely minor such as irritation or tearing! to a more serious

response li#e acute and re"ersi'le li"er or #idney damage! to an e"en more serious and

permanent disa'ility such as cirrhosis of the li"er or li"er cancer.

• E)p!s+re *to cause an ad"erse effect! a toxicant must first come in contact with an

organism. The means 'y which an organism comes in contact with the su'stance is the

route of exposure (e.g.! in the air! water! soil! food! medication for that chemical.

• D!se *the total amount of a toxicant administered to an organism at specific time

inter"als. The ,uantity can 'e further defined in terms of ,uantity per unit 'ody weight or

per 'ody surface area.

• Itera#3a4s!r4ed d!se *the actual ,uantity of a toxicant that is a'sor'ed into the

organism and distri'uted systemically throughout the 'ody.

• De#i/ered3effecti/e3tar$et !r$a d!se *the amount of toxicant reaching the organ

(#nown as the target organ that is ad"ersely affected 'y the toxicant.

• Ac+te e)p!s+re *exposure o"er a 'rief period of time (generally less than /0 h. ften it

is considered to 'e a single exposure (or dose 'ut may consist of repeated exposures

within a short time period.

• 0+4ac+te e)p!s+re *resem'les acute exposure except that the exposure duration is

greater! from se"eral days to one month.

• 0+4chr!ic e)p!s+re *exposures repeated or spread o"er an intermediate time range.

2or animal testing! this time range is generally considered to 'e 134 months.

• Chr!ic e)p!s+re *exposures (either repeated or continuous o"er a long (greater than 4

months period of time. ith animal testing this exposure often continues for the

maority of the experimental animals life! and within occupational settings it is generally

considered to 'e for a num'er of years.

• Ac+te t!)icit% *an ad"erse or undesira'le effect that is manifested within a relati"ely

short time inter"al ranging from almost immediately to within se"eral days following

exposure (or dosing. &n example would 'e chemical asphyxiation from exposure to a

high concentration of car'on monoxide (7.




• Chr!ic t!)icit% *a permanent or lasting ad"erse effect that is manifested after exposure

to a toxicant. &n example would 'e the de"elopment of silicosis following a long8term

exposure to silica in wor#places such as foundries.

• L!ca# t!)icit% *an ad"erse or undesira'le effect that is manifested at the toxicants site

of contact with the organism. Examples include an acids a'ility to cause 'urning of the

eyes! upper respiratory tract irritation! and s#in 'urns.

• 0%ste"ic t!)icit% *an ad"erse or undesira'le effect that can 'e seen throughout the

organism or in an organ with selecti"e "ulnera'ility distant from the point of entry of the

toxicant (i.e.! toxicant re,uires a'sorption and distri'ution within the organism to produce

the toxic effect. Examples would 'e ad"erse effects on the #idney or central ner"ous

system resulting from the chronic ingestion of mercury.

• Re/ersi4#e t!)icit% *an ad"erse or undesira'le effect that can 'e re"ersed once exposure

is stopped. 9e"ersi'ility of toxicity depends on a num'er of factors! including the extentof exposure (time and amount of toxicant and the a'ility of the affected tissue to repair

or regenerate. &n example includes hepatic toxicity from acute acetaminophen exposure

and li"er regeneration.

• De#a%ed !r #atet t!)icit% *an ad"erse or undesira'le effect appearing long after the

initiation andor cessation of exposure to the toxicant. &n example is cer"ical cancer

during adulthood resulting from in utero exposure to diethylstil'estrol (:E;.

• A##er$ic reacti! *a reaction to a toxicant caused 'y an altered state of the normal

immune response. The outcome of the exposure can 'e immediate (anaphylaxis ordelayed (cell8mediated.

• Idi!s%cratic reacti! *a response to a toxicant occurring at exposure le"els much

lower than those generally re,uired to cause the same effect in most indi"iduals within

the population. This response is genetically determined! and a good example would 'e

sensiti"ity to nitrates due to deficiency in <&:= (reduced8form nicotinamide adenine

dinucleotide phosphate3 methemoglo'in reductase.

• echais" !f t!)icit% *the necessary 'iologic interactions 'y which a toxicant exerts

its toxic effect on an organism. &n example is car'on monoxide (7 asphyxiation dueto the 'inding of 7 to hemoglo'in! thus pre"enting the transport of oxygen within the

'lood.

• T!)icat *any su'stance that causes a harmful (or ad"erse effect when in contact with a

li"ing organism at a sufficiently high concentration.




• T!)i *any toxicant produced 'y an organism (floral or faunal! including 'acteria> that

is! naturally produced toxicants. &n example would 'e the pyrethrins! which are natural

pesticides produced 'y pyrethrum flowers (i.e.! certain chrysanthemums that ser"e as the

model for the man made insecticide class pyrethroids.

• 5!is! * toxicant that cause immediate death or illness when experienced in "ery small

amounts.

• 6a7ard *the ,ualitati"e nature of the ad"erse or undesira'le effect (i.e.! the type of

ad"erse effect resulting from exposure to a particular toxicant or physical agent. 2or

example! asphyxiation is the ha-ard from acute exposures to car'on monoxide (7.

• 0afet% *the measure or mathematical pro'a'ility that a specific exposure situation or

dose will not produce a toxic effect.

• Ris8 *the measure or pro'a'ility that a specific exposure situation or dose will produce atoxic effect.

• Ris8 assess"et *the process 'y which the potential (or pro'a'ility of ad"erse health

effects of exposure are characteri-ed.

& t!)ic a$et is anything that can produce an ad"erse 'iological effect. +t may 'e chemical!

physical! or 'iological in form. 2or example! toxic agents may 'e chemical (such as cyanide)!

physical (such as radiation) and 'iological (such as snake venom).

& distinction is made for diseases) due to 'iological organisms. Those organisms that in"ade and

multiply within the organism and produce their effects 'y 'iological acti"ity are not classified as

toxic agents. &n example of this is a "irus that damages cell mem'ranes resulting in cell death.

+f the in"ading organisms excrete chemicals! which are the 'asis for toxicity! the excreted

su'stances are #nown as 4i!#!$ica# t!)is. The organisms in this case are referred to as t!)ic

!r$ais"s. &n example is tetanus. Tetanus is caused 'y a 'acterium! Clostridium tetani. The

'acteria C. tetani itself does not cause disease 'y in"ading and destroying cells. 9ather! it is a

toxin that is excreted 'y the 'acteria that tra"els to the ner"ous system (a neurotoxin) that

produces the disease.

Toxic su'stances may 'e organic or inorganic in composition)




Toxic su'stances may 'e s%ste"ic t!)is or !r$a t!)is.

& s%ste"ic t!)i is one that affects the entire 'ody or many organs rather than a specific site.

2or example! potassium cyanide is a systemic toxicant in that it affects "irtually e"ery cell and

organ in the 'ody 'y interfering with the cell?s a'ility to utili-e oxygen.

Toxicants may also affect only specific tissues or organs while not producing damage to the

'ody as a whole. These specific sites are #nown as the tar$et !r$as or tar$et tiss+es.

∗ @en-ene is a specific !r$a t!)i in that it is primarily toxic to the 'lood8forming

tissues.

∗ Lead is also a specific organ toxin> howe"er! it has three tar$et !r$as (central nervous

system, kidney, and hematopoietic system).

1.&. DO0E-RE05ON0E RELATION06I5

D!se 'y definition is the amount of a su'stance administered at one time. =owe"er! other

parameters are needed to characteri-e the exposure to xeno'iotics. The most important are the

num'er of doses! fre,uency! and total time period of the treatment.

2or example)

∗ 65A mg Tylenol as a single dose

∗ 5AA mg Benicillin e"ery C hours for 1A days

∗ 1A mg ::T per day for DA days

There are numerous t%pes !f d!ses! e.g.! exposure dose! a'sor'ed dose! administered dose andtotal dose.




racti!ati$ a total dose usually decreases the pro'a'ility that the total dose will cause

toxicity. The reason for this is that the 'ody often can repair the effect of each su'toxic dose if

sufficient time passes 'efore recei"ing the next dose. +n such a case! the total dose! harmful ifrecei"ed all at once! is non8toxic when administered o"er a period of time. 2or example! 4A mg

of strychnine swallowed at one time could 'e fatal to an adult whereas 4 mg of strychnine

swallowed each day for ten days would not 'e fatal.

The +its used in toxicology are 'asically the same as those used in medicine. The $ra" is the

standard unit. =owe"er! most exposures will 'e smaller ,uantities and thus the "i##i$ra" 9"$

is commonly used. 2or example! the common adult dose of Tylenol is 65A milligrams.

The clinical and toxic effects of a dose must 'e related to age and 'ody si-e. 2or example! 65A

mg is the adult dose of Tylenol. That would 'e ,uite toxic to young children! and thus 7hildren?sTylenol ta'lets contain only CA mg. & 'etter means to allow for comparison of effecti"eness and

toxicity is the amount of a su'stance administered on a 'ody weight 'asis. & common dose

measurement is "$38$ which stands for mg of su'stance per #g of 'ody weight.

&nother important aspect is the ti"e o"er which the dose is administered. This is especially

important for exposures of se"eral days or for chronic exposures. The commonly used time unitis one day and thus! the usual dosage unit is "$38$3da%.

;ince some xeno'iotics are toxic in much smaller ,uantities than the milligram! smaller fractionsof the gram are used! such as "icr!$ra" 9;$. ther units are shown 'elow)

E/ir!"eta# e)p!s+re +its are expressed as the amount of a xeno'iotic in a unit of the

media.

∗ mgliter ("$3# for li,uids

∗ mg3gram ("$3$ for solids

∗ mgcu'ic meter ("$3"( for air

;maller units are used as needed! e.g.! ;$3"#. ther commonly used dose units for su'stances in

media are parts per million 9pp"! parts per 'illion 9pp4 and parts per trillion 9ppt.

1.&.1. D!se Resp!se

The importance of understanding the dose at which a chemical 'ecomes toxic (harmful wasrecogni-ed centuries ago 'y Baracelsus (10D431501! who essentially stated this concept as “ &ll

su'stances are poisons> there is none which is not a poison. The right dose differentiates a poison

and a remedy.”




Toxicants (toxic chemicals are agents capa'le of producing ad"erse effects in a 'iological

system. & reasona'le ,uestion for one to as# 'ecomes “hich group of chemicals do weconsider to 'e toxic” or “hich chemicals do we consider safe” The short answer to 'oth

,uestions! of course! is &LL 7=EF+7&L;> for e"en relati"ely safe chemicals can 'ecome toxic

if the dose is high enough! and e"en potent! highly toxic chemicals may 'e used safely ifexposure is #ept low enough.

@ecause all chemicals are toxic at some dose! what udgments determine their use To answer

this! one must first understand the use of the dose3response relationship 'ecause this pro"idesthe 'asis for estimating the safe exposure le"el for a chemical. & dose3response relationship is

said to exist when changes in dose produce consistent! nonrandom changes in effect! either in the

magnitude of effect or in the percent of indi"iduals responding at a particular le"el of effect. 2or

example! the num'er of animals dying increases as the dose of strychnine is increased! or withtherapeutic agents the num'er of patients reco"ering from an infection increases as the dosage is

increased. +n other instances! the se"erity of the response seen in each animal increases with an

increase in dose once the threshold for toxicity has 'een exceeded.

The dose8response relationship is a fundamental and essential concept in toxicology. +t

correlates exposures and the spectrum of induced effects. %enerally! the higher the dose! themore se"ere is the response. The dose8response relationship is 'ased on o'ser"ed data from

experimental animal! human clinical! or cell studies.

1.&.&. The Basic C!"p!ets !f Tests Geerati$ D!se'Resp!se Data

The design of any toxicity test essentially incorporates the following fi"e 'asic components)

1. The selection of a test organism

/. The selection of a response to measure (and the method for measuring that response

4. &n exposure period0. The test duration (o'ser"ation period

5. & series of doses to test

Gnowledge of the dose8response relationship)

∗ esta'lishes the lowest dose where an induced effect occurs 8 the threshold effect

∗ determines the rate at which inury 'uilds up 8 the slope for the dose response

∗ esta'lishes causality that the chemical induces 3 the o'ser"ed effects




The d!se-resp!se c+r/e normally ta#es the form of a sigmoid cur"e. +t conforms to a smooth

cur"e as close as possi'le to the indi"idual data points. 2or most effects! small doses are not

toxic. The point at which toxicity first appears is #nown as the thresh!#d dose le"el. 2rom that point! the cur"e increases with higher dose le"els. +n the hypothetical cur"e a'o"e! no toxicity

occurs at 1A mg whereas at 45 mg 1AAH of the indi"iduals experience toxic effects.

& thresh!#d for toxic effects occurs at the point where the 'ody?s a'ility to detoxify a xeno'ioticor repair toxic inury has 'een exceeded. 2or most organs there is a reser"e capacity so that loss

of some organ function does not cause decreased performance. 2or example! the de"elopment of

cirrh!sis in the li"er may not result in a clinical effect until o"er 5AH of the li"er has 'eenreplaced 'y fi'rous tissue.

Gnowledge of the shape and s#!pe of the dose8response cur"e is extremely important in

predicting the toxicity of a su'stance at specific dose le"els. Faor differences among toxicantsmay exist not only in the point at which the threshold is reached 'ut also in the percent of

population responding per unit change in dose (i.e., the slope. &s illustrated a'o"e! Toxicant &

has a higher threshold 'ut a steeper slope than Toxicant @.

1.&.(. D!se Esti"ates !f T!)ic Effects

:ose8response cur"es are used to deri"e dose estimates of chemical su'stances. & common dose

estimate for acute toxicity is the LD,< ( Lethal Dose 50%. This is a statistically deri"ed dose at

which 5AH of the indi"iduals will 'e expected to die. The figure 'elow illustrates how an L:5A

of /A mg is deri"ed.

ther dose estimates also may 'e used. L:A represents the dose at which no indi"iduals are

expected to die. This is ust 'elow the threshold for lethality. L:1A refers to the dose at which

1AH of the indi"iduals will die.


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2or inhalation toxicity! air concentrations are used for exposure "alues. Thus! the L75A is utili-ed

which stands for Lethal 7oncentration 5AH! the calculated concentration of a gas lethal to 5AH

of a group. ccasionally L7A and L71A are also used.

Effecti/e D!ses (EDs are used to indicate the effecti"eness of a su'stance. <ormally! effecti"e

dose refers to a 'eneficial effect (relief of pain). The usual terms are)

T!)ic D!ses (TDs are utili-ed to indicate doses that cause ad"erse toxic effects. The usual dose

estimates are listed 'elow)

The #nowledge of the effecti/e and t!)ic d!se le"els aides the toxicologist and clinician in

determining the relati"e safety of pharmaceuticals. &s shown a'o"e! two dose8response cur"esare presented for the same drug! one for effecti"eness and the other for toxicity. +n this case! a

dose that is 5A8I5H effecti"e does not cause toxicity whereas a DAH effecti"e dose may result in

a small amount of toxicity.

:ue to differences in slopes and threshold doses! low doses may 'e effecti"e without producing

toxicity. &lthough more patients may 'enefit from higher doses! this is offset 'y the pro'a'ility

that toxicity or death will occur. The relationship 'etween the Effecti"e :ose response and the

Toxic :ose response is illustrated a'o"e.







Gnowledge of the slope is important in comparing the toxicity of "arious su'stances. 2or some

toxicants a small increase in dose causes a large increase in response (toxicant , steep slope).

2or other toxicants a much larger increase in dose is re,uired to cause the same increase inresponse (toxicant !, shallo" slope).

1.&.*. Therape+tic Ide)

The Therape+tic Ide) 9TI is used to compare the therapeutically effecti"e dose to the toxicdose. The TI is a statement of relati"e safety of a drug. +t is the ratio of the dose producing

toxicity to the dose needed to produce the desired therapeutic response. The common method

used to deri"e the T+ is to use the 5AH dose8response points. 2or example! if the L:5A is /AA andthe E:5A is /A mg! the T+ would 'e 1A (#00$#0). & clinician would consider a drug safer if it had

a T+ of 1A than if it had a T+ of 4.

The use of the ED,< and LD,< doses to deri"e the TI may 'e misleading as to safety! depending

on the slope of the dose8response cur"es for therapeutic and lethal effects. To o"ercome this

deficiency! toxicologists often use another term to denote the safety of a drug 8 the ar$i !f0afet% 9O0.

The O0 is usually calculated as the ratio of the dose that is ust within the lethal range (L: A1

to the dose that is DDH effecti"e (E:DD. The F; J L:A1E:DD. & physician must use cautionin prescri'ing a drug in which the F; is less than 1.

1.&.,. NOAEL ad LOAEL

Two terms often encountered are N! O4ser/ed Ad/erse Effect Le/e# 9NOAEL and L!=

O4ser/ed Ad/erse Effect Le/e# 9LOAEL. They are the actual data points from human

clinical or experimental animal studies.;ometimes the terms N! O4ser/ed Effect Le/e# 9NOEL and L!=est O4ser/ed Effect Le/e#

9LOEL may also 'e found in the literature. <ELs and LELs do not necessarily imply toxic

or harmful effects and may 'e used to descri'e 'eneficial effects of chemicals as well.The <&EL! L&EL! <EL! and LEL ha"e great importance in the conduct of ris#

assessments.

1.&.. act!rs if#+eci$ D!se'Resp!se c+r/es

A. Or$ais"-Re#ated act!rs





7haracteristics of the test species or the human population may alter the dose3response cur"e or

limit its usefulness. The following "aria'les should 'e considered when extrapolating toxicity

data)

91 R!+te !f E)p!s+re

The exposure pathway! rate and site of a'sorption! through which a su'stance comes in contact

with the 'ody determines

how much of it enters (rate and extent of a'sorption through the lungs (after inhalation!the s#in (after dermal application! or the gastrointestinal (%+ tract (after oral ingestion

which organs are initially exposed to the largest concentration of the su'stance! thus

altering the organ toxicity that is o'ser"ed

rate of meta'olism and excretion of the chemical

;o! changing the route of exposure may alter the dose re,uired to produce toxicity.

9& Geder%ender characteristics may affect the toxicity of some su'stances. omen ha"e a larger percent

of fat in their total 'ody weight than men! and women also ha"e different suscepti'ilities toreproduction system disorders and teratogenic effects.

ne well8#nown pathway for sex8related differences occurs in rodents where the male animals ofmany rodent strains ha"e a significantly greater capacity for the li"er meta'olism and 'rea#down

of chemicals as they ha"e more cytochrome B05A. This greater capacity for oxidati"e

meta'olism can cause the male animals of certain rodent strains to 'e more or less suscepti'le totoxicity from a chemical depending on whether oxidati"e meta'olism represents a 'ioacti"ation

or detoxification pathway. 2or example! in the rat! strychnine is less toxic to male rats when

administered orally 'ecause their greater li"er meta'olism allows them to 'rea# down and clearmore of this poison 'efore it reaches the systemic circulation. This allows them to sur"i"e a dose

that is lethal to their female counterparts. &lternati"ely! this greater capacity for oxidati"e

meta'olism renders male rodents more suscepti'le to the li"er toxicity and carcinogenicity of a

num'er of chemicals that are 'ioacti"ated to a toxic! reacti"e intermediate during oxidati"emeta'olism.

9( A$e

lder people ha"e differences in their musculature and meta'olism! which change the

disposition of chemicals within the 'ody and therefore the le"els re,uired to induce toxicity. &t

the other end of the spectrum! children ha"e higher respiration rates and different organsuscepti'ilities Kgenerally they are less sensiti"e to central ner"ous system (7<; stimulants and

more sensiti"e to 7<; depressants! differences in the meta'olism and elimination of chemicals!

and many other 'iological characteristics that distinguish them from adults in the considerationof ris#s or chemical ha-ards.

9* Effects !f Che"ica# Iteracti! 9Additi/it%> 0%er$is"> 5!tetiati!> ad Ata$!is"




Fixtures represent a challenge 'ecause the response of one chemical might 'e altered 'y the

presence of another chemical in the mixture. & synergistic reaction 'etween two chemicals

occurs when 'oth chemicals produce the toxicity of interest! and when com'ined! the presence of 'oth chemicals causes a greater8than8additi"e effect in the anticipated response. Botentiation

descri'es that situation when a chemical that does not produce a specific toxicity ne"ertheless

increases the toxicity caused 'y another chemical when 'oth are present. &ntagonists arechemicals that diminish another chemicals measured effect.

TABLE: Fathematical 9epresentations of 7hemical +nteractions

Effect Re#ati/e T!)icit%

9h%p!thetica#

E)a"p#e

&dditi"ity / M 4 J 5 rganophosphate pesticides

;ynergistic / M 4 J /A 7igarette smo#ing M as'estos

Botentiation / M A J 1A &lcohol M car'on tetrachloride

&ntagonism 5 M (35 J A Toluene M 'en-ene! caffeine M alcohol

@&L M mercury

=umans are normally exposed to se"eral chemicals at one time rather than to an indi"idual

chemical. Fedical treatment and en"ironment exposure generally consists of multipleexposures. Examples are)

• hospital patients on the a"erage recei"e 6 drugs daily

• home influen-a treatment consists of aspirin! antihistamines! and cough syrup ta#en

simultaneously

• drin#ing water may contain small amounts of pesticides! hea"y metals! sol"ents! andother organic chemicals

• air often contains mixtures of hundreds of chemicals such as automo'ile exhaust and

cigarette smo#e

• gasoline "apor at ser"ice stations is a mixture of 0A85A chemicals

<ormally! the toxicity of a specific chemical is determined 'y the study of animals exposed to

only one chemical. Toxicity testing of mixtures is rarely conducted since it is usually impossi'le

to predict the possi'le com'inations of chemicals that will 'e present in multiple8chemical

exposures.

Neno'iotics administered or recei"ed simultaneously may act independently of each other.

=owe"er! in many cases! the presence of one chemical may drastically affect the response to

another chemical. The toxicity of a com'ination of chemicals may 'e less or it may 'e more

than would 'e predicted from the #nown effects of each indi"idual chemical. The effect that one

chemical has on the toxic effect of another chemical is #nown as an iteracti!.




There are four 'asic types of interactions. Each is 'ased on the expected effects caused 'y the

indi"idual chemicals. The types of interactions are)

This ta'le ,uantitati"ely illustrates the percent of the population affected 'y indi"idual exposureto chemical & and chemical @ as well as exposure to the com'ination of chemical & and

chemical @. +t also gi"es the specific type of interaction)

The interactions descri'ed can 'e categori-ed 'y their chemical or 'iological mechanisms as

follows)

∗ chemical reactions 'etween chemicals

∗ modifications in a'sorption! meta'olism! or excretion

∗ reactions at 'inding sites and receptors

∗ physiological changes

Additivity

Additi/it% is the most common type of drug interaction. Examples of chemical or drug

additi"ity reactions are)

o Two central ner"ous system (7<; depressants ta#en at the same time! a tran,uili-er and

alcohol! often cause depression e,ual to the sum of that caused 'y each drug.

o rganophosphate insecticides interfere with ner"e conduction. The toxicity of the

com'ination of two organophosphate insecticides is e,ual to the sum of the toxicity of

each.

o 7hlorinated insecticides and halogenated sol"ents 'oth produce li"er toxicity. The

hepatotoxicity of an insecticide formulation containing 'oth is e,ui"alent to the sum of

the hepatotoxicity of each. Antagonism

Ata$!is" is often a desira'le effect in toxicology and is the 'asis for most antidotes.

Examples include)




Potentiation

5!tetiati! occurs when a chemical that does not ha"e a specific toxic effect ma#es another

chemical more toxic. Examples are)

• The hepatotoxicity of car'on tetrachloride is greatly enhanced 'y the presence of

isopropanol. ;uch exposure may occur in the wor#place.

•

<ormally! warfarin (a "idely used anticoaulant in cardiac disease) is 'ound to plasmaal'umin so that only /H of the warfarin is acti"e. :rugs which compete for 'inding siteson al'umin increase the le"el of free warfarin to 0H causing fatal hemorrhage.

Synergism

0%er$is" can ha"e serious health effects. ith synergism! exposure to a chemical may

drastically increase the effect of another chemical. Examples are)

• Exposure to 'oth cigarette smo#e and radon results in a significantly greater ris# for lung

cancer than the sum of the ris#s of each.

• The com'ination of exposure to as'estos and cigarette smo#e results in a significantly

greater ris# for lung cancer than the sum of the ris#s of each.

• The hepatotoxicity of a com'ination of ethanol and car'on tetrachloride is much greater

than the sum of the hepatotoxicity of each.

:ifferent types of interactions can occur at different target sites for the same com'ination of two

chemicals. 2or example! chlorinated insecticides and halogenated sol"ents ("hich are often used

toether in insecticide formulations) can produce li"er toxicity with the interaction 'eing

additi"e.

The same com'ination of chemicals produces a different type of interaction on the central

ner"ous system. 7hlorinated insecticides stimulate the central ner"ous system whereas

halogenated sol"ents cause depression of the ner"ous system. The effect of simultaneous

exposure is an antagonistic interaction.

!des !f Che"ica# Iteracti!

7hemical interactions can 'e increased or decreased in one of four ways.

1. 2unctional*'oth chemicals affect the same physiologic function.




/. 7hemical*a chemical interaction 'etween the two compounds affects the toxicity of one of

the chemicals.

4. :ispositional*the a'sorption! meta'olism! distri'ution! or excretion of one of the chemicalsis altered 'y the second chemical.

0. 9eceptor8mediated*when two chemicals 'ind to the same tissue receptor! the second

chemical! which differs in acti"ity! competes for the receptor and there'y alters the effect produced 'y the first chemical.

9, Geetic a8e+p

e are not all 'orn physiologically e,ual! and this pro"ides 'oth ad"antages and disad"antages.

2or example! people deficient in glucose868phosphate dehydrogenase (%6B: deficiency are

more suscepti'le than others to the hemolysis of 'lood 'y aspirin or certain anti'iotics.

9 6ea#th 0tat+s

+n addition to the genetic status! the general well8'eing of an indi"idual! specifically! their

immunologic status! nutritional status! hormonal status! and the a'sence or presence of

concurrent diseases! are features that may alter the dose3response relationship.

B. Che"ica#-0pecific act!rs

92 Che"ica# C!"p!siti!

The physical (particle si-e! li,uid or solid! etc. and chemical ("olatility! solu'ility! etc. properties of the toxic su'stance may affect its a'sorption or alter the pro'a'ility of exposure.

2or example! the lead pigments that were used in paints decades ago were not an inhalation

ha-ard when applied 'ecause they were encapsulated in the paints. =owe"er! as the paint aged!

peeled! and chipped! the lead 'ecame a ha-ard when the paint chips were ingested 'y smallchildren.

9? E)p!s+re C!diti!s

The conditions under which exposure occurs may affect the applied dose of the toxicant! and as a

result! the amount of chemical that 'ecomes a'sor'ed. 2or example! chemicals 'ound to soils

may 'e a'sor'ed through the s#in poorly compared to a'sorption when a neat solution is applied 'ecause the chemical may ha"e affinity for! and 'e 'ound 'y! the organic materials in soil.

7oncentration! type of exposure (dermal! oral! inhalation! etc.! exposure medium (soil! water!

air! food! surfaces! etc.! and duration (acute or chronic are all factors associated with the

exposure conditions that might alter the applied or a'sor'ed dose.

1.(. T!)icit%

Neno'iotics cause many types of toxicity 'y a "ariety of mechanisms. ;ome chemicals are

themsel"es toxic. thers must 'e meta'oli-ed (chemically chaned "ithin the &ody) 'efore they

cause toxicity.Fany xeno'iotics distri'ute in the 'ody and often affect only specific tar$et !r$as. thers!

howe"er! can damage any cell or tissue that they contact. The target organs that are affected may

"ary depending on dosage and route of exposure. 2or example! the target for a chemical after

acute exposure may 'e the ner"ous system! 'ut after chronic exposure may 'e the li"er.




Toxicity can result from ad"erse cellular! 'iochemical! or macromolecular changes. Examples

are)

cell replacement! such as fi'rosis

damage to an en-yme system

disruption of protein synthesis

production of reacti"e chemicals in

cells

:<& damage interference with nutrition

1.(.1. act!rs If#+eci$ T!)icit%

The toxicity of a su'stance depends on the following)

form and innate chemical acti"ity

dosage! especially dose8time

relationship

exposure route

species

age

gender

a'ility to 'e a'sor'ed

meta'olism

distri'ution within the 'ody

excretion

presence of other chemicals

(1) Form and innate chemical activity

The f!r" of a su'stance may ha"e a profound impact on its toxicity especially for metallic

elements. 2or example! the toxicity of mercury "apor differs greatly from methyl mercury.&nother example is chromium. 7r 4M is relati"ely nontoxic whereas 7r 6M causes s#in or nasal

corrosion and lung cancer.

The iate che"ica# acti/it% of su'stances also "aries greatly. ;ome can ,uic#ly damage cellscausing immediate cell death. thers slowly interfere only with a cell?s function. 2or example)

hydrogen cyanide 'inds to cytochrome oxidase resulting in cellular hypoxia and rapid

death

nicotine 'inds to cholinergic receptors in the 7<; altering ner"e conduction and inducing

gradual onset of paralysis

(2) Dosage

The d!sa$e is the most important and critical factor in determining if a su'stance will 'e an

acute or a chronic toxicant. Oirtually all chemicals can 'e acute toxicants if sufficiently largedoses are administered. ften the toxic mechanisms and target organs are different for acute and

chronic toxicity. Examples are)

(3) Exposure route

E)p!s+re r!+te is important in determining toxicity. ;ome chemicals may 'e highly toxic 'y

one route 'ut not 'y others. Two maor reasons are differences in a'sorption and distri'utionwithin the 'ody. 2or example)




ingested chemicals! when a'sor'ed from the intestine! distri'ute first to the li"er and may

'e immediately detoxified

inhaled toxicants immediately enter the general 'lood circulation and can distri'utethroughout the 'ody prior to 'eing detoxified 'y the li"er

2re,uently there are different target organs for different routes of exposure.

() Species

Toxic responses can "ary su'stantially depending on the species. Fost species differences are

attri'uta'le to differences in meta'olism. thers may 'e due to anatomical or physiologicaldifferences. 2or example! rats cannot "omit and expel toxicants 'efore they are a'sor'ed or

cause se"ere irritation! whereas humans and dogs are capa'le of "omiting.

0e#ecti/e t!)icit% refers to species differences in toxicity 'etween two species simultaneously

exposed. This is the 'asis for the effecti"eness of pesticides and drugs. Examples are)

an insecticide is lethal to insects 'ut relati"ely nontoxic to animals

anti'iotics are selecti"ely toxic to microorganisms while "irtually nontoxic to humans

(!) Age

A$e may 'e important in determining the response to toxicants. ;ome chemicals are more toxicto infants or the elderly than to young adults. 2or example)

parathion is more toxic to young animals

nitrosamines are more carcinogenic to new'orn or young animals

(") #ender

&lthough uncommon! toxic responses can "ary depending on se). Examples are)

male rats are 1A times more sensiti"e than females to li"er damage from ::T

female rats are twice as sensiti"e to parathion as male rats

($) A%ility to %e a%sor%ed

The a4i#it% t! 4e a4s!r4ed is essential for systemic toxicity to occur. ;ome chemicals are

readily a'sor'ed and others poorly a'sor'ed. 2or example! nearly all alcohols are readily

a'sor'ed when ingested! whereas there is "irtually no a'sorption for most polymers. The ratesand extent of a'sorption may "ary greatly depending on the form of the chemical and the route

of exposure. 2or example)

ethanol is readily a'sor'ed from the gastrointestinal tract 'ut poorly a'sor'ed through the

s#in

organic mercury is readily a'sor'ed from the gastrointestinal tract> inorganic lead sulfateis not

(&) 'eta%olism

eta4!#is"! also #nown as 'iotransformation! is a maor factor in determining toxicity. The

products of meta'olism are #nown as meta'olites. There are two types of meta'olism 8

det!)ificati! and 4i!acti/ati!. :etoxification is the process 'y which a xeno'iotic iscon"erted to a less toxic form. This is a natural defense mechanism of the organism. %enerally




the detoxification process con"erts lipid8solu'le compounds to polar compounds. @ioacti"ation

is the process 'y which a xeno'iotic may 'e con"erted to more reacti"e or toxic forms.

() Distri%ution

The distri4+ti! of toxicants and toxic meta'olites throughout the 'ody ultimately determines

the sites where toxicity occurs. & maor determinant of whether or not a toxicant will damagecells is its lipid solu'ility. +f a toxicant is lipid8solu'le it readily penetrates cell mem'ranes.

Fany toxicants are stored in the 'ody. 2at tissue! li"er! #idney! and 'one are the most common

storage depots. @lood ser"es as the main a"enue for distri'ution. Lymph also distri'utes somematerials.

(1) Excretion

The site and rate of e)creti! is another maor factor affecting the toxicity of a xeno'iotic. The#idney is the primary excretory organ! followed 'y the gastrointestinal tract! and the lungs (for

ases). Neno'iotics may also 'e excreted in sweat! tears! and mil#.

& large "olume of 'lood serum is filtered through the #idney. Lipid8solu'le toxicants arerea'sor'ed and concentrated in #idney cells. +mpaired #idney function causes slower

elimination of toxicants and increases their toxic potential.

(11) Presence o* other chemicals

The presece !f !ther che"ica#s may decrease toxicity (antagonism)! add to toxicity (additive)!or increase toxicity (synergism or potentiation) of some xeno'iotics. 2or example)

alcohol may enhance the effect of many antihistamines and sedati"es

antidotes function 'y antagoni-ing the toxicity of a poison (atropine counteracts

poisonin &y oranophosphate insecticides)

1.*. 0%ste"ic T!)ic EffectsToxic effects are generally categori-ed according to the site of the toxic effect. +n some cases!

the effect may occur at only one site. This site is referred to as the specific tar$et !r$a. +n

other cases! toxic effects may occur at multiple sites. This is referred as s%ste"ic t!)icit%.

2ollowing are types of systemic toxicity)

&cute Toxicity

;u'chronic

Toxicity

7hronic Toxicity

7arcinogenicity

:e"elopmental

Toxicity

%enetic Toxicity(somatic cells)

(1) Acute toxicity

Ac+te t!)icit% occurs almost immediately (hours$days) after an exposure. &n ac+te e)p!s+re is

usually a single dose or a series of doses recei"ed within a /0 hour period. :eath is a maorconcern in cases of acute exposures. Examples are)

♣ +n 1DCD! 5!AAA people died and 4A!AAA were permanently disa'led due to exposure to

methyl isocyanate from an industrial accident in +ndia.

♣ Fany people die each year from inhaling car'on monoxide from faulty heaters.

<on8lethal acute effects may also occur! e.g.! con"ulsions and respiratory irritation.




(2) Su%chronic +oxicity

0+4chr!ic t!)icit% results from repeated exposure for se"eral wee#s or months. This is acommon human exposure pattern for some pharmaceuticals and en"ironmental agents.

Examples are)

♣ +ngestion of coumadin ta'lets (&lood thinners) for se"eral wee#s as a treatment for"enous throm'osis can cause internal 'leeding.

♣ or#place exposure to lead o"er a period of se"eral wee#s can result in anemia.

(3) ,hronic +oxicity

Chr!ic t!)icit% represents cumulati"e damage to specific organ systems and ta#es many

months or years to 'ecome a recogni-a'le clinical disease. :amage due to su'clinical indi"idual

exposures may go unnoticed. ith repeated exposures or long8term continual exposure! thedamage from these su'clinical exposures slowly 'uilds8up (cumulative damae) until the

damage exceeds the threshold for chronic toxicity. Pltimately! the damage 'ecomes so se"ere

that the organ can no longer function normally and a "ariety of chronic toxic effects may result.

Examples of chronic toxic effects are)♣ cirrhosis in alcoholics who ha"e ingested ethanol for se"eral years

♣ chronic #idney disease in wor#men with se"eral years exposure to lead

♣ chronic 'ronchitis in long8term cigarette smo#ers

♣ pulmonary fi'rosis in coal miners (&lack lun disease)

() ,arcinogenicity

Carci!$eicit% is a complex multistage process of a'normal cell growth and differentiation

which can lead to cancer. &t least two stages are recogni-ed. They are iitiati! in which anormal cell undergoes irre"ersi'le changes and pr!"!ti! in which initiated cells are stimulated

to progress to cancer. 7hemicals can act as iitiat!rs or pr!"!ters.

The initial neoplastic transformation results from the mutation of the cellular genes that control

normal cell functions. The mutation may lead to a'normal cell growth. +t may in"ol"e loss of

suppresser genes that usually restrict a'normal cell growth. Fany other factors are in"ol"ed

(e.., ro"th factors, immune suppression, and hormones).

& t+"!r (neoplasm) is simply an uncontrolled growth of cells. Bei$ t+"!rs grow at the site

of origin> do not in"ade adacent tissues or metastasi-e> and generally are treata'le. a#i$at

t+"!rs (cancer) in"ade adacent tissues or migrate to distant sites (metastasis). They are more

difficult to treat and often cause death.

(!) Developmental +oxicity

De/e#!p"eta# T!)icit% pertains to ad"erse toxic effects to the de"eloping em'ryo or fetus.This can result from toxicant exposure to either parent 'efore conception or to the mother and

her de"eloping em'ryo8fetus. The three 'asic types of de"elopmental toxicity are)




7hemicals cause de"elopmental toxicity 'y two methods. They can act directly on cells of the

em'ryo causing cell death or cell damage! leading to a'normal organ de"elopment. & chemical

might also induce a mutation in a parent?s germ cell which is transmitted to the fertili-ed o"um.;ome mutated fertili-ed o"a de"elop into a'normal em'ryos.

(") #enetic +oxicity

Geetic T!)icit% results from damage to :<& and altered genetic expression. This process is

#nown as "+ta$eesis. The genetic change is referred to as a "+tati! and the agent causing

the change as a "+ta$e. There are three types of genetic change)

+f the mutation occurs in a germ cell the effect is herita4#e. There is no effect on the exposed

person> rather the effect is passed on to future generations. +f the mutation occurs in a s!"atic

cell! it can cause altered cell growth (e.. cancer) or cell death (e.. teratoenesis) in the exposed

person.

1.,. Or$a 0pecific T!)ic Effects

Types of organ specific toxic effects are)

∗ @lood7ardio"ascular Toxicity

∗ :ermalcular Toxicity

∗ %enetic Toxicity (erm cells)

∗ =epatotoxicity

∗ +mmunotoxicity

∗ <ephrotoxicity

∗ <eurotoxicity

∗ 9eproducti"e Toxicity

∗ 9espiratory Toxicity

(1) -lood and ,ardiovascular +oxicity

B#!!d ad Cardi!/asc+#ar T!)icit% results from xeno'iotics acting directly on cells in

circulating 'lood! 'one marrow! and heart.

Examples of 'lood and cardio"ascular toxicity are)

• hypoxia due to car'on monoxide 'inding of hemoglo'in pre"enting transport of oxygen

• decrease in circulating leu#ocytes due to chloramphenicol damage to 'one marrow cells




• leu#emia due to 'en-ene damage of 'one marrow cells

• arteriosclerosis due to cholesterol accumulation in arteries and "eins

(2) Dermal +oxicity

Der"a# T!)icit% may result from direct contact or internal distri'ution to the s#in. Effects range

from mild irritation to se"ere changes! such as corrosi"ity! hypersensiti"ity! and s#in cancer.Examples of dermal toxicity are)

∗ dermal irritation due to s#in exposure to gasoline

∗ dermal corrosion due to s#in exposure to sodium hydroxide (lye)

∗ dermal hypersensiti"ity due to s#in exposure to poison i"y

∗ s#in cancer due to ingestion of arsenic or s#in exposure to PO light

(3) Eye +oxicity

E%e T!)icit% results from direct contact or internal distri'ution to the eye. The cornea andconuncti"a are directly exposed to toxicants. Thus! conuncti"itis and corneal erosion may 'e

o'ser"ed following occupational exposure to chemicals. Fany household items can cause

conuncti"itis. 7hemicals in the circulatory system can distri'ute to the eye and cause corneal

opacity! cataracts! retinal and optic ner"e damage. 2or example)

∗ acids and strong al#alis may cause se"ere corneal corrosion

∗ corticosteroids may cause cataracts

∗ methanol ("ood alcohol) may damage the optic ner"e

() .epatotoxicity

6epat!t!)icit% is toxicity to the li"er! 'ile duct! and gall 'ladder. The li"er is particularly

suscepti'le to xeno'iotics due to a large 'lood supply and its role in meta'olism. Thus it isexposed to high doses of the toxicant or its toxic meta'olites. The primary forms of

hepatotoxicity are)

(!) /mmunotoxicity

I""+!t!)icit% is toxicity of the immune system. +t can ta#e se"eral forms) hypersensiti"ity

(allery and autoimmunity)! immunodeficiency! and uncontrolled proliferation (leukemia and

lymphoma). The normal function of the immune system is to recogni-e and defend againstforeign in"aders. This is accomplished 'y production of cells that engulf and destroy the

in"aders or 'y anti'odies that inacti"ate foreign material. Examples are)

• contact dermatitis due to exposure to poison i"y




• systemic lupus erythematosus in wor#ers exposed to hydra-ine

• immunosuppression 'y cocaine

• leu#emia induced 'y 'en-ene

(") 0ephrotoxicity

The #idney is highly suscepti'le to toxicants for two reasons. & high "olume of 'lood flowsthrough it and filtrates large amounts of toxins which can concentrate in the #idney tu'ules.

Nephr!t!)icit% is toxicity to the #idneys. +t can result in systemic toxicity causing)

• decreased a'ility to excrete 'ody wastes

• ina'ility to maintain 'ody fluid and electrolyte 'alance

• decreased synthesis of essential hormones (e.., erythropoietin)

($) 0eurotoxicity

Ne+r!t!)icit% represents toxicant damage to cells of the central ner"ous system (&rain and

spinal cord) and the peripheral ner"ous system (nerves outside the C'). The primary types of

neurotoxicity are)

• neuronopathies (neuron inury)

• axonopathies (axon inury)

• demyelination (loss of axon insulation)

• interference with neurotransmission

(&) eproductive +oxicity

Repr!d+cti/e T!)icit% in"ol"es toxicant damage to either the male or female reproducti"e

system. Toxic effects may cause)

1. decreased li'ido and impotence/. infertility

4. infant death or childhood mor'idity

0. altered sex ratio and multiple 'irths5. chromosome a'normalities and 'irth defects

6. childhood cancer

I. interrupted pregnancy (a&ortion, fetal death, or premature delivery)

() espiratory +oxicity

Respirat!r% T!)icit% relates to effects on the upper respiratory system (nose, pharynx, larynx,and trachea) and the lower respiratory system (&ronchi, &ronchioles, and lun alveoli). The

primary types of respiratory toxicity are)

1. pulmonary irritation/. asthma'ronchitis

4. reacti"e airway disease

0. allergic al"eolitis5. fi'rotic lung disease

6. pneumoconiosis




I. lung cancer

1.. Ai"a# Testi$ f!r T!)icit%

&nimal tests for toxicity are conducted prior to human clinical in"estigations as part of the non8

clinical la'oratory tests of pharmaceuticals. 2or pesticides and industrial chemicals! humantesting is rarely conducted. &nimal test results often represent the only means 'y which toxicity

in humans can 'e effecti"ely predicted.

ith animal tests)

1. chemical exposure can 'e precisely controlled/. en"ironmental conditions can 'e well8controlled

4. "irtually any type of toxic effect can 'e e"aluated

0. the mechanism 'y which toxicity occurs can 'e studied

Fethods to e"aluate toxicity exist for a wide "ariety of toxic effects. ;ome procedures for

routine safety testing ha"e 'een standardi-ed. 0tadardi7ed ai"a# t!)icit% tests are highlyeffecti"e in detecting toxicity that may occur in humans. 7oncern for animal welfare hasresulted in tests that use humane procedures and only the num'er of animals needed for

statistical relia'ility.

To 'e standardi-ed! a test procedure must ha"e scientific acceptance as the most meaningful

assay for the toxic effect. Toxicity testing can 'e "ery specific for a particular effect! such as

dermal irritation! or it may 'e $eera#! such as testing for un#nown chronic effects.

0tadardi7ed tests ha"e 'een de"eloped for the following effects)

&cute Toxicity ;u'chronic Toxicity

7hronic Toxicity 7arcinogenicity9eproducti"e Toxicity :e"elopmental Toxicity

:ermal Toxicity cular Toxicity

<eurotoxicity %enetic Toxicity

0pecies se#ecti! "aries with the toxicity test to 'e performed. There is no single species of

animal that can 'e used for all toxicity tests. :ifferent species may 'e needed to assess differenttypes of toxicity. +n some cases! it may not 'e possi'le to use the most desira'le animal for

testing 'ecause of animal welfare or cost considerations. 2or example! use of mon#eys and dogs

is restricted to special cases! e"en though they represent the species that may react closest tohumans.

9odents and ra''its are the most commonly used la'oratory species due to their a"aila'ility! low

costs in 'reeding and housing! and past history in producing relia'le results.The toxicologist attempts to design an experiment to duplicate the potential exposure of humans

as closely as possi'le. 2or example)

1. The r!+te !f e)p!s+re should simulate that of human exposure. Fost standard tests useinhalation! oral! or dermal routes of exposure.




/. The a$e !f test ai"a#s should relate to that of humans. Testing is normally conducted

with young adults! although new'orn or pregnant animals may 'e used in some cases.

4. 2or most routine tests! 4!th se)es are used. ;ex differences in toxic response areminimal! except for toxic su'stances with hormonal properties.

0. D!se #e/e#s are normally selected so as to determine the threshold as well as dose8

response relationship. Psually! a minimum of three dose le"els are used.

Acute +oxicity

Ac+te t!)icit% tests are generally the first tests conducted. They pro"ide data on the relati"e

toxicity li#ely to arise from a single or 'rief exposure. ;tandardi-ed tests are a"aila'le for oral!

dermal! and inhalation exposures. @asic parameters of these tests are)

1..1. echais" !f ac+te t!)icit%

Su%chronic +oxicity

0+4chr!ic t!)icit% tests are employed to determine toxicity li#ely to arise from repeated

exposures of se"eral wee#s to se"eral months. ;tandardi-ed tests are a"aila'le for oral! dermal!and inhalation exposures. :etailed clinical o'ser"ations and pathology examinations are

conducted. @asic parameters of these tests are)

,hronic +oxicity




Chr!ic t!)icit% tests determine toxicity from exposure for a su'stantial portion of a su'ect?s

life. They are similar to the su'chronic tests except that they extend o"er a longer period of time

and in"ol"e larger groups of animals. @asic parameters of these tests include)

,arcinogenicity

Carci!$eicit% tests are similar to chronic toxicity tests. =owe"er! they extend o"er a longer

period of time and re,uire larger groups of animals in order to assess the potential for cancer.

@asic parameters of these tests are)

eproductive +oxicity

Repr!d+cti/e t!)icit% testi$ is intended to determine the effects of su'stances on gonadal

function! conception! 'irth! and the growth and de"elopment of the offspring. The oral route is

preferred. @asic parameters of these tests are)




Developmental +oxicity

De/e#!p"eta# t!)icit% testing detects the potential for su'stances to produce em'ryotoxicity

and 'irth defects. @asic parameters of this test are)

Dermal +oxicity

Der"a# t!)icit% tests determine the potential for an agent to cause irritation and inflammation of

the s#in. This may 'e the result of direct damage to the s#in cells 'y a su'stance. +t may also 'e

an indirect response due to sensiti-ation from prior exposure. There are two dermal toxicity

tests)

cular +oxicity

Oc+#ar t!)icit% is determined 'y applying a test su'stance for one second to the eyes of 6 testanimals! usually ra''its. The eyes are then carefully examined for I/8hours! using a magnifying

instrument to detect minor effects. The ocular reaction may occur on the cornea! conuncti"a! or

iris. +t may 'e simple irritation that is re"ersi'le and ,uic#ly disappears or the irritation may 'e

se"ere and produce corrosion! an irre"ersi'le condition.




The eye irritation test is commonly #nown as the @Drai7e Test.@ This test has 'een targeted 'y

animal welfare groups as an inhumane procedure due to pain that may 'e induced in the eye.

The test allows the use of an eye anesthetic in the e"ent pain is e"ident. The :rai-e Test is a

relia'le predictor of human eye response. =owe"er! research to de"elop alternati"e testing

procedures that do not use li"e animals is underway. hile some cell and tissue assays are

promising! they ha"e not as yet pro"ed as relia'le as the animal test.

0eurotoxicity

& 'attery of stadardi7ed e+r!t!)icit% tests has recently 'een de"eloped to supplement the

de#a%ed e+r!t!)icit% test in domestic chic#ens (hens). The hen assay determines delayed

neurotoxicity resulting from exposure to anticholinergic su'stances! such as certain pesticides.

The hens are protected from the immediate neurological effects of the test su'stance and

o'ser"ed for /1 days for delayed neurotoxicity. ther neurotoxicity tests include measurements

of)

#enetic +oxicity

Geetic t!)icit% is determined using a wide range of test species including whole animals and

plants (e.., rodents, insects, and corn)! microorganisms! and mammalian cells. & large "ariety

of tests ha"e 'een de"eloped to measure gene mutations! chromosome changes! and :<&

acti"ity. The most common $ee "+tati! tests in"ol"e)




Chr!"!s!"a# effects can 'e detected 'y a "ariety of tests! some in"ol"ing whole animals (in

vivo). ;ome use cell systems (in vitro). ;e"eral assays are a"aila'le to test for chemically

induced chromosome a'errations in whole animals. The most common tests are)

1.2. 0i$ificace !f T!)icit% testi$

Toxicity studies pro"ide general idea and information a'out)

i. potential therapeutic dose of the drug and possi'le side effects relati"e to different doses (that

is! the dose response relationshipii. suita'le route of administration to attain the therapeutic concentration in target site

iii. suita'le dosage form for formulation

&. Discip#ies !f T!)ic!#!$%

The field of toxicology can 'e di"ided into the following su'8disciplines or su'specialities)

&. E/ir!"eta# T!)ic!#!$% is concerned with the study of chemicals that contaminate food!

water! soil! or the atmosphere. +t also deals with toxic su'stances that enter 'odies of waters such as

la#es! streams! ri"ers! and oceans. This su'8discipline addresses the ,uestion of how "arious plants!animals! and humans are affected 'y exposure to toxic su'stances.

@. Occ+pati!a# 9Id+stria# T!)ic!#!$% is concerned with health effects from exposure tochemicals in the wor#place. This field grew out of a need to protect wor#ers from toxic su'stances

and to ma#e their wor# en"ironment safe.

7. Re$+#at!r% T!)ic!#!$% gathers and e"aluates existing toxicological information to esta'lishconcentration8'ased standards of “safe” exposure. The standard is the le"el of a chemical that a

person can 'e exposed to without any harmful health effects.

:. !!d T!)ic!#!$% is in"ol"ed in deli"ering a safe and edi'le supply of food to the consumer.:uring processing! a num'er of su'stances may 'e added to food to ma#e it loo#! taste! or smell

'etter. 2ats! oils! sugars! starches and other su'stances may 'e added to change the texture and taste

of food. &ll of these additi"es are studied to determine if and at what amount! they may produce

ad"erse effects. & second area of interest includes food allergies. &lmost 4AH of the &merican people ha"e some food allergy. 2or example! many people ha"e trou'le digesting mil#! and are

lactose intolerant. +n addition! toxic su'stances such as pesticides may 'e applied to a food crop in




the field! while lead! arsenic! and cadmium are naturally present in soil and water! and may 'ea'sor'ed 'y plants. Toxicologists must determine the accepta'le daily inta#e le"el for those

su'stances.

E. C#iica# T!)ic!#!$% is concerned with diseases and illnesses associated with short term or long

term exposure to toxic chemicals. 7linical toxicologists include emergency room physicians who

must 'e familiar with the symptoms associated with exposure to a wide "ariety of toxic su'stances inorder to administer the appropriate treatment.

2. !resic T!)ic!#!$% is used to help esta'lish cause and effect relationships 'etween exposure to a

drug or chemical and the toxic or lethal effects that result from that exposure.

“There are no harmless substances, only harmless ways of using substances.”

PHRM310 Ch1 General Toxicology 9703

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Transcript of PHRM310 Ch1 General Toxicology 9703