Chapter-1: GENERAL TOXICOLOGY

Contents
1. INTRODUCTION TO TOXICOLOGY 1.1. Basic defi iti! s a d ter"i !#!$% 1.&. D!se-resp! se re#ati! ship 1.&.1. D!se Resp! se 1.&.&. The Basic C!"p! e ts !f Tests Ge erati $ D!se'Resp! se Data 1.&.(. D!se Esti"ates !f T!)ic Effects 1.&.*. Therape+tic I de) 1.&.,. NOAEL a d LOAEL 1.&.-. .act!rs i f#+e ci $ D!se'Resp! se c+r/es 1.(. T!)icit% 1.(.1. .act!rs I f#+e ci $ T!)icit% 1.*. 0%ste"ic t!)ic effects 1.,. Or$a 0pecific T!)ic Effects 1.-. A i"a# Testi $ f!r T!)icit% 1.-.1. 1echa is" !f ac+te t!)icit% 1.2. I"p!rta ce !f t!)icit% st+d% &. Discip#i es !f T!)ic!#!$%

1. INTRODUCTION TO TOXICOLOGY 1.1. BA0IC DE.INITION0 AND TER1INOLOGY 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
Page 1

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-ards.toxicities 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. I ter a#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 . 1ften 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. 5ith animal testing this exposure often continues for the ma(ority of the experimental animal6s 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 (71 .

PHRM310; Chapter-1: General Toxicology

Page 2

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 toxicant6s site of contact with the organism. Examples include an acid6s 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 extent of 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 #ate t t!)icit%*an ad"erse or undesira'le effect appearing long after the initiation and.or 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 or delayed (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 phosphate 3 methemoglo'in reductase. 1echa is" !f t!)icit%*the necessary 'iologic interactions 'y which a toxicant exerts its toxic effect on an organism. &n example is car'on monoxide (71 asphyxiation due to the 'inding of 71 to hemoglo'in! thus pre"enting the transport of oxygen within the 'lood. T!)ica t*any su'stance that causes a harmful (or ad"erse effect when in contact with a li"ing organism at a sufficiently high concentration.

PHRM310; Chapter-1: General Toxicology

Page 3

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 (71 . 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 a toxic effect. Ris8 assess"e t*the process 'y which the potential (or pro'a'ility of ad"erse health effects of exposure are characteri-ed.

& t!)ic a$e t is anything that can produce an ad"erse 'iological effect. +t may 'e chemical! physical! or 'iological in form. 2or example! toxic agents may 'e chemical (such as cyanide)! physical (such as radiation) and 'iological (such as snake venom). & distinction is made for diseases) due to 'iological organisms. Those organisms that in"ade and multiply within the organism and produce their effects 'y 'iological acti"ity are not classified as toxic agents. &n example of this is a "irus that damages cell mem'ranes resulting in cell death. +f the in"ading organisms excrete chemicals! which are the 'asis for toxicity! the excreted su'stances are #nown as 4i!#!$ica# t!)i s. The organisms in this case are referred to as t!)ic !r$a is"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)

PHRM310; Chapter-1: General Toxicology

Page 4

Toxic su'stances may 'e s%ste"ic t!)i s or !r$a t!)i s. & s%ste"ic t!)i is one that affects the entire 'ody or many organs rather than a specific site. 2or example! potassium cyanide is a systemic toxicant in that it affects "irtually e"ery cell and organ in the 'ody 'y interfering with the cell?s a'ility to utili-e oxygen. Toxicants may also affect only specific tissues or organs while not producing damage to the 'ody as a whole. These specific sites are #nown as the tar$et !r$a s or tar$et tiss+es. @en-ene is a specific !r$a tissues. t!)i in that it is primarily toxic to the 'lood8forming

Lead is also a specific organ toxin> howe"er! it has three tar$et !r$a s (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 and total dose.

PHRM310; Chapter-1: General Toxicology

Page 5

.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 if recei"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?s Tylenol 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 unit is one day and thus! the usual dosage unit is "$38$3da%. ;ince some xeno'iotics are toxic in much smaller ,uantities than the milligram! smaller fractions of the gram are used! such as "icr!$ra" 9;$:. 1ther units are shown 'elow)

E /ir! "e ta# e)p!s+re + its are expressed as the amount of a xeno'iotic in a unit of the media. mg.liter ("$3# for li,uids mg3gram ("$3$ for solids mg.cu'ic meter ("$3"( for air ;maller units are used as needed! e.g.! ;$3"#. 1ther 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 was recogni-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.
PHRM310; Chapter-1: General Toxicology Page 6

Toxicants (toxic chemicals are agents capa'le of producing ad"erse effects in a 'iological system. & reasona'le ,uestion for one to as# 'ecomes 5hich group of chemicals do we consider to 'e toxicE or 5hich chemicals do we consider safeE 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 if exposure is #ept low enough. @ecause all chemicals are toxic at some dose! what (udgments determine their useE To answer this! one must first understand the use of the dose3response relationship 'ecause this pro"ides the '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 with therapeutic 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! the more 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! e ts !f Tests Ge erati $ 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 period 0. 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 in(ury 'uilds up 8 the slope for the dose response esta'lishes causality that the chemical induces 3 the o'ser"ed effects

PHRM310; Chapter-1: General Toxicology

Page 7

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'iotic or repair toxic in(ury 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 'een replaced '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. Fa(or differences among toxicants may 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.

1ther 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.

PHRM310; Chapter-1: General Toxicology

Page 8

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. 1ccasionally 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"es are 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.

PHRM310; Chapter-1: General Toxicology

Page 9

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 in response (toxicant !, shallo" slope). 1.&.*. Therape+tic I de) The Therape+tic I de) 9TI: is used to compare the therapeutically effecti"e dose to the toxic dose. 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 and the E:5A is /A mg! the T+ would 'e 1A (#00$#0). & clinician would consider a drug safer if it had a T+ of 1A than if it had a T+ of 4. The use of the ED,< and LD,< doses to deri"e the TI may 'e misleading as to safety! depending on the slope of the dose8response cur"es for therapeutic and lethal effects. To o"ercome this deficiency! toxicologists often use another term to denote the safety of a drug 8 the 1ar$i !f 0afet% 91O0:. The 1O0 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 F1; J L:A1.E:DD. & physician must use caution in prescri'ing a drug in which the F1; is less than 1. 1.&.,. NOAEL a d 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. <1ELs and L1ELs do not necessarily imply toxic or harmful effects and may 'e used to descri'e 'eneficial effects of chemicals as well. The <1&EL! L1&EL! <1EL! and L1EL ha"e great importance in the conduct of ris# assessments.

1.&.-. .act!rs i f#+e ci $ D!se'Resp! se c+r/es A. Or$a is"-Re#ated .act!rs

PHRM310; Chapter-1: General Toxicology

Page 10

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&: Ge der %ender characteristics may affect the toxicity of some su'stances. 5omen ha"e a larger percent of fat in their total 'ody weight than men! and women also ha"e different suscepti'ilities to reproduction system disorders and teratogenic effects. 1ne well8#nown pathway for sex8related differences occurs in rodents where the male animals of many 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 to toxicity 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 clear more 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"e meta'olism. 9(: A$e 1lder people ha"e differences in their musculature and meta'olism! which change the disposition of chemicals within the 'ody and therefore the le"els re,uired to induce toxicity. &t the other end of the spectrum! children ha"e higher respiration rates and different organ suscepti'ilities Kgenerally they are less sensiti"e to central ner"ous system (7<; stimulants and more sensiti"e to 7<; depressantsL! differences in the meta'olism and elimination of chemicals! and many other 'iological characteristics that distinguish them from adults in the consideration of ris#s or chemical ha-ards. 9*: Effects !f Che"ica# I teracti! 9Additi/it%> 0% er$is"> 5!te tiati! > a d A ta$! is":

PHRM310; Chapter-1: General Toxicology

Page 11

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 are chemicals that diminish another chemical6s measured effect. TABLE: Fathematical 9epresentations of 7hemical +nteractions Effect &dditi"ity ;ynergistic Botentiation &ntagonism Re#ati/e T!)icit% 9h%p!thetica#: /M4J5 / M 4 J /A / M A J 1A 5 M (35 J A E)a"p#e 1rganophosphate pesticides 7igarette smo#ing M as'estos &lcohol M car'on tetrachloride 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 multiple exposures. 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! and other 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 i teracti! .
PHRM310; Chapter-1: General Toxicology Page 12

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 exposure to 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 1rganophosphate 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 A ta$! is" is often a desira'le effect in toxicology and is the 'asis for most antidotes. Examples include)

PHRM310; Chapter-1: General Toxicology

Page 13

Potentiation 5!te tiati! 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 anticoa%ulant in cardiac disease) is 'ound to plasma al'umin so that only /H of the warfarin is acti"e. :rugs which compete for 'inding sites on al'umin increase the le"el of free warfarin to 0H causing fatal hemorrhage. Synergism 0% er$is" can ha"e serious health effects. 5ith 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 to%ether 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. 1!des !f Che"ica# I teracti! 7hemical interactions can 'e increased or decreased in one of four ways. 1. 2unctional*'oth chemicals affect the same physiologic function.
PHRM310; Chapter-1: General Toxicology Page 14

/. 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 chemicals is 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,: Ge etic 1a8e+p 5e 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 small children. 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. 1thers must 'e meta'oli-ed (chemically chan%ed "ithin the &ody) 'efore they cause toxicity. Fany xeno'iotics distri'ute in the 'ody and often affect only specific tar$et !r$a s. 1thers! 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.
PHRM310; Chapter-1: General Toxicology Page 15

Toxicity can result from ad"erse cellular! 'iochemical! or macromolecular changes. Examples are) cell replacement! such as fi'rosis production of reacti"e chemicals in cells damage to an en-yme system :<& damage disruption of protein synthesis interference with nutrition 1.(.1. .act!rs I f#+e ci $ 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. 7r4M is relati"ely nontoxic whereas 7r6M causes s#in or nasal corrosion and lung cancer. The i ate che"ica# acti/it% of su'stances also "aries greatly. ;ome can ,uic#ly damage cells causing immediate cell death. 1thers 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 large doses are administered. 1ften 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 ma(or reasons are differences in a'sorption and distri'ution within the 'ody. 2or example)
PHRM310; Chapter-1: General Toxicology Page 16

 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'ute throughout 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. 1thers may 'e due to anatomical or physiological differences. 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$e may 'e important in determining the response to toxicants. ;ome chemicals are more toxic to infants or the elderly than to young adults. 2or example) parathion is more toxic to young animals nitrosamines are more carcinogenic to new'orn or young animals (") #ender &lthough uncommon! toxic responses can "ary depending on se). Examples are) male rats are 1A times more sensiti"e than females to li"er damage from ::T female rats are twice as sensiti"e to parathion as male rats ($) 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 rates and 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 sulfate is not (&) 'eta%olism 1eta4!#is"! also #nown as 'iotransformation! is a ma(or 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 is con"erted to a less toxic form. This is a natural defense mechanism of the organism. %enerally
PHRM310; Chapter-1: General Toxicology Page 17

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. & ma(or determinant of whether or not a toxicant will damage cells 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 some materials. (1)) Excretion The site and rate of e)creti! is another ma(or 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 are rea'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 prese ce !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 or%anophosphate insecticides) 1.*. 0%ste"ic T!)ic Effects Toxic 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 7hronic Toxicity :e"elopmental Toxicity ;u'chronic 7arcinogenicity 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 ma(or concern 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.
PHRM310; Chapter-1: General Toxicology Page 18

(2) Su%chronic +oxicity 0+4chr! ic t!)icit% results from repeated exposure for se"eral wee#s or months. This is a common 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. 5or#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. 5ith repeated exposures or long8term continual exposure! the damage from these su'clinical exposures slowly 'uilds8up (cumulative dama%e) 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 !$e icit% is a complex multistage process of a'normal cell growth and differentiation which can lead to cancer. &t least two stages are recogni-ed. They are i itiati! in which a normal cell undergoes irre"ersi'le changes and pr!"!ti! in which initiated cells are stimulated to progress to cancer. 7hemicals can act as i itiat!rs or pr!"!ters. The initial neoplastic transformation results from the mutation of the cellular genes that control normal cell functions. The mutation may lead to a'normal cell growth. +t may in"ol"e loss of suppresser genes that usually restrict a'normal cell growth. Fany other factors are in"ol"ed (e.%., %ro"th factors, immune suppression, and hormones). & t+"!r (neoplasm) is simply an uncontrolled growth of cells. Be i$ t+"!rs grow at the site of origin> do not in"ade ad(acent tissues or metastasi-e> and generally are treata'le. 1a#i$ a t t+"!rs (cancer) in"ade ad(acent tissues or migrate to distant sites (metastasis). They are more difficult to treat and often cause death. (!) Developmental +oxicity De/e#!p"e ta# 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)

PHRM310; Chapter-1: General Toxicology

Page 19

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 Ge etic T!)icit% results from damage to :<& and altered genetic expression. This process is #nown as "+ta$e esis. The genetic change is referred to as a "+tati! and the agent causing the change as a "+ta$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.%. terato%enesis) in the exposed person. 1.,. Or$a 0pecific T!)ic Effects Types of organ specific toxic effects are) @lood.7ardio"ascular Toxicity :ermal.1cular Toxicity %enetic Toxicity (%erm cells) =epatotoxicity +mmunotoxicity (1) -lood and ,ardiovascular +oxicity B#!!d a d 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
PHRM310; Chapter-1: General Toxicology Page 20

<ephrotoxicity <eurotoxicity 9eproducti"e Toxicity 9espiratory Toxicity

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 and con(uncti"a are directly exposed to toxicants. Thus! con(uncti"itis and corneal erosion may 'e o'ser"ed following occupational exposure to chemicals. Fany household items can cause con(uncti"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 is exposed 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 (aller%y and autoimmunity)! immunodeficiency! and uncontrolled proliferation (leukemia and lymphoma). The normal function of the immune system is to recogni-e and defend against foreign 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
PHRM310; Chapter-1: General Toxicology Page 21

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 flows through 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 in)ury) axonopathies (axon in)ury) demyelination (loss of axon insulation) interference with neurotransmission (&) 1eproductive +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 'irths 5. chromosome a'normalities and 'irth defects 6. childhood cancer I. interrupted pregnancy (a&ortion, fetal death, or premature delivery) (() 1espiratory +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"eolitis 5. fi'rotic lung disease 6. pneumoconiosis
PHRM310; Chapter-1: General Toxicology Page 22

I. lung cancer 1.-. A i"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! human testing is rarely conducted. &nimal test results often represent the only means 'y which toxicity in humans can 'e effecti"ely predicted. 5ith 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. 0ta dardi7ed a i"a# t!)icit% tests are highly effecti"e in detecting toxicity that may occur in humans. 7oncern for animal welfare has resulted 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 $e era#! such as testing for un#nown chronic effects. 0ta dardi7ed tests ha"e 'een de"eloped for the following effects) &cute Toxicity ;u'chronic Toxicity 7hronic Toxicity 7arcinogenicity 9eproducti"e Toxicity :e"elopmental Toxicity :ermal Toxicity 1cular 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 different types 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 to humans. 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 use inhalation! oral! or dermal routes of exposure.

PHRM310; Chapter-1: General Toxicology

Page 23

/. The a$e !f test a i"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 are minimal! 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. 1echa is" !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
PHRM310; Chapter-1: General Toxicology Page 24

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 !$e icit% 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)

1eproductive +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)

PHRM310; Chapter-1: General Toxicology

Page 25

Developmental +oxicity De/e#!p"e ta# 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)

2cular +oxicity Oc+#ar t!)icit% is determined 'y applying a test su'stance for one second to the eyes of 6 test animals! 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! con(uncti"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.

PHRM310; Chapter-1: General Toxicology

Page 26

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. 5hile 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 sta dardi7ed 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. 1ther neurotoxicity tests include measurements of)

#enetic +oxicity Ge etic 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 $e e "+tati! tests in"ol"e)

PHRM310; Chapter-1: General Toxicology

Page 27

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$ ifica ce !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 relationship ii. suita'le route of administration to attain the therapeutic concentration in target site iii. suita'le dosage form for formulation &. Discip#i es !f T!)ic!#!$%
The field of toxicology can 'e di"ided into the following su'8disciplines or su'specialities) &. E /ir! "e ta# T!)ic!#!$% 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# 9I d+stria#: T!)ic!#!$% is concerned with health effects from exposure to chemicals in the wor#place. This field grew out of a need to protect wor#ers from toxic su'stances and to ma#e their wor# en"ironment safe. 7. Re$+#at!r% T!)ic!#!$% gathers and e"aluates existing toxicological information to esta'lish concentration8'ased standards of safe exposure. The standard is the le"el of a chemical that a person can 'e exposed to without any harmful health effects. :. .!!d T!)ic!#!$% 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
PHRM310; Chapter-1: General Toxicology Page 28

the field! while lead! arsenic! and cadmium are naturally present in soil and water! and may 'e a'sor'ed 'y plants. Toxicologists must determine the accepta'le daily inta#e le"el for those su'stances. E. C#i ica# T!)ic!#!$% is concerned with diseases and illnesses associated with short term or long term exposure to toxic chemicals. 7linical toxicologists include emergency room physicians who must 'e familiar with the symptoms associated with exposure to a wide "ariety of toxic su'stances in order to administer the appropriate treatment. 2. .!re sic T!)ic!#!$% 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; Chapter-1: General Toxicology

Page 29