Chapter 2: Toxicology

ToxicologyandIndustrialHygiene
Toxicology Chapter#2
Howdotoxicantsenterbiologicalsystems?
Howaretheyeliminatedfrombiologicalsystems?
Whateffectdotheyhaveonbiologicalsystems?
IndustrialHygiene Chapter#3
Whatcanwedotopreventorreducetheentryofhazardoussubstances
intobiologicalsystems?

2
 Definitions
Toxicology: - entry of toxicants into organism
- elimination from organism Quantitative
- effects on organism

Industrial hygiene: prevention or reduction of entry

Toxicant: - chemical agents

- physical agents: particulates < 5 m,
noise, radiation

Toxicity: property related to effect on organism

Problem: organisms respond via a
distribution of effects
Toxic hazard: likelihood of damage based on exposure
reduction by appropriate techniques
Toxicants
Toxicology:studyofinteractionofhumanswithchemicalorphysical
agents
Toxicant: chemicalorphysicalagentwhichcancauseharmtoabiological
system.Agentsorhazardsincludechemicals,dusts,fibers,noise,
radiation
Industrialhygiene:studyofmethodstopreventorreduceexposureand
intrusionoftoxicantsintobiologicalsystems

4
 ToxicChemicals
Whatmakesasubstanceharmfultohumans?
Intrinsicnature
Dose:amountandtimeofexposure

Medicines,water,nitrogen,forexample,arebeneficialinproper
amountsbuteachcanbeharmful.How?

Therearenoharmlesssubstances,only
harmlesswaysofusingsubstances

5
 Toxicity
Toxicity: anintrinsicpropertyofanagentthatcausesa
particulareffectonaperson
Toxichazard:likelihoodofdamagingeffectfrom
exposuretoagent
Magnitudeofeffectonapersoncanbereducedand
controlledbyhygiene methods
Acutetoxicity:shortperiodexposure,<24hr
Chronictoxicity: multipleexposuresduringlong
exposureperiod

6
Toxicity
Entry Routes for Toxicants

ROUTE ENTRY CONTROL

Ingestion Mouth, stomach Rules on eating, drinking,
smoking
Inhalation * Mouth, nose Ventilation, hoods,
protection equipment
Injection Cuts in skin Protective clothing

Dermal Absorption Skin Protective clothing

* industrially most significant

ExposureroutesofToxicants
Inhalation:airbornedustconcentrationscanreducethetransferof
gasesinlungs.Particulates2 5mcanreachandremaininthe
bronchialtubesandalveoli.
Chemicalabsorptionthroughskin:ratevarieswidelywithchemicals
andskinconditions
Injection: highestbloodconcentrations
Ingestion: e.g.,throughcontaminationoffood

9
Distribution and elimination

DIGESTIVE TRACK BLOOD TARGET ORGAN

LIVER KIDNEYS / LUNGS

EXCRETION kidneys (urine), liver (bile), lungs, skin

DETOXIFICATION liver
STORAGE fat tissue
 (Crowl, D.A. and Louvar, J.F., Chemical Process Safety, 2nd ed., Prentice Hall, 2002)

blood

lungs

Moredamageforhigherlevels
andtimeintervals

Fig21Bloodlevelsexhibitwidevariationduetorateandextentofabsorption,
distribution,biotransformation,excretion

11
EliminationofToxins:BiologicalControl
Excretion:kidneys,lungs,digestivetract
Detoxification:liver,digestivetract,wherechemicalscanbeconverted
tolessharmfulproducts
Storage:fatcells,liver,kidney,bones.Fatdepositsmaylaterbe
metabolizedwithreleaseofthestoredtoxinsintotheblood
Highinfusionoftoxinsmaydamagekidneys,liver,lungsthereby
reducingeliminationamountsandefficiency.

12
KineticModels
Involveuptake,distribution,transformation,
elimination
Flow
Solubility
Masstransfercoefficient
Reactions
SimultaneousD.E.developedandmodel
behavior
SingleExposureDoseResponse
Levelsofresponsetotoxicantswithnumbersor%affectedateach
doselevel
Responsesofalargenumberofpeoplefollowanormal(Gaussian)
distribution
Mustbecarefulwithconflictingvariables(e.g.,gender,age,
ethnicity,etc.)

2

1 x

1 2
f (x) e
2

14
NormalDistribution

f(x):fractionofindividualswithaspecificresponse
level
x:response
:meanoftheresponse(curveposition)
:standarddeviationoftheresponse(curve
spread);1 ,68.2%;2 ,95.4%;3 ,99.7%
Numberofindividualsaffectedwithaspecific
response=f(x)N,whereN=totalnumber

15
 ToxicologicalStudies
toxicant
targetortestorganism
effectorresponsetobemonitored
doserange
periodoftest(AcuteorChronic)
Modeofexposure

16
 ToxicologicalStudies
Quantifytheeffectofatoxicantonatargetsystem
Doseversusresponse susceptibilitytoadosevariesdueto,e.g.,age,
sex,weight,diet,health
x f (x ) i i
i
, discrete
f (x ) i
i

2 (x ) f (x )
i
2
i
2
i

f (x ) i
i

f(x)isthefractionexperiencingaspecificresponse,x
x=responselevel;=standarddeviation; =meanresponselevel
Areaundercurvereflectssumofindividuals 17
Crowl, D.A. and Louvar, J.F., Chemical Process Safety, 2nd ed., Prentice Hall, 2002
 Mean value,
(x = 0)

Fig23Effectofthestandarddeviation,, ofaGaussian(normal)
distribution.Valuearoundthemeanisbroaderifthe islarger.

18
Crowl, D.A. and Louvar, J.F., Chemical Process Safety, 2nd ed., Prentice Hall, 2002
 ExposureDoseResponseCurves
Adistributioncurveforasingledoselevelofanagent,
asshowninFig25representstheresponselevelsfor
thatdose.
Onecanconstructadoseresponsecurvefromthe
meanresponsesforalldoselevelsofanagent.
Display 1 or68%ofresponsesand
drawacurvethroughtheaverageresponsevaluesfor
alldoselevels

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DoseResponseCurveFromAcuteToxicityData

ED effectivedose(minor/
reversible)

TD toxicdose(irreversible
effect)

LD lethaldose
LD50 doselethalfor50%
20
(Crowl, D.A. and Louvar, J.F., Chemical Process Safety, 2nd ed., Prentice Hall, 2002)
Definitions
LD = lethal dose
TD = toxic dose (not lethal) but subject suffers
irreversible organ damage
ED = Effective dose (reversible irritation)
LD50 = 50% lethality of the subjects
TD50 = 50% of the subjects response to the agent
is toxic (not lethal but irreversible).
 PredictConsequenceofExposure

Theaverageresponsevs.thelog(dose)foreach
causeyieldsasimilarsigmoidcurve.

Developaconvenientequationtopredictthe
consequenceseverityofacausativevariable,e.g.,
concentrationandtime,pressure,impulse,radiation
intensityandtime.

Whattypeofequationispreferable?

22
ProbitMethod:SingleExposures
Topredict%affectedbyacause,e.g.,chemical
Convertdoseresponsecurvetoalinearequation
Usethenormaldistributionfunction,f(x),to
representthedoseresponsedata
Letu=(x)/

2
1 x u2

1 2
1 2
f (x) e 2
e
2
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 ProbitMethod

Yistheprobit variabletoestimateprobabilityor%
ofindividualsaffected

1 Y 5 u 2
Probability=
2
exp du
2

Onalinearprobit scale,thesigmoidaldose
responsecurveisconvertedtoastraightline.
 Conversion from Probit to %

Y 5 Y 5
P 50 1 erf (2-6)
Y 5 2
P = Percentage
Y = probit
erf = error function (available on spreadsheet)

This is very useful for spreadsheet calculations.

 %

Probit

(Crowl, D.A. and Louvar, J.F., Chemical Process Safety, 2nd ed., Prentice Hall, 2002)

Fig210,Theprobit transformationconvertsthesigmoidalresponsevsln
dosecurveintoastraightlineonalinearprobit scale.

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ProbitMethodandEquation
ProbitvariableY rangesfrom~2to8.
Y5areunitsof fromthemean,
Y Y 5 Probability^,%
2 3 0.3
3 2 2
4 1 16
5 0 50x=(mean)
6 1 85
7 2 98
8 3 99.7
Y=k1+k2lnVtorepresentdoseresponsedataforallagents,
wherek1,k2 areprobitparameters,andVisthecausative
variable
Probability x 100 = %

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 ProbitProcedure
Y=k1+k2lnV,whereVrepresentsthedoselevelofa
causativeagent
Probit parameters(k1,k2) andcausativevariables,V,fora
varietyofexposuresinTable25.
Method:CalculateYandconvertto%usingaprobit table.
Note:Probit tableyieldsmean %ofaffectedindividualsor
average consequence
Useprobit estimatesconservativelyrecognizingthewide
rangesofindividualsusceptibilitiestotoxicants.

28
Probit
Correlation

Y=k1+k2lnV

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Probit
Correlation

Y=k1+k2lnV
 Table24
THETRANSFORMATIONFROMPERCENTAGETOPROBIT

*D. J. Finney, Probit Analysis, 1971, p.25. Reprinted by permission of Cambridge University
Press

31
Crowl, D.A. and Louvar, J.F., Chemical Process Safety, 2nd ed., Prentice Hall, 2002
ExampleProbitEstimation
Ablastproducesapeakoverpressureof47,000Pa.
Whatfractionofstructureswillbedamagedby
exposuretothisoverpressure?
Whatfractionofpeopleexposedwilldieasa
resultoflunghemorrhage?
Whatfractionwillhaveeardrumsruptured?
Whataresomeconclusionsabouttheeffectsof
thisblast?

32
Solution usingTable25
(verifytheseinclass)

Structuredamage99.6%

Deathsfromlunghemorrhage0%

Eardrumrupture57%

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RelativeToxicity,DoseLevels

Toxicitydegreevarieswidelywithdifferencesin
agentandsusceptibility.
AwiderangeisshowninTable26forlethaldosesof
manychemicalagentsfora70kgperson,depending
onthechemical.
Dose/(bodyweight)andintrinsicnaturearethe
mainparameters
Thepoisonisinthedose.

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 35
Crowl, D.A. and Louvar, J.F., Chemical Process Safety, 2nd ed., Prentice Hall, 2002
RelativeToxicity,TwoToxicants

Therelativeeffectsoftwotoxicantscanbevery
differentatlowandhighdoses.

Responsedataarethereforeneededoverwide
rangesofdosestocharacterizerelativehazards
oftoxicagents.

36
(Crowl D.A and Louvar J.F., Chemical Process Safety, 2nd ed., Prentice Hall, 2002)

B>A A>B

Fig2.8Logarithmofthedose

37
Toxicology Experiment Example

Start with 50 rabbits.

Expose each to a fixed concentration.
Wait for a period of time.
Measure responses.
Determination of Response Curve

Response Number Fraction

Least 1 2 0.04
2 14 0.28
3 18 0.36
4 15 0.30
Worst 5 1 0.02
50 1.00

Average = (1x2+2x14+3x18+4x15+5x1)/50 =
response = 149/50 = 2.98
 Bar Chart

Average

20

15
Number

10

0
1 2 3 4 5
Response
Repeat experiment at different doses.

Dose Average Response

D1 R = 2.98
1

D2 R
2

D R
3 3

D4 R
4
 Plot Response vs. Dose

Average X
Response X
X

R X
1

D1
Dose
This form not very useful, particularly at low doses.
 Log response curve

X
Average X

Response
X

Log ( Dose )

Get S-shaped curve - better at low dose

values
 Transform into Probit
Change S-shape into straight line using a
mathematical transformation called a probit.
See Table 2-4 in text for numerical conversion.

X
Probit
X
X

Log ( Dose)
Threshold Limit Values
Published by ACGIH: American Conference of
Governmental Industrial Hygienists, a
professional organization without legal
authority.
Cannot be used as indication of relative toxicity.
Cannot be used for air pollution exposures.

Some toxicants have zero thresholds

 Threshold Limit Values
THRESHOLD DOSE: NO DETECTABLE EFFECT
Threshold Limit Value TLV: workers lifetime
This is for 8 hours per day, 40 hours per week.
NOT CONTINUOUS EXPOSURE!

TLV - TWA * Time weighed average

TLV - STEL Short term exposure limit

TLV - C Ceiling limit

See Table 2-7 for detailed definitions of these.

See Table 2-8 for specific values for a number of
chemicals. More values are available for TWAs
than for STEL or C.
Threshold Limit Values
TLV Example Values Table AG-1
Conversion from mg/m3 to ppm
Vv mv / v
C ppm 10 6
10
6

Vb Vb

Rg T mv mv kg/m3 (mg/m3) 106
10 6

Vb
PM Vb

Rg T T
C ppm mg/m 3
0.08205
PM
mg/m 3

PM

Equation (2-7)

For liquid mixtures ppm = mg/m3, but this is

not true for vapors!
PEL - Permissible Exposure Level
Published by OSHA, and have legal authority.
Defined the same as TLV.
Most PELs are same as TLVs.
Not updated as regularly as TLVs.
Most companies use lowest of the two values.

For some chemicals, i.e., benzene, vinyl chloride, a specific

OSHA regulation has been published. Each regulation is unique,
but most require EXPLICIT data that workers are not exposed.
See OSHA.gov web site for regulations.
PEL - Permissible Exposure Level
NFPA (Natl Fire Protection Association) Rating

Familiar NFPA Diamond symbol

Used to inform
Not legal limits
FromChemicalProcessSafety,ThirdEdition,
ByDanielA.CrowlandJosephF.Louvar(ISBN:0131382268)

Figure 2-14 The NFPA Diamond used to identify

chemical hazards.
Copyright 2011 Pearson Education, Inc. All rights reserved.