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Chapter 2: Toxicology

Toxicology and Industrial Hygiene
• Toxicology – Chapter #2
• How do toxicants enter biological systems?
• How are they eliminated from biological systems?
• What effect do they have on biological systems?
• Industrial Hygiene – Chapter #3
• What can we do to prevent or reduce the entry of hazardous substances 
into biological systems? 

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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 μm,
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:  study of interaction of humans with chemical or physical 
agents
• Toxicant: chemical or physical agent which can cause harm to a biological 
system.  Agents or hazards include chemicals, dusts, fibers, noise, 
radiation
• Industrial hygiene: study of methods to prevent or reduce exposure and 
intrusion of toxicants into biological systems

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Toxic Chemicals
• What makes a substance harmful to humans?
• Intrinsic nature
• Dose: amount and time of exposure

• Medicines, water, nitrogen, for example, are beneficial in proper 
amounts but each can be harmful.  How?

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

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Toxicity • Toxicity: an intrinsic property of an agent that causes a  particular effect on a person • Toxic hazard: likelihood of damaging effect from  exposure to agent • Magnitude of effect on a person can be reduced and  controlled by hygiene methods • Acute toxicity: short period exposure. < 24 hr • Chronic toxicity: multiple exposures during long  exposure period 6 .

Toxicity .

smoking Inhalation * Mouth. stomach Rules on eating. drinking. hoods. nose Ventilation.Entry Routes for Toxicants ROUTE ENTRY CONTROL Ingestion Mouth. protection equipment Injection Cuts in skin Protective clothing Dermal Absorption Skin Protective clothing * industrially most significant .

• Chemical absorption through skin: rate varies widely with chemicals  and skin conditions • Injection: highest blood concentrations • Ingestion: e. Particulates 2 ‐ 5 µm can reach and remain in the  bronchial tubes and alveoli.g. through contamination of food 9 ..Exposure routes of Toxicants • Inhalation: airborne dust concentrations can reduce the transfer of  gases in lungs.

Distribution and elimination DIGESTIVE TRACK BLOOD TARGET ORGAN LIVER KIDNEYS / LUNGS EXCRETION kidneys (urine). lungs. skin DETOXIFICATION liver STORAGE fat tissue . liver (bile).

(Crowl. and Louvar. excretion 11 .F..  distribution. D. biotransformation. Prentice Hall. 2002) blood lungs More damage for higher levels  and time intervals Fig 2‐1  Blood levels exhibit wide variation due to rate and extent of absorption. J.A. Chemical Process Safety. 2nd ed..

  Fat deposits may later be  metabolized with release of the stored toxins into the blood • High infusion of toxins may damage kidneys. digestive tract • Detoxification: liver. bones. where chemicals can be converted  to less harmful products • Storage: fat cells. lungs thereby  reducing elimination amounts and efficiency. digestive tract. lungs. liver.Elimination of Toxins: Biological Control • Excretion: kidneys. 12 . liver. kidney.

 distribution.E.Kinetic Models •Involve uptake.  elimination •Flow •Solubility •Mass transfer coefficient •Reactions •Simultaneous D. developed and model  behavior . transformation.

Single Exposure Dose‐Response • Levels of response to toxicants with numbers or % affected at each  dose level  • Responses of a large number of people follow a normal (Gaussian)  distribution  • Must be careful with conflicting variables (e. age.g.  ethnicity. gender. etc.) 2  1 x     1 2   f (x)  e  2 14 ..

 68.7% • Number of individuals affected with a specific  response = f(x)N. 3  . 99. where N = total number 15 . 1  .4%.Normal Distribution • f(x): fraction of individuals with a specific response  level • x: response • µ: mean of the response (curve position) • : standard deviation of the response (curve  spread). 95. 2  .2%.

Toxicological Studies •toxicant •target or test organism •effect or response to be monitored •dose range •period of test (Acute or Chronic) •Mode of exposure 16 .

 σ = standard deviation. age. D.F.g. x x = response level. diet.  sex. discrete  f (x ) i i 2σ  (x   ) f (x ) i 2 i  2  i  f (x ) i i x f(x) is the fraction experiencing a specific response. weight.. Chemical Process Safety. e.A.. J. Prentice Hall. and Louvar. Toxicological Studies • Quantify the effect of a toxicant on a target system • Dose versus response – susceptibility to a dose varies due to. μ = mean response level Area under curve reflects sum of individuals 17 Crowl.. health μ  x f (x ) i i  i . 2002 . 2nd ed.

Mean value.  Value around the mean is broader if the σ is larger. Chemical Process Safety. Prentice Hall. μ (μx = 0) Fig 2‐3  Effect of the standard deviation..F. 2002 . J. and Louvar. σ. 2nd ed.  18 Crowl..A. of a Gaussian (normal)  distribution. D.

• Display ± 1σ or 68% of responses and • draw a curve through the average response values for  all dose levels 19 .  as shown in Fig 2‐5 represents the response levels for  that dose. • One can construct a dose‐response curve from the  mean responses for all dose levels of an agent. Exposure Dose‐Response Curves • A distribution curve for a single dose level of an agent.

and Louvar. Chemical Process Safety.F. J. 2nd ed. 2002) .. Prentice Hall.A.Dose‐Response Curve From Acute Toxicity Data ED – effective dose (minor /  reversible) TD – toxic dose (irreversible  effect) LD – lethal dose LD50 – dose lethal for 50% 20 (Crowl. D..

.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).

 the log(dose) for each  cause yields a similar sigmoid curve. e. pressure. • Develop a convenient equation to predict the  consequence severity of a causative variable. impulse. Predict Consequence of Exposure • The average response vs.g. radiation  intensity and time. • What type of equation is preferable? 22 .  concentration and time..

g. to  represent the dose‐response data • Let u = (x–µ)/ σ 2 1 x   u2       1 2     1  2  f (x)  e  2 e  2 23 . f(x).. chemical • Convert dose‐response curve to a linear equation  • Use the normal distribution function.Probit Method: Single Exposures • To predict % affected by a cause. e.

 the sigmoidal dose‐ response curve is converted to a straight line. Probit Method • Y is the probit variable to estimate probability or %  of individuals affected 1 Y 5  u 2  • Probability    =   2  exp du  2  • On a linear probit scale. .

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. .

J.A. 2nd ed.F. Prentice Hall... D. 2002) Fig 2‐10. and Louvar. Chemical Process Safety. % Probit (Crowl. The probit transformation converts the sigmoidal response vs ln  dose curve into a straight line on a linear probit scale. 26 .

 and V is the causative  variable Probability x 100 = % 27 . k2 are probit parameters.  where k1. µ Y Y‐ 5 Probability^.3 3 ‐2 2 4 ‐1 16 5 0 50   x = µ (mean) 6 1 85 7 2 98 8 3 99. % 2 ‐3 0.7 • Y =  k1+ k2 lnV to represent dose‐response data for all agents. • Y‐5 are units of σ from the mean.Probit Method and Equation • Probit variable Y ranges from ~ 2 to 8.

 k2) and causative variables. V. where V represents the dose level of a  causative agent • Probit parameters (k1. Probit Procedure • Y =  k1+ k2 lnV.  • Method: Calculate Y and convert to % using a probit table. for a  variety of exposures in Table 2‐5. • Note: Probit table yields mean % of affected individuals or  average consequence • Use probit estimates conservatively recognizing the wide  ranges of individual susceptibilities to toxicants.   28 .

Probit Correlation Y=k1+k2lnV 29 .

Probit Correlation Y=k1+k2lnV .

and Louvar. Chemical Process Safety.F. J. Reprinted by permission of Cambridge University Press 31 Crowl.. Prentice Hall. Probit Analysis. 2002 . Table 2‐4 THE TRANSFORMATION FROM PERCENTAGE TO PROBIT *D.25. 1971. 2nd ed. p. Finney. J.. D.A.

Example Probit Estimation • A blast produces a peak overpressure of 47.000 Pa.  • What fraction of structures will be damaged by  exposure to this overpressure?  • What fraction of people exposed will die as a  result of lung hemorrhage?  • What fraction will have eardrums ruptured?  • What are some conclusions about the effects of  this blast? 32 .

Solution – using Table 2‐5 (verify these in class) • Structure damage …99.6% • Deaths from lung hemorrhage … 0% • Eardrum rupture … 57% 33 .

 depending  on the chemical. Dose Levels • Toxicity degree varies widely with differences in  agent and susceptibility. • Dose/(body weight) and intrinsic nature are the  main parameters • “The poison is in the dose.Relative Toxicity. • A wide range is shown in Table 2‐6 for lethal doses of  many chemical agents for a 70 kg person.” 34 .

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

36 . •Response data are therefore needed over wide  ranges of doses to characterize relative hazards  of toxic agents. Two Toxicants •The relative effects of two toxicants can be very  different at low and high doses.Relative Toxicity.

.8 Logarithm of the dose 37 . 2nd ed.. Chemical Process Safety.F.(Crowl D.A and Louvar J. 2002) B>A A>B Fig 2. Prentice Hall.

Measure responses. . Expose each to a fixed concentration. Wait for a period of time.Toxicology Experiment Example Start with 50 rabbits.

28 3 18 0.02 50 1.36 4 15 0.Determination of Response Curve Response Number Fraction Least 1 2 0.30 Worst 5 1 0.98 .04 2 14 0.00 Average = (1x2+2x14+3x18+4x15+5x1)/50 = response = 149/50 = 2.

Bar Chart Average 20 15 Number 10 5 0 1 2 3 4 5 Response .

Dose Average Response D1 R = 2.98 1 D2 R 2 D R 3 3 D4 R 4 .Repeat experiment at different doses.

. particularly at low doses. Dose Average X Response X X R X 1 D1 Dose This form not very useful. Plot Response vs.

Log response curve X Average X Response X X Log ( Dose ) Get S-shaped curve .better at low dose values .

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

Cannot be used for air pollution exposures. Cannot be used as indication of relative toxicity. Some toxicants have zero thresholds . a professional organization without legal authority.Threshold Limit Values Published by ACGIH: American Conference of Governmental Industrial Hygienists.

40 hours per week. Threshold Limit Values THRESHOLD DOSE: NO DETECTABLE EFFECT Threshold Limit Value TLV: worker’s lifetime This is for 8 hours per day.STEL Short term exposure limit TLV .C Ceiling limit See Table 2-7 for detailed definitions of these.TWA * Time weighed average TLV . See Table 2-8 for specific values for a number of chemicals. . More values are available for TWAs than for STEL or C. NOT CONTINUOUS EXPOSURE! TLV .

Threshold Limit Values .

TLV – Example Values Table AG-1 .

but this is not true for vapors! .08205    PM   mg/m 3   PM  Equation (2-7) For liquid mixtures ppm = mg/m3.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.

For some chemicals. . Most PELs are same as TLVs.PEL . vinyl chloride. i. Most companies use lowest of the two values. Each regulation is unique. Not updated as regularly as TLVs.e. a specific OSHA regulation has been published. but most require EXPLICIT data that workers are not exposed.Permissible Exposure Level Published by OSHA. benzene. See OSHA.. and have legal authority. Defined the same as TLV.gov web site for regulations.

PEL .Permissible Exposure Level .

NFPA (Nat’l Fire Protection Association) Rating Familiar NFPA Diamond symbol Used to inform Not legal limits .

All rights reserved. Third Edition. Crowl and Joseph F. Copyright © 2011 Pearson Education. . Louvar (ISBN: 0131382268) Figure 2-14 The NFPA Diamond used to identify chemical hazards. Inc.From Chemical Process Safety.  By Daniel A.