Tobacco Documents Online

YVES ALARIE, PH.D, DEPARTMENT OF INDUSTRIAL ENVIRONf4ENTAL HEALTH SCIENCES GRADUATE SCHOOL OF PUBLIC HEALTH UNIVERSITY OF PITTSBURGH PITTSBURGH, PA 15261 "INHALATION AND TOXIC RESPONSES OF LUNG" MID-AMERICA TOXICOLOGY COURSE KANSAS CITY, MISSOURI I. DESCRIPTION OF CONTAMINANTS, TERMS AND UNIT USED A. GAS B. VAPOR C. AEROSOL FUMES DUSTS MISTS FOGS SMOKE HAZE SMOG HOMOGENOUS, HETEROGENOUS MONODISPERSED, POLYDISPERSED l 279

II, CONCENTRATION UNITS A, MG/M3 B, PPM C. VOLUME PERCENT D, PPM TO MG/M3 E, MG/M3 TO PPM F. FIBERS/CC 6, I FT3 = Hr INDUSTRIAL AND TOXICOLOGICAL APPLICATIONS 0 DILUTION To TLV 0 A LITTLE GOES A LONG WAY 0 SATURATION CONCENTRATION CONCEPT III, OTHER CONCENTRATION UNITS A. PARTIAL PRESSURE B, PV = NRT C, HENRY'S LAW, OSTWALD COEFFICIENT IV. ACUTE INHALATION TOXICOLOGY A, LC50 B, LT50 C, LCT50 D. HABER'S RULE E. EXPRESSION OF TOXICITY F. BEST G. SECOND BEST H. COMPARING LC50 I, COMPARING LT50 J. COMPARING BOTH LT50 AND LC50 280

G, SPECIFIC OCCUPATIONAL PULMONARY DISEASE 1, CADMIUM AND BERYLLIUM 2. SILICOSIS 3. SILICOTUBERCULOSIS 4, ASBESTOSIS 5, COAL WORKER'S PNEUMOCONIOSIS ~ 6. . KAOLIN 7. SIDEROSIS. NICKEL 8. METAL FUME FEVER, ZINC, CADMIUM 9. TEFLON FUME FEVER H, LUNG CARCINOMA 1. CLASSIFICATION 2. HUMAN CARCINOGENS 3, MESOTHELIOMA 283

X. STANDARDS FOR AIRBORNE CONTAMINANTS A. DEFINITIONS, PROMYLGATING AGENCIES I) TLV-TWA ii) TLV (C) III) STEL iv) PEL v) EEL vi) AQS B, OSHA HEALTH HAZARD CATEGORIES I) SYSTEM II) EXAMPLES C, NIOSH/OSHA I) POCKET GUIDE TO CHEMICAL HAZARDS D, AIR QUALITY STANDARDS E. ESTABLISHING TLVs A) TYPE OF DATA B) TYPE OF EFFECTS c) TLV ARE NOT TOXIC INDICES XI. FEDERAL HAZARDOUS SUBSTANCES ACT A) Toxic B) HIGHLY Toxic 284

2, HIGH REACTIVITY, Low WATER SOLUBILITY 3, Low REACTIVITY, No METABOLISM A. PHYSICAL PARAMETERS B. PHYSIOLOGICAL PARAMETERS C. INFLUENCE OF METABOLISM 4. QUICK SUMMARY o APPLICATION IN TOXICOLOGY 5. PRACTICAL USE, ALVEOLAR AIR o EXAMPLE OF INDUSTRIAL EXPOSURE 0 BREATH ANALYSIS IX, EFFECTS ON THE RESPIRATORY TRACT A. SENSORY IRRITANTS B, PULMONARY IRRITANTS C, BRONCHOCONSTRICTORS D. RESPIRATORY IRRITANTS E. PULMONARY SENSITIZERS F, TISSUE REACTIONS 1. OBSTRUCTIVE PULMONARY DISEASE, CHRONIC BRONCHITIES 2. CENTRILOBULAR EMPHYSEMA 3, ASTHMA 4. OXIDANT INJURY 5, PULMONARY EDEMA 282

V. CHAMBERS A. BEST DESIGN B. DESIGN FOR VERY HIGH LEVEL OF AEROSOL C. CHEAP CHAMBER, GOOD RESULTS D. VERY SHORT EXPOSURE E. DON'T EXPOSE ANIMALS UNLESS SURE F. GUIDE FOR EQUILIBRATION TIME G. AIR CHANGES VI, FACTORS INFLUENCING THE DOSE FOR AEROSOLS A. FACTORS INFLUENCING TOTAL DOSE (TOTAL DEPOSITION) B. FACTORS INFLUENCING REGIONAL DEPOSITION I) SEDIMENTATION II) IMPACTION III) DIFFUSION IV) ELECTROSTATIC FORCES V) INTERCEPTION VI) QUICK SUMMARY VII, RETENTION - CLEARANCE A, B, C . D, E, MODEL INPUT ABSORPTION - TRANSLOCATION IMPLICATION OF THE MODEL MAN VS, LABORATORY ANIMALS PROCESSES VIII. FACTORS INFLUENCING THE DOSE FOR GASES, VAPORS 1. HIGH WATER SOLUBILITY AND REACTIVITY 0 IMPORTANCE IN TOXICOLOGICAL STUDIES, MAN VS. MOUSE 4 291

I, DESCRIPTION OF CONTAMINANTS, TERMS USED A, GAS A STATE OF MATTER IN WHICH THE MOLECULES ARE PRACTICALLY UNRESTRICTED BY COHESIVE FORCES, A GAS HAS NEITHER SHAPE NOR VOLUME FOR OUR USE, IT IS A SUBSTANCE WHICH HAS A CRITICAL TEMPERATURE BELOW 20OC AND THUS CANNOT BE CONDENSED AT ANY PRESSURE AT THIS TEMPERATURE, EXAMPLES: METHANE (-82), FLOURINE (-129), HELIUM (-268), B. VAPOR SUBSTANCE DISPERSED IN AIR AS INDIVIDUAL MOLECULES, BELOW ITS CRITICAL TEMPERATURE AND THUS COULD BE CONDENSED TO A LIQUID AT 200C BY INCREASING THE PRESSURE. THE WORDS VAPOR AND GAS ARE OFTEN USED INTERCHANGEABLY, VAPOR IS MORE FREQUENTLY USED FOR A SUBSTANCE WHICH, THOUGH PRESENT IN THE GASEOUS PHASE AT 20OC, GENERALLY EXISTS AS A LIQUID OR SOLID AT THIS TEMPERATURE AND NORMAL ATMOSPHERIC PRESSURE, EXAMPLES: IODINE (512), BENZENE (289), CARBON DISULFIDE (279), WE CAN ALSO SAY THAT S02 (157), CL2 (144), N02 (158) AND C02 (289) CAN BE OBTAINED AS "VAPOR" SINCE AT 200C THEY CAN BE CONDENSED IN THE LIQUID PHASE BY INCREASING THE PRESSURE, THE DIFFERENCE BETWEEN THE TWO SETS OF EXAMPLES IS SIMPLY THAT FOR THE FIRST SET THEY ARE SOLID OR LIQUID AT ATMOSPHERIC PRESSURE AND 200C WHILE FOR THE SECOND SET THEY ARE NOT, 285

OTHER EXAMPLES (FROM REFERENCE 1) SUBSTANCE WATER/GAS QIL/GAS BLOOD/GAS SPECIES ACETONE 395 86 245 MAN BENZENE 2,8 492 7,8 MAN CARBON TETRACHLORIDE 0.25 . 361 2.4 MAN CYCLOPROPANE 0.21 11,5 0,55 MAN METHYL ETHYL KETONE 254 263 202 MAN SULFUR HEXAFLUORIDE 0.006 MAN OTHER EXAMPLES (GARGAS AND ANDERSON, SOT, L985) SUBSTANCES SALINE/GAS BLOOD/GAS 1.1 DICHLOROETHYLENE 0.4 5,0 BROMOCHLOROMETHANE 8 41 DIETHYL ETHER 11 12 METHYL CHLOROFORM 0,75 5.8 293

0 HOMOGENOUS: REFERS TO CHEMICAL CONSTITUTION, I.E.o SULFURIC ACID$ 0 HETEROGENOUS: REFERS TO CHEMICAL CONSTITUTION. I.E. COAL DUSTI •0 MONODISPERSED: REFERS T0- DISTRIBUTION OF PARTICLES AROUND THE GEOMETRIC MEAN OR MEDIAN, USUALLY WHEN GEOMETRIC STANDARD DEVIATION IS 1.2 OR LESS AEROSOL IS SAID TO BE MONODISPERSED1 0 POLYD RSED: AS ABOVE, GEOMETRIC STANDARD DEVIATION LARGER THAN 1.2. HETERODISPERSED ALSO USED. NOTE: AEROSOLS CAN BE HOMOGENOUS AND POLYDISPERSED, HOMOGENOUS AND HETERODISPERSED, ETC. SOME AUTHORS ALSO USE HOMOGENOUS FOR MONODISPERSED, BE CAREFUL, THIS IS WRONG. 287

III, OTHER CONCENTRATION UNITS A, PARTIAL PRESSURE FRACTION (VOLUME/VOLUME COMPOSITION) OF THE TOTAL PRESSURE OF A MIXTURE EXERTED BY A COMPONENT OF THE MIXTURE. FOR EXAMPLE, AT SEA LEVEL. l ATMOSPHERE (760 MMHG, 760 TORRS, 11013 BAR, 1.03 KG/CM2, OR 14.7 P,S,I,A,), IF WE KNOW THE VOLUME COMPOSITION OF EACH COMPONENT IN THE MIXTURE, WE CAN CALCULATE THE PARTIAL PRESSURE OF EACH. ASSUMING THE FOLLOWING COMPOSITION: N2 02 C02 H20 TOTAL 78.6% = 597 MMHG PARTIAL PRESSURE 20Z = 159 MMHG PARTIAL PRESSURE 0,04% = 0.3 MMHG PARTIAL PRESSURE 0,5% = 3.7 MMHG PARTIAL PRESSURE 100% = 760 MMHG TOTAL PRESSURE THE VOLUME COMPOSITION CAN BE IN % OR PPM, SEE ABOVE, SINCE BOTH ARE VOLUME/VOLUME UNIT. THEREFORE, 0,1% OR 1,000 PPM = 0.76 MMHG AT SEA LEVEL, B, PV = NRT IF THE CONCENTRATION IS GIVEN AS MOLES/LITER (N/V), THE PARTIAL PRESSURE P(IN MMHG) CAN BE OBTAINED USING THE VALUE OF THE GAS CONSTANT R AS 62 AND THE TEMPERATURE T IN DEGREE KELVIN. C, HENRY'S LAW ANI~ CO-EF CIENT ( S ~ THE AMOUNT (/tMOLES) OF A GAS DISSOLVED IN A LIQUID IS DIRECTLY PROPORTIONAL TO THE PARTIAL PRESSURE OF THE GAS IN THE GAS PHASE ABOVE THE LIQUID. AT EQUILIBRIUM THE PARTIAL PRESSURE IN BOTH PHASES IS EQUAL BUT THE AMOUNT, IN MOLES, WILL VARY ACCORDING TO EACH GAS. THIS RATIO, $, IS CALLED THE SOLUBILITY COEFFICIENT, 291

CAEROSOL N+ d- STABLE OR QUASI-STABLE SUSPENSION OF SOLID OR LIQUID PARTICLES IN A GASS VARIOUS TERMS ARE USED TO BETTER DEFINE AN AEROSOL DEPENDING ON ITS ORIGIN OR STATE. THESE ARE: o FUMES: SOLID PARTICLES FORMED BY CONDENSATION GENERALLY USED FOR METALS SUCH AS CD, PB, ETC, . BUT CAN BE USED FOR ANY SOLID AFTER HEAT TREATMENT SUCH AS TEFLON OR PVC FUMES. USUALLY BELOW .I UM AND FAIRLY HOMOGENOUS, IN THE CASE OF METALS. o DUSTS: SOLID PARTICLES, FORMED DISINTERGRATION PROCESSES OF A MECHANICAL NATURE, MINING, GRINDING, ETC, USUALLY ABOVE I UM, HETEROGENOUS. LESS STABLE BECAUSE OF LARGER SIZE POLY- DISPERSED, ,P~~ ~""`- 0 MISTS: REFER TO LIQUID PARTICLES. FORMED BY CONDENSATION OF A VAPOR (SMALL PARTICLE. HEMOGENEOUS. STABLE) OR BY ATOMI- ZATION OF A LIQUID (LARGER PARTICLE AND LESS STABLE)l (ke%lvuvt o FOG: A MIST WHICH APPRECIABLY REDUCES VISIBILITY. 0 SMOKE: NPART~~ SS IN SUSPENSION IN AIR RESULTING FROM COMBUS- TION OR PYROLYSIS OF ORGANIC MATERIALS. 0 HAZE: COMBINATION OF VAPOR, DUST, FUME, MIST. 0 $MOG: COMBINATION OF SMOKE AND FOG AS IN THE LONDON SMOG BUT MORE RECENTLY. USED TO DESCRIBE THE RESULTING COMBINATION OF GASES AND AEROSOLS FORMED DURING U-V IRRIADIATION OF HYDRO- CARBONS AND OXIDES OF NITROGEN. OZONE, ETC. . L.A. SMOG. DENVER SMOG, ETC. 286

F, BEST 0 FIX DURATION OF EXPOSURE, ACCORDING TO' SITUATIONS (I.E „ SPILLS, WORKDAY, ETC). VARIOUS CONCENTRATIONS, 0 TRY TO GET DEATHS TOWARD END- OF EXPOSURE OR BEGINNING OF A SHORT POST-EXPOSURE PERIOD (NO MORE THAN 1/3 OF DURATION OF EXPOSURE). CALCULATE LC50 AND ALSO OBSERVE ANIMALS FOR 14 DAYS AND CALCULATE LC50 INCLUDING THIS POST-EXPOSURE PERIOD. RATIO OF THE TWO GIVES INDICATION OF DELAYED TOXICITY1 G, SECOND BEST WHEN IT IS MECHANICALLY IMPOSSIBLE TO GENERATE CONCENTRA- TIONS HIGH ENOUGH FOR ACUTE TOXICITY DURATION OF EXPOSURE CAN BE INCREASED. - CGQ Al-us HOWEVER, COMPARISON OF LC50 FOR TWO MATERIALS WHEN THE DURA- TION OF EXPOSURE IS DIFFERENT BY MORE THAN A FACTOR OF 2 IS RISKY (SEE ABOVE) 297

S =CONCENTRATION IN MOLES (OR MILLIGRAMS) IN LIQUID/CONCEN- TRATION (SAME UNITS) IN GAS PHASE, S=CL CG SOME EXAMPLES # CL 1 O OlS = L N H O CG . ow: ITROGEN, ELIUM XYGEN 100 CL 150 55 = M C0 N 0 - 0 CG 100 , ODERATE: 2 2t CL 50 5S = M = 1 V E CG 100 , ODERATE: INYL THER CL _ 1500 = CG 100 - 15S = HIGH: DIETHYL ETHER CL __ 110000 = 1.1005 = VERY HIGH: ETHANOL CG 100 LIQUID = BLOOD (WATER) T = 37OC 292

H, SEE REFERENCE 1. MODELING OF INHALATION EXPOSURE TO VAPORS: UPTAKE, DISTRIBUTION AND ELIMINATION. VOLUME I AND VOLUME II, V. FISEROVA- BERGEROVA, ED,. CRC PRESS, INC., BOCA RATON, FLORIDA, 1983, 1, INDUSTRIAL AND TOXICOLOGICAL APPLICATIONS 0 DILUTION TO TLV. ASSUME I GRAM OF TOLUENE DIISOCYANATE (TDI), (SPECIFIC GRAVITY 1.2) EVAPORATES COMPLETELY, 0 THRESHOLD LIMIT VALUE (TLV), 1979 IS 0,02 PPM OR 0,14 MG/M3 FOR DILUTION TO 1 PPM: NEED 141 M3 FOR DILUTION TO 0,02 PPM: NEED 7,000 M3 EQUIVALENT TO A BUILDING OF 30 X 15 x 420 FEET o A LITTLE GOES A LONG WAY ASSUME TDI IS STORED AT ABOUT 1000F, WHEN A 55 GALLON DRUM IS FILLED, 55 GALLONS OF "SATURATED" TDI VAPOR ARE LIBERATED, 55 GALLONS 2001 OR 200,000 ML DILUTION TO I PPM: NEED 200,000 ML . DILUTION TO 0.02 PPM: NEED 107M3, A HUGE BUILDING! 0 A LARGE AMOUNT, EVEN WITH HUGE DILUTION GOES A LONG WAY. THE EPISODE IN BOPHAL ILLUSTRATES THE POINT, WITH TONS OF EVAPORATING METHYL ISOCYANATE (MIC), EVEN WITH LARGE AIR DILUTION, THE LC50 FOR 4 HOURS IS PROBABLY AROUND 30 PPM (A BEST GUESS) AND. THEREFORE. THE RESULTS CAN BE ~ DEVASTATING, 269

0 SATURATION CONCENTRATION (CS) VERSUS TOXIC LEVEL C_ MW z 273 = P•• 106 = MGIM3 S 22.4 - T- 760 MW: MOLECULAR WEIGHT P: VAPOR PRESSURE (TORR OR MMHG) T: TEMPERATURE °K 22.4: VOLUME OCCUPIED BY I MOLE OF GAS AT O°C. LITER FOR TDI, AT 25°C, P = 2 x 10-2 0 174,2 •,273 ; 2x10-2~ 106 3 25 C C = 171 / 24 5 S, 24,5 e 298 •' 760 MG M OR , PPM 0 IF TOXIC LEVEL IS 1 PPM IF TOXIC LEVEL IS 5 PPM IF TOXIC LEVEL IS 20 PPM HAZARD LEVEL FOLLOWS, 290

II, CONCENTRATION UNITS AND VOLUME UNITS A MG/M3 - Ap"4-i cohi aP,o~-C--C_ MILLIGRAMS OF POLLUTANT PER CUBIC METER OF AIR, CAN BE USED FOR GAS, VAPOR, AEROSOL. B. P P M tGA- v' wAc°" q `"_ n 01, t,r,~ ;!.,-o vO1LXo-v PARTS PER MILLION = VOLUME OF GAS/VOLUME `OF AIR RELATION- SHIPI VOLUME OF VAPOR OR GAS POLLUTANT X 106 TOTAL VOLUME OF CONTAINER OR TOTAL VOLUME OF AIR SAMPLE C. VOLUME PERCENT SAME VOLUME/VOLUME RELATIONSHIP AS PPM, USED FOR HIGH CONCENTRATION. I.E., 1% OR 0.1% INSTEAD OF 10,000 OR 1,000 PPM RESPECTIVELY, l D. MG/M3 TO PPM = MG/M3 x 24.5 = PPM (AT 250C, 760 MMHG) (22.4 M,W, AT 0°C 760 MMHG) k E. MPpm G/M~0 _ PPMo M~~ESULAR WEIGHT = MG/M3 (AT 25oC. 66OMMHG) 22,4 AT 0 C. 760 MMHG) F, FIBERS/CC NUMBER OF FIBERS/CUBIC CENTIMETER OF AIR, ASBESTOS G. 1 FT3 =28.32 LITERS 288

IV, ACUTE INHALATION TOXICOLOGY A. LC50 ATMOSPHERIC CONCENTRATION, STATISTICALLY ESTIMATED, TO KILL 50% OF THE ANIMALS EXPOSED FOR A FIXED TIME, WITHIN A SPECIFIED POST-EXPOSURE PERIOD, 5/10 EXPOSURE RECOVERY 5/10 EXPOSURE RECOVERY EXPOSURE: I HOUR, RECOVERY 14 DAYS EXPOSURE: 4 HOUR, RECOVERY 14 DAYS 0 TIME: FIXED 0 CONCENTRATIONS: VARIABLE 0 LC50: MG/M3 OR PPM, FOR A SPECIFIC EXPOSURE PERIOD AND A SPECIFIC RECOVERY PERIOD, 294

B. DESIGN FOR VERY HIGH LEVEL OF AEROSOL EXPOSURE THE DECISION TO USE A CHAMBER OR HEAD ONLY EXPOSURE IS IMPOSSIBLE TO MAKE WITHOUT SOME PRELIMINARY WORK WITH MATERIAL. THIS WORK CAN BE DONE USING A SMALL CHAMBER AND A FEW ANIMALS. IN GENERAL, CONCENTRATION OF THAN 50 MG/M3 ARE DIFFICULT TO WORK WITH UNLESS THE PARTICLE SIZE IS SMALL, HED ONLY EXPOSURE IS INDICATED. THIS PRESENTS SOME PROBLEMS, CAGE CONTROL AND HEAD ONLY EXPOSURE CONTROL MUST BE USED, HIGH LABOR, BUT IT CAN BE DONE WELL AND HAS BEEN DONE WELLI THERE HAS BEEN SOME TALK ABOUT AN EPA RECOMMENDED LEVEL OF 5 GRAM/LITER OF AEROSOL. THIS IS IMPOSSIBLE TO ACHIEVE FOR MOST SOLID OR LIQUID AND KEEPING THE PARTICLE SIZE REASONABLY SMALL FOR RATS TO INHALE AND AT THE SAME TIME USING AN INHALATION CHAMBER. DON'T WASTE YOUR TIME TRYING THISI 0 50 MG/M3, SMALL PARTICLES#: OK; LARGER PARTICLES: OK 0> 50 MG/M3. SMALL PARTICLES: OK; LARGER PARTICLES: MORE DIFFI- CULT. 0 500 MG/M3. SMALL PARTICLES: OK; LARGER PARTICLES: LARGE PARTICLES WILL DEPOSIT. 0 5,000 MG/M3, SMALL PARTICLES: OK; LARGER PARTICLES: TOO MUCH DEPOSITION, ~ 1-2 UM MMD AND BELOW, ~ 0 ~ w 0 rn Ln 0 Ln 304

0 WITH REACTIVE GASES "CONDITIONING" OF THE CHAMBER SHOULD BE DONE PRIOR TO LOADING ANIMALS IN THE CHAMBER, ONCE THIS IS DONE, ADDITION OF ANIMALS WILL DROP THE CONCENTRATION BY AT LEAST 50% AND SOMETIMES BY AS MUCH AS 95%. THIS IS NOT SERIOUS FOR A LONG-TERM CHRONIC STUDY. INDEED DURING THE FIRST WEEK OF SUCH STUDY ADJUSTMENT CAN BE MADE TO THE DELIVERY SYSTEM TO BRING THE CONCENTRATION UPWARD TO THE DESIRED LEVEL. IN CASES OF ACUTE STUDIES, IF YOU WANT TO KNOW WHAT THE ANIMALS ARE LIKELY TO 't SOAK" COLLECT DEAD ANIMALS. KEEP THEM REFRIGERATED AND THEN PLACE IN YOUR CHAMBER. THERE WILL BE NO DIFFERENCE BETWEEN LIVE AND DEAD ANIMALS SINCE THE AMOUNT OF POLLUTANT INHALED BY THE LIVING ANIMALS IS EXTREMELY SMALL, THE MAJOR CONTRIBUTION COMES FROM REACTION WITH THE FUR. PROBABLY THE BEST DESIGN IS HEAD ONLY EXPOSURE FOR THESE SITUATIONS, REDUCING THE POSSIBILITY OF INTERFERENCE. 302

~~45C~er~ C, CONCENTRATION X TIME (HABER'S RULE) LCT50: MG ; MIN/M3 OR PPM= MIN USE TO COMPARE ORANGES1 APPLES AND 'ABER1S RULE, WORKS WITHIN LIMITED RANGE ~ nr~ RESPONSE: C r T C OR T WITHIN 2 OR 3, WILL NOT WORK WITH SUBSTANCES HAVING OBVIOUS THRESHOLD (CO) UNLESS QUITE ABOVE THRESHOLD, WORKS BETTER WITH PROGRESSIVE. CUMMULATIVE EFFECT. HABER'S RULE G7 ~ 50% MORTALITY AT 10 MG/M3 10 MIN, C•'T = 100 ~k(5C% MORTALITY AT 5 MG/M3 20 MIN, C, T= 100 50% MORTALITY AT 1 MG/M3 100 MIN, Ci-T = 100: INCORRECT E. EXPRESSION OF TOXICITY DOSE: MG: NONE OF THE ABOVE, RATHER, INTENSITY OF EXPOSURE KG IS INVOLVED, ~ FURTHER READING ON CONCEPT OF DOSE IN INHALATION TOXICOLOGY: MACFARLAND, H,N „ RESPIRATORY TOXICOLOGY, CHAPTER 5 IN ESSAYS IN TOXICOLOGY, VOL, 7, PP. 121-154, 1976, ACADEMIC PRESSI 296

H. COMPARING LC50 I) REGARDLESS OF STATISTICAL SIGNIFICANCE, LC50 FOR TWO MATERIALS ARE COMPARABLE IF WITHIN A FACTOR OF 3. II) IF ABOVE A FACTOR OF 3: START TO THINK ABOUT ITI III) IF ABOVE A FACTOR OF 10. WILL DEFINITIVELY MAKE A DIFFERENCE IN REAL LIFE SITUATIONS. J, COMPARING LTSO NO GOOD GENERAL RULE, A FACTOR OF MAYBE 0,5 OF THE ABOVE, USE LT50 TO COMPARE RAPIDITY OF EFFECT OF TWO MATERIALS AT SIMILAR CONCENTRATION OR FOR TWO MATERIALS FOR THE SAME SITUATION, I,E, SATURATED VAPOR, IDEA OF TENABILITY LIMITS, WHEN COMPARING LT50, MAKE SURE THAT YOU ARE COMPARING THE SAME LEVEL OF EFFECT, FOR EXAMPLE, 99 RATS ARE EXPOSED FOR 4 HOURS TO A SATURATED VAPOR ATMOSPHERE OF MATERIAL A OR MATERIAL B. FOR MATERIAL A THE 5OTH DEATH OCCURRED AT 2 HOURS AND 66 DEATHS OCCURRED BY 4 HOURS, FOR MATERIAL B THE 50TH DEATH OCCURRED AT 2 HOURS AND ALL THE ANIMALS WERE DEAD BY 3 HOURS. COMPARING LT50 IS A TRICKY BUSINESS, 298

B, LT50 TIME FOR 50% OF THE ANIMALS TO DIE AT A.PARTICULAR CONCEN- TRATION, OFTEN USED FOR SATURATED VAPORS. NOT A MEASURE OF TOXICITY, 5/9 EXPOSURE RECOVERY 5/9 EXPOSURE RECOVERY ~ \' Y Y 5/9 EXPOSURE RECOVERY 0 TIME: VARIABLE 0 CONCENTRATION: FIXED 0 FAST ACTING, $LOW ACTING. HAZARD CONCEPT 0 RESEMBLES ANESTHETIC GASES COMPARISONS ON THEIR POTENCY (MG/ML OF BLOOD) AND SPEED OF INDUCTION (TIME FOR A PARTICULAR LEVEL OF ANESTHESIA). ---~ ~ . ! a l -~'L '~21~~a „ vte ~ 0 ~ ~ 0 a, F ~ O\ 295

0 PERMITED DAILY VARIATION REACTION GASES 20% OF DESIRED NON-REACTIVE GASES 15% OF DESIRED AEROSOL "l*1 UM 20% OF DESIRED AEROSOL=1-5 UM 20% OF DESIRED AEROSOL '>5 UM DON'T USE THEM IN LARGE CHAM ER. HEAD ONLY EXPOSURE. RELEVANCE IS IN QUESTION. RATS DO NOT INHALE ROCKS! BIG PROBLEM: CONSUMER SPRAY CAN PRODUCTS. SPRAY PAINTS. POSSIBLY: REDUCE TO SMALLER SIZE SET-UP ELUTRIATION SYSTEMS, 3 03

V, CHAMBER ~~ ALL THERE IS T KNOW ABOUT INHALATION CHAMBERS WAS WRITTEN BY SILVERS IN 1946 (SILVER, S.D. - CONSTANT GASSING CHAMBERS: PRINCIPLES INFLUENCING DESIGN AND OPERATION, J. LAB. CLIN, MED, 31, 1153-1161, 1946). ANYONE STARTING AN INHALATION STUDY WITHOUT READING IT IS MAKING A BIG MISTAKE. A, BEST DESIGN THERE IS. NO SUCH THING AS "BEST DESIGN" CHAMBER TO ANSWER ALL THE NEEDS OF INHALATION TOXICOLOGY STUDIES, THE "BEST DESIGN° IS A CHAMBER THAT WORKS ACCORDING TO THE FOLLOWING CRITERIA: 0 FAIRLY UNIFORM DISTRIBUTION OF CONTAMINANTS, VARIATION OF 10- 15% BETWEEN SAMPLING PORTS ARE QUITE ACCEPTABLE, 0 AIRFLOW (LITERS/MINUTE) EQUAL TO THE TOTAL VOLUME (LITER) OF CHAMBER IS.A GOOD BET TO RUN A CHAMBER. THIS IS GENERALLY SUFFICIENT TO PREVENT TEMPERATURE RISE IF CHAMBER IS CONSTRUCTED WITH METAL, KEEP C02 AND AMMONIA LEVEL LOW. AMMONIA LEVEL SHOULD BE VERIFIED WITH HIGH ANIMAL LOAD PARTICULARLY WHEN REACTION WITH POLLUTANTS IS POSSIBLE, CL2, S02, N02, ETC. IF THIS AIRFLOW PRESENTS A PROBLEM (HIGH COST OF POLLU- TANT, AVAILABILITY OF POLLUTANT, CLEANING, ETC.) IT CAN BE REDUCED BUT PROBABLY NOT BELOW 0,2 THE TOTAL VOLUME OF THE CHAMBER WITHOUT CREATING PROBLEMS WITH TEMPERATURE, AMMONIA, ETC, ,.-IACFARLAND HAS REVIEWED SILVER'S ARTICLE AND EXPANDED IT, SEE FUND, APPL, ToxlcoL, 3, 603-613, 1983. 1 300

0 ANIMAL LOAD SHOULD BE LOWER THAN 1% TO 5% OF CHAMBER VOLUME, CALCULATE AS FOLLOWS: TAKE BODY WEIGHT OF EACH ANIMAL TO BE SAME AS ITS VOLUME (I.E.. 200 GRAMS RAT =.Z LITER) AND MULTIPLY BY NUMBER OF ANIMALS. THUS, TO EXPOSE 100 RATS OF 200 GRAMS (20 LITERS OF RATS) YOU NEED A CHAMBER VOLUME OF MINIMUM 2,000 LITERS AND PREFERABLY THERE WILL BE ONLY ONE LAYER OF ANIMALS -THIS CAN BE REDUCED TO A 400 LITER CHAMBER (5%) BUT LIKELY TO NEED 2 LAYERS. THIS ONE LAYER IS PREFERABLE IF WORKING WITH HIGHLY REACTIVE GASES WHICH WILL REACT WITH FUR OF ANIMALS OR WITH LARGE PARTICLES BUT IS NOT NECESSARY WITH AEROSOL AROUND I UM AND WITH NON REACTIVE GASES SUCH AS CO ETC. OR VAPORS SUCH AS BENZENE, CARBON TETRACHLORIDE, ETCt I 0 DO NOT U§E THE CHAMBER FOR MIXING. THE ADDED POLLUTANT SHOULD BE MIXED WITH THE INCOMING DILUTING AIR IN A MIXING DEVICE PRIOR TO ENTERING THE CHAMBER OR MIXED AT THE TOP OR ENTRANCE OF THE CHAMBER. THE IDEA OF PLACING BAFFLES, ETC, IN A CHAMBER FOR BETTER MIXING IS ABSURD. THE GOLDEN RULE: MIX YOUR MARTINI BEFORE YOU DRINK IT. NOT AFTER, o DO NOT USE FAN IN A CHAMBER FOR MIXING A FAN WILL INCREASE TURBULANCE WHICH WILL INCREASE AEROSOL COAGULATION. STRATI- FICATION AND DEPOSITION ON VARIOUS SURFACES. , t 301

D, VERY SHORT EXPOSURE (10-15 MINUTES) FOR VERY SHORT-EXPOSURE A CHAMBER OPERATED AS ABOVE WOULD BE INAPPROPRIATE UNLESS THE AIRFLOW WAS RAISED TO ABOUT 500 LITERS/MINUTE TO REDUCE EQUILIBRATION TIME, THIS MAY PRESENT SOME PROBLEMS. INSTEAD A CHAMBER HAVING A VOLUME OF 10 LITERS CAN BE MADE OUT OF A GLASS CYLINDER AND USED FOR HEAD ONLY EXPOSURE WITH AN AIRFLOW OF 50 LITERS/MINUTE (SEE BARROW, ARCH, ENV, HLTH, 32, 68-76, I977), ) I 306

G. AIR CHANGES AN AIR CHANGE IS SAID TO OCCUR WHEN A VOLUME OF AIR EQUAL TO THE VOLUME OF THE CHAMBER HAS PASED THROUGH THE CHAMBER. THIS IS A CONVENIENT TERM FOR VENTILATION ENGINEERS BUT IS NOT STRICTLY SPEAKING CORRECT. WHEN SUCH OCCURS, FROM EQUATION 2. ONLY 63% OF THE AIR HAS BEEN '1CHANGED". FROM EQUATION 3, THE TIME FOR ONE "AIR CHANGED" MUST BE MULTIPLIED BY A FACTOR OF 4.6 BEFORE EVEN 99% OF THE EXPECTED CHANGE CAN BE DONE. THEREFORE, IF A AND B ARE EQUAL. THERE IS ONE °AIR CHANGE" EVERY 4.6 MINUTES OR IZ/HOUR, THE BEST THING TO DO IS TO FORGET ABOUT °AIR CHANGE" AND GIVE A AND B. THEN WE KNOW. ) I 310

THE TIME REQUIRED FOR EQUILIBRATION OF THE CHAMBER TO 99% CAN BE CALCULATED BY SETTING EQUATION 2 EQUAL TO 99, -BT -BT 99 = 100 (I-E A) OR E A = 10000 99 =,01 TRANSFORMED INTO LOGARITHM FORM BT - - = LN 0.01 = -4.6052 A AND T99 (MINUTES) = 4,6052 A (3) T99 SHOULD BE CALCULATED FOR EACH SITUATION SO THAT THE TIME TO REACH EQUILIBRATION IS VERY SHORT COMPARED TO THE DURATION OF EXPOSURE, THUS, WHEN A AND B ARE EQUAL X IS ABOUT 5 MINUTES. 309

C. CHEAP CHAMBER, GOOD RESULTS FOR ACUTE, SUB-ACUTE OR CHRONIC WORK USING 10-20 RATS OR 20- 50 MICE AN ALL-GLASS 100-LITER AQUARIUM IS JUST PERFECT, A COVER CAN BE MADE OUT OF PLYWOOD OR PLEXIGLASS WITH THE INSIDE OF THE COVER LINED WITH TEFLON OR POLYETHYLENE FILM, SUCH A CHAMBER COST ABOUT $100 WITH ALL FITTINGS, OPERATED AT 100 LITERS/MIN EQUILIBRIUM CONCENTRATION WILL"BE REACHED IN ABOUT 5 MINUTES WITH UNIFORM DISTRIBUTION OF CONTAMINANTS, GASES OR AEROSOLS (SEE BARROW, TAP, 49, 89-95, 1979). -I 1 ~ -----1- -4 A --> 305

F. RAPID GUIDE FOR EQUILIBRATION TIME AND ITS USE AS A GAS OR AEROSOL IS INTRODUCED AT A UNIFORM RATE IN THE CHAMBER MAINTAINED AT A CONTINUOUS FLOW, THE CONCENTRATION WITHIN THE CHAMBER INCREASES UNTIL IT IS PRACTICALLY CONSTANT. ASSUMING PERFECT MIXING (FROM SILVER, SEE REFERENCE ABOVE)l -BT C = w Q-E A ) B C = CONCENTRATION IN MG/LITER AT TIME T W = MILLIGRAMS OF AGENT INTRODUCE/MINUTE A = VOLUME OF THE CHAMBER IN LITER B = VOLUME OF AIR THROUGH THE CHAMBER IN LITERS/MIN E = THE BASE OF NATURAL LOG, 2.7182 THUS, THE % OF THE DESIRED CONCENTRATION W OBTAINED IN TIME B -BT % = 100 (1-E A ) (1) T IS: (2) 308

DOSE VT F C' T = MG/KG KG ~ REMEMBER; THIS GIVES ONLY TOTAL DEPOSITED, DOES NOT GIVE REGIONAL DEPOSITION WHICH IS HIGHLY IMPORTANT. THIS DOES NOT TAKE CLEARANCE INTO ACCOUNT1 To GET A°BALL PARK" FIGURE, ASSUME 50% (0,5) FOR aI THUS: 0.5 X SOO ML X 15 X I MG X 60 MIN MIN 1,000 ML 70 KG = MG/KG As CAN BE SEEN. WE NOW HAVE THE PROPER UNITS FOR TOXICITY INSTEAD OF JUST HAVING AN EXPOSURE CONCENTRATION IN MG/L OR MG/M3, COM- PARISONS OF TOTAL DOSE RECEIVED CAN BE MADE BETWEEN VARIOUS ANIMALS, EXPOSED AT TH~ SAME CONCENTRATION, ON THE BASIS OF MG/KG OF BODY WEIGHT OR MG/M OF BODY SURFACE AREA OR PULMONARY SURFACE AREA. MG/ML, 312

VI, FACTORS INFLUENCING THE DOSE FOR AEROSOLS 0 A. FACTORS INFLUENCING TOTAL DOSE I) CONCENTRATION IN AIR, C, MG/M3 OR MG/L 11) PARTICLE SIZE.~gp WHICH WILL DETERMINE THE FRACTION OF AEROSOL DEPOSITED) III) MINUTE VENTILATION, MV, WHICH IS DETERMINED BY TIDAL VOLUME (VT) AND NUMBER OF BREATHS PER MINUTE (F) IV) DURATION OF EXPOUSRE IN MINUTES (T) V) BODY WEIGHT, KG USEFUL VALUES AT REST SPECIES VT (ML) F MAN (70 KG) 800 15 MOUSE (.02 KG) 0.1 - 0.2 250 RAT (.2 KG) 2 120 GUINEA PIGS (.2 KG) 2 120 MONKEYS (3 KG) 40 35 MAN (MO DERATE EXERCISE) 1.450 15 f DEPOSITION: ALL FACTORS WHICH DETERMINE WHAT FRACTION OF THE INSPIRED AEROSOL WILL BE CAUGHT IN THE RESPIRATORY TRACT (NOSE TO ALVEOLI) AND FAIL TO EXIT WITH THE EXPIRED AIR, 0 REQUIRED READING FOR ANYONE PLANNING TO WORK WITH AEROSOLS: DEPOSITION AND RETENTION MODELS FOR INTERNAL DOSIMETRY OF THE HUMAN RESPIRATORY TRACT, TASK GROUP ON LUNG DYNAMICS HEALTH PHYSICS 1?. 173-207, 1966, RECENT REVIEW: J,D, BRAIN AND P,A, VALBERG. AMER. REV, RESP. DISEASE 120, 1325-1373, 1979, 311

B. FACTORS AFFECTING REGIONAL DEPOSITION: SIZE, SHAPE, DENSITY I) SEDIMENTATION (GRAVITY), SETTLING ALL PARTICLES WITH DENSITY GREATER THAN AIR EXPERIENCE A DOWNWARD FORCE DUE TO GRAVITY F GRAV = V PART'(D PART - D AIR) G V PART = VOLUME OF THE PARTICLE D = DENSITY G = GRAVITATIONAL ACCELERATION THUS. THE PARTICLE ACCELERATES DOWNWARD UNTIL ITS VELOCITY INCREASES TO THE POINT WHERE THE RETARDING FORCE DUE TO ITS MOTION THROUGH AIR JUST BALANCES ITS WEIGHT1 IF PARTICLE IS SPHERIC AND SMALL ENOUGH SO THAT VISCOUS FORCES ARE THE PRIMARY RESISTIVE FORCES STOKE'S LAW APPLIES TO PREDICT RETARDING FORCES. F RESIST=3%~D N V D = DIAMETER OF PARTICLE N = VISCOSITY OF AIR V= VELOCITY OF THE PARTICLE 313

I) DIFFUSION, BROWNIAN MOVEMENT MOTION CAUSED BY RANDOM MOLECULAR COLLISON THIS PROCESS CAN BE DESCRIBED AS FOLLOWS: A = ~ 6DT A: ROOT-MEAN SQUARE DISPLACEMENT AFTER A TIME. T D: DIFFUSION COEFFICIENT OF PARTICLES WHICH IS EXPRESSED AS FOLLOWS: KT D = 3~7 ND T: TEMPERATURE. KELVIN K: BOLTZMANN CONSTANT (1,3g X].Q-16 ERGS/KO) N: GAS VISCOSITY D: DIAMETER OF PARTICLE IT IS IMPORTANT FOR PARTICLES ]. UM, IMPORTANT TO REMEMBER THAT PARTICLE DIAMETER IS THE PRIMARY FACTOR. 316

THE VELOCITY AT WHICH THIS RESISTIVE FORCE EQUALS THE GRAVITA- TIONAL FORCE IS THE TERMINAL VELOCITY, VT VT =(D PART - D AIR) GD2 18N EXAMPLE: I UM PARTICLE, D = I. VT = 33 UM/S AND WOULD BE ESTABLISHED IN 10 US FOR PARTICLE STARTED FROM REST9 APPLIES TO PARTICLES 1-40 UM. CORRECTION CAN BE MADE FOR 0.001 UM TO 200 UM BUT NOT RELEVANT FOR OUR USE@ FOR NON-SPHERICAL PARTICLES, THIS CANNOT BE CALCULATED BUT MEASURED EXPERIMENTALLY AND CHARACTERIZED AS '1 AERODYNAMIC DIAMETER~~. IT HAS THE SAME SETTLING VEOLICTY OF A UNIT-DENSITY SPHEREI i 314

E. DON'T EXPOSE ANIMALS UNLESS You ARE SURE PRIOR TO EXPOSING ANIMALS YOU SHOULD HAVE A GOOD EXPERIENCE WITH AN EMPTY CHAMBER. INCLUDING THE HOUSING CAGES, YOU SHOULD KNOW HOW LARGE A DIFFERENCE THERE IS BETWEEN THE NOMINAL CONCEN- TRATION AND ACTUAL CONCENTRATION, NOMINAL CONCENTRATION = AGENT FLOW IN MILLIGRAMS/MINUTE AIRFLOW IN LITERS/MINUTE ACTUAL CONCENTRATION = OBTAINED FROM SAMPLING AND ANALYSIS, f ~~`~ ~t rGi v~ LJ -b 307

II) IMPACTION, INTERTIA WHEN AN OBSTACLE IS PLACED IN THE PATH OF THE AIRFLOW OR BIFURCATIONS OR TORTUOUS PATHS SUCH AS IN THE NOSE OR TRACHEO- BRONCHIAL TREE ARE PRESENT SMALL PARTICLES WILL FLOOW THE GAS FLOW LINES BUT LARGE PARTICLES, BECAUSE OF GREATER INTERTIA ARE UNABLE TO CHANGE DIRECTION AND WILL IMPACT ON THE SIDEN IMPACTION WILL DEPEND ON 4 FACTORS LG AIR VELOCITY tr0 DENSITY OF THE PARTICLE ~D SQUARE OF THE PARTICLE DIAMETER L-9 ANGLE OF AIRSTREAM DEFLECTION IMPORTANT: 3 UM, NASOPHARYNGEAL AREA. CENTRAL AIRWAYS, 315

VI, CHARACTERISTICS OF THE AEROSOL, INFLUENCING THE TOXICITY WE NEED TO KNOW: I, MASS CONCENTRATION: MG/M3, DIRECT SAMPLING, GRAVIMETRIC OR OTHER ANALYSIS 2. SIZE AND DISTRIBUTION SIZE OR MASS ARE GIVEN AS COUNT MEDIAN DIAMETER (CMD) /(J\ AND MASS MEDIAN DIAMETER (MMD) WITH THE GEOMETRIC STANDARD 31, DEVIATION (GSD), SINCE TOXICITY IS MORE LIKELY TO BE RELATED TO MASS THE MMD IS THE EXPRESSION OF CHOICE, WE ALSO LIKE TO DEFINE IT AS AN 11 AERODYNAMIC DIAMETER" WHICH TAKES INTO ACCOUNT SHAPE AND DENSITY OF THE PARTICLES WHICH INFLUENCE THEIR BEHAVIOR (SEE ABOVE) AND THIS IS OBTAINED EXPERIMENTALLY, SOLUBILITY IN BODY FLUID WILL AFFECT RETENTION, SYSTEMIC EFFECT, STRICTLY SPEAKING IT IS NOT THE SOLUBILITY IN WATER, UNLESS MATERIAL IS HIGHLY WATER SOLUBLE AND NON- REACTIVE, BUT INCLUDES OTHER PARAMETERS SUCH AS REACTION WITH BIOLOGICAL MOLECULES WHICH MAY INCREASE TRANSPORT (CARRIERS ETC) AND WILL ALSO VARY WITH PARTICLE SIZE. THEREFORE, THE TERM "TRANSLOCATION" IS MORE APPROPRIATE, 0 3 CATEGORIES (TASK GROUP ON LUNG DYNAMICS) Y: (YEAR): VERY INSOLUBLE W: (WEEKS): SOMEWHAT SOLUBLE D: (DAYS): VERY SOLUBLE 319

IV) ELECTROSTATIC FORCES ALL AEROSOL PARTICLES HAVE A + (NON-METALLIC) OR - (METALLIC) CHARGE WHICH MAY AFFECT DEPOSITION. HOWEVER, LITTLE IS KNOWN ABOUT THE EFFECT OF CHARGE$ V) INTERCEPTION OF IMPORTANCE FOR FIBERS AS THE INSPIRED AIR COMES IN CLOSE CONTACT WITH A SURFACE. FIBER DEPOSITION MODELS ARE MUCH LESS WELL DEVELOPED THAN FOR PARTICLES1 l 317

VI, QUICK SUMMARY Directional Chan9es Air Velocity Very abrupt ++++ Nearlv straight +++ Abrupt ++ Mild + 0 Nasopharyngeal • [ \ / ronchiole Pulmonary \S=70m2 V=3,000m1 Cross Importance of Mechanisms Sectional Residence Area Time 2 cm + cm2+ 2 10 cm + brief brief brief ~ 5 2 > 10 cm large ~ Impaction Sediment'ation Diffusiona +++ + ++ + + + +++ ++ + + ++++ ++++ (a) diffuslonal deposition of very small particles and reactive gases may be high in nasopharYnx and tracheobronchial regions. FROM CASSARETT, MODIFIED BY MCCLELLAN GL59 05h05

} F- ) PHYSICAL DIAMETER, µm { 1.0 2.0 3.0 4.0 5.0 AERODYNAMIC DIAMETER (Def), µm- Figure 11•11. Deposition of inhaled monodisperse aerosols of fused aluminosilicate spheres in small rodents showing the deposition in the extrathoracic (ET) region, the tracheobronchial (TB) region, the pulmonary (P) region, and in the total respiratory tract based upon Raabe et a{. (1977). COMPARE THIS FIGURE WITH THE PREVIOUS ONE GIVEN FOR MANI 326

t K. COMPARING BOTH LC50 AND LT50 THIS CAN BE DONE BUT REQUIRES THAT A "STANDARD" BE USED AND THEN COMPARISONS ARE MADE TO THE STANDARD, ANYTHING CAN BE USED AS THE STANDARD OR REFERENCE MATERIAL. FIRST A PERIOD OF TIME MUST BE SELECTED, RELEVANT TO THE SITUATION TO BE INVESTIGATED, IN THE EXAMPLE BELOW, 30 MINUTES WAS SELECTED. THEN THE LC50 I5 DETERMINED, ARRANGING SO THAT 50% OF THE ANIMALS DIE CLOSE TO THE END OF THAT PERIOD. THE TIME WILL BE THE LT50 (22 MINUTES IN THE EXAMPLE GIVEN BELOW FOR WOOD SMOKE AS THE REFERENCE MATERIAL). THEN THE OTHER MATERIALS ARE TESTED, IN THIS PROTOCOL, THE LEVEL OF EFFECT IS FIXED, I,E „ 50% LETHALITY AND WE ASK WHAT WILL BE THE CONCENTRATION TO KILL 50% (LC50) AND THE TIME TO DO THIS (LT50), HOWEVER, REMEMBER THAT A FIXED MAXIMUM TIME WAS SELECTED AND THAT RANKING CAN CHANGE IF ANOTHER TIME PERIOD IS SELECTED, THIS CONCEPT OF CONCENTRATION AND TIME DOES NOT BELONG ONLY TO INHALATION EXPERIMENTS, IT IS ALSO OF IMPORTANCE IN CHRONIC STUDIES WHEN CONSIDERING THE DOSE TO PRODUCE 50% EFFECT (ANY EFFECT SUCH AS TUMORS, ETC) AND THE TIME REQUIRED FOR THIS GIVEN LEVEL OF EFFECT TO OCCUR, THE SAME APPLIES IN AQUATIC TOXICOLOGY. G[.u.arl CONCENTRATION - RESPONSE I MUCH MORE~ MOLE TOXIC ~ AS TOXIC TOXIC TNANITNAN WOOO{AS WOOD ~ WOOD I E 0.1 CIASS 0 7.01 1 1 1l 1 I I 1 11 1 1 1111111 I 1 1111111 Fm. t. Each paint represents the amount ut matetial (grun on the X aais) which produced eufflciem smoke to kBt 50% of the anima0 (LC50) and the time (minutes on the Y asul required to kiB 50% of the animals (LTS/) using that amaunt of material. Reading the gtaph vertically each ma• tesial is classificd in terms of patency while eseh nuterisl is classified In terms of onset of ecsion by reading IlorizontaBy. To cambine both, pamVel quadrants sepamte class A. B. C. and D. For clarity some mmesials listed in Table I have been umitted. However. Table 2 contains the coults far alt macends. FROM TOXICOL, APPLr PHARMACOL, 51, 181-188, 1981, 1.0 10.0 10410 1000.0 GRAMS1 ' <,tW103[~ t 1 s.r wooo I rp.ne ..... . i eGC ~. .~LrO 299

VII, RETENTION - CLEARANCE A, MODEL A MODEL PROPOSED BY THE ASK GROUP ON LUNG DYNAMICS IS USED. THIS MODEL INCLUDES THE FOLLOWING AS PRESENTED IN THE NEXT FIGURE AND THE TABLE BELOW, B, INPUTS DI: TOTAL DUST CONCENTRATION IN INHALED AIR D2: TOTAL DUST CONCENTRATION IN EXHALED AIR D3: TOTAL DUST DEPOSITED IN N-P COMPARTMENT Dl}: TOTAL DUST DEPOSITED IN T-B COMPARTMENT D5: TOTAL DUST DEPOSITED IN P COMPARTMENT C, ABSORPTION - TRANSLOCATION PROCESSES A: UPTAKE INTO SYSTEMIC BLOOD FROM N-P (MIN) B: UPTAKE INTO G,I, TRACT FROM CILIARY MUCUS TRANSPORT (MIN) C: UPTAKE INTO SYSTEMIC BLOOD FROM T-B (MIN) D: UPTAKE INTO G,I, TRACT FROM CILIARY MUCUS TRANSPORT E: FROM T-B (MIN-DAYS) UPTAKE INTO BLOOD FROM DIRECT TRANSLOCATION TO SYSTEMIC BLOOD FROM P(MIN. SOLUBLE) F: UPTAKE INTO G,I, TRACT FROM RELATIVELY RAPID CLEARANCE, DEPENDENT ON RECRUITABLE MACROPHAGES AND COUPLED TO CILIARY - MUCUS TRANSPORT G: UPTAKE INTO G,I, TRACT MUCH SLOWER THAN F, STILL H: DEPEND_ --O.N. -_ENDOCYTOSt_S- AND_--GILT,a,RY - MIIrIIS FOR CLEARANCE (YEAR) UPTAKE BY SLOW REMOVAL VIA LYMPHATIC SYSTEM (YEAR) I: UPTAKE FROM LYMPH TO LYMPH NODES TO BLOOD (YEAR) N J: UPTAKE•FROM G,I, TRACT TO BLOOD AND VICE VERSA, r ~ . o 322

2, HIGH REACTIVITY, Low WATER SOLUBILITY poa~e THESE WILL PENETRATE DEEPER INTO THE LUNG, NO2, 03, COCL2. TDI, METHYL ISOCYANATE. REACT WITH PULMONARY TISSUES, GENERALLY PRODUCE EDEMA. CALCULATE LIKE AEROSOL, ASSUME 100% FOR ?,, __ ~ ~ ~I~~/[n~ni"`~ ~ / ~}.U R2~ n . - 330

1.Or A - "v[" B - 2150m1 u.yu r- 0 V.tM 0 RT 0.80F:'hb . N-P 0.80~- AW z o 0.70~- -Nasa4P V 0.70E- N~U - ,-•• / rSl i Q 0.60~ _ LL 0.60 z ~:4~t- ® 1 N ~:4~ 0 0.30 IL 1110FAMM~ w 0.30 O 0.20 T~Brondiial ' 0.20 0.10 0.10 0 0 0.01 0.05 0.1 0.5 1.0 5 10 50 100 0.01 MASS MEDIAN AERODYNAMIC DIAMETER (µm) 0.10 1.0 10 100 MASS MEDIAN AERODYNAMIC DIAMETER (µm) Figure 6-7. Regional deposition predictions based on model proposed by the International Commission on Radiological Protection Committee li Task Crroup on Lung Dynamicst4f indicating effect of variations in oi and flow rate. (A) Each of the shaded areas (envelopes) indicates the variable deposition for a given mass median (aerodynamfc) diameter in each compartment when the distribution parameter e, varies from 1.2 to 4.5 and the tidal volume is 1,450 m1. (B) Two ventilatory states, 750 and 2,150 ml tidal volume (- ll and -32 liter/min volumes, respectively), are used to indicate the order and direction of change in compartmental deposition that are induced by such factors. Reprinted with permission of Pergamon Press, Ltd., and Task Group Chairman. From Health Physlcs 12:173-207, 19G6."' ' 321

3. Low REACTIVITY WITH SURFACE OF RESPIRATORY SYSTEM. ASSUME INERT GAS AND No METABOLISM, USE THE FOLLOWING SYSTEM: 333

MAN VS, LABORATORY ANIMALS IN AEROSOL EXPOSURE WITH LABORATORY ANIMALS, IT IS IMPORTANT TO RECOGNIZE THAT ALTHOUGH THE SAME PARTICLE SIZE IS USED, DEPOSITION AND RETENTION IS LIKELY TO BE DIFFERENT, FEW STUDIES HAVE BEEN MADE (SEE PALM ET AL „ ARCH, IND, HLTH, 13, 355, 1956, ~ MCMAHON ET AL „ INHALED PARTICLES, VOL. IV, 23, 1977). SOME GENERAL CONCLUSIONS: 0 THE MAJOR FACTOR CONTROLLING NET DOSE RECEIVED SEEMS TO BE MINUTE VENTILATION AND, THEREFORE, THE SMALL ANIMALS WILL RECEIVE A HIGHER TOTAL DOSE BECAUSE OF THEIR HIGHER VENTILATION TO BODY WEIGHT RATIO, HOWEVER, THERE IS A LARGE VARIATION BETWEEN ANIMALS OF SAME SPECIES, AND DEPOSITION SITES WILL VARY DESPITE SIMILAR PARTICLE SIZE BEING USED, 0 THE SMALLER THE ANIMAL THE LARGER THE PROBABILITY OF NASAL ~ RETENTION, A 2 UM PARTICLE: SAME PROBABILITY OF BEING RETAINED IN THE MOUSE NOSE AS AN g UM PARTICLE IN MAN, IMPORTANT FOR LARGE PARTICLES, 0 THE LARGER THE PARTICLES ARE ABOVE 3 UM THE MORE CHANCE OF DIFFERENCE IN REGIONfAL DEPOSITION WITH MAN. TOTAL NET DOSE MAY BE THE SAME BUT BIOLOGICAL EFFECTS MAY BE DIFFERENT. 0 TO HAVE THE SAME RELATION WITH MAN BETWEEN ATMOSPHERIC PARTICULATE CONCENTRATION AND RATE OF DEPOSITION OF PARTICLES IN THE LUNGS, FAIRLY UNIFORM PARTICLES AROUND 1-3 ~ UM (MMD) SEEMS TO BE HIGHEST TO USE WITH SMALL RODENTS, 325

I (OOOi9 01 N0IMOlSNV211 1401) - (000'1S 01 NOI111001SNV2l1 H9IH) 1300W 3H1 d0 SNOIIVDIIdWI ' ,t

-13- I01 VT= 500 ml t=2sec 10l E ~ . ~ 105 v . r^~` Q) 0 I ~ 106~ ~ 1 1 i03 107' S 02 lobar t r a c h e a bronchi rbl alv IOg 0 5- 10 15 20 25 Model Segments figurc 4. Reprinted from IkJiiton, C., Thiclkc. J., and Frank, R., 1972. 332

INSPIRED - CONCENTRATION ~ EXPIRED CONCENTRATION VENTILATION DIFFUSION 1 CARDIAC OUTPUT AMOUNT OF BLOOD TISSUE DISTRIBUTI01 AND METABOLISM WATER: 40 LITERS FAT: 15 LITERS 336

VIII. FACTORS INFLUENCING THE DOSE FOR GASES, VAPORS 1. HIGH WATER SOLUBILITY AND REACTIVITY FOR THESE GASES, S02, HCL, HF, HCHO. CALCULATE LIKE AEROSOL ASSUME IOOX FOR . ESSENTIALLY COMPLETELY REMOVED BY SOLUTION AND REACTION AT THE SURFACES OF THE RESPIRATORY TRACT AND VERY EFFICIENTLY SCRUBBED BY THE UPPER RESPIRATORY TRACT, VERY LITTLE PENETRATION TO THE ALVEOLAR REGION UNTIL HIGH CONCENTRATIONS ARE REACHED. FEW GASES HAVE BEEN INVESTIGATED FOR REGIONAL PENETRA- TION, S02, 03, SEVERAL ALDEHYDES. HIGH WATER SOLUBILITY DOES NOT SEEM TO BE SUFFICIENT SINCE ACETONE IS NOT ENTIRELY REMOVED BY THE NOSE WHILE S02 IS. WITH S02 THE REACTION WITH WATER AT PH 7.4 WILL YIELD SO? + H20 I:z ' H2S03 ,-' H+ + HS03- HS03 - ~ H+ + S03 = THEN REACTION OF HS03 AND S03 = WITH PROTEIN DISULFIDE BONDS TO YIELD SULFONATES1 SIMILAR SCHEMES CAN BE PRESENTED FOR SEVERAL WATER SOLUBLE AND REACTIVE CHEMICALS$ 0 IMPORTANCE IN TOXICOLOGICAL STUDIES: SINCE MICE, RATS, GUINEA PIGS. HAMSTERS ARE OBLIGATORY. NOSE BREATHERS. THE FIRST AREA AFFECTED BY THESE GASES WILL BE THE NOSE. NASAL CARCINOMA IN RATS AND MICE DUE TO FORMALDEHYDE IS A GOOD EXAMPLE. J)y.v~_ ' 0 (J (} 1 0 CALCULATE DOSE SAME AS FOR AEROSOL, USE 100% RETENTION1 328

j---DIAMETER OF AVERAGE MASS (2.056pm) C M ASS MEAN (5L.374~m) I A PA.TICI,L Di 1~z~o~~ /71~C~t-P«TL~S N

\ 'C7 0 10~ 169 ->.2- VT= 500 ml t = 2 sec 0 5 10 15 20 25 Model Seyments Figure 3. Reprinted frcr.rtlcJilton, C., Thielke, d., and Frank, R., 1972. 331

10`G ., ~..~~, 4~ `~ (4') ~ __: _ --- --- . LYMPH .. . . -- ~

C, BRONCHOCONSTRICTORS I) DEFINITION: CHEMICAL WHICH WHEN INHALED WILL INDUCE AN INCREASE IN RESISTANCE TO AIRFLOW WITHIN THE CONDUCTING AIRWAYS OF THE LUNG, THE ACTION CAN BE VIA DIRECT EFFECT ON ~ SMOOTH MUSCLES OF THE CONDUCTING AIRWAYSt BY AXONAL REFLEX, BY VAGO-VAGAL OR - TRIGEMINAL-VAGAL REFLEXES FOLLOWING, STIMULATION OF NERVE ENDINGS BELONGING TO THESE SYSTEMS OR ~ BY LIBERATION OF HISTAMINE, II) OTHER CHARACTERISTICS: MOST OF THESE CHEMICALS ARE ALSO SENSORY IRRITANTS. THEIR ACTION ON THE BRONCHIAL MUCOSA PRODUCES A PAINFUL SENSATION. III) TYPICAL EXAMPLES: SULFUR DIOXIDE, AMMONIA, INERT PARTICLES. SENSITIZATION BY ALLERGENS SUCH AS FOREIGN PROTEINS OR CHEMICALS ACTING AS HAPTEN SUCH AS TOLUENE DIISOCYANATE. AEROSOLS OF HISTAMINE OR CHOLINERGIC AGONISTS, 343

A. PHYSICAL PARAMETERS I) CONCENTRATION IN AIR (MMHG) DETERMINES MAXIMUM CONCEN- TRATION (MMHG) IN BLOOD SINCE EQUILIBRIUM WILL BE ESTABLISHED AT SOME TIME. ii) KNOWING S# GIVES THE MAXIMUM CONCENTRATION IN MOLES OR MILLIGRAMS/LITER OF BLOOD WHICH CAN BE ACHIEVED. I.El. AT EQUILIBRIUM$ III) SUBSTANCES WITH HIGH $ WILL TAKE A LONG TIME TO REACH EQUILIBRIUM (METHANOL, ETHANOL, ACETONE, ETHER. ETC,)l SUBSTANCES WITH LOW S(METHANE, ETC.) WILL REACH EQUILIBRIUM VERY QUICKLY. S VALUE CAN BE TAKEN FOR WATER AT 37OC BUT BE CAREFUL (SEE ABOVE). B, PHYSIOLOGICAL PARAMETERS I) MINUTE VENTILATION: IMPORTANT FOR HIGH S SUBSTANCES II) CARDIAC OUTPUT: IMPORTANT FOR LOW S SUBSTANCES III) AMOUNT OF BLOOD TO BE SATURATED. 5 LITERS AND TOTAL BODY WATER. 40 LITERS. IV) OIL/WATER PARTITION COEFFICIENT: FROM BLOOD TO TISSUES, ADt SOURCES: REFERENCE No. 1, GOLDSTEIN ET AL „ PRINCIPLES OF DRUG ACTION AND REF. 1t S = SOLUBILITY COEFFICIENT t 334

loo O PARrIAL PR8SSy RE ,mumN1,3:N BRo~ a Ti m E -_......~ loo,n,,,, N Pri R a /d0rtn.n H,~ 8ceeD 4 0 O.F.F G G O v c 0 0 0 o a p O o oooa o-0 00000 0 hi4k S „Co~ S J 335 w 0 ~ w 0

5. PRACTICAL USE OF THE CONCEPT (ADAPTED FROM R,D, STEWART) 0 BLOOD CONCENTRATION = ALVEOLAR AIR CONCENTRATION X S ry'~K - L~ HUMAN EXPOSURE TO TRICHLORETHYLENE. 200 PPM. 7 RHS/DAY FOR 5 DAYS, ALVEOLAR AIR CONCENTRATION (PPM) k 1ST DAY 2ND DAY 3RD DAY 4TH DAY 5TH DAY PRE-EXPOSURE (MORNING) 0.01 1.2 1.6 1.6 1.6 3 HOURS 76 75 76 79 76 30 MIN AFTER LUNCH 10.3 10,9 11.5 8.4 8.5 1 HR POST- EXPOSURE 8,3 9.4 9.0 7,7 8,7 3 HR POST- EXPOSURE 5.1 4.4 3,5 3,5 3,6 6 HR POST- EXPOSURE 3.3 2.8 2.4 2.9 2.9 90 HRS, POST-5 DAY EXPOSURE: 0.2 DOES NOT REACH EQUILIBRIUM WITH INSPIRED AIR No CUMMULATION INCOMPLETE RELEASE `~'-V ~ ~~ ~ Ci l~~lc~ }N~•~ C~ ~" ~ ~f vi^~ klN 0 ALCOHOL BREATH TEST ANALYSIS TO DETERMINE THE BLOOD CONCENTRATION FROM A SAMPLE OF ALVEOLAR AIR, SINCE ALVEOLAR AIR IS AT EQUILIBRIUM WITH CAPILLARY BLOOD. BY KNOWING THE AMOUNT IN ALVEOLAR AIR AND THE SOLUBILITY COEFFICIENT ONE KNOWS THE CONCENTRATION IN THE BLOOD, 338

I INSPIRABLE 6D MASS FRACTION 60 EHTERS VIA NOSE ~ DR MOUTN ) 40 9 W EJ J THORACIC MASS FRACTION ( RNETRATION PAST EARYHR I T r E 10 20 30 40 60 60 70 80 90 100 THORACIC PARTICULATE MASS 5 i0 15 20 25 30 35 40 45 50 RESPIRABLE MASS FRACTION ( PENETIIATION /ASS TGMINA{ RRONCNIOEES ( 20~ xm` RESPIRABLE PARTICULATE MASS 80~ 6% 40.J 20. 0 INSPIRABLE PARTICULATE MASS 0 2 4 6 8 10 12 14 18 18 20 AERODYNAMIC DIAMETER (Nml ~ Figure1-1-Thethreeaerosolmassfractionsrecommendedforuseinparticalsize-selectiveaerosotsamplingbytheA CGIHNrSamplingProceduresCommittee. 9ZS 9 061t0S

IX. EFFECT ON THE RESPIRATORY TRACT* A. SENSORY IRRITANT I) DEFINITION: CHEMICAL WHICH WHEN INHALED VIA THE NOSE WILL STIMULATE TRIGEMINAL NERVE ENDINGS, EVOKE A BURNING, SENSATION OF THE NASAL PASSAGE AND INHIBIT RESPIRATION,'{ ALSO MOST WILL INDUCE COUGHING FROM LARYNGEAL STIMULATIOND II) OTHER CHARACTERISTICS: THESE CHEMICALS ARE ALSO CAPABLE OF STIMULATING TRIGEMINAL NERVE ENDINGS OF THE CORNEA AND INDUCE TEARING, AT HIGH CONCENTRATION, PARTICULARLY ON MOIST FACIAL SKIN, THEY ARE CAPABLE OF INDUCING A BURNING SENSATION, SOME HAVE ODORANT AND/OR GUSTATORY QUALITIES, MOST WILL INDUCE BRONCHOCONSTRICTION, USUALLY AT CONCENTRATIONS IN THE AIR HIGHER THAN REQUIRED FOR STIMULATION OF NERVE ENDINGS IN THE NASAL PASSAGES1 III) EQUIVALENT TERMS TO DESCRIBE THEIR ACTION: UPPER RESPIRATORY TRACT IRRITANT, NASAL OR CORNEAL TRIGEMINAL STIMULANT, COMMON CHEMICAL SENSE STIMULANT, CHEMOGENIC PAIN STIMULANT, SUFFOCANT, LACHRYMATOR, STERNUTATOR, IV) TYPICAL EXAMPLES: CHLORACETOPHENONE. O-CHLOROBENZYLIDENE MALONONITRILE, B-NITROSTYRENE, DIPHENYLAMINOCHLOROARSINE, SULFUR DIOXIDE, AMMONIA, CROLEIN, FORMALDEHYDEt PRACTICAL, INDUSTRIAL CLASSIFICATION FOR A, B, C, D- FROM ALARIE, CRC, CRIT, REV, ToxICOL „ 2, 299, L973, 341

Table I. (cont'd.) Industrial Compound Symptoms Reference ;Platinum salts Asthma, dermatitis Freedman and Krupey, 1968; Cleare et ! al., 1976 Sodium bichromate Asthma Kobayashi, 1974 'Spiramycin Asthma, dermatitis Davies and Pepys, 1975 I ( FT_annic acid _ _ Asthma, urticaria, Johnston et a1., 1951 I rhinitis Tetracycline Asthma Menon and Das, 1977 ~ ,Toluene diisocyanate Asthma, urticaria Avery et.al., 1969; (TDI) ~ Pepys et al., 1972; I Karol e t a1. , 1979b Trimellitic anhyd- Asthma ; Zeiss et al., 1977 ; ride ; 347

E, PULMONARY SENSITIZERS (HYPERSENSITIVITY, DIFFERENT FROM HYPERSUSCEPTIBILITY) I) DEFINITION: CHEMICALS WHICH WHEN INHALED STIMULATE IMMUNOLOGIC SYSTEM SUCH THAT UPON RE-EXPOSURE TO A VERY LOW CONCENTRATION A PULMONARY REACTION OCCURS, A) FOREIGN PROTEINS: DEPENDENT ON MOLECULAR WEIGHT, EXAMPLE: SUBTILISINS (PROTEOLYTIC ENZYMES) 10w "1-v ) SIMPLE CHEMICALS WHICH ACT AS HAPTENS HAPTEN: ANY SMALL MOLECULE WHICH WHEN ATTACHED TO A MACROMOLECULE INDUCES FORMATION OF ANTIBODIES TO THE CHEMICAL AND WHICH CAN REACT WITH SPECIFIC ANTIBODIES. EXAMPLE: TOLUENE DIISOCYANATE (TDI). TRIMELLITIC ANHYDRIDE. POTASSIUM CHLOROPLATINATE. PHTALLIC ANHYDRIDE, II) TYPE OF PULMONARY REACTIONS A. IMMEDIATE HYPERSENSITIVITY: ASTHMA ATTACK, OCCURS WITHIN 1 HR OF EXPOSURE, CLASS OF ANTIBODY RESPONSIBLE MAINLY IGE ALSO 1 GG4 POSSIBLY OTHERS. B. LATE REACTION: STARTS AFTER 1 HR. . LAST 2-3 HRS, OR START AFTER 3-4 HRS. LAST 24-36 HRS, MAINLY 1GG PRECIPITATING ANTIBODIES, BIRD FANCIERS DISEASE, FARMERI S LUNG DISEASE (THERMOPHYLLIC ACTINOMYCETES) ALLERGIC ALVEOLITIS1 C, GRANULOMA FORMATION: CELL-MEDIATED MECHANISM INSTEAD OF ANTIBODIES, TUBERCULOSIS, BERYLLIUM, 345

D, RESPIRATORY IRRITANTS I) DEFINITION: CHEMICAL WHICH WHEN INHALED CAN ACT AS SENSORY IRRITANT, BRONCHOCONSTRICTOR AND PULMONARY IRRITANT. THESE CHEMICALS ARE CAPABLE OF ALL THREE ACTIONS AND THERE IS LITTLE DIFFERENCE BETWEEN THE CONCENTRATION AT WHICH THEY ARE SENSORY IRRITANT AND PULMONARY IRRITANTS1 II) OTHER CHARACTERISTICS: SIMILAR TO SENSORY IRRITANTS AND LUNG IRRITANTS. III) EQUIVALENT TERM TO DESCRIBE THEIR ACTION: ANY OF THE TERMS MENTIONED IN THIS TABLE, DEPENDING ON THE EXPOSURE CONDITIONS INVOLVEDI iv) TYPICAL EXAMPLES: CHLORINE, KETENE, CHLOROPICRIN, DICHLOROMETHYL ETHER. CHLORINE PENTAFLUORIDE, DIEPOXYBUTANE, METHYL ISOCYANATE8 344

4. QUICK SUMMARY (ADAPTED FROM A. GOLDSTEIN ET AL.) AGENT S TIME TO EQUILIBRIUM QUANTITY IN MOLES PHYSIOLOGICAL FACTOR - LIMITING UPTAKE ETHYL ETHER 15 S LOW LARGE VENTILATION CHLOROFORM HALOTHANE 7.3 2.5 T ~ X 1.0 50/50 NITROUS OXIDE 0.5 EHTYLENE 0.15 FAST SMALL CARD IAC OUTPUT oAppe, N1 o u ser 00 337

( Microscopic'•. . Pathology of Status Asthmaticus PAS-positive matrix Polymorphonuclear ~ neutrophils 349 Tenacious, viscid mucous plugs in airways Regional or ditfuse hyperinflation

metaar totai tbw ~ thrYl 311 • chamber GC ~p. ! n ftowmeter f!1/mM action port Integrator GLC gas ehrom"raph ~y~OZ electrode. H20 scrubber C02 xrubber Lrce pu IvaN 1~ valves u bber diaphragm pump Fto. 1. Chamber configuration used for gas uptake studies. . • eontroi o . amhwtrLzON pyrazols e.CC4 i \ \ /`.&k-(t~w" U.~OYui-v e e A ,w 40 TIME (min0utee) 120 Fta. 9. Semilogarithmic plots of chamber concentration vcrsus time for rats pretreated with pyrazole, aminotriazole and CCI.. The rate constants for the slow phase on a weight basis were: controls, 0.272 hr' kg-'; aminotriazole, 0.096 hr' kg-'; pyrazole, 0.037 hr' kg-'; and CCl„ 0.020 hr' kg''. The total weights of the nine rats used in each of these exposures were, respectively, 2.33, , 2.11, 2.05, and 2.15 kg. - FROM ANDERSEN ET, AL „ T,A,P, ~,7, 395-409, 1979 340

Table I. Respiratory Hypersensitivity from Industrial Chemicals Industrial Compound Symptoms Reference , :Cement dust Asthma ' Kobayashi, 1974 --•---• -----------dyspnea, cyano- - 1946 sis ; ~ . Amprolium hydro- Asthma ; Greene and Freedman, chloride --•-- i _---- 1976 Beryllium Rhinitis, cough, Hardy and Tabershaw, 1979 Diphenylmethane _•_Zeiss et al., -1980; diisocyanate (tIDI) j Konzen et al., I 1966 " lChloramine _ _----Asthma I - - - - - - Bourne et al. i .. -- -• ~ - i iEnflurane I :Ethylenediamine Formalin Naphthylene diiso- cyanate cyanate ; Ilickel sulfate I Persulfate salts Phenyiglycine acid chloride Phenylmercuric pro- . prionate Asthna Asthma ' Asthma ( I Asthma ' I Asthma f Asthma, derma- titis : As thma I , I i Asthma, urticaria I :Phthalic anhydride i • Asthma, rhinitis i 2 Schwettmann and Casterline, 1976 •Lam and Chan-°eung, 1980 Hendrick and Lane, 1975 Harries et al., 1979 - McConnell et al., 1973 Pepys et al., 1976 Baur et al. , 1979 Kammermeyer and Mathews, 1973 Koszewski and'Hub- bard, 1956; Mathews, 1968; Morris, 1960 Kern, 1939; Piaccia et al., 1976 346

Pulmonary Edema Pathway of normal pulmonary fluid resorption - Central perivascular and interstitial spaces ~ ' Thin Thick l ' ' side side +~~ t ' Interalveolar septum ,, Lymph Lymphatics •cuats -Surfactant layer Capillary endothelium Basement membrane (fused) Type I pneumocyte Alveolar epithelium Type II pneumocyte 359

Hypothesis of the Role of a,-Antitrypsin A. a,-Antilrypsin present In sufficient amount Circulating granulocyte Proteolytic enzyme (trypsin) a,-Antitrypsin Granulocyte engulfing and digesting bacteria and/or particulate matter Granulocyte lysed, releasing proteolytic enzymes Proteolytic enzymes inactivated by a,-antitrypsin Granulocyte lysed, releasing proteolytic enzymes Proteolytic enzymes attack lung parenchyma; . alveolar walls and respiratory bronchioles weakened, resulting in panacinar emphysema Emphysema with a,-antitrypsin deficiency tends to be more marked at base, probably due to gravity-induced increase in perfusion and sequestration of granulocytes 355

B. PULMONARY IRRITANT I) DEFINITION: CHEMICAL/ WHICH WHEN INHALED WILL STIMULATE SENSORY RECEPTORS WITHIN THE LUNG AND INCREASE RESPIRATORY RATE WITH A DECREASE IN TIDAL VOLUME RESULTING IN RAPID SHALLOW BREATHING. THEIR ACTION, AS OPPOSED TO THAT OF SENSORY IRRITANTS. OR BRONCHOCONSTRICTORS EVOKE A SENSATION OF DYSPNEA AND BREATHLESSNESS RATHER THAN A CONSCIOUS PAINFUL SENSATION$ II) OTHER CHARACTERISTICS: THESE CHEMICALS ARE CAPABLE OF INDUCING PULMONARY EDEMA WHICH IS THEN ACCOMPANIED BY PAINFUL BREATHING, THEY HAVE NO OR LITTLE ACTION AS SENSORY IRRITANTS OF THE EYE OR NASAL PASSAGES AT CONCENTRATION SUFFICIENT FOR PULMONARY IRRITATION AND, THEREFORE THEY PROVIDE LITTLE WARNING OF THEIR PRESENCE. SOME HAVE ODORANT OR GUSTATORY QUALITIES AND SOME EXERT A BRONCHOCONSTRICTING ACTION. III) EQUIVALENT TERMS TO DESCRIBE THEIR ACTION: LOWER RESPIRATORY IRRITANT, LUNG IRRITANT, DEEP LUNG IRRITANT. IV) TYPICAL EXAMPLES: PHOSGENE, NITROGEN DIOXIDE, SULFURIC ACID MIST, OZONE, SULFUR AND NITROGEN MUSTARD, SULFUR PENTAFLUORIDE, CADMIUM FUMES. ~,unn ~ j~~ UJ 1h~t~ ~.~•----- 342

H. Lucia, C. S. Barrow, M. F. Stock and Y. Alarie Ethmoid Sinus I with Turbinates (7) I v r Direct Passage to Pharynx . 1 I ~ SECTIONS 3 i 2 I `. _i __ I `~ External Nares (Squamous) ~•Maxilloturbinate `~'Maxillary Sinus ~'Canine •--•Canal from Nose to Mouth (Squamous) Figure 1. Parasagital view of the nore, showing the sections used In proc- e.uing and for microscopic examination. SECTION t EXTERNAL NARES Nasaturbinate ~ Pseudo- stratif ied ••Maxil lary Calumnar-° Sinus Epithelium -Maxillo- turbinate -- C' &.I:::: M y Bone "'-Squamous Epithelium Figure 3. Corone/ section #2, normal anatomy. SECTION 3 Figure 2 Coronal section st l, normal anatomy. H. Lucia, C. S. Barrow, M. F. Stock and Y. Alarie k t A •sessing Damage Sustained by Upper Respiratory Tract of Laboratory Moua~ SECTION 2 - RESPIRATORY ,Olfactory Mucosa Nasal Bone•-, Frontal ' ' ' ; // I I • !YJ ~r '\ I ' ' P late t . 1 I SECTION 4 Skull---; .•Brain , , -Ethmoid Sinus Columnar Epithelium Psaudosirutitied , Cartilage-•, Nasal Bone ~ Jaw Muscules - Palate -i-Saucmaus Epithelium Figure 4. Corona/ section #3, normal anatomy. Table 1. Rating System for Evaluation of the Damage Due to Exposure to Airborne Chemicals in the Upper Respiratory Tract of Mice. 0 no damage seen at 24 hours 1+ 1-50% of the mucosa is damaged, but underlying tissues are intact ' Cartilage--I 1 Palate LDirect Passage `J`MOlar to Pharynx fonly Nomaeactory Muee.al Figure & Coronal section #4, normal anatomy 2+ 25-75% of the mucosa is destroyed, and some damage to the submucosa is noted 3+ 50-99% of the mucosa is destroyed, and there is damage to the submucosa and underlying support structures 4+ 100% of the mucosa is destroyed and there is extensive destruction of all underlying tissues Anteriatmost Ethmoid •--Olfaetory Turbinate , Muaosa , :• Nasoturbioate _ rna.mary eone FOR BETTER FIGURES, SEE BUCKLEY et al., T.A.P. 74, 417-429, 1984. 329

Hypersensitivity Pneumonitis (continued) Acute bagassosis: small nodular and miliary Chronic bagassosis: intense fibrosis and bulious densities throughout both lungs. Deposits may emphysema after many episodes ot respiratory be more hazy and homogeneous in some cases Illness during 9 years of industrial exposure c Tissue reaction in bagassosis. Alveolar walls thickened with infiltrate of plasma cells and lymphocytes. Some alveolar spaces contain edema fluid and desquamated histiocytes with vacuolated cytoplasm. High-power section inset above shows macrophages with vacuolated cytoplasm filling alveolar space :rj~ ' Extensive subpieural and ~ i 1 . nteraiveofar fibrosis ith i fi • w n ammatory cell infiltration character- istic of advanced stage of farmer's lung (low- power section) 351

EMPHYSEM Normal Lung Acinu. (Secondary Lobute) Terminal bronchiole Septum of acinus 7st order 2nd order Respiratory bronchioles 3rd order Alveolar ducts Alveolar sacs Centriacinar (Centrilobular) Emphysema Distended respiratory bronchioles of all orders communicating with one another Panacinar (Panlobular) Emphysema All airways and alveoli involved with breakdown of dividing walls r 353

Centriacinar (Centrilobular) Emphysema Magnified section. Distended, inter- communicating, saclike spaces in central area of acini Microscopic section. Distention of airspaces with rupture of alveolar walls Gross specimen. Involvement tends to be most marked in upper part of lung 354

Pulmonary Defenses Against Oxidant and Other Noxious Injuries M X F E Q Inhaled High 02 Ozone (O3) NOZ Pho`-ige'ne ~ Type I cells Damaged or destroyed (more susceptible 5q to injury) _ .7 Btoodborne Busulfan Thiourea Olei~-_'1' J/ a a fi Gtydolysis - GI ucose--rt GI ucose-6-P- t I ceqs Pentose shunt a 6-P-gluconate 6-P-GD~_,COz Ribulose-5-P 9 *- H+-.NADPH NADP c Lacfate~-YPyruvate G-6-PD Oxal\acetate Oxidized glutathione Hydroxy fatty acid Reduced glutathione Fatty acid tSSS-- Poly- peroxide ~ unsaturated fatty acid / a-Tocopherol (vit. E); may Malate --'-r H+-~ ~' protect against peroxidation Type il cells Proliferated (resistance ! ~ increased Ill{ to high oxidant { ` exposure) ) 358

.-+ V 501190 6553

Complicateo sillcasis. Maemve librosis and Conglomerete noClpation. Plewa mitkeneo. noEulaleC. and aaheaive ~+J~i~ TS/~;GSA Typical aNicotlC nodule. ConCentnc ("onionekui') m ol colla en liban arran m g ge . - 4 a $oma of which are hyanmzeC Complicated allkosu. Eatensive flbrotic opacificatwn with hyperlucency at baaes 361

Mechanism of Type 1(Immediate) Hypersensitivity I A. Genetically atopic patient exposed to specific antigen (ragweed pollen illustrated) Light chain Heavy chain Disulfide bonds ~F, fragment F,, fragment Cytotropism 6. Plasma cells In iymphoid tissue of respiratory mucosa release immune globulin E (IgE) Smooth muscle contraction Mucous gland hypersecretion Increased capillary permeability and inflammatory reaction Eosinophii attraction C. Mast cells and basophils sensitized by attachment of IgE to cell membrane E. Antigen reacts with antibody (IgE)- on membrane of sensitized mast cells and/or basophils which respond by secreting pharmacologic mediators , VaguS nerve F. End-organ (airway) response compounded by nonspecific reactions (ciiiostasis, , particle retention, and cell Injury) FROM F, NETTER, CIBA COLLECTION, VOL. 7 SRS-A (slow-reacting substance of anaphyiaxis) ECF-A (eosinophii chemotactic factor of anaphylaxis) •---- Prostaglandins ? ---- Serotonin ? -f---- Kinins 348

I Silicotubercutosis Tuberculosis with cavitation superimposed on sittcosis Caplan's Syndrome (Rheumatoid Pneumoconiosis) ~ ~. s. Section through margin of Caplan's nodule. A = necrotic central area, B = clefts, C= zone of fibroblasts and inflammatory cells, D = collagen 362 Silicotuberculosis. Supervention of tuberculosis on silicosis may be difficult or impossible to recognize radiographically Caplan's nodules of various sizes In lung with silicotie nodules and coal dust deposits ; Caplan's nodules in both lungs with some evidence of i diffuse fibrosis

5D44D 6561 Pulmonary Edema; Some Etiologies and Hypotheses of Mecharusms Brain lesion (trauma, hemorrhage) Systemic vasoconsiriction with shift of blood to pulmonary circulalion I Pulmonary arterial hypertension Narcotic High altitude overdose y Contaminants Hypopyrfusion Hypovenlilation I ' Hypoxemia r----~ Increased i Nonuniform arterlolar constriction f Nonuniform transmission o/ pressure to capillary bed HzO Hp0 I Hz0 Alveolar edema ~~lerstitial ® Noxious gas inhalation permeabnity Impaired ventilation a 'Y. a, W, 1 Altered blood osmolalily S Pulmonary veins L. heart failure or obstruction Pulmonary venous hypertension

Coal Worker's Lung Whcle lung thin section with massive black deposits as well as smaller nodules, necrotic areas, and emphysematous changes 363 Slightly magnified detail of lung showing indurated coal nodules Microscopic section through a coal nodule. There are large amounts of coaldust, both intracellular and extracellular, with irregularly arranged collagen fibers near an artery (fibrosis) ,~' .Yo-v r' S c CIBA Chest x-ray film of retired coal miner showing massive upper lobe lesions, sometimes referred to as "angel wings"; also associated nodular disease

SATURATION (Y 70e.V"e , ' p 1063) - ' 2 ' ~ C2H4 (0.85) 1 ...... ....... ».. 1 C2H4 0.14 N20 0.47 C3H6 0.47 Halothane 2.60 Ether 15.0 I 10 3 50 MINUTES DESATURATION : r. .. ~ .......................... 10 350 MINUTES FIGURE 4. Relation between equilibration rates predicted from blood-air partition coefficients and shape of saturation and desaturation curves. To calculate the equilibra- tion curves (values indicated in parenthesis), the following blood-gas partition coef(i- cients were substituted into Equation 21: 0.14 for ethylene, 0.47 for nitrous oxide and cyclopropane, 2.6 for hafothane, and 13 for ethyl ether. The saturation and desatura- tion curves were simulated by Eger." For saturation, alveolar concentrations are ex- pressed as fractions of the exposure concentration. For desaturation, the ratios of al- veolar concentration at time interval t (minutes after the end of exposure) to alveolar concentration at the end of exposure, c., are used. (Adapted from Eger, E. f., ff, in Uptake and Distribution of Anesthefia Agents, l?apper, E. M. and Kitz, R. !., Eds.. McGraw-Hill, New York, 1963, chap. 8.3Vith permission.) - ALVEOLAR VENTILATION PERFUSION ..... AR.TERIAL..I3.LOOD. . ........................~ Inspir. a. ...................: a = DEAD SPACE a m . ................. J 1? PaW GV LG p- VRG J f I 1 I'~_~JI iPVaG .......Pmix-ven f Vart FG (7 VFG TCFG .I .3 : ether (0.05) ., r--~ .2 .i f' . r . - 6 • CgH6 (0.63) •9 I-S -- ~.4 V U t1 ~ .7 r halothane (0.26) ~ r7 .6 r V .6 a t •'' V Q U .5' FIGURE 10. Schematic comparison of the physiological multicompartment model and its electrical analogue. Related parameters are listed opposite each other in Table 5. The abbreviations LG, VRG, MG, and FG are explained in Table 4. The partial pressure, p (analogue of voltage, V); can be replaced by concentrations divided by appropriate partition coefficients or Expla- nation in text. FR0"i REFERENCE 1. 339 MG IRaG

E. ESTABLISHING TLV a) TYPES OF DATA 0 HUMAN EXPOSURE, LABORATORY EXPERIMENTS 0 ANIMALS ACUTE EXPOSURE 0 ANIMALS LONG-TERM EXPOSURE 0 HUMANS EXPOSED ON THE JOB 0 HUMANS EXPOSED ACCIDENTALLY 0 REPORTS FROM INDUSTRIAL HYGLENISTS 0 REPORTS FROM PHYSICIANS TLV ARE UNDER CONTINUOUS REVIEW b) TYPES OF EFFECT 0 ANY TYPE OF EFFECT CAN BE CONSIDERED 0 ALSO "GOOD HOUSEKEEPING" 0 NO TLV ABOVE lOmg/m3 FOR DUST -__~l 0 NO TLV ABOVE, 1,000 ppm FOR GASES OR VAPORS (EXCEPT C02, TLV = 5,000 ppm). C) TLV ARE NOT TOXIC INDICES 394

Bronchogenic Carcinoma: Epidermoid (Squamous Cell) Type Low power (H and E); nests of tumor cells separated by fibrous bands. Keratin (horn) pearls present `- A& -} b }. High power: nuclear pleomorphism and individual cell keratinization (pink) 368 Tumor typical ly located near hilus. projecting ] into bronchi - Cytologic smear from sputum or broncho- scopic scraping. Ce{Is with dark nuclei and cytoplasm strongly pink because of keratin

Etiologic Agents in Hypersensitivity Pneumoni5s i Disease Farmer's lung Y•-r- r agassosis Mushroom picker's disease Humidifier, air-conditioner or heating system disease Fog fever (cattle) Maple bark stripper's disease Sequoiosis Suberosis Paper mill worker's disease Pulpwood handler's disease Brewer's or malt worker's lung Cheese washer's lung Paprika slicer's disease Wheat thresher's lung or grain measurer's lung Pigeon breeder's disease Budgerigar fancier's disease Chicken handler's or feather plucker's disease Turkey handler's disease Pituitary snuff disease Smallpox handler's lung Thatched roof disease (Papuan or New Guinea lung) Tobacco grower's disease Joiner'sdisease Tea grower's disease Bible printer's disease Coptic or mummy disease Detergent disease (asthmalike symptoms-true pneumonitis not identified) Furrier's lung Coffee worker's lung ' Doghouse disease Lycopenlonosis Antigen Micropolyspora faenf, Thermoactinomyces vulgaris L saccharil and possibly other organisms M. faeni, TT vulgarfs Thermophilic actinomycetes and otherorganisms Same as farmer's lung CryptosUoma corticale Graphium, Pullularia, Aureobasidium pullulans and otherfungi Penicillium species Altemaria Same as above Aspergillus clavatus, A. fumigatus P. casef Mucorstofonifer Sitopht7us granarius Avian proteins Parakeet proteins Chicken proteins Turkey proteins Porcine, bovine proteins Unknown Unknown Unknown Unknown Unknown Unknown Unknown Bacillus subtilis Unknown Coffee bean dust Aspergillus versfcofor Unknown PuUularia water ' Exposure Moldy hay or grain Stored sugar cane fiber (bagasse) Moldy vegetable compost Contaminated forced air system Moldy hay Maple tree logs or bark Redwood sawdust Moldy cork dust Moldy wood pulp Moldywood pulp Malt or barley dust CI(eese mold - Moldy paprika pods Wheat flour containing weevils Pigeon serum and droppings Contact with parakeets Contact with chickens Contact with turkeys Porcine, bovine pituitary gland (Pitressin snuff) Smallpox scabs Dried grass and leaves Tobacco plants Sawdust Tea plants Moldy typesetting water Cloth wrappings of mummies Enzyme detergents Animal hairs Coffee beans Moldy straw Puffball spores (Lycoperclonpyriform) _ i /Sauna-taker's disease Contaminated sauna bath 'F 350

Mesothelioma of Pleura Neoplastic growth encasing right lung, : infiltrating interlobar fissure, and invading parietal pleura and pericardium. Hemorrhagic fluid in remainder of pleural cavity. Asbestosis of lung Fibrosarcomatous type of tumor Epithelial cell type Mottled shadow over r. lung area with effusion. of tumor In advanced cases, lung may be totally obscired tn 0 t w 0 rn Ln N O 369

t Pulmonary Siderosis Iron dust inhalation is believed to be relatively benign, producing little change other than brick-red discoloration unless mixed with other dusts (chiefly silica, silicates, and/or carbon). The mild fibrosis, nodulation, and emphysema shown are probably due to such admixture Vri • a~'.5 ~,. . 7.~.~4. ~ . ..'.MC. Mixed-Dust Fibrosis Fibrosis surrounding deposits of iron oxide, carbon, and silica. found in sandblasters, steel dressers, oxyacetylene cutters, and welders long exposed to such mixed dusts • ~. ~ ' ~ '' y ? j+'' = , .-,~ .. ,,,.-' .aY ~ 4 ~''ilr,~' . i~,yy ~. o( ' , i A y ':+!~~~.'SiM e: S Y `ir •.' , - • : ~Y~ ! S, l .. '•._\Lir { ' ~~ ~:• ^~' :.._. !-,M~..+.l3~ 1•\.t'.2• r.li i• Tungsten Inhalation Effects Cellular infiltration and increased collagen in lung interstitium. Alveoli show epithelial metaplasia and contain cellular exudate with some multinucleated cells : Nickel Inhalation Effects quamous cell carcinoma with overlying metaplastic bronchial mucosa, believed attributable to this metal 365~

Copyright 1978 by American Conference of t3overn- mental Industrial Hygienists. The American Conference of Governmental Industrial Hygienists will welcome requests for permission to re- publish or reprint these Threshold Umit Values. Re- quests for such permission should be directed to the Executive Secretary, P.O. Box 1937, Cincinnati, Ohio 45201. PRICE EACH 1-49 ................................. ...................... $1.50 50-199 .................................................... 1.25 200-999 .................................................. 1.10 1004-4999 ............................................... .75 5000 or more ............................................ .65 Documentation of the Threshold Lfmit Values for Sub- stances in Workroom Air.® A separate companion piece to the Chemical TLVs is Issued by ACGIH under this title. This publication gives the pertinent scientific information and data with reference to literature sources that were used to base each limit. Each documentation also con- tains a statement defining the type of response against which the limit Is safeguarding the worker. For a better understanding of the TLVs it is essential that the Docu- mentation be consulted when the TLVs are being used. Information concerning the availability of copies of the Documentation of the Threshold Limit Values for Substances In Workroom Air should be directed to the Executive Secretary, ACGIH (third edition, fourth print- ing,1978, $20.00). ' TLVs® Threshold Limit Values for Chemical Substances in Workroom Air Adopted by ACGIH for 1978 ~ 0 c a 0 rn ~ a Ln i 374

XI. FEDERAL HAZARDOUS SUBSTANCES ACT: FROM PRINCIPLES AND PROCEDURES FOR EVALUATING THE TOXICITY OF HOUSEHOLD SUB- STANCES. NATIONAL ACADEMY OF SCIENCES, 1977. ) TOXIC: SHALL APPLY TO ANY SUBSTANCE (OTHER THAN RADIO- ACTIVE SUBSTANCE) WHICH HAS THE CAPACITY TO PRO- DUCE PERSONAL INJURY OR ILLNESS TO MAN THROUGH INGESTION, INHALATION, OR ABSORPTION THROUGH ANY BODY SURFACE. ) HIGHLY TOXIC: MEANS ANY SUBSTANCE WHICH FALLS WITHIN ANY OF THE FOLLOWING CATEGORIES. A. ORAL: 50mg/kgOR LESS, RATS B. INHALATION: PRODUCES DEATH WITHIN 14 DAYS IN HALF OR MORE THAN HALF OF A GROUP OF 10 OR MORE LABORATORY WHITE RATS EACH WEIGHING BETWEEN 200 AND 300 GRAMS, WHEN INHALED CONTINUOUSLY FOR A PERIOD OF 1 HOUR OR LESS AT AN ATMOS- PHERIC CONCENTRATION OF 200 PARTS PER MILLION BY VOLUME OR LESS OF GAS OR VAPOR OR 2 MILLIGRAMS PER LITER BY VOLUME OR LESS OF MIST OR DUST, PROVIDED SUCH CONCENTRATION IS LIKELY TO BE ENCOUNTERED BY MAN WHEN THE SUBSTANCE IS USED IN ANY REASONABLY FORESEEABLE MANNER. C. SKIN: 200 mg/kg, RABBITS 395

criteria f ®r a recommended standard. . . . OCCUPATIONAL EXPOSURE TO ~ ~D5 W ''DiISOCYANATES ~- 1~- 7< ~ U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service Center for Disease Control National Institute for Occupational Safety and Health September 1978 rn ~ m m 387

Classification of Bronchogenic Carcinoma (= 95% of All Lung Carcinoma) Epidermoid (squamous cell) Small cell anaplastic (oat cell) •Adenocarcinoma Large cell anaplestic EK~ ~k '.f,',~ ,ey4. '1p1 WIM, +S. `t~~';`.YT]. Relatively slow Late; then primarily to hilar nodes Fair Hitar; but metastasea often present when first dis- covered r_'r~, , '" 0 50% 100% Peripheral (usually < 4 cm) k w a 0 50% 100% O Variable; peripheral or central 4' /6CIBA 0 Moderate Great Moderate Great Moderate Great Very rapid Intermediate Rapid Very early; to mediastinum or distally Intermediate Early 0 Poor Poor 0999 Q6h0S

o, m ~ 0 r 0 ~ I CONTENTS PREFACE REVIEW CONSULTANTS FEDERAL AGENCIES L RECOMMENDATIONS FOR A DIISOCYANATES STANDARD Section f - Environmental (Workplace Air) Section 2 - Medical Section 3 - Labeling and Posting Section 4- Personal Protective Equipment and Clothing Section S- Informing Employees of Hazards from Diisocyanates Section 6 - Work Practices Section 7 - Sanitation Section 8 - Monitoring and Recordkeeping ii. INTRODUCTION III. BIOLOGIC EFFECTS OF EXPOSURE Extent of Exposure Historical Reports Effects on Humans Epidemiologic Studies Animal Toxicity Correlation of Exposure and Effect Carcinogenicity, Mutagenicity, Teratogenicity, and Effects on Reproduction IV. ENVIRONMENTAL DATA Environmental Concentrations Engineering Controls Sampling and Analysis V. WORK PRACTICES VI. DEVELOPMENT OF STANDARD Basis for Previous Standards Basis for the Recommended Standard vii 388 Page iii v vi I 2 2 4 5

Transactions -1964 parative Theoretical Approach and Its Applications With Regards to Exposure Monitoring. tnt. Arch. Occup. Environ. Health 38:231-246 (1977). 33. Ramsey, I-C., J.D. Young, R.J. Karbowski et al: Pharmacokinetics of Inhaled Styrene in Human Volunteers. Toxicol. Appl. Pharmacol. 53:54-63 (1980). 34. Fields, R.L. and S.W. Horstman: Biomonitoring of Industrial Styrene Exposures. Am. Ind. Hyg. Assoc. 1. 40:451-459 (1979). 35. Bauer, D. and M. Guillemim Human Exposure to Styrene. I. The gas chromatographic determination of urinary phenylglyoxylic acid using diazomethane derivatization. Int. Arch. Occup. Environ. Health 37:47-55 (1976). 36. Bardodej, Z., B. Malek, B. Volfova and E. Zelena: The Hazard of Styrene in the Production of Glass Laminates. Ceskosloven- ska Hygiena 5:541-546 (1960). 37. Karbowski, R.J. and W.H, Braun: Quantitative Determination of Styrene in Biological Samples and Expired Air by Gas Chromatography-Mass Spectrometery (Selected Ion Monitoring). 1. Chromatog. 160:141-145 (1978). Ann. Am. Con/ Ind. Byg. VoL I! (1584) Pagc 118 386

Asbestosis'i / M m W rid ~tiI?~>~4-, 1 J rj '_ ~' `Extensive fibrosis with emphysematous changes and great pleural thickening: ~ visceral, parietal, and diaphragmatic. Lower lobe predominantly involved ' 17 r~( . r r i ® .~ AY li FZM I!f © 6' ! ~ . • ~ 1 ~ . . .. '.~-. %i F.. , IM Vf , E AE Section of moderately advanced asbestosis with extensive fibrosis and distorted alveoli. Asbestos bodies (some fragmented) in airspaces and interstitium. Also a few asbestos fibers 364 Oblique chest x-ray film. Calcified pleural plaques and irregular densities, chiefly in tower part of lungs Pleural plaques in pulmonary asbestosis "a , 41' ~.~sy1 Ilt Asbestos bodies in sputum i

~-Pr ~ AIR QUALITY CRITERIA FOR SULFUP' .1XIDES TABLE OF CONTENTS Chapter Pape Preface .................................................................................................... . Introduction ................... .. ................................... ................................ iii x 1 Physical and Chemical Properties and the Atmospheric Reactions of the Oxides of Sulfur ..................................:....................---.................. 1 2 Sources and Methods of Measurements of Sulfur Oxides in the Atmosphere .................. .. ........................................ ............................... 17 3 Atmospheric Concentrations of Sulfur Oxides ...................................... 31 4 Effects of Sulfur Oxides in the Atmosphere on Materials .................. 49 5 Effects of Sulfur Oxides in the Atmosphere on Vegetation .................. 59 6 Toxicological Effects of Sulfur Oxides on Animals .............................. 71 7 Toxicological Effects of Sulfur Oxides on Man .................................... 89 8 Combined Effects of Experimental Exposures to Sulfur Oxides and Particulate Matter on Man and Animals .......... ................................... 103 9 Epidemioloe cal Appraisal of Sulfur Oxides ... ..... ...... ........................ 113 10 Summary and Conclusions ........................... .......................................... 151 Appendicea A Symbols .......................................................... ........ ................................... 164 B Abbreviations ............................................................................................ 165 C Conversion Factors .................................................................................... 166 D Glossary ............................................................................ .......................... 167 Author Index .............................................................................................. 172 Subject Index .............................................................................................. 175 ~ Aeknowledgements ..................••---..........................:.................................. 178

POLLUTANTS continued Table 1 National ambient air quaiity standards Pollutant Averaging time Primary'•D standards Secondary standards SO2 Annual 80µg/m' arithmetic mean (0.03 ppm) 24 hr 365pg1m' (0.14 ppm) 3hr - , 1300pglm' Total Annual 75yglm' (0.5 ppm) 60pglm' suspended particulate geometric mean 24 hr 260Pg/m' . 150Pg/m' Lead Quarterly i.5pg/mx Same as primary average standard CO 8 hr 10 mglm' Same as primary 3 1 hr 1 hr (9 ppm) 40 mgJm' (35 ppm) 235µg1m'tl . standard Same as primary (0.12 ppm) standard Total 3 hr 160Nglm3° Same as primary nonmethane (0.24 ppm). standard hydrocarbons Nitrogen Annual 100pg/m' Same as primary dioxide arithmetic mean (0.05 ppm) standard °Environmental Protection Agency, Federal Register36 (84), 8197 (April30, 1971). bNational standards other than ozone and those based on annual arithmetic means or annual geometric means are not be be exceeded more than once per year. The ozone standard is written so that the average number of days per year above the standard must be less than or equal to one. `Environmental Protection Agency, Federal Register 43 (194), 46246-46277 (October 5, 1978). dEnvironmental Protection Agency, Federal Register 44 (28), 8202-8237 (February 8, 1979). °A planning standard used to develop ozone control strategies. Table 2 Prevention of significant deterioration increment levels in pglm' Pollutant Total suspended particulate Sulfur dioxide Averaging time Annual average 24 hr average - Annual average . ' 24hr average 3 hr average Class I 5 10 2 5 25 Class ff 19 , 37 20 91 512 Class Ill 37 75 40 182 700 38 : FEBRUARY 1980 393

aels STYRENE, monomer CAS 100-42-5 CH6HSCHCH2 RECOMMENDED BEI indices • Mandelic acid in urine Styrene in mixed-exhaled air • Phenylglyoxylic acid in urine '• Styrene in mixed exhaled air (confirmatory test) '* Styrene in venous blood (confirmatory test) CH=CH= Time BEI Current Experience End of shift G 1 g/L or below Satisfactory G 0.8 g1g of creatinine Prior to shift 40 ppb or below Satisfactory End of shift G 250 mg/L or below Satisfactory G 240 mg/g of creatinine During shift 18 ppm or below Satisfactory End of shift 0.55 mg/L or below Fair Prior to shift 0.02 mg/L or below Physical Properties Highly soluble in fat, poorly soluble in water (0.3 mg/mL at 20°C). Partition coefficients at 37°C:11i water/gas 4.5; blood/gas 55; oiVgas 5000. At room temperature styrene is present as vapor, saturated vapor pressure is 5.8 torr. Absorption Inhalation absorption is most significant. Pulmonary reten- tion levels off at 65°k.1=a1 Skin absorption is significanL'° Possible Nonoccupational Exposure Uncommon. (Present in a do-it yourself auto body patching compound). Elimination The major elimination pathway is metabolic clearance. Only a small fraction of pulmonary uptake is exhaled un- changed after exposure. Urinary excretion of unchanged styrene is negligible. Because of high solubility in fat, it ac- cumulates in the body over the workweek.,&r Metabolic Pathways The metabolic pathways for styrene are shown in Figure 3. Metabolism of styrene is capacity-limited. Landry et a/te, show that elimination of styrene in man follows first-order kinetics up to exposure concentrations of 80 ppm. At ex- posure concentrations above 200 ppm, metabolic pathways become saturated and styrene concentrations in tissues and styrene mandelic phenylglyoxylic glycol acid acid ~HZOH 'OOH COOH _*10X urine f00H ~ONHCH2COOH benzoic acid Figure 3 - Metabolic pathways of styrene. OH CHOH C=0 hippuric acid Ann. Am. Con(. lrtd. Xyg.. VaG 11 (1984) 381 _ P+qe 113

X. STANDARDS FOR A11d8ORNE GUNIAMINANIb I 50490 6571 ~Y- Standards, Definitions, and Promulgating Agencies for Airborne Contaminant Standards Standard Responsible Agency Definition ~ Threshold Limit Value American Conference of Govern- "The time-weighted average concentration for a normal 8- (TLV)- Time-Weighted mental Industrial Hygienists hour workday or 40-hour workweek, to which earl all Average (TWA) workers, may be repeatedly exposed, day after day, with- out adverse effect." ** (2) Threshold Limit Value- American Conference of Govern- "The'concentration that should not be exceeded even Ceiling (TLV-C) mental Industrial Hygienists instantaneously." (2) Sliort-Term Exposure American Conference of Govern- "The maximal concentration to which workers can be'exposed Limit (STEL) mental Industrial Hygienists for a period of up to 15 minutes continuously without suffering from 1) intolerable irritation, 2) chronic or . irreversible tissue change, or 3) narcosis....provided that no more than four excursions per.day are pormitted ... The STEL should be considered a maximal allowable concentration or absolute ute ceiling, not to be exceeded..." (2) Exposure Occupational Safety and Set in accordance with Sec 6(b)5 of Public Law 91-596 ".. Limit (PEL) ' Health'Administration standard which most adequately assures to the extent feas- O~ ibTe, on the basis of the best available evidence, that no ~ ~"'17 employee will suffer material impairment of health or func- l l h l ti it if h ona capac y, even suc oyee as regu ar exposure emp ~ ~ ~~ to the hazard dealt with by such standard for the period of " . his working life. (6) Emergency Exposure Committee on Toxicology, "The EEL for short-term exposure to an airborne contaminant Limit (EEL) National Academy of s a concentration which, when inhaled for a specified is single, brief period, rare In the lifetime of an individual a period of disability or inte is believed not to result In forence with the performance of his assigned task." (7) Air Quality ' Environmental Protection "They prescribe pollutant exposures or levels of effect tha Standard (AQS) Agency should not be exceeded nes a political jurisdiction determi ~~ (8) in a specific geographic area... ** Tlle 1968 TLVs (as 8-hour TWA) have been designated as consensus standards by OSHA until a PEL is established for any given compound, From: A.I.H.A. Journal 40, 207-229, 1979. , r- t I

i ~ . ~~ ~ s , ~t.~ f»c r i• ~~ Cadmium + I h l ti n a a on 7~~~ ~ AA ® do C~~a~t Lw1~ I.~`• _ 2 Acute effect of cadmium inhalation: metaplasia . of alveolar epithelium. Acute inflammation of the tracheobronchial tree and upper respiratory tract may also occur Renal effects of chronic cadmium poisoning. PAS-positive cast material in tubules Effects Bullous emphysema with consolidation at base possibly attributable to chronic cadmium inhalation is d . a ,,.,ip- 1~ • •" • 0 • i• I ~ ~• V.3. R.~~.•t~:~+ , ® ~! ; : f ~ r j p ~ ~ ~ -' , r ~ ; ~ _. ®~~ yt ~~! l44946N ' ~ il`~~ ff ' 1 ts.,a,Y:~ ~ • p JM-At?T . 1 ~ - W ~; ~ ~ . . ~,,,: . ~~`• ~, ~ d _. ., _ :. r. ~ ~ . .. ~ Granuloma with interstitial fibrosis resembling sarcoidosis: central deposition of endothelioid cells, some multinucleated, with surrounding cuff of lymphocytes and fibrous tissue. Skin and other tissues may show similar lesions. High-power inset above shows detail of giant cells containing Schaumann bodies 366

50450 5591 ~ OSMA/A(,'GIM SU9STAaCETOXICITY REPORT ••• FILF COvTFO Nv qURSTANCE •0• FIELn NO CODE SUBqTANCE -- ----- ------------------ ---------------------- S Pn005 AMATf, 13 0010 ACETAIOEMYOE % "196~ 13 0020 ACETIC ACID ~Ov G '9(17 13 0030 ACETIC ANMYOyIDE 7 0060 ACETANE 4 0060 aCETONITRII.E PMY ST A - ------------- 1'--- -------------------- OiNA PEL PPM M(i/N7 ACGIN PEL HEALTH HA7AR0 PP" M4/M3 CATEGORY - R NONE NONf 2S 2n L 1000 2400 L 40 T0 . 1 C006S 2-ACETYLAMINO£LUORENE S STO 1910,1014 16 0070 ACETVLENE 0 NONE NONE 3 0080 ACETYLENE TETRABROMIDE L 1 14 1] 0110 ACROLEIN I. 0.1 0.25 6 011+ ACRYLAMIDE - SKIN S 0,3 4 0120 ACRYLONITRILE - SKiN L 20 45 10 A C 5 1000 40 06/29/76 PAGE 3 --------- ---------- (CYANOSIS) NONE NONE CANCER A F - SIMPLE ASPHYXIATION 1 14 CUMULATIVE LIVER t LIING DAMAGE 0.1 0.25 MARKED•IRRITATION - EYE, NbSE. THROAT. LUNGS . SKIN w 10 CHOLINEtTEoARE INHIBITION HEALTH HAZARII CLASSIFICATION -------------- O-UP TO 3XPEL S-AROVE .IXPEL 1P0 MARKEO IRRITATION -. S-AT CURRENT EYE, NOSE, THROAT. SKIN OSHA PEL OF 200 PPM 2S MARKED IRRITATION- 0-lIP TO )XPEL EYE. NOSE, THROAT. SKIN S-AROVE TXPEL ?6 MARKED IRRITATION- EYE. NOSF.. TMMOAT SKIN S- ABOVE S PPM 2400 MILD IRRITATION-EYE O- IlP TO 3XPEL . NOSE• THROAT/ NARCOSIS S- AenVE 3xPEL 70 MILD IRRITATION - EYE, NOSE, THROAT/ ACUTE TOKICITY S 0.] ACUTE SYSTEMIC TOXICITY ICNSI 20 4S MODERATE IRRLTATION- EYE, NO.SE• THROAT/ ACUTE TOXICITY (CYANOSISI S 0-BELOY 5000 PPM S-AR9VE 5000 PPM S S S S

Ttansactions - 1984 Factors Affecting Interpretation of BEI Phenylglyoxylic acid is also a metabolite of ethyl benzene, styrene oxide, styrene glycol, and mandelic acid t9.=•1 justification Phenylglyoxylic acid is the minor metabolite of styrene. About 10% of styrene retained during an 8-hour exposure is excreted in urine as phenylglyoxylic acid.i•) To correlate phenylglyoxylic acid in urine with exposure concentration, urine samples at the end of the shift were collected. Gotell et aP"z1 derived correlation equations for exposure concen- tration in ppm, .,, and phenylglyoxylic concentration in urine in mg/L, PGA, (urine density not given): c,,, - 0.37 PGA - 29 (4) A similar correlation equation was derived by Ikeda et a1t2e1 for urine density of 1.016: c-p - 0.25 PGA - 20 (5) and for phenylglyoxylic acid related to 1.0 g of creatinine, PG'9cr c.„ - 0.25 PGA, - 9.5 (6) These correlation equations are valid for urine samples col- lected at the end of an 8-hour shift and exposure concentra- tions below 150 ppm. At exposure concentrations larger than 150 ppm, the elimination of styrene via phenylglyoxylic acid is saturated, and there is no linear correlation between ex- posure concentration and concentrations of_phenylglyoxylic acid in urine."=) According to the above equations, phenylglyoxylic acid in urine collected at the end of an 8-hour exposure to 50 ppm is 214 mg/L and 278 mg/L, respective- ly, or 238 mg/g of creatinine. Sampling and Storage Venous blood should be collected at the end of the workweek in vacutainers containing EDTA anticoagulant. Since timing is critical at the beginning of exposure and short- ly after exposure, sampling at the end of the shift or prior to the shift is recommended. The vacutainer must be filled completely with blood. Samples must be stored under refrigeration and contact of samples with rubber and {ilastic material must be prevented. Levels Without Occupational Exposure No styrene is present in blood of unexposed subjects. Kinetics Styrene concentration in blood rises during exposure and starts to decline immediately after exposure with half-times of the two apparent decays of one-half hour and 13 hours. Additional decay, with a half-time of 3 days, can be derived from clearance of adipose tissue.(b1 From data by Ramsey et aj,(331 it can be derived that after 8-hour exposure to 50 ppm of styrene, styrene concentration in blood, c, in mg/L, declines according to equation: c, - 0.50e-12, + 0.044e-u.os3.1 (7) where: t- the time interval (in hours) between end of the exposure and sampling Factors Affecting Interpretation of BEI Styrene in blood is a specific indicator of styrene exposure. Current Information Available Elimination of phenylglyoxylic acid was studied in man. The studies provide satisfactory information for establishing BEI. The recommended BEI is based on kinetic studies in man (controlled and field studies). Recommendation The Committee recommends that the concentration of phenylglyoxylic acid in urine collected at the end of the shift does not exceed 250 mg/L or 240 mglg of creatinine. lnterfer- rence by exposure to some other chemicals is possible. STYRENE IN VENOUS BLOOD INDEX Method - Gas chromatography - mass spectrometry13J1 is recom- mended. justification The recommended values are based on pharmacokinetic evaluations of data from controlled human studies!33) Current Information Available Fair (extrapolation from controlled human studies with ex- posures shorter than 8 hours). Recommendation The recommended concentrations for styrene in venous blood, 0.55 mg/L at the end of the shift and 0.02 mglL prior to the shift are based on a kinetic study in man. At the end of the working week, styrene concentrations in blood are slightly higher than at the beginning of the week. This BEI is recommended as a confirmatory test. Other BEI In contrast to animal species, hippuric acid is a minor metabolite of styrene in man. Hippuric acid was considered as a biological exposure index by some investigators,00-11•24) Page 116 384 Mn. Mi. CunL rnd. Hyg.. VoL 11 (r994)

Threshold limit values for chemical substances and_ physical agents in the work environment and. p biological exposure indices with intended changes a 8Ad f 1 8 o r 9- /~CS ~ Y/~ Preface chemical substances Threshold limit values refer to airborne concentra- tions of substances and represent conditions under which it is believed that nearly all workers may be repea- tedly exposed day after day without adverse effect. Be- cause of wide variation in individual susceptibility, how- ever, a small percentage of workers may experience discomfort from some substances at concentrations at or below the threshold limit; a smaller percentage may be affected more seriously by a'ggravation of a pre- existing condition or by development of an occupational illness. Threshold limits are based on the best available infor- mation from industrial experience, from experimental human and animal studies, and, when possible, from a combination of the three. The basis on which the values are established may. differ from substance to substance; protection against impairment of health may be a guid- ing factor for some, whereas reasonable freedom from irritation, narcosis, nuisance or other forms of stress may form the basis for others. The amount and nature of the infonnation available for establishing a TLV varies from substance to sub- stance; consequently, the precision of the estimated TLV is also subject to variation and the latest Documentation should be consulted in order to assess the extent of the data available for a given substance. These limits are intended for use In the practice of industrial hygiene and should be interpreted and applied only by a person trained in this discipline. They are not intended for use, orfor modification for use, (1) as a rela- tive Index of hazard or toxicity, (2) in the evaluation or control of community air pollution nuisances, (3) in es- timating the toxic potential of continuous, uninterrupted exposures or other extended work periods, (4) as proof or disproof of an existing disease or physical condition, or (5) for adoption by countries whose working condi- tions differ from those in the United States of America and where substances and processes differ. The TLV-TWA should be used as guides in the control of health hazards and should not be used as fine lines between safe and dangerous concentrations. In spite of the fact that serious injury is not believed likely as a result of exposure to the threshold limit con- centrations, the best practice Is to maintain concentra- tions of all atmospheric contaminants as low as is practical. Legal Status. The Threshold Limft Values, as Issued by ACGIH, are recommendations and should be used as guidelines for good practices. Wherever these values (of whatever year) have been used or included by reference in Federal and/or State statutes and registers, the TLVs do have the force and effects of law. "Notice of Intent." At the beginning of each year, pro- posed actions of the Committee for the forthcoming year are issued in the form of a"Notice of Intended Changes." This Notice provides not only an opportunity for comment, but solicits suggestions of substances to be added to the list. The suggestions should be accom- panied by substantiating evidence. The list of Intended Changes follows the Adopted Values in the TLV booklet. Values listed in parenthesis in the "Adopted" list are to, be used during the period in which a proposed change forthat Value is listed in the Notice of Intended Changes. Definitions. Three categories of Threshold Limit Val- ues (TLVs) are specified herein, as follows: a) The Threshold Limit Value-Time Weighted Average (TLV-TWA)-the time-weighted average concentration for a normal 8-hour workday and a 40-hour workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. b) Threshold Limit Value-Short Term Exposure Limit (TLV-STEL)-the concentration to which workers can be exposed continuously for a short period of time with- out suffering from 1) irritation, 2) chronic or irreversible tissue damage, or 3) narcosis of sufficient degree to in- crease the likelihood of accidental injury, impair self- rescue or materially reduce work efficiency, and provid- ed that the daily TLV-TWA is not exceeded. It is not a separate independent exposure limit, rather it supple- ments the time-weighted average (TWA) limit where there are recognized acute effects from a substance whose toxic effects are primarily of a chronic nature. STELs are recommended only where toxic effects have been reported from high short-term exposures in either humans or animals. A STEL is defined as a 15-minute time-weighted average exposure which should not be exceeded at any time during a work day even if the eight-hour time- weighted average is within the TLV. Exposures at the STEL should not be longer than 15 minutes and should not be repeated more than four times per day. There should be at least 60 minutes between successive expo- sures at the STEL. An averaging period other than 15 minutes may be recommended when this is warranted by observed biological effects. c) Threshold Limit Value-Ceiling (TLV-C)-the con- centration that should not be exceeded even instantan- eously. For some substances, e.g., irritant gases, only one category, the TLV-Ceiling, may be relevant For other substances, either two or three categories may be rele- vant, depending upon their physiologic action. It is im- portant to observe that if any one of these three TLVs is exceeded, a potential hazard from that substance is pre- sumed to exist. The committee holds to the opinion that limits based on physical irritation should be considered no less bind- m ~ N Ann. Am. Con(. lnd. tlyg,. Vot f I(f994) 373. p,.r 27i

MOOERATE 14 ~h MIL~ ,IS IN CATFGORI7,ING qUBSTANCES AS EITHER SkRIOUS OR OTHER. ONLY THE TOYICOIOGIC PROPERTIES nF A CHEMICAL SUBSTANCE wEoE 'JSEO. NO ATTEMPT WAS MADE TO INCLUDE AN EVALUATION OF THE INDUSTRIAI_ PROCESSES FnR SUBSTANCES OR THE LIKLIH00D THAT ANY GIVEN MAfERIAL COULD ExCEED THE PEL. HACICALLrr EIf,HT MAJOR CATEGOR1Eti wERE USED A5 FOLLOWS' OSHA/ACC.IH SURSTANCF_ TOXICITY REPORT CRITERIA FOR RATING A SUBSTANCE SERIOUS OR OTHER ----------------"---------_--_------_-----_----- HAJOR HEALTH HAZARD CATEGORY SUBSET EXPLANATION CODE 0 ---------------------------- -_---------------- I CANCER NEGULATED AT PkESENT AS CARCINOGENS BY OSHaI CHIEFLY WORK PaACTICE STANDApOS I --_~----H~--ON--IC-(--CUMU--~L-a-T--IV-E-I _-- T~X---IC_I--TY --------__-m ---~--_-~_-------~-'--__--_--------- m ---------------- ---- 2 ---- II C SUSPECT CA~CINOOFNS ALSO NO EVIDENCE OF CANCEO POTENTtAl AT PRESENT 3 ------------------------------------- --------------------- ---____---------- ----------- ----------------------_--- III ACUTE SYSTEMIC TOXICITY 4 --'-m ---- ------------ ------- ------- m----------------------- _-------- -------- -------------- ------------ _--_- IV NERVOUS SYSTEM DISTURBANCES CHOLINESTENASE INHIBITION 5 CNS EFFECTS OTHER THAN NARCOSIS ' 0+ NARCOSIS , 7 ----------------------- _----------- -__-_--_------ --------------------- ------------------------------ ---_--------- V RESPIRATORY EFFECTS OTHER RESPIRATORY SENSITIZATIONIA5THMAI A THAN IRGITATION CUMULATIVE LUNG OAMAGE(PNEUMOrONIOSISI 9 ACUTE LUNG DAMAGE WITH EDEMA 10 --_'-.•------------------------------------------ --------------------------------------------- _---------__--_-.•-__ VI HEMATOLOGIC(BLOnD) DISTUR- HEMOLYTIC ANEMIA i 11 - HANCES METHEMOGE.OBINFHIA 12 ---- m ---------------- ---..--_----------------------- --------------------- ----------- __..------------ ---------- VII IRRITATION-EYE.NOSErT!'P.OATr MARKED 13 t ------------ -------------------------------- -------------- ----- ----------- --_----_____--__------- ------_---_- VIII GENERAL LOW RISK HEALTH EFFECTS I AHPHYXIANTS.ANOXIANTS i~.. "INE'7T"(NUiqANCEI PARTICIJI.ATES 17 ODOR lA G000 HOUSEKEEPING 19 0 THE DOCUMENTATION PRESENTEO BY ACGIH FOR EACH SUBSTANCE WAS REVIEWED AND GQEAT WEIGHT WAS GIvEN TO ACGIH'S REASONS FOR ESTABLISHING THE PEL AS WELL AS SCIENTIFIC EVIDENCE FROM EITHER HUMAN 04 ANIMAI, EXPERIENCE. ' AN EXPOSURE ABOVE THE PEL WAS CONSIDERED TO RE A POTENTIALLY SERIOUS VIOLATIOM IF THE SUBSTANCE WAS OOC11- HENTED AS CAPABLE OF PRODUCING THE EFFECTS AT THE SPECIFIED PF.LiOTHER THAN f.ODES 1Sr17.18.A191t IF THE TOXIC EFFECTS WERE CUMUt.ATIVEt AND/nR IF THE TOXIC EFFECTS WERE POTENTIALLY IRRE4F.R,;I9LF. ALL OTHERSWERE EITHER NONSERIOUS OR NONSERIOUS WITH SOME tIPPER LIMIT AHOVE THE TLV WHERE CONTINIIED EXPOSU4E wOULO LEAD TO IRNEVERSIRLE EFFECTS. '~ 0659 0 b h n S

BEfs Recommendation The Committee recommends that the concentration of mandelic acid in urine collected at the end of the shift at the end of the week does not exceed 1.0 g/L or 0.8 g/g of creatinine. Interferrence by exposure to some other chemicals is possible. STYRENE IN EXHALED AIR INDEX Method Suitable specific methods are: gas chromatography,11o.u IR-spectrophotometry,j1p1 UV-spectrophotometry,1r•13, and detection tubes.("' Sampling and Storage Sampling prior to the shift and at the end of the shift is recommended. Sampling prior to the shift must be performed in a clean atmosphere wearing uncontaminated clothes. Samples collected in glass containers should be analyzed im- mediately. Samples absorbed in ethanol or on activated char- coal can be store&1=, Contact with plastic material should be prevented because of absorption of styrene by plastic Levels Without Occupational Exposure No styrene is present in exhaled air of unexposed subjects. Kinetics During Exposure Since pulmonary retention levels off between 60-70°1°(2•A113=) styrene concentration in mixed-exhaled air accounts for 35% of exposure concentration. (According to Stewart et al,]Ta the exhaled concentration accounts for on- ly 25% of exposure concentration.) Therefore, the average concentration of styrene during the shift should not exceed 18 ppm in mixed-exhaled air (2 ppm in end-exhaled air) if the TLV-TWA of 50 ppm is maintained. Following Exposure Only a small fraction of uptake is exhaled (Stewart et af,101 0.7%; Landry et af,(9) 1%). The desaturation curve shows two exponential decays with half-times of 13-52 minutes and 4-20 hours.110•311 An additional decay, with a half-time of 3 days, can be derived from clearance of adipose tissue.1e The relation between exposure concentration in ppm, c„0, and styrene concentration in mixed-exhaled air in ppm, c,, col- lected t-hours after the end of an 8-hour exposure, is described by an exponential term: c„0 - cf(0.0093e-0a + 0.0014eo°ru) The equation was adapted from data by Ramsey et at(13i and is valid for exposure concentrations below 150 ppm. Factors Affecting Interpretation of BEI Styrene in exhaled air is a specific indicator of styrene ex-_ posure. If exhaled air samples are collected prior to the shift then contact with styrene prior to sampling must be avoided since exposure to traces of styrene would lead to overestima- tion of exposure. Justification The recommended values are based on evaluation of kinetic data and match the current TLV. The values are deriv- ed from experimental data in controlled studies,'Un and in field studies.t'=,3,) Current Information Available Elimination of styrene was studied extensively in man and in animals. The studies provide satisfactory information for establishing BEL Recommendation The Committee recommends the following concentrations of styrene in exhaled air as BEls for styrene exposure: Dur- ing exposure, 18 ppm in mixed-exhaled air. The measured concentration indicates the recent exposure. Sixteen hours after exposure the concentration of 40 ppb in mixed-exhaled air is not measurable by usual analytical methods. In other words, the preshift samples should be negative if the TLV is maintained. Styrene in exhaled air is a specific BEI and analysis of exhaled air during exposure is recommended as a confirmatory test. PHENYLGLYOXYLIC ACID 1N URINE INDEX Method Specific methods like liquid chromatography,(191 iso- tachophoresis,(2°) gas chromatography,12031•rsi and polarographyaw are recommended. Colorimetric methods are not recommended because of their low specificity.t=••351 Sampling and Storage Samples of urine should be collected at the end of the shift. Timing is critical. Since phenylglyoxylic acid decomposes in acid solution, the storing should be carefully controlled:2=) Levels Without Occupational Exposure Concentrations in unexposed subjects depend on the method used. Kinetics The peak concentration of phenylglyoxylic acid in urine appear at the end of exposure. Following exposure, the con- centration declines, with a half-time about 7 to 10 hours.0 1•24•=6) Ma Am. Conf rn6 rryg.. Yd tl (lBBp 383 hgc 115

Transactions - 1984 blood increase faster than exposure concentrations. The non- linear, capacity-limited elimination of styrene was cor- roborated by other investigators.-141 In the range of exposure concentrations permissible in industrial conditions, the linear correlation between exposure concentration and concentra- tions of styrene and its metabolites in excreta is acceptable. At high exposure concentrations, however, the metabolite elimination is smaller, and styrene in exhaled air is larger than expected front a linear correlation. As is common for capacity- limited enzymatic reactions, styrene metabolism is com- petitively inhibited by the presence of other xenobiotics!1%1a1 Therefore, when inhaled in mixtures, styrene exposure is underestimated if assessed from metabolite excretion, and overestimated if assessed from styrene exhalation. No reports of protein binding were found. TLV-TWA The recommended TLV-TWA of 50 ppm (= 215 mglm3) is based on preventing "Styrene sickness" (drowsiness, headache, fatigue and dizziness); TLV has sufficient safety factor to prevent other toxic effects (1980). Summary The linear correlation between exposure concentration and concentrations of styrene indices applies only if the exposure concentration is lower than 150 ppm. Determination of mandelic acid in urine is the most convenient BEI. Phenylglyoxylic add is preferred by some investigators, since the correlation between elimination of phenylglyoxylic acid and exposure concentration is linear over a broader range of exposure concentrations. Styrene determinations in exhaled air and in blood are recommended as confirmatory tests since mandelic acid and phenylglyoxylic acid are also metabolites of other chemicals. MANDELIC ACID IN URINE INDEX Method Liquid chromatography,m) isotachophoresis,em gas chro- matography,al-2r, polarography=4) are suitable, specific methods. Colorimetric methods,t4•25, are not recommended because of their low specificity. Sampling and Storage Samples of urine should be collected in glass containers at the end of the shift. Timing is critical. Samples stored under refrigeration are stable at least 14 days. Ethanol intake should be avoided 24 hours prior to sampling. Level Without Occupational Exposure , Mandelic acid is not present in urine of unexposed subjects. Kinetics The peak concentration of mandelic acid in urine appears at the end of exposure. Following exposure to styrene mandelic acid elimination is biphasic with half-times of 4 hours and 25 hours!2^.:n Factors Affecting Interpretation of BEI Mandelic acid is also a metabolite of ethyl benzene, styrene glycol, styrene oxide, phenyl glycol, and a-phenyl- aminoacetic acids.e,=^1 Exposure to such chemicals would be manifested by increased excretion of mandelic acid. Ethanol intake'71 and exposure to some other chemicalst15•1^, is manifested by decreased excretion of mandelic acid. justification Mandelic acid is the major metabolite of styrene in man. According to Bardodej,41 following 8-hour exposure to styrene, 85% of styrene uptake is excreted in urine as mandelic acid. Concentrations of mandelic acid in urine samples collected at the end of an 8-hour shift are used for correlation with exposure concentration. The correlation be- tween exposure concentration in ppm, c,,,, and concentra- tion of mandelic acid in urine in g/L, MA, was described by Gottell et aff121 (urine density not given): c.w- 54.3MA-8..1 (1) A similar correlation equation was derived by Ikeda et aP'a for urine density 1.016: - c. - 80 MA - 14.5 (2) and for mandelic acid related to one gram of creatinine, MA~: c,,, - 65 MA,, - 3.6 (3) These correlation equations are valid only if exposure con- centration (TWA) is below 150 ppm and urine is collected at the end of an 8-hour exposure. According to equations 1 and 2, concentration of mandelic acid in urine of a person exposed 8 hours to a TLV of styrene equals 1.1 g/L and 0.8 g/L, respectively (or 825 mg/g of creatinine). Bardodej(r41 suggests that the concentration of 1.3 g/l. for urine density 1.024 or 830 mg/g of creatinine cor- responds to exposure of 50 ppm of styrene. If the value sug- gested by Bardodej is corrected for a density of 1.016, then the corrected value 0.86 gIL agrees well with the value sug- gested by Ikeda.a^) Harkonen et aN0•r9•ra also corroborate these data. Current Information Available There is sufficient information on man available to support the following BEI. The recommended BEI is based on kinetic studies in man (controlled and field studies). rige 114 382 Ann. Am. Conf. rnd. Hyg.. VoL 11 (1984)

Supplemental Documentation HYDROGEN FLUORIDE CAS 7664-39-3 HF CEILING LIMIT, 3 ppm (= 2.5 mg/m'), as F• Hydrogen fluoride is a colorless gas at temperatures above its boiling point of 19.54°C; at lower tempe'ratures it is a fum- ing liquid. HF has a molecular weight of 20.02, a specific gravity of 0.988, and a freezing point of -83°C. There is association of molecules at normal room temperatures, so that the actual density of the gas is greater than would be calculated from the formula HF. A water solution, contain- ing up to 70% HF, hydrofluoric acid, is frequently used. It is slightly soluble in water and soluble in most organic com- pounds. Anhydrous HF is employed as a catalyst in numerous reac- Ytons of chemical synthesis; as a fluorinating agent in the pro- duction of fluorine and aluminum fluoride, and in refining uranium. Hydrofluoric acid is used to etch glass, for pick- ling stainless steel, in the production of gasoline and aluminum, and for acidizing oil wells. Ronzanim found no injurious action of fluoride in animals exposed for 30 days at 3 ppm HF. At that time, much higher concentrations (40 ppm) were employed in inhalation therapy for pulmonary tuberculosis:0 Machle et ahs1 reported that guinea pigs and rabbits survived 40 ppm for 41 hours; deaths resulted from 300 ppm for two hours or more. Stokinger and associatesm found that animals tolerated 7 ppm of HF with only mild irritation of the respiratory tract in repeated daily exposures. Largenfls' reported that repeated exposures at 17 ppm resulted in damage to the lungs, liver, and kidneys of animals, but at 8.6 ppm pathologic changes were insignificant, except for lung injury in one dog. Repeated experimental human exposures six hours a day for 10 to 50 days at concentra- tions as high as 4.7 ppm were tolerated without severe ef- fects. Redness of skin, and some burning and irritation of the nose and eyes were noted at concentrations above 3 ppm. Three subjects who inhaled approximately 3 ppm had average urinary excretion of 6.69, 11.47, and 9.4 mg/day of fluoride.1s.ei Prolonged inhalation of HF in high concentrations would presumably lead to fluorosis, which has been more often observed as a result of the inhalation or ingestion of fluoride salts (q.v.). Kleinfeld(n reported a fatal case of acute pulmonary edema resulting from an accident involving hydrofluoric acid. • Ceiling limit proposed in 1984. In its criteria document for hydrogen fluoride, NIOSH recommends a workplace environmental limit of 2.5 mgimt as a TWA, with a 15-minute ceiling of 5 mgfm;, correspond- ing to 3.06 and 6.1 ppm, respectively!- Additional references cited which support these limits include a PHS study,(91 which showed that no significant changes in pulmonary function resulted from occupational exposure at an average concentration of 1.03 ppm of HF. A report by Rye/101 indicated no increase in respiratory complaints among workers exposed at concentrations of HF and SiF, below 2.5 mg/ms. The study by Derryberry et ail", is inter- preted as indicating a threshold for minimal increases in bone density due to fluoride (fluorosis) of below 3.38 mg1m3 of fluoride, or 4.3 ppm of HF. The Committee considers hydrogen fluoride a primary irri- tant, therefore a ceiling limit of 3 ppm is recommended. This should also minimize the occurrence of fluorosis. Other recommendations:0Z Australia, Belgium, Finland, West Germany, Japan, Netherlands, Sweden and Yugoslavia, 3 ppm; Switzerland and Italy, 1.5 ppm; Czechoslovakia, East Germany, and Romania, 1.2 ppm; and the USSR, 0.6 ppm. References: t. Ronzani, E.: Arch. f. Hyg. 70:217 (1909). 2. Roholm, K.: Fluorine Intoxication. H.E. Lewis & Co., London (1937). 3. Machle, W., F. Thamann, K. Kitzmiller and ). Cholak: J. Ind. Hyg. 16:129 (1934). 4. Stokinger, H.E. et al: Pharmacology and Toxicology of Uranium Compounds, Chap. 17. NNES VI 2. McGraw Hill, New York (1949). 5. largent, E.).: Fluorosis. Ohio State University Press, Columbus, OH (1961). 6. idem: Arch. Ind. Health 21:318 (1960). 7. Kleinfeld, M.: Arch. Env. Health 10:912 (1965). 8. NIOSH: Criteria for a Recommended Standard - Occupational Exposure to Hydrogen Fluoride. DHEW Pub. No. (NIOSH) 76-143 (1976). 9. Leiden, NA_ et al: Enviornmental and Medical5urvey, Blockson Works, Olin Mathieson Corp. DHEW, PHS Occupational Pro- gram (September 1967). 10. Rye, WA: Proceedings of 13th Int. Congress on Occupational Health, July 1960, pp. 361-364 (1961). 11. Derryberry, O.M., M.D. Bartholomew and R.B.L Fleming: Arch. Env. Health 6:503 (1963). 12. Occupational Fxposure Limits for Airborne Toxic Substances, 2nd (rev.) ed., pp. 128-129. Occupational Safety and Health Series No. 37. Intematinal Labour Office, Geneva (1980). ~ 0 ~ a © ~ Lr1 J V ) Mn.•Mc ConJ tnd ltyg. vnt 11 11984) 376 Palic 325

19a4-sB rLYs squamous cell carcinoma, rats, @ 0.05 ppm, in 13 months OR 1b. Dermal. Elicit cancer within 20 weeks by skin-painting, twice weekly at 2 mg/kg body weight or less per application for a total dose equal to or less than 1.5 mg, In a biologically inert vehicle: Examples: 7, 12-Dimethylbenz(a)anthracene - skin tumors @ 0.12-0.8 mg T.D. in four weeks Benzo(a)pyrene, mice 12 µg, 3X/wk for 18 mas. T.D. 2.6 mg, 90.9% skin tumors OR tc. Gastrointestinal. Elicit cancer by daily in- take via the gastrointestinal tract, within six months, with a six-month holding period, at a dosage below 1 mg/kg body weight per day; total dose, rat, s_ 50 mg; mouse, 5 3.5 mg; Examples: 7, 12-Dimethylbenz(a)anthracene - mammary tumors from 10 mg 1X 3-Methylcholanthrene - Tumors @ 3 sites from 8 mg in 89 weeks Benzo(a)pyrene, mice, 3.9% leu- kemias, from 30 mg T.D. 198 days 2. Elicit cancer by all three routes in at least two animal species at dose levels prescribed for high or intermediate potency. B. Industrial Substances of Intermediate Carcinogenic Potency in Experimental Animals. To qualify as a carcinogen of intermediate po- tency, a substance should elicit cancer in two an- imal species at dosages intermediate between those described In A and C by two routes of ad- ministration. Example: Carbamic acid ethyl ester Dermal, mammary tumors, mice, 100%, 63 weeks, 500-1400 mg T.D. Gastrointes- tinal, various type tumors, mice 42 weeks, 320 mg T.D. Gastrointestinal, various type tumors, rats, 60 weeks, 110-930 mg T.O. C. Industrial Substances of Low Carcinogenic Potency in Experimental Animals. To quality as a carcinogen of low potency, a sub- stance should elicit cancer in one animal species by any one of three routes of administration at the following prescribed dosages and conditions: la. Respiratory. Elicit cancer from (1) dosages greater than 10 mg/m3 (or equivalent ppm) via the respiratory tract In 6- to 7-hour, daily re- peated Inhalation exposures, for 12 months' exposure and 12 months' observation period; or (2) from intratracheally administered dos- ages totaling more than 10 mg of particulate or liquid per 100 ml or more of animal minute respiratory volume; Examples: Beryl (beryllium aluminum silicate) malig. lung tumors, rats, @ 15 mg/m3@ 17 months Benzidine, var. tumors, rats, 10-20 mg/m3 @ > 13 mos. OR 1b. Dermal. Elicit cancer by skin-painting of mice in twice weekly dosages of > 10 mg/kg body weight in a biologically inert vehicle for at least 75 weeks, i.e., a 1.5g T.D. Examples: Shale tar, mouse, 0.1 ml x 50 = sg T.D. 59/60 skin tumors Arsenic trioxide, man, dose un- known, but estimated to be high 1c. Gastrointestinal. Elicit cancer from daily oral dosages of 50 mg/kg/day or greater during the lifetime of the animal. Appendix B Substances of Variable Composition Bt Polytetratluoroethylene'decomposition products. Thermal decomposition of the fluorocarbon chain in air leads to the formation of oxidized products containing carbon, fluorine and oxygen. Because these products decompose in part by hydrolysis in alkaline solution, they can be quantitatively de- termined in air as fluoride to provide an Index of exposure. No TLV is recommended pending de- termination of the toxicity of the products, but air concentrations should be minimal. B2 Welding Fumes -Total Particulate (NOC)t TLV, 5 mg/m3 Welding fumes cannot be classified simply. The composition and quantity of both are dependent on the alloy being welded and the process and elec- trodes used. Reliable analysis of fumes cannot be made without considering the nature of the welding process and system being examined; reactive metals and alloys such as aluminum and titanium are arc- welded in a protective, inert atmosphere such as argon. These arcs create relatively little fume, but an intense radiation which can produce ozone. Similar processes are used to arc-weld steels, also creating a relatively low level of fumes. Ferrous alloys also are arc-welded in oxidizing environments which generate considerable fume, and can produce carbon monox- ide instead of ozone. Such fumes generally are com- posed of discreet particles of amorphous slags con- taining iron, manganese, silicon and other metallic constituents depending on the alloy system Involved. Chromium and nickel compounds are found in fumes when stainless steels are arc-welded. Some coated and flux-cored electrodes are formulated with fluorides and the fumes associated with them can- contain significantly more fluorides than oxides. Be- -Trade Names: Algollon. nuon, Halon, Teflon, Tetran. t Not otherwise dassified (NOC). I Ann.,rna Can6 rrtd. Hyg., Vd [I (r984/ 37 rage 787 9

19s4-a5 TcUs I ( AOOPTEO VALUES TWA STEt. Substance [CAS #1 PPm"r mg/mab1 Ppm", mg/m3"' $ Calcium prbonate/ marble [1317-65-3] ............... D - (20) $Catcium cyanamide (156-62-71 ................. 0.5 (1) Calcium hydroxide [1305-62-0] ............... 5 Calcium oxide (1305-78-8] 2 Calcium siicate [1344-95-21 ............... D Camphor, synthetic [76-22-21 .................. 2 12 ' 3 18 Caprolactam [105-60-21 Oust ........................ - 1 . - 3 Vapar ....................... 5 20 10 40 Captafol (2425-06-1) - Skin ........................ 0.1 - - tCaptan [133-06•21........... 5 - (15) tCarbaryl [63-25-21 .......... 5 - (10) Carboturan (1563-66-21.... 0.1 - - $Carbon black [1333-86-4].. 3.5 - (7) tCarbon dioxide [12438-91. 5,000 9,000 (15, 000) (27, 000) Carbon d]sulfide [75-15-0] - Skin ..................... 10 30 - Carbon monoxide [630-OS-01 ................. 50 55 400 440 Carbon tetrabromide [558-13-4] ................. 0.1 1.4 0.3 4 t t hl id - C b rac e or e t ar on [56-23-51-Skin ........ 5; A2 30, A2 (20, A2) (125, A2) Carbonyl chloride, see Phosgene Carbonylfktoride [353-50-01 ................. 2 5 5 15 Catechol (Pyrocatechol) [120-80-91 ................. 5 20 $Cellulose (paper fiber) [9004-34-6] ............... D (20) Cesium hydroxide (21351-79-1 ] .............. 2 Chlordane (57-74-91 - Skin ........................ 0.5 2 Chlorinated camphene [8001-35-2] - S kin ..... 0.5 1 Chlorinated diphenyl oxide (55720-99-5] .............. 0.5 2 Chlorine [7782-50-5] ....... 1 3 3 9 Chlorine doxide (10049-04-4] .............. 0.1 0.3 0.3 0.9 Chlorine tri0uoride [779091-21 ............... C 0.1 C 0.4 Chloroacetaldehyde [107-20-01 ................. Gt C3 arChloroacetophenone [532-27-0] (Phenacyl chloride) ................... 0.05 0.3 Chloroacetyl chloride [79-04-9] .................. 0.05 0.2 Chlorabenzene (108-90-7] (Monochlorobenzene).... 75 350 a-CMorobenrylidene malononitrile [2698-41-1 ] - Skin ..... C 0.05 C 0.4 Chlorobramomethane (74-97-51...••...••••••..•• 200 1,050 250 1,300 2-Chloro-1, 3-butadiene,see F Chloroorene nna Am. Conf. rna. Hyg, VoL r r U984) 375 ADOFTEO VALUES • TWA STEL Substance [CAS #1 ppm"' mg/ma0/ ppm" mglill Chlorodi0uaromethane [75-05-6] .................. 1,000 3,500 1,250 4,375 Chlorodiphenyl (42% Chlorine) (53469-21-9] -Skin ..................... - 1 - 2 Chlorodipherryl (54% Chlorine) (11097-69-1] r -Skin ..................... - 0.5 - 1 t 1-Chloro, 2, 3-epoxy-propane, see Epichlorohydrin 2-Chloroethanol, see Ethylene chlarohydrin Chloroethylene, see Mnyl chloride $Chloratorm [67-66-3]..•...• 10, A2 50, A2 (50, A2) (225, A2) bis-Chbromethyl ether [542-88-1] ................. 0.001, 0.005, Ala Ala Chloromethyl methyl ether [107-30-21 ................. A2 A2 1-Chloro-l-nitropropane [600-25-97 ................. 2 10 Chloropentafluoroethane [76-15-3] .................. 1,000 6,320 - - Chloropicrin (76-06-2]...... 0.1 0.7 0.3 2 p-Chloroprene [126-99-8] -Skin ..................... 10 45 - - o-Chiorostyrene (1331-28-81 ............... 50 285 75 430 o-Chlorotoluene [95-49-8I. 50 250 75 375 2-Chloro- 6-(trichloromethyl) pyridine, see Nitrapyrin Chlorpyrifos [2921-88-2] -Skin ..................... - 0.2. - 0.6 Chromite ore processing (Chramate), as Cr........ - 0.05. Ala Chromium [7440-47-3] Metal ....................... - 0.5 - Chromium (1]) compounds, as Cr ....................... - 0.5 Chromium (III) compounds, as Cr........ - 0.5 Chromium (VI) compounds, as Cr Water soluble ............. - 0.05 Certain water insoluble .. - 0.05, Ala Chmmy] chloride [14977-61-81 .............. 0.025 0.15 Chrysene (218-01-91........ A2 A2 Clopidoi[2971-90-61........ - 10 Coal tar pitch vo1a01es [8007-05-2], as benzene sclubles .................... - 0.2, Ala $Cobart (7440-08-4], as Co metal, dust & fume ...... - (0.1) Cobalt carbonyl [00000-00-01, as Co..... - 0.1 Cobalt hydrocarbonyl [16842-03-8], as Co..... - 0.1 Capital letters A, 8, 0 & E refer to Appendices; C denotes ceiWng 6mit, tSee Notice of Intended Changes. d) Lint-free dust as measured by the vertical elutriator cotton-dust sampler desaibed in the Transac6ons of the National Conrernce on Cot- tan Oust, p. 33 by J. R. Lyndt, (May 2. 1970). 20 ftse ns

Transactions - 1984 Chlorornethyl methyl ether - Chromates of lead and zinc, as Cr 0.05 mg/m3 Chrysene 3, 3'-Dichlorobenzitline - Skin Dimethylcarbamyl chloride 1, 1-Dimethyl hydrazine - Skin Dimethyl sulfate - Skin Ethylene dibromide -Skin 0.5 ppm 0.1 ppm $Ethylene oxide 1 ppm Formaldehyde 1 ppm Hexachlorobutadiene 0.02 ppm Hexamethyl phosphoramide - Skin - Hydrazine -Skin 0.1 ppm 4, 4'-Methylene bis (2-chioroaniline) - Skin 0.02 ppm t4,4-Methylene dianiline 0.1 ppm Methyl hydrazine -Skin C 0.2 ppm Methyl iodide - Skin 2 ppm 2-Nitropropane 10 ppm N-Nitrosodimethylamine - Skin - N-Phenyl-beta-naphthylamine Phenylhydrazine - Skin Propane suitone 5 ppm beta-Propiolactone 0.5 ppm Propyleneimine - Skin 2 ppm o-Tolidine - #o-Toluidine - Skin 2 ppm tp-Toluidine - Skin 2 ppm Vinyl bromide _ 5 ppm Vinyl cyclohexene dioxide 10 ppm For the above, worker exposure by all routes should be carefully controlled to levels consis- tent with the animal and human experience data (see Documentation), including those sub- stances with a listed TLV. * * * THE COMMITTEE GUIDELINES FOR CLASSIFICATION OF EXPERIMENTAL ANIMAL CARCINOGENS The following guidelines are offered in the present state of knowledge as an aid in classifying substances in the occupational environment found to be carcin- ogenic in experimental animals. A need was felt by the Threshold Limits Committee for such a classifica- tion in order to take the first step in developing an appropriate TLV for occupational exposure. Determination of Approximate Threshold of Response Requirement. In order to determine in which category to classify an experimental carcinogen for the pur- pose of assigning an industrial air limit (TLV), an ap- proximate threshold of neoplastic response must be determined. Because of practical experimental diffi- culties, a precisely defined threshold cannot be at- tained. For the purposes of standard-setting, this is of t 1984 Addition. t19e4 Adoption. little moment, as an appropriate risk, or safety, factor can be applied to the approximate threshold, the magnitude of which is dependent on the degree of potency of the carcinogenic response. To obtain the best 'practical' threshold of neoplastic response, dosage decrements should be less than logarithmic. This becomes particularly important at levels greater than 10 ppm (or corresponding mg/ml). Accordingly, after a range-finding determination has been made by logarithmic decreases, two additional dosage levels are required within the levels of "ef- • fect" and "no effect" to approximate the true thresh- old of neoplastic response. The second step should attempt to establish a me- tabolic relationship between animal and man for the particular substance found carcinogenic in animals. If the metabolic pathways are found comparable, the substance should be classed highly suspect as a car- cinogen for man. If no such relation is found, the sub- stance should remain listed as an experimental an- imal carcino gen until evidence to the contrary is found. Proposed Classification of Experimental Animal Car- cinogens. Substances occurring in the occupational environment found carcinogenic for animals may be grouped into three classes, those of high, intennedi- ate and low potency. In evaluating the incidence of animal cancers, significant incidence of cancer is de- fined as a neoplastic response which represents, in the judgment of the Committee, a significant excess of cancers above that occurring in negative controls. EXCEPTlONS: No substance is to be considered an occupational carcinogen of any practical significance which reacts by the respiratory route at or above 1000 mg/m3 for the mouse, 2000 mg/m3 for the rat; by the dennal route, at or above 1500 mg/kg for the mouse, 3000 mg/kg for the rat; by the gastrointestinal route at or above 500 mglkg/d for a lifetime, equivalent to about 100 g T.D. for the rat, 10 g T.D. for the mouse. These dosage limitations exclude such substances as dioxane and trichlorethylene from consideration as carcinogens. Examples: Dioxane - rats, hepatocellular and nasal tumors from 1015 mg/kg/d, oral Trichloroethy(ene - female mice, tumors (30198@ 900 mg/kg/d), oral A. Industrial Substances of High Carcinogenic Potency in Expefimental Animals. 1. A substance to quality as a carcinogen of high potency must fulfill one of the three following conditions in two animal species: ta. Respiratory. Elicit cancer from (1) dosages below I mg/ma (or equivalent ppm) via the respirato ry tract in 6- to 7-hour daily repeat- ed inhalation exposures throughout life- time; or (2) from a single intratracheally ad- ministered dose not exceeding 1 mg of particulate, or liquid, per 100 ml or less of animal minute respiratory volume; Examples: bis-Chloromethyl ether, malignant tumors, rats, @ 0.47 mg/m3 (0.1 ppm) in 2 years; Hexamethyl phosphoramide, nasal Payt Iae ' Ann. Artt Conf. lnd: Nyg. VoL 1 f(1981) 372

1 PULMONARY FUPICTIOPI TESTS OBSTRUCTIVE DISEASES RESTRICTIVE DISEASES 7ests o1 Pulmonary Function i _ .. _. '"._..... ~ ~ Lwqvelum.r ....'~F-. . -~ .. _, ..,.-.. ~7 ~Obatruetloq .J:.:•, , am1 aPaNXes !p ~ Vital apUly..'~`J.. - . Inspiratory ppaeilK'`? • ..•: ~ Fxpfntcry ieeerve.~ ; , vdum~ . „ • TWal.l~ol,~lm.S: .. ..~.. _... . FundlonaGreaidW uiC^. Y•~a> 5 r. `Hi dlfutbn .. ,.- . ur bcdY' , F It ; II F:---,.,?A I I IvtMM1WPJ )-TLC __ Reeidual voh3ma;';. ~ t '. RV' : FRC-ERV ~ Tolel lung•eapaUry _'? TLC' t VCiflVOr FRC+iC i_ ., - J L.:i J u .~~JJ `. -~JJ tiaplratory flow rFlaa Force, ezpiratory volUmt in f second : in 1 secands : ~ FEF,• reauceo or normal . _ , . r - 3 2 I 0 5 < 3 2 1 Time Isee/ Time Iseel . . • FEV,rFVC. o >70 FEV./FVC.° , . FEV,rFVC.o >95 FEVr/FVC': Decreasee FEF,rr,. wiee range FEF_s.a•. ------------------------------------------------- M MVV is reduced in both obstruetive and restrictive disease. In both cases it is proportional to FEV, FEV, rt 40 approximates MVV). Useful a5 test of consistency of patient pErformarlcG. Ia very -12 sec-ri dependent on patient effort and cooperation ..,_~ .,: •._.,._., _. ._...... -------------------------------- ----=-ei l~ ----- -_ ~ ' Normal I,•~ Obstrumion I~ Restritl pon Maximal vuluntary' ~ '` braathes as hard•~ ventilation or ~' and as rapidly as Masimal breathing • MBC PosslblC for 12 sec• capacity . ' Tohl vol. noted I - - ~ _ Maximal exPirateryd racprdag of IIGw .. . i • : - .' ya volume - flow at 75 ,x M D.., n..• • w.Gilegraten ~ VCr V"~' Pnelimctechograph' 25J ' a e Lung elasticity Slatlc recoit pressure Atlway rMlslanCe.. Statip c•ompllaic.r Pleura/ pressure ' is recorded with ' efophageal balloon while aidlow is arreited at . dfRerent Iung . wNUmes:,changes Csla' ~in'lung volume ratorded w1!1 . , ep4cmtler or . :' pnaumaaChograCh . apply •. ~plamysmograph : to determine 9ar ~ alveolar pressure • z aM' prieumc- . ' tatMgraph to ° meaaun sirlfow Dinusug aapaidlr . . ' ' : . . • 1'°W eonpc. tmnon • D00 of CO inhaled: ., axplr.d'gu .. . . _...._._._,-. ,_ ._.~_an°flaatl /ar CO aaw :m Hr0/ sect Normal 356 .ung vol. Il) Obatrr3oUon 0 Restriction Restriction Ft,J.: FVC.`S anc FEVsi FVC.v'% usually normal Slalic elastic recoil of lung is increased and static compliance reduced in diseases such as pulmonary fibrosis. Conversely in emphysema• static lung comotiance R Inereased and elastic recoil is reduced In bostr:chve lung disease aitway ~Obshudlon remstance is mereased. II obstruc[non Involves Gnlv small \ ~ Euways (<2 mm ditmcyq, only \`\ •~ResPldlon minimal changes ' o'~ rall ' resistance may re• /It, n t NCrmal restrictive Sa 'rdE 3. s2'anca is Ir°°ge ohe^ reduc-d becau-: of me: esad traction or mtrathoraac mnvly waps 7f1tL-ng caGacrty is reduced when aneolar wai s are cesuoyed ;no pmmonary capillaries re Obliterated by empnysema anc xnen alveolar-capolary memb'ane 5 thlGkened by edema. corsolidalwn, or.hbrosis

1984-85 TLVs l Notice of Intended Changes Dust Substance TLV SlLICA, Si02 Crystalline t Quartz ................0.1 mg/m', Respirable dust [14808-60-7] tCristobalite.......... 0.05 mg/m3, Respirable dust (14464-46-1] tTddymite ............0.05 mg/m3, Respirable dust [15468-32-31 Silica, fused.........Use quartz value. (60676-86-0] Tripoli ................0.1 mg/m3of contained quartz, , ro [1317-95-9] respirable dust water insoluble Amorphous compounds .............. t Diatomaceous earth Coal tar pitch volatiles .... (uncalcined) ...... 10 mg/m3, Total dust [60676-86-0] Nickel sulfide roasting, Precipitated silica 5 mg/ma, Respirable dust ~ fume & dust ............. and si6ca ge1.....10 mg/m3, Total dust Vinyl chloride .............. SILICATES and OTHER DUSTS (< 1% quartz) t Barium sulfate ......10 mglma, Total dust [7727-43-7] Graphite (natural)...2.5 mg/m3, Respirable dust (7782-42-5] 5 mg/ms, Total dust tGraphite (synthetic) 10 mg/m3, Total dust t Mica (12001-26-2] .3 mg/m3, Respirable dust t Perlite ................10 mg/ma, Total dust tPortland Cement.... 10 mg/m3, Total dust Soapstone........... 3 mg/m3, Respirable dust 6 mg/m3, Total dust Talc (containing Use asbestos TLV. However, asbestos fibers)..should not exceed 2 mg/m3 respirable dust. tNuisance particulates (see Appendix D) 10 mglm3l^' of total dust < 1% quartz COAL OUST If > 5% quartz, use respirable quartz value. Generic Listing All mppcf values for mineral dusts will be eliminated in favor of equivalent respirable mass or total mass val- ues, i.e., Appendix F. Footnote: m) Containing < 1% quartz; if quartz content > 1%, use quartz value. Appendix A Cancinogens The Committee lists below those substances in in- dustrial use that have proven carcinogenic in man, or have induced cancer in animals under appropriate ex- perimental conditions. Present listing of those sub- stances carcinogenic for man takes two forms: Those for which a TLV has been assigned (la) and those for which environmental conditions have not been suffi- ciently defined to assign aTLV (lb). Ann. Anc Con/. !rsd Hyg., VoL 11(IA94J 377 Ala. Human'Carcinogens•Substances,orsu associated with industrial processes, nized to have carcinogenic or cocarcin potential, with an assigned TLV: Asbestos Amosite .................. Chrysotile ................ Crocid olite ............... Other forms ............. 0.5 fiber > 5µm/cc 2 fibers > 5µm/cc 0.2 fiber > 5p.mlcc 2 ~fib r'Um/cc 0.001 ppm 0.05 mg/m3, as Cr 0.2 mg/m3, as benzene solubles 1.0 mg/ma, as Ni 5 ppm Atb. Human Carcinogens. Substances, or sub- stances associated with industrial processes, recognized to have carcinogenic potential with- out an assigned TLV: 4-Aminodiphenyl (p-Xenylamine) - Skin Benzidine -Skin {3-Naphthyfamine 4-Nitrodlphenyl ' For the substances in 1b, no exposure or con- tact by any route - respiratory, skin or oral, as detected by the most sensitive methods - shall be permitted. The worker should be properly equipped to insure virtually no contact with the carcinogen. A2. Industrial Substances Suspect of Carcinogenic Potential for MAN. Chemical substances or sub- stances associated with industrial processes. which are suspect of inducing cancer, based on either (1) limited epidemiologic evidence, exclu- sive of clinical reports of single cases, or (2) demonstration of carcinogenesis in one or more animal species by appropriate methods. r/bis (Chloromethyl) ether Chromite ore processin (chromate) .............. certain Ch mium (VI) tAcrylonitrile - Skin 2 ppm "Amitrole - Antimony trioxide production* - Arsenic trioxide production - Benzene 10 ppm Benzo(a)pyrene - Beryllium 2.0 µg/m3 t1, 3-Butadiene 10 ppm Cadmium oxide production - Carbon tetrachloride - Skin 5 ppm Chloroform 10 ppm "See No6ce of Intended Changes. t 1984-1985 Addition. f 1984-1985 Pdoption. ' Cigarette smoking can enhance the incidence of respiratory cancers from this or others of Ihese substances or processes. ?age 2W ,

Tests of Pulmonary Function (continued) rrMNttad , ~ • . . . .. .. . ..., •.:. ~ - . • Tests fa'small 30i Small Normal afrwaY dh:sw.'. I airway Maximal expiratory ' OY,we a; Spirometer or flow•volume curve , , pneumdaphograph breathing 80% He ' to record flow and 20% 0, ' V aw r/ and vcfume t Gas eacMnge Partiai pressure in of 0' artanal bleod Pano: ^ _._ of COr in ~ arterial blood Arterial blood pH lionrinqa fYll Inspiralloe of 01• •a Vi the 0xpired iurq . :n velume frgm TLC ' expired k'lb qV is pk.:ed air }'against the N, ~Conc.ntrMion . l`6mPNageN ~ ballcon to ; mees ve Dleural ~ pres_:.ro and spirometer or pneumetaelwgrapn to record vefume Artedel blcod ^ppa . anaarobicaliy,. heparinized TLC 5 Airways in lower lung zones close at low lung volumes and only those alveoli at too Cf lungs continue to empty. Since conceniranon of Np • alveoli of upper zones .: tigFer. slope of curve abruptly +creases (phase IV). Phase IV beglns at larger lung volumes in individuals with even minor degree5 of airway obstruction increasing both CV and CC _ Lung vol. (1) ___________ _____________________-__-_ Fiow iU 6ee) dlsaase__~ NpnnaFlow Smag airway disaaae He-0r (I/sec172 -He-0a CVuw 8 _ fI ~ Air 6V.,., m d ~V iao V .-V isc ~' 00 50 0 too 50 Vpl. f% VC) VGI. (% VC) Ounng a maximal expiratory maneuver. resistance to airllow q normally due to turbufence and convective acceleratlon. Breathing He, nllieh is less dense than air. lowen resistance and increases flow at all but lowest volumes. In small airway dbease• resistance to lammar tWw makes up larger portion of total resistance and aidlow, ,is relatively independent of gas eensity. tncrease in expiratory flow at 50 : of VC while breathing He-Oa faV.., tn1 wdl be :eis, and volume at wllich flows while breathing He-0e and while breathing air are identical IV iso V) will be higher in patients with small airway disease than in normal individuals ' NamN 1.0 i C`tv°-O.Si '~Y dlaase Cvar 15 30 <5 e0 75 90 Breathing Ireguenay (breaths/min) Oynamic comptlance is determined irom changes in lung volume and difference in pleuml presaure at end-inapiration and end<xpirafion. Normally Cayn closely approxfmates Cnat and remains essentially unchanged as breathing freouenry, increases Small airway disease is characterized by patchy increases in airway resistance. Ounng ouim breathing, ventilation may be evenly distributed througnout lung but as breathing beouency increases. alveoli will fill and empty unevenly and asynchronously as air tends to go to these areas which otfer least resistance. Change in pleural pressure for a given change in lung voNme increases ano pynamm compliance talis Normal values AbnerrmaliBea 60 to 100 mm Hg bleathing ropm air Hypoxemia indicative of ventilation-perfusion abnormalities. shuate. at sea level. Falls dilfusion defectt alveolar hypoventliation slightly with age _ ___ _: :C 44 mm Hg Pa<pr proponbnal to mefabolic rate (COr production) and ==v=rs=1y related to volume of alveolar ventilation -_ 7 i5 to 7.45 pH Acidosis (pH <7.35) Respimtory (inatleguate alveolar ventilationl Metabolic (gain of acid and/or loss of base) Alkalosis (pH > 7.45) ~ Sw+ Respuatory (excessive alveolar vemilationi ,~y ~dl~ Metabolic (gain ol base or loss of acidl Alveolar-anerial ps '. <t0 mm Hg Primarily reflects mismatching of ventilation and pertusion and/ar 0, difference ,~ MaO p s AaPOS ,.•breathing room air shunts• May aleb be affected by diffusion derebts - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Oeed space•tidal OetermfhiG Imm Elevated ratio indicates wasted ventilation: i.e that volume ot gas : Vp/VT artmtat and mixF : <0.3 vbfume . which does not take part in gas exchange retb . . a•Dirad Pcos. . ______ _________. __-_________-_____- - __- • ' ~' Delermined Im- Elevatron Indicates inareased amount or mixed venous blood entenng Shunt fraction ba/4uT P302 after systemic circulatwn without coming into contact with alveolar air. a piod of <5°° either because of shunting of blood past lungs to left side of heart or breathing te0". r~. perfusion of regions of lung which are not ventilated I 357

1984-85 TLYs limit values for mixtures, and methods for their develop- ment, amplified by specific examples are given in Appen- dix C. Nuisance Particulates. In contrast to fibrogenic dusts which cause scar tissue to be formed in lungs when in- haled in excessive amounts, so-called "nuisance•" dusts have a long history of little adverse effect on lungs and do not produce significant organic disease or toxic ef- fect when exposures are kept under reasonable control. The nuisance dusts have also been called (biologically) "Inert" dusts, but the latter term is inappropriate to the extent that there is no dust which does not evoke some cellular response in the lung when inhaled in sufficient amount. However, the lung-tissue reaction caused by in- halation of nuisance dusts has the following characteris- tics: (1) The architecture of the airspaces remains intact. (2) Collagen (scar tissue) ls not formed to a significant extent (3) The tissue reaction is potentially reversible. Excessive concentrations of nuisance dusts in the workroom air may seriously reduce visibility, may cause unpleasant deposits in the eyes, ears and nasal passages (Portland Cement dust), or cause injury to the skin or mucous membranes by chemical or mechanical action per se or by the rigorous skin cleansing procedures nec- essary for their removal. A threshold limit of 10 mg/m3, or 30 mppcf, of total dust < 1%quartz, or, 5 mglma respirable dust's recorn- mended for substances in these categories and for which no specific threshold limits have been assigned. This limit, for a normal workday, does not apply to brief exposures at higher concentrations. Neither does it apply to those substances which may cause physiologic impairment at lower concentrations but for which a threshold limit has not yet been adopted. Some nuisance, particulates are given in Appendix 0. Simple Asphyxiants -"lnerf" Gases or Vapors. A number of gases and vapors, when present in high con- centrations In air, act primarily as simple asphyxiants without other significant physiologic effects. A TLV may not be recommended for each simple asphyxiant be- cause the limiting factor is the available oxygen. The minimal oxygen content should be 18 percent by volume under normal atmospheric pressure (equivalent to a par- tial pressure, p0z of 135 mm Hg). Atmospheres deficient in Ox do not provide adequate warning and most simple asphyxiants are odorless. Several simple asphyxiants present an explosion hazard. Account should be taken of this factor in limiting the concentration of the asphyx- iant. Specific examples are listed in Appendix E. Physical Factors. It is recognized that such physical factors as heat, ultraviolet and ionizing radiation, humid- ity, abnormal pressure (altitude) and the like may place added stress on the body so that the effects from expo- sure at a threshold limit may be altered. Most of these stresses act adversely to increase the toxic response of a substance. Although most threshold G'mits have built-in safery factors to guard against adverse effects to moder- ate deviations from normal environments, the safety fac- tors of most substances are not of such a magnitude as to take care of gross deviations. For example, continu- ous work at temperatures above 90'F, or overtime ex- tending the workweek more than 25%, might be consid- ered gross deviations. In such instances judgment must be exemised in the proper adjustments of the Threshold Limit Values. Unlisted Substances. Many substances present or handled in industrial processes do not appear on the TLV list. In a number of instances the material is rarely present as a particulate, vapor or other airborne conta- minant, and a TLV is not necessary. In other cases suffi- cient informatidn to warrant development of a TLV, even on a tentative basis, is not available to the Committee.- Other substances, af low toxicity, could be included in Appendix 0 pertaining to nuisance particulates. This list (as well as Appendix E) is not meant to be all inclusive; the substances serve only as examples. In addition there are some substances of not incon- siderable toxicity, which have been omitted primarily be- cause only a limited number of workers (e.g., employees of a single plant) are known to have potential exposure to possibly harmful concentrations. , Trade Names. Because many chemtcal substances t are marketed under several trade names, the trade t names have been replaced with their generic equivalent in the alphabetical listing. Appendix H was created to ease this transition and the CAS number appears with the generic name to aid identificatlon. Operational Guidelines: The ACGIH Board of Direc- tors has adopted operational guidelines for the Chemical Substances TLV Committee. These guidelines prescribe: charge, authority, policies, membership, organization, and operating procedures. The policies include the ap- peals procedures. Copies of the guidelines d,ocument are available from the Publications Office at a cost of $5 per copy. Threshold limit values and short-term exposure limits adopted byACGIH for 1984-85 ADOPfED VALUES TWA sTE[. Substance [CAS #1 ppm"' mg)m;p1 ppm°, ml Acetaldehyde (75-07-01..... 100 180 150 270 Acetic acid [64-19-7] ....... 10 25 15 37 Acetic anhydride (108-24-7) ................. C 5 C 20. - - Acetone [67-64-11........... 750 1,780 1,000 2,375 Acetoniuile (75-05-8] - Skin ........................ 40 70 60 105 Acetylene [74-86-2] ......... E - - - Acetylene dichlaride, see 1, 2-Dichloroethylene #Acetylene tetrabromide [79-27-6] .................. 1 15 Acetylsa8cylicacid (Aspirh) [50-78-2]....... - 5 Acrolein [107-02-81......... 0.1 0.25 Acrylamide (79-06-1 ] - Skin ........................ - 0.3 Acrylic acid [79-10-71....... 10 30 'AcryloniVile [107-13-11- Skin ........................ 2, A2 4.5, A2 $Aktrin[309-00-21-Skin.. - 0.25 (1.5) (20) - - 0.3 0.8 - 0.6 - (0.75) a) Parts of vapor or gas per million parts of cantaminated air by volume at 25°C and 760 mm Hg pressure. b) Approximate milligrams df substance per cubic meter of air. tSee Notice of Intended Changes. -1984-1985Addition. Capital letters A, 8• D & E refer to Appendices: C denotes ceiling Gmit. .+z,..Ux. con,S Jna mJ9, vn[ tl (1984) 3 73 Page 373 ~-----'

BEIs who agree that hippuric acid is elevated only if the TLV is greatly exceeded, and that excretion of large amounts of en- dogenous hippuric acid makes it unsuitable as a biological exposure index. Determination of the ratio of mandelic acid to phenylgtyoxylic acid, and determination of the sum of the two acids were also recommended for biological monitor- ing of exposure.a6•2t) Since the kinetic constants of these two metabolites are not the same and depend on exposure con- centrations, the interpretation of the sums or ratios require sophisticated pharmacokinetic analysis. We do not recom- mend them as a BEt. References: 1. Fiserova-Dergerova, V.: Gases and Their Solubility: A Review of Fundamentals. Modeling of Inhalation Exposure to Vapors: Uptake, Distribution, and Elimination, Vol. 1, pp. 3-28. CRC Press, Boca Raton, FL (1983). 2. Wigaeus, E., A. Lof, R. Bjurstram and M. Byfalt Nordqvist: Ex- posure to Styrene. Uptake, Distribution, Metabolism and Elimina- tion in Man. Scand.l. Work Environ. Health 9:479-488 (1983). 3. Fiserova-Bergerova, V. and J. Teisinger, Pulmonary Styrene Vapor Retention. Ind. Med. Surg. 34:620-622 (1965). 4. Bardodej, Z. and E. Bardodejova: Biotransformation of Ethyl Benzene, Styrene and Alpha-Methylstyrene in Man. Amer. Ind. Hyg. Assoc. 1. 31:206-209 (1970). ' . 5. Dutkiewicz, T. and H. Tyras: Skin Absorption of Toluene, Styrene and Xylene in Man. Brit.1• Ind. Med. 25:243 (1968). - 6. Engstrom, J., R. Bjurstrom, I. Astrand and P. Ovrum: Uptake, Distribution, and Elimination of Styrene in Man. Concentration in Subcutaneous Tissue. Scand.l. Work Environ. Health. 4:1-9 (1978). 7. Astrand 1.: Effect of Physical Exercise on Uptake, Distribution, and Elimination of Vapors in Man. Modeling of Inhalation Ex- posure to Vapors: Uptake, Distribution, and Elimination, Vol. 2, pp. 107-130. V. Fiserova-Bergerova, Ed. CRC Press, Boca Raton, FL (1983). 8. Landry, T.D., R.R. Miller, M.J. McKenna et al: Applications of Pharmacokinetic Principles to Problems in Inhalation Toxicology. Ibid., pp. 39-65. 9. Ohtsuji, H. and M. Ikeda[The Metabolism of Styrene in the Rat and the Stimulatory Effect of Phenobarbital. Toxicol. Appl. Pharmacol. 18:321-328 (1971). 10. Stewart, R.D., H.C. Dodd, E.D. Baretta and A.W. Schaffer: Human Exposure to Styrene Vapor. Arch. Environ. Health 16:656-662 (1968). 11. Ikeda, M, T. Imamura, M. Hayashi et al: Evaluation of Hippuric, Phenylglyoxylic and Mandelic Acids in Urine as Indices of Styrene Exposure. tnt. Arch. Arbeitsmed. 32:93-101 (1974). 12. Gotell, P., O. Axelson and B. Lindelof: Field Studies on Human Styrene Exposure. Work Environ. Health. 9:76-83 (1972). 13. Harkonen, H., P. Kalliokoski, S. Hietala and S. Hernberg: Con- - centrations of Mandelic and Phenylglyoxylic Acid in Urine as Indicators of Styrene Exposure. Ibid. 11:162-169 (1974). 14. Bardodej, Z., E. Bardodejova and I. Gut: Metabolism of Styrene in Rats. Ceskosfovenska Hygiena 16:243-245 (1971). 15. Ikeda, M. and T. Hirayama: Possible Metabolic Interaction of Styrene with Oraganic Solvents. Scand.l- Work Environ. Health 4 (Suppl. 2):41-46 (1978). 16. Ikeda, M., H. Ohtsuji and T. Imamura: In vivo Suppression of Benzene and Styrene Oxidation by Co-administered Toluene in Rats and Effects of Phenobarbital. Xenobiotica 2:101-106 (1972). 17. Wilson, H.K., S.M. Robertson, H.A. Waldron and D. Gompertz: Effect of Alcohol on the Kinetics of Mandelic Acid Excretion in Volunteers Exposed to Styrene Vapour. Brit.1. lnd. Med. 40:75-80 (1983). i8. Dossing, M.: Antipyrine Clearance During Occupational Exposure to Styrene. lbid. 40:224-228 (1983). 19. Poggi, G., M. Giusiani, U. Palagi et al: High-Performance Liquid Chromatography for the Quantitative Determination of the Urinary Metabolites of Toluene, Xylene, and Styrene. Int. Arch. Occup. Environ. Health 50:25-31 (1982). 20. Sollenberg, J. and A. Baldesten: Isotachophoretic Analysis of Mandelic Acid, Phenylglyoxylic Acid, Hippuric Acid and Methylhippuric Acid in Urine After Occupational Exposure to Styrene, Toluene and/or Xylene. /. Chromatog. 132:469-476 (1977). 21. Slob, A.: A New Method for Determination of Mandelic Acid Excretion at Low Level Styrene Exposure. Brit. l. /nd. Med. 30:390-393 (1973). 22. Guillemin, N. and D. Bauer: Human Exposure to Styrene. II. Quantitative and specific gas chromatographic analysis of urinary mandelic and phenylglyoxylic acids as an index of styrene ex- : posure. 7nt. Arch. Occup. Ehviron. Health 37:57-64 (1976). 23. Flek, ). and V. Sedivec: Simultaneous Gas Chromatographic Determination of Urinary Mandelic and Phenylglyoxylic Acids Using Diazomethane Derivatization. Ibid. 45:181-188 (1980). 24. Bardodej, Z.: Styrene Metabolism. Ceskolovenska Hygiena 9:223-239 (1964). 25. Ohtsuji, H. and M. Ikeda: A Rapid Colorimetric Method for the Determination of Phenylglyoxylic and Mandelic Acids. Its Ap- plication to the Urinalysis of Workers Exposed to Styrene Vapor. Brit. l. Ind. Med. 27:150-154 (1970). 26. Guillemin, M.P. and D. Bauer. Human Exposure to Styrene. Ill. Elimination kinetics of urinary mandelic and phenylglyoxylic acids after single experimental exposure. Int. Arch. Occup. Environ. Health 44:249-263 (1979). i 27. Sedivec, V., J. Flek and M. Mraz: Urinary Excretion of Mandelic and Phenyiglyoxylic Acids After Human Exposure to Styrene Vapours. Pracov Lek. 35:365-373 (1983). 28. Ikeda, M., A. Koizumi, M. Miyasaka and T. Watanabe: Styrene Exposure and Biologic Monitoring in F.R.P. Boat Production Plants. Int. Arch. Occup. Environ. f-Ihh. 49:325-339 (1982). 29. Engstrom, K., H. Harkonen, P. Kalliokoski and J. Rantanen: Urinary Mandelic Acid Concentration After Occupational Ex- posure to Styrene and Its Use as a Biological Exposure Test. Scand. 1. Work Environ. Health 1:21-26 (1976). 30. Engstrom, K., K. Harkonen, K. Pekari and J. Rantanen: Evalua- tion of Occupational Styrene Exposure by Ambient Air and Urine • (.n Analysis. Ibid., Suppl. 2:121-123 (1978). ~ 31. Van Rees, H.: De Respiratoire Opname Van Niet-inerte Gassen Q en Dampen. Proefschrift, Leiden (1964). - 32. Droz, P.O. and j.G, Fernandez: Effect of Physical Workload on Un Retention and Metabolism of Inhaled Organic Solvents. A Com- yrn Ann. Am. Conf. Ind. Xyg., VoL 11 (t9&il 385 . rage 117

Transactions - 1984 ing than those based on physical impainnent. There is increasing evidence that physical irritation may initiate, promote or accelerate physical impairment through in- teraction with other chemical or biologic agents. Time-Weighted Average vs Ceiling Limits. Time- weighted averages permit excursions above the limit provided they are compensated by equivalent excursions below the limit during the workday. In some instances it may be permissible to calculate the average concentra- tion for a workweek rather than for a workday. The rela- tionship between threshold limit and permissible excur- sion is a rule of thumb and in certain cases may not apply. The amount by which threshold limits may be ex- ceeded for short periods without injury to health de- pends upon a number of factors such as the nature of the contaminant, whether very high concentrations - even for short periods - produce acute poisoning, whether the effects are cumulative, the frequency with which high concentrations occur, and the duration of such periods. All-factors must be taken into consider- ation in arriving at a decision as to whether a hazardous condition exists. Although the time-weighted average concentration provides the most satisfactory, practical way of monitor- ing airborne agents for compliance with the limits, there are certain substances for which it is inappropriate. In the latter group are substances which are predominantly fast acting and whose threshold limit is more appropri- ately based on this particular response. Substances with this type of response are best controlled by a ceiling "C" Nmit that should not be exceeded. ft is implicB in these definitions that the manner of sampling to determine noncompliance with the limits for each group must differ a single brief sample, that is applicable to a"C' limit, is not appropriate to the tim,e-weighted limit; here, a sufficient number of samples are needed to permit a time-weighted average concentration throughout a com- plete cycle of operations or throughout the work shift. Whereas the ceiling limit places a definite boundary which concentrations should not be permitted to exceed, the time-weighted average limit requires an explicit limit to the excursions that are permissible above the listed values. It should be noted that the same factors are used by the Committee in determining the magnitude of the value of the STELs, or whether to include or exclude a substance for a "C" listing. Excursion Limits. For the vast majority of substances with a TLV, there is not enough toxicological data avail- able to warrant a STEL Nevertheless, excursions above the TWA-TLV should be controlled even where the eight- hour TWA is within recommended limits. Earlier editions of the TLV list included such limits whose values de- pended on the TWA-TLVs of the substance in question. While no rigorous rationale was provided for these particular values, the basic concept was intuitive: in a well controlled process exposure, excursions should be held within some reasonable limits. Unfortunately, nei- ther toxicology nor collective Industrial hygiene experi- ence provide a sogd basis for quantifying what those limits should be. The approach here is that the maximum recommended excursion should be related to the varia- billty generally observed in actual industrial processes. Leidel, Busph and Crouse,' in reviewing large numbers of industrial hygiene surveys conducted by NIOSH, found 'Leidel. N.A., K.A. Busch and W.E. Crouse: Exposuri Measurement, Action - Lavd and Oawpfiana! Environmental Varia0lAty. NK1SM Pub. No. 76~131 (December 1975). that short-term exposure measurements were generally log normally distributed with geometric standard devia- tions mostly in the range of 1.5 to 2.0. While a complete discussion of the theory and prop- erties of the log normal distribution is beyond the scope of this section, a brief description of some important terms is presented. The measure of central tendency in a log normal distribution is the antilog of the mean loga- rithm of the sample values. The distribution is skewed and the geometric mean is always smaller than the arith- metic mean by an amount which depends on the geo- metric standard deviation. In the log normal distribution, the geometric standard deviation (sd,) is the antilog of the standard deviation of the sample value logarithms and 68.26"/0 of all values lie between m,/sd, and m, x sd,. If the short-term exposure values in a given situation have a geometric standard deviation of 2.0, 5% of all val- ues exceed 3.13 times the geometric mean. If a process displays a variability greater than this, it is not under good control and efforts should be made to restore con- trol. This concept is the basis for the new excursion limit recommendations which are as follows: Short-term exposures should exceed three times the TLV-TWA for no more than a total of 30 minutes dur- ing a work day and under no circumstances should they exceed fNe times the TLV, provided that the TLV- TWA is not exceeded. The approach is a considerable simplification of the idea of the log normal concentration distribution but is considered more convenient to use by the practicing in- dustrial hygienist. If exposure excursions are maintained within the recommended limits, the geometric standard deviation of the concentration measurements will be near two and the goal of the recommendation will be accomplished. - When the toxicologic data for a specific substance are available to establish a STEL, this value takes prece- dence over the excursion limit regardless of whether it is more or less stringent. "Skin" Notation. Listed substances followed by the designation "Skin" refer to the potential contribution to the overall exposure by the cutaneous route including mucous membranes and eye, either by air borne, or more particularly, by direct contact with the substance. Vehicles can alter skin absorption. Little quantitative data are available describing ab- sorption of vapors and gases through the skin. The rate of absorption is a function of the concentration to which the skin is exposed. Substances having a skin notation and a low TLV may present a problem at high airborne concentrations, par- ticularly if a significant area of the skin Is exposed for a long period of time. Protection of the respiratory tract, while the rest of the body surface is exposed to a high concentration, may present such a situation. .Biological monitoring should be considered to deter- mine the relative contribution of dermal exposure to the total dose. This attention-calling designation is intended to sug- gest appropriate measures for the prevention of cutan- eous absorption so that the threshold limit is not invali- dated. Mixtures. Special consideration should be given also to the application of the TLVs in assessing the health hazards which may be associated with exposure to mix- tures of two or more substances. A brief discussion of basic considerations involved In developing threshold 1 flgt 272 372 An2 Am. Conf. lnd. Hyg„ Vot 1111984)

NIOSH/OSHA POCKET GUIDE TO CHEMICAL HAZARDS Editors Frank W. Mackison National Institute for Occupational Safety and Health R. Scott Strcoff Lawrence J. Partridga, Jr. A. 0. Little, Inc. U.S. OEPAATb.~- . ' OF HEALTH, EDUCATION, AND WELFARE U.S. DEPARTMENT OF tABOR Public Health Service Occupational Safery and Health Administration I . Center to Di3ea6e Control Nationat )netitute for Occupational Safety and Health eQa'el 4 ,% TJ F% ~ Yo,f's'I%U~ EJ' September 1978 e,•d t oHIo. frzz6 EUtyl elhw oiatltyl aewr, EMyi ®da: 400 ppm 19,c00 ColaAeaa Fquid wilh MW: 74 EOUr,Oq0lyl ok,d~ (1200 mglmy pqo a duractelisec, BP:95 F C.M,OC}i. SWMC esnr sweK ether ador ~,7-5 9 F Pemqs~bfe IOLN PnyviN Oea.alpsar etlamreal and Pbyalr~l Neanpaaeinee tHa!unrsn NOalt~is d ~~ Enppve.linit level Pmpntls 1AWwdand Famda SN (Sa. Ta_^4 1) Eelyl tamute ENmeUVma1« Fara6c 100 PPm 6,000 Cdatesa Atpid wilh MW:74 aad e61y1 nlar (300 ngNny ppm a Inoy ader aP: 170 F NCOOC.l4 Bq: 13.6% RP.-4F 98 ENyt mxnptae ECCanNMOh, Ethyl 10 ppm cea 2,500 suleqdraN (25 mp/m0) ppm 6N.SX i I EMyt aFUte (G,N,).Si7 EOrylarwne C.H,Pai, Pa.emr' PrWectipn and Sanitalion (Sia Tabie f} Rpql aaOnQ Gog WN Char.ge: NA RemawcAnywetaened(Aamm) qett»g: i.apeat prpWng Gcgglet Rusqn preb WarJY PnorrrylN uppn wet Ounge NA Aanprs Ary enet snmed (namm) Cpewxj Repeat acbng Goggks Reason prab Wavts Romplly uppn contam Cnarge: NA Remove: Aiq wet immed (namm) (ACGM) 0.5 ppn TN traNmyl n,~'sn~rSAEe (650 ~m7 plow Pm pN06JiCalY, Telrae111piysdarN Eyyynwy. nilytltalK 70 ppm 4000 AemweMfana~ (1 a ing/mq ppm Mprnelhyl~ Resp'rata S.kcopn Upqr L]nit Oerlcas Pamkn.d (See Tabte 71 1000 ppnr CCROV 4000ppm:SA/SCBA 19,0q0 ppnc GMOV/b/SAF/SCaAF Eswpe:GMOV/SCBA 1000 ppnx CCROVF 5000 ppm: GMOV/SAF/SCBAF e000 ppm: SAF:PO,PP,CF. Esrape GMGY/SGBA 100ppm:SA/SCBA S00ppm:SAF/SCBAF 2500 ppm: SAPD,PP.CF Esrape: GMOV/SCBA Gobrtess [qufd w:N MW: 62 a sewg akwrk•Gke aP. 85 F ador Sub 11% RP:-55F ColtMlnss Iiquid wilh MW:20e amld.swwt BP.= F a1mlaFpk.cda Sd:ne.cb RP:g9F Gpbdesiquidn MW:45 gaa wiM n strag BP: 62 F ammeniakke odd Sol: MrssrEle RP.<0F RaAe Symptcmalq 4) (Sae _ _ Tab . _ Ola, drowsy. beaa exiled, narpave: ruq vaml: krn eyes, upp.r esp; skin IM Imt eyes, nsp sys; Ing rtarccsn Can Haatlh Nat.rds VP•. 442 mm Stnang midrars Qur, FP•,-160 ~ aprate: UEC96% F LEl L9% VP. 194 mm NtratH, strpq CTr, Mv-110 muduars.atray, tS: F aeul~abagaab GC UEL- 16% U LEL. 26% VP•.442mm Strongmfdpan MP: -234 F UEL• 16% tEL• 2.8% VP: 2 mnt SOdg ~dt.n, wawr Resrq MP, -121 CS: UEL•I7% . 5 lEL• 1.1% VP. 1.1e atm MR-114 F UEL• 14% tEL 93% Sp+rs ~g N.60, 11s .aK K Frat Aid (Sae TatJe 5) Target Organs Eye h immad Skue Water wa>A promplly BreaM Mresp Swalbwc Salt water, vpma CNS, skkl, resp sya, eyes Eyr. Rr irnrned Eyes. resp sys Skae Waler Ilush immed Breatll: A6resp Srallo,r. Salt water, vonit IrJI Head, nau, irrit muc Eye: Irr immetl Ing msm.b, tMCaC In arYmels: Sk'vr Saap wash immed Con tncpaGnatime para: pWm Breath: Art resp anC kver, kdney tlama9e Swalbw Satt water, vomM Rasp,y.V wnya: 99 in animalc f,ver, kidmys Goerng: F::w,aat prplong 1000 ppm: CCR0VF/GMOV/SAF/SCBAF IM Irrit eyes, nase Gqg:es: Rea+Gn pmn Esrape: GMOV/SCaA Irg ; Wasb: FrrpPyuxnwet CeI ` Gunge: NA R~: tay wet enmed (namm) • CbMrg: Reascn p.ob GeggwY hy coss Wash: Irve,.! upon eontam Charga: NA. Remo.e: Nm anr wet/conlam nommp Rp.as Ere.ash, quwk dranch 500 ppnc SAF/SCBAF 4000 ppm: SAF PD,PP,CF Esr,pe: GMS/SCBA Eye: Irr Immed Reap ays. I~, Skm: Snap wesh k,Lneya, b:aud. Bmath Art~resP 56m swalipw•, WaGx,vonut 1M Irrrt eyas, bum skln; rasp Eye: Irr immed Resp syR e}as, Abs mt: d'crm Skin: Waler Ilysh immad skin 6reath: Art resp tr 9 n Bwalkw.: Walar, *Omil

BIOLOGICAL EXPOSURE INDICES Notice of Intent to Establish Preface Biological Exposure Indices (BEis) represent warning levels of biological response to the chemical, or warning levels of the chemical or its metabolic productfs) in tissues, fluids, or exhaled air of exposed workers, regardless of whether the chemical was inhaled, ingested,_or absorbed via skin. In• troduction of the BEI is a step in the evolution of the concept of TLVs. The BEI provides the health personnel with an ad- duionai tool to provide protection fa the worker. Use of body fluids and appendages such as hair or nails for measuring the absorbed amount of a substance has long been a standard practice for certain substances. Lead is a classical example of a substartce for which blood cancentratians have long been considered theaiticai value in determining "safe" veisus "utr safe" exposures. Two problems hindered the wider use of biological measurements as indicators of "safe" environmen• tal exposurcs: 1) the relatively wide range in individual response to a substance and the wide range of "nomul•' that has to be considered; and 2) the lack of simple specific analytical methods of sufficient sensitivity. Both problems are capable of solution, and we believe that sufficient progress has been' made to begin utilizing selected BEB which can be used as a guide to "safe" exposures to toxic dhemicais. The BEI is considered supplementary to an airbome TLV. TLVs are intended to provide the industrial hygienist wlth ' an additional measure to aid in the design of engineering con- trds or for temporary use of personnel protective equipment which will protect almost all exposed workers from untoward effects of chemical exposure. In principle, TWMTLVs are designed to prevent exposures which may cause acute or chronic adverse effects. They are also intended to avoid at- tendant deterioration of normal physiological function. This approach is based on the assumption that for nearly all workers there is a tolerable exposure limit and a tolerable body burden o(airbome materiaf. If this assumption is valid, there should be a range of safe biologically insignificant changes of various measures of body funtxion. TLVs are a measure of the composition of the external en- vironment surrounding the worker. BEts are a measure of the amount of chemical absorbed into the body. The concept of the BEI is particularly useful in evaluating exposures to substances with significant absorption through the skin. - The biological determinant on which the BE1s are based can fumish two kinds of Information useful in the control of worker eaposure; 1) measure of the worker's individual response, and 2) measure of the worker's individual overall exposure. Measurements of response fumish an estimate of the physiological status of the worker and can be made by, a) detennining dunges in thearnpxu of a critiai biochemical constituent, b/ determining changes in activity of a critical enzyme, and U determining dianges in a physiological furic- tion. Measurements of exposure can be made by, a) deter- mining the chemical in exhaled air, urine, blood, hair, nails, body tissues and fluids, b1 determining the rnetaboiite(s) of the chemical in tissues and fluids, and rJ determining the ex- tent of specific biochemical and physiological changes in- duced by the chemical. Recommended values of BEIs are based on data obtained in epidemiological and field studies or determined as bio- equivalent to a TLV by mearas of pharmacokinetic analysis of data from controlled human studies. Must chemicals Gn- duding organic solvents) are initially absorbed and eliminated fairly rapidly - usually with initial ftaif-life values measured in a few hours or even minutes. Rapidly changing cortcert- uations in body fluids complicate the Interpretation of data and the average body burden of a chemial attained during a work shift can easily be over-predicted or urder.predicoed. Furthermore, biological measuremeftts fail in most instartoes to detEtt transient periods of over2xposure during the work shifL Because elimination of chemicals and their metabolic products, as well as biological changes induced by exposure to the chemical, are kinetic events, the listed BEIs are strictly related to 8fiour exposures and to the specified timing for the collection of biological samples. Them are other factors to be considered when the BEI is applied. Among the facrors which must be consideteed in us- ing BEIs are: a) changes induced by strenuous physical ac- tivity; b) changes induced by environmental conditions (al6tude, heat, diet, etc.); d changes induced by water in- take; dl changes in physiological functions induced by preex- isting disease or congenital variation; e) changes in metabolism induced by congenital variation of metabolic pathways; and N changes in metabolic pathway induced by simultaneous administration of another chemical (induction or inhibition of activity of a critical enzyme by medication or by preexposure or coexposure to another chemical). For BEIs based on urine analysis, a simple measurements of concentrations can provide sufficient information on ex- posure; but in many instances, measurements of elimination rates provide more precise information. Urinary concentra- tions related to creatinine represent a reasonable compromise between the accuracy of the information ard the technical means of obtaining the data. Some BEIs are not protective of an identificd population, or are nonspecific, or the correiation between the exposure and biological determinant is weakened by variables hmaduc- ed by large interindividual variation in response to the chemical or by timing and fluctuation of exposure concen- tration. In such ases the BEIs arry Ihe following notations: "R" Notation. Indicates that an identifiable population group might have an increased susceptibility to the efk*ct of the dterrtical which kaves it unprotected by the recommerd- ed BEI. The specific documentation should be consulted for detailed information. "•" Notation. Some determinants are nonspecific, since different chemicals may bear the same biological response. AOL Aa. Ge/. W Mq. ttd 1I ftilN/ . ~ ~ . . . ~ ~ ~ "P Its 380