The O ccu p atio n al S afety and H ealth A ct of 1970 em p hasizes the need for standards to protect the health and provide for the safety of workers occupationally exposed to an ever-increasing number of potential hazards. The National Institute for O ccu p atio n al S afety and H ealth (NIOSH) evaluates all available research data and criteria and recommends standards for occupational exposure. The Secretary of Labor will w eigh th e se reco m m en d atio n s along with other considerations, such as feasibility and means of implementation, in promulgating regulatory standards. NIOSH will periodically review the recommended standards to ensure continuing p r o te c tio n of w orkers and will m ake su ccessiv e re p o rts as new re s e a rc h and epidem iolo g ic stu d ie s a re c o m p le te d and as sampling and analytical methods are developed. The co n trib u tio n s to th is do cu m en t on d iiso cy an ates by NIOSH staff, other F ed e ra l ag en cies or departm ents, the review consultants, the reviewers selected by th e S ociety for O ccu p atio n al and Environmental Health and the American Medical A ssociation, and R o b e rt B. O'C onnor, M.D., NIOSH c o n su lta n t in occupational medicine, are gratefully acknowledged. The views and co nclusions ex p ressed in th is d o cu m en t, to g e th e r w ith the re co m m en d atio n s for a sta n d a rd , a re th o se of NIOSH. They are not necessarily those of th e co nsultants, the reviewers selected by professional societies, or other F ed e ra l agencies. However, all comments, whether or not incorporated, have been s e n t w ith th e c r i t e r i a d o c u m e n t to th e O c c u p a t io n a l S a f e ty and H ealth A d m in istratio n for c o n sid e ra tio n in setting the standard. The review consultants and th e F e d e ra l agencies which received the document for review appear on pages v and vi.#
NIOSH reco m m en d s th a t employee exposure to diisocyanates in the workplace be c o n tro lle d by adherence to the following sections. The standard is designed to p ro te c t the h e a lth and provide for th e s a fe ty of employees for up to a 10-hour workshift, 40-hour workweek, over a working lifetime. Compliance with all sections of the recommended standard should prevent adverse effects of diisocyanates on the h e a lth of u n sen sitized workers and provide for their safety. Sufficient technology ex ists to p erm it co m p lian ce w ith th e reco m m en d ed standard. Although NIOSH considers th e w orkplace e n v iro n m en ta l lim its to be safe levels based on current in fo rm atio n , th e em ployer should regard them as the upper boundaries of exposure and m ake every effort to keep the exposure as low as possible. The recommended standard will be reviewed and revised as necessary. D iis o c y a n a te s i r r i t a t e th e re s p ira to ry t r a c t and can a c t as re s p ira to ry s e n s itiz e rs , producing asthma-like symptoms in sensitized individuals with exposure a t very low c o n c e n tra tio n s .
Exposure to diisocyantes may also result in chronic impairment of pulmonary function.
NIOSH published criteria for a recommended standard for toluene diisocyanate (TDI) in 1973. The p re se n t reco m m en d ed stan d ard is ex panded to include all d iiso c y an ate s, but not their polymerized forms. It includes most of the provisions recom m end ed in th e TDI document but differs where appropriate to reflect newer in fo rm atio n or special provisions for other diisocyanates. Most of the information c u rre n tly av ailab le on effects of exposure to diisocyanates concerns TDI and, to a lesser e x te n t, d ip h en y lm eth an e d iiso c y an ate (MDI). In addition to TDI and MDI, occupational exposure limits are recommended for other diisocyanates that have had w idespread in d u strial a p p lic a tio n : hexamethylene diisocyanate (HDI), naphthalene d iis o c y a n a te (NDI), isophorone d iiso c y an ate (IPDI), and dicyclohexyl m eth an e diisocyanate (hydrogenated MDI).
"O ccu p atio n al exposure to d iiso c y an ate s" is defined as exposure to airborne d iiso c y an ate s a t c o n c e n tra tio n s above o n e-h alf th e recommended time-weighted a v e ra g e (TWA) occupational exposure limit or above the recommended ceiling limit. Exposure to diisocyanates shall be controlled so that no employee is exposed at c o n c e n tra tio n s g re a te r th a n the limits specified below. These limits expressed in U g/cu m are equivalent to a vapor concentration of 5 ppb as a TWA concentration fo r up to a 1 0 -h o u r w o r k s h if t, 40-hour w orkw eek, and 20 ppb as a ceiling c o n c e n tra tio n for any 10-minute sampling period. The yg equivalents for selected diisocyanates are as follows: If o th e r diisocyanates are used, employers should observe environmental limits eq u iv alen t to a ceiling concentration of 20 ppb and a TWA concentration of 5 ppb.
TWA

# (b)
Sampling and Analysis E n v ir o n m e n ta l sam p les shall be c o lle c te d and an aly zed by th e m ethods described in A ppendix I or by any o th e r method at leaSt equivalent in accuracy, precision, and sensitivity. Section 2 -Medical M edical su rv eillan ce shall be made available as outlined below to all workers exposed to diisocyanates in the workplace.

# (a)
Preplacement examinations shall include at least: (1) C o m p reh en siv e m ed ical and work histories, with special emphasis d ire c te d to ev id en ce of p re e x istin g re s p ira to ry co n d itio n s such as asthm a. A smoking history should also be compiled.
P hysical e x am in atio n giving particular attention to the respiratory tract.
(3) S pecific clin ica l te s ts including a 14-x 17-inch posteroanterior c h est roentgenogram and baseline measurements of forced vital capacity (FVC) and forced expiratory volume at 1 second (FEV 1).
A judgm ent of th e w orker's a b ility to use negative and positive pressure respirators.

# (b)
P erio d ic e x am in atio n s shall be m ade a v ailab le a t le a s t annually, as determined by the responsible physician, and shall include: (1) Interim medical and work histories.
(2) P hysical e x am in atio n giving particular attention to the respiratory tra c t and including measurements of FVC and FEV 1.

# (c)
During ex am in atio n s, a p p lic a n ts or em p lo y ees found to have medical c o n d itio n s t h a t c o u ld be d i r e c t l y or in d ire c tly a g g ra v a te d by exp o su re to d iiso c y an ate s, eg, respiratory allergy, chronic upper or lower respiratory irritation, chronic obstructive pulmonary disease, or evidence of sensitization to diisocyanates, shall be co unseled on th e ir in c re ased risk from w orking with these substances. Chronic bronchitis, emphysema, disabling pneumoconiosis, or cardiopulmonary disease w ith sig n ifican tly im paired ventilatory capacity similarly suggest an increased risk from exposure to d iiso c y an ate s.
If a h isto ry of allerg y o th er than respiratory allerg y is e lic ite d , ap p lic a n ts should be counseled that they may be at increased risk of adverse health effects from exposure to diisocyanates. Employees shall also be advised th a t exposure to d iiso cy an ates may result in delayed effects, such as coughing or difficulty in breathing during the night.

# (d)
Pertinent medical records shall be maintained. Records of environmental exposures ap p licab le to an em p lo y ee shall be included in the employee's medical r e c o r d s .
S u ch r e c o r d s s h a ll be k e p t fo r a t le a s t 30 y ears a f te r th e la st o ccu p a tio n a l exposure to diisocyanates. These records shall be made available to th e d esig n ated m ed ical representatives of the Secretary of Health, Education, and W elfare, of th e S e c re ta ry of Labor, of th e em p lo y er, and of th e employee or former employee. Section 3 -Labeling and Posting (a)
Warning signs shall be p rin ted both in English and in the predominant language of non-English-reading workers. Workers unable to read labels and posted signs shall be instructed concerning hazardous areas and shall be orally informed of the instructions printed on labels and signs. In any a r e a w here there is a likelihood of emergency situations arising, signs req u ire d by S ectio n 3(c) shall be supplemented with signs giving emergency and firs t-a id in s tru c tio n s and p ro ced u res, th e lo c a tio n of first-aid supplies and e m e r g e n c y e q u ip m e n t, and th e lo c a tio n s of em erg en cy show ers and eyew ash fountains.

# Section k -Personal Protective Equipment and Clothing
T he e m p lo y e r s h a ll use en g in eerin g co n tro ls w here need ed to keep th e c o n c e n tra tio n of airb o rn e diisocyanates at or below the limits specified in Section (l)(a). The em ployer sh all also provide em p lo y ees with protective clothing and equipm en t of m aterials resistant to penetration by diisocyanates, such as rubber or p o ly v in y l c h l o r i d e , w h en n e c e s s a r y to p r e v e n t skin and ey e c o n ta c t w ith diisocyanates. Protective equipment suitable for emergency use shall be located at clearly identified stations outside the work area.
(a)
Eye Protection
The employer shall provide face shields (20-cm minimum) with goggles and shall ensure that employees wear the protective equipment during any operation in which splashes of liquid diisocyanates are likely to occur. Protective devices for the eyes and fa c e shall be s e le c te d , used, and m a in tain ed in a c c o rd a n c e w ith 29 CFR 1910.133. (b) Skin Protection
The em ployer shall provide a p p ro p ria te p ro te c tiv e clothing and eq u ip m en t th a t are r e s is ta n t to p e n e tra tio n by d iiso c y a n a te s, including gloves, aprons, su its, and boots, and shall ensure that employees weai these when needed to p rev en t skin c o n ta c t w ith liquid d iiso c y an ate s.
W orkers w ithin 10 feet of spraying o p eratio n s, or at greater distance when there is a greater drift of spray, shall be p r o te c te d w ith im pervious clo th in g , gloves, and footwear in addition to required respiratory protection. Rubber shoes or rubbers over leather shoes shall be worn w henever th e re is a po ssib ility th at liquid diisocyanates may be present on floors. (1)
To d eterm in e the type of respirator to be used, the employer shall m easure th e concentrations of airborne diisocyanates in the workplace initially and th e re a fte r whenever control, process, operation, worksite, or clim atic changes occur that are likely to increase the concentration of airborne diisocyanates.
The employer shall provide respirators in accordance with Table 1-1 and s h a ll en su re th a t th e em p lo y ees use them p roperly when re s p ira to rs are required. The respiratory protective devices provided in conformance wih Table 1-1 shall be those approved by NIOSH and the Mine Safety and Health Administration as specified in 30 CFR 11.  Use of supplied-air suits may be necessary to prevent skin contact during exposure a t high concentrations of airborne, diisocyanates.
(3) R e s p ira to rs sp ecified for use at higher concentrations of airborne diisocyanates may be used in atmospheres with lower concentrations. (4) The em p lo y er shall en su re that employees are properly instructed and drilled at least annually in the use of respirators assigned to them and on how to test for leakage, proper fit, and proper operation.
The em ployer shall e sta b lish and conduct a program of cleaning, san itizin g , inspecting, maintaining, repairing, and storing respirators to ensure that employees are provided with clean respirators that are in good operating condition. (6) R e s p ira to rs shall be easily a c c e ssib le , and em p lo y ees shall be informed of their location. A ll c u rr e n t and p ro sp e c tiv e em p lo y ees w orking w here o ccu p a tio n a l exposure to diisocyanates may occur shall be informed orally and in writing of the h a z a r d s , r e l e v a n t s ig n s a n d s y m p to m s of ex p o su re, a p p ro p ria te em erg en cy p ro ced u res, and proper conditions and precautions concerning safe use and handling of d iiso c y an ate s.
The in s tru c tio n a l program shall include a description of the g eneral nature of the environmental and medical surveillance procedures and of the a d v an tag es to th e em p lo y ee of p a rtic ip a tin g in th e se su rv eillan ce procedures. Em ployees exposed to diisocyanates should be warned that symptoms of exposure to d iiso c y an ate s, such as nocturnal dyspnea, may occur several hours after the end of th e workshift. They should also be advised that improper home use of polyurethane products co n tain in g unpolym erized diisocyanates, such as foam kits and varnishes, may in c re ase th e ir risk of w o rk -re la te d h ealth p ro b lem s.
E m ployees shall be in s tru c te d on th e ir re sp o n sib ilitie s for follow ing work p ra c tic e s and sanitation p ro ced u res to help protect the health and provide for the safety of themselves and of fellow employees.

# (b)
The em ployer shall institu te a continuing education program, conducted a t le a st annually by persons qualified by experience or training, to ensure that all em ployees have cu rren t knowledge of job hazards, proper maintenance and cleanup m ethods, and p ro p er re s p ira to r use. As a minimum, instruction shall include the in fo rm atio n p re sc rib e d in paragraph 5(c) below. This information shall be readily available to all employees involved in the manufacture, use, transport, or storage of diisocyanates and shall be posted in prominent positions within the workplace.
(c) R eq u ired in fo rm a tio n shall be rec o rd e d on th e "Material Safety Data Sheet" shown in A ppendix II or on a sim ilar form approved by the Occupational Safety and Health Administration, US Departm ent of Labor.

# Section 6 -Work Practices (a)
Control of Airborne Diisocyanates
(1) E ngineering c o n tro ls, such as pro cess enclosure or local exhaust v e n tila tio n , shall be used w hen need ed to keep exp o su re to diisocyanates at or below th e recom mended environmental limit. Ventilation systems, if used, shall be designed to prevent accumulation or recirculation of diisocyanates in the workplace en v iro n m en t and to e f fe c tiv e ly rem ove diisocyanates from the breathing zone of employees.
Exhaust ventilation systems discharging to outside air must conform to applicable local, state, and Federal air pollution regulations.
V en tilatio n system s shall be reg u larly maintained and cleaned to ensure e ffe c tiv e n e ss , w hich shall be verified by semiannual airflow measurements. A log showing design airflo w and th e re su lts of semiannual inspections shall be kept.
B efore m a in te n a n c e w ork is u n d ertaken, sources of diisocyanates shall be shut o ff and iso la ted .
The need for and use of respiratory protective equipment shall be determined as outlined in Section 4.

# (b)
Confined Spaces
In confined a re a s w here work is p e rfo rm e d routinely, such as spray booths, exposure to diisocyanates shall be kept at or below the recommended limits by the use o f e n g in e e r in g c o n t r o l s as d escrib ed in S ection 6(a). When nonroutine o p eratio n s such as cleaning and maintenance must be performed in confined spaces not equipped with such engineering controls, the following requirements shall apply.
(1) E ntry into confined spaces, eg, tanks, pits, or process vessels, that may contain diisocyanates shall be controlled by a permit system. Permits shall be signed by an authorized representative of the employer, certifying th a t preparation of the con fin ed sp ace, precautionary measures, and personal protective equipment are ad eq u a te and th a t p rescrib e d procedures will be followed. Each work permit shall also be signed by the employee entering the confined space.
(2) C onfined spaces that have contained diisocyanates shall be isolated by shutting off and sealing sources of diisocyanates.
The confined space shall be cleaned with a solvent, flushed, washed w ith w a te r, purged with air, and thoroughly ventilated. It shall then be inspected and te s te d for oxygen d e fic ie n c y , diisocyanates, and the presence of combustible gases and o th e r su sp e cted c o n ta m in a n ts b efo re being e n te re d and reinspected periodically at 1-hour intervals while occupied. (4) Each em p lo y ee entering the confined space shall be equipped with a se lf-c o n ta in e d b re a th in g a p p a ra tu s as sp ecified in Section 4, a harness, and a lifeline.
At le a st one o th e r em ployee equipped for entry with the same type of p ro te c tiv e equipment shall be stationed outside to monitor the operation. At least one ad d itio n al person shall be av ailab le to assist in an emergency. (1) D iiso cy an a tes should be stored in closed containers and should be p ro te c te d from h e a t and d ire c t sunlight. They should not be stored near bases, prim ary or seco n d ary am in es, acids, or alcohols, since these chemicals may react violently with diisocyanates.
(2) D iiso cy an a te c o n ta in e rs should be k ep t clo sed to prevent water from en te rin g th e c o n ta in e rs , since w a te r and diisocyanates react to produce a w ater-in so lu b le u re a and carb o n dioxide, w hich can generate enough pressure to ru p tu re the c o n ta in e rs.
All c o n ta in e rs of d iiso c y an ate s should be periodically insp ected for signs of increased pressure within the containers and to ensure that the in te g rity of containers and seals are maintained. Leaking containers should be rem oved to the outdoors or to an isolated, well-ventilated area before the contents are tra n s fe rre d to o th e r su ita b le containers, and leaks of diisocyanates should be cleaned up immediately.

# (d) Control of Spills and Leaks
(1) A dequate fa c ilitie s for handling spills of diisocyanates shall be provided and shall include suitable floor drainage and readily accessible hoses, mops, buckets, ab so rb en t or d e c o n ta m in a tin g m a te ria ls , and protective equipment and clothing.
All spills or leaks of diisocyanates shall be given prompt attention by trained personnel, and all unessential personnel shall be evacuated from the area during cleanup.
(3) Waste m aterial contam inated with diisocyanates shall be disposed of in a m anner not hazard o u s to em p lo y ees. D isposal m eth o d s m ust conform to ap p licab le local, state, and Federal regulations and shall not constitute a hazard to th e surrounding popu latio n or e n v iro n m en t.
Spills of diisocyanates shall not be allow ed to e n te r public sewers or drains in amounts that could cause explosion or fire hazards.

# (e)
Emergency Procedures E m ergency plans and p ro ced u res shall be developed for all work areas where there is a potential for exposure to diisocyanates. The measures shall include those sp ecified below and any o th e rs considered appropriate for a specific operation or p r o c e s s .
Em ployees shall be tra in e d to im p lem en t th e plans and p ro ced u res effectively.
P r e a r r a n g e d plans shall be in s titu te d for o b tain in g em erg en cy m edical care and for the transportation of injured workers. A sufficient number of em ployees shall be tra in e d in first aid so that assistance is available immediately when necessary.
Em ployees who have sig n ific a n t skin c o n ta c t with diisocyanates should w ash w ith w a te r or show er to rem ove th e com pound from the skin and should th en wash the a f f e c te d areas with alcohol. Contam inated clothing shall be removed and discarded or cleaned before reuse.
In th e ev en t of a fire involving d iiso c y a n a te s, all u n essen tial personnel shall be evacuated from the area. The types of extinguishing media that should be used in fig h tin g d iiso cy an ate-su p p o rted fires are dry chemical powder, c a r b o n d io x id e, or foam .
W ater should be used only if la rg e q u a n titie s a re av ailab le.
F ire fig h te rs should be cautioned of the possibility of exposure to other hazardous chemicals, such as hydrogen cyanide, phosgene, and carbon monoxide. (4) After the fire has been extinguished, the area shall be inspected by properly p r o te c te d personnel and shall be decontaminated to remove any suspected diisocyanate residues before unprotected workers are perm itted to enter the area.

# (f) Laundering
(1) B efore being la u n d ered , contam inated clothes shall be placed in a d e c o n ta m in a tin g solution of water containing 10% ammonia in a container that is impervious to diisocyanates. When diisocyanates are used in laboratory activities, the following provisions, in addition to other sections, shall be followed.
M echanical pipetting aids shall be used for all pipetting procedures.
(2) Experim ents, procedures, and equipment that could produce aerosols or vapors of diisocyanates shall be confined to laboratory-type hoods, glove boxes, or o th e r sim ilar c o n tro l ap p ara tu s. Exposure chambers and associated generation apparatus shall be separately ventilated.
(3) S u rfaces on which diisocyanates are handled shall be impervious to absorption or penetration by these compounds.
L a b o ra to ry vacuum systems, hoods, and exposure chambers shall be e x h a u s t-v e n tila te d in a m anner c o n siste n t w ith F e d e ra l and local air pollution regulations.
A irflow in th e laboratory shall be established in a pattern flowing from th e least to the most contam inated area. Contaminated exhaust air shall not be recirculated or discharged to other work areas.

# Section 7 -Sanitation (a)
Preparing, storing, dispensing (including vending machines), and consuming food and smoking shall be prohibited in work areas where occupational exposure to diisocyanates may occur.

# (b)
Em ployees who handle d iiso c y an ate s or eq u ip m en t contam inated with d iiso c y an ate s shall be advised to wash th e ir hands thoroughly with soap or mild detergent and water before using toilet facilities, eating, or smoking.
(c) P lan t fa c ilitie s shall be maintained in a sanitary manner in accordance with sanitation requirements listed in 29 CFR 1910.141. (d) The em ployer shall provide ap p ro p ria te changing and shower rooms as required in 29 CFR 1910.141(d,e). Surveys shall be re p e a te d a t le a st annually and as soon as practicable after any change likely to result in increased concentrations of airborne diisocyanates.

# (b)
Personal Monitoring
If it has been determined that there is occupational exposure to diisocyanates, the employer shall fulfill the following requirements:
A program of p erso n al m o n ito rin g shall be instituted to identify and m e a s u r e , o r p e r m i t c a l c u l a t i o n o f, th e e x p o s u r e o f e a c h e m p lo y e e o ccu p atio n ally exposed to diisocyanates. Personal monitoring may be supplemented by source and area monitoring.
In all p erso n al m onitoring, samples representative of the exposure in the breathing zone of the employee shall be collected.
F o r e a c h d e t e r m i n a t i o n of th e d iiso c y a n a te c o n c e n tra tio n , a s u ffic ie n t num ber of sam p les shall be ta k e n to characterize employee exposure. V ariations in th e em ployee's work sch ed u le, lo c atio n , or d u tie s and changes in p ro d u c tio n schedules shall be co n sid ered in deciding when sam p les a re to be collected.
Sam ples from eac h o p e ra tio n in eac h work a r e a and each shift s h a ll be ta k e n a t le a s t once ev ery 6 m onths or as o th e rw ise in d ic a te d by a profession al in d u strial hygienist. If monitoring shows that an employee is exposed to d iiso c y an ate s a t concentrations above the environmental limits recommended in Section 1(a), additional monitoring shall be promptly initiated. If this confirms that exposure is ex cessiv e, co n tro l m easu res shall be initiated as soon as possible to red u ce th e c o n c e n tra tio n of d iiso c y a n a te s in the employee's environment to less than or equal to th e lim its recommended in Section 1(a). The affected employee shall be n o tified of th e ex cessiv e exposure and of th e co n tro l measures being im p lem en ted .
M onitoring of th e employee's exposure shall be conducted at least every 30 days and shall co n tinue until two consecutive determinations, at least 1 w eek a p a r t , in d i c a te t h a t th e e m p lo y e e 's exposure no longer ex ce ed s the recom m en d ed en v iro n m en ta l limits. At that point, semiannual monitoring may be resumed.

# (c)

# Recordkeeping
Environm ental monitoring records and other pertinent records shall be kept for a t le a s t 30 y ears a f te r th e la st o ccu p a tio n a l exposure to d iiso c y an ate s. The reco rd s shall include the dates and times of measurement, duties and job locations w ithin th e w o rk site, sam pling and analytical methods used, the number, duration, and resu lts of samples taken, concentrations of diisocyanates in air estim ated from th e se sam ples, the type of personal protection in use at the time of sampling, and i d e n t i f i c a t i o n of th e exposed em ployee.
E m ployees shall be able to obtain in fo rm atio n on th e ir own en v iro n m en ta l ex p o su res.
E n v iro n m en tal monitoring reco rd s shall be m ade av ailab le to designated representatives of the Secretary of Labor, th e S e c re ta ry of H ealth , E d u catio n , and W elfare, and th e employee or former employee. P e rtin e n t medical records shall be retained by the employer for 30 years after th e l a s t o c c u p a tio n a l ex p o su re to d iiso c y an ate s. R eco rd s of en v iro n m en ta l exposures ap p licab le to an employee should be included in records. These medical reco rd s shall be m ade available to the designated representatives of the Secretary of Labor, of the Secretary of Health, Education, and Welfare, of the employer, and of the employee or former employee.

# II. INTRODUCTION
This re p o rt presents the criteria and the recommended standard based thereon th a t w ere p re p a re d to m e e t the need for preventing impairment of health arising from o ccu p a tio n a l exposure to d iiso c y an ate s. The criteria document fulfills the responsib ility of th e S e c re ta ry of H ealth , Education, and Welfare under Section 20(a)(3) of th e O ccu p atio n al S afety and H ealth Act of 1970 to "develop criteria dealing w ith toxic materials and harmful physical agents and substances which will d e sc rib e ...e x p o su re levels a t w hich no em p lo y ee will su ffe r im paired health or f u n c ti o n a l c a p a c i t i e s or dim inished life e x p e c ta n c y as a re s u lt of his work experience."
A fter review ing d a ta and consulting with others, NIOSH formalized a system for th e d ev elo p m en t of c r ite r ia on which standards can be established to protect th e h e a lth and to provide for th e s a fe ty of em p lo y ees exposed to hazardous chem ical and physical agents. C riteria for a recommended standard should enable m a n ag em en t and labor to develop b e tte r en g in eerin g controls resulting in more h e a lth fu l work environments, and simply complying with the recommended standard should not be regarded as the final goal. O ccu p atio n al exp o su re to som e of the diisocyanates has produced respiratory illness in w orkers.
In addition to irritating the upper and lower respiratory tract, diisocyanates can cause sensitization, and sensitized individuals may develop asthma upon exposure to d iiso c y an ate s in very sm all am o u n ts. Chronic impairment of pulm onary fu n ctio n has b een re p o rte d in some workers exposed to diisocyanates. Diisocyanates are also irritating to the skin and eyes. F u rth e r re se a rc h is need ed in a num ber of a re a s re le v a n t to co n tro llin g occupational exposure to diisocyanates. The possibilities of carcinogenic, mutagenic, te ra to g e n ic , and reproductive effects from diisocyanates have not been adequately in v e stig a te d .
Studies in w hich e f f e c ts on individuals a re correlated with their a c tu a l exposures are also needed. Screening tests should be developed to permit e arly reco g n itio n of adverse respiratory effects resulting from sensitization to the d ii s o c y a n a te s .
A n im a l e x p e rim e n ts should be p e rfo rm e d to d e te rm in e how c o n c e n tra tio n and len g th of exposure a f f e c t th e d ev elo p m en t of sensitization. Im proved en g ineering co n tro ls should be developed to protect workers in certain diisocyanate applications, such as spraying.

# III. BIOLOGIC EFFECTS OF EXPOSURE
The d iiso c y an ate s are ch em ical compounds in which two isocyanate groups, -NCO, are a tta c h e d to carb o n ato m s of an org an ic ra d ic a l. The chemical and p h y sic a l p ro p e rtie s of various d iiso c y an ate s a re liste d in Table XI
-1  . Synonyms for these compounds are listed in Table XI-2.
Many d iiso cy an ates exhibit high chemical reactivity . In the presence of w a te r they r e a c t exothermically to produce an unstable carbamic acid that rapidly d isso cia tes to form a p rim ary amine and carbon dioxide. The primary amine can react further with excess isocyanate to form a urea derivative.
Iso cy an ates also r e a c t vigorously with organic compounds containing reactive hydrogens, esp ecially where the hydrogen atom is attached to oxygen, nitrogen, or sulfur  .
In biologic m acrornolecules, these groups occur abundantly, and the iso cy an a tes will th e re fo re r e a c t and com bine w ith a v a rie ty of sites on these m olecules.
Polyfunctional isocyanates, such as the diisocyanates, can act as crosslinking agents with biologic macromolecules.

# Extent of Exposure
The m ost com m on method of synthesis of the diisocyanates is the reaction of p rim ary am ines w ith phosgene  .
In th is p ro cess, a p rim ary a lip h a tic or a ro m a tic am ine, dissolved in a so lv en t such as xylene, m onochlorobenzene, or dich lo ro b en zen e, is mixed with phosgene dissolved in the same solvent and allowed to re a c t for sev eral hours a t te m p e ra tu re s of ab o u t 200 C. More phosgene is added during the process, and the final reaction mixture is fractionated to recover th e iso cy an a te p ro d u ct, as w ell as h y d ro ch lo ric acid , u n re a c te d phosgene, the solvent for recycling, and the distillation residue for incineration.
Diisocyanates are used to produce polyurethane foams, coatings, elastomers, and spandex fib ers. Toluene d iiso c y an ate (TDI), w hich is co m m ercially available as stan d ard m ix tu res of th e 2,4-and 2 ,6 -iso m ers, is g en erally used in producing flexible p o ly u reth an e fo am s. Methylene diphenyl diisocyanate (MDI), especially in p a rtia lly polym erized forms, is used more frequently in rigid foams. A substantial am ount of MDI (40-50% of th e am o u n t produced) is used in the manufacture of p o ly u r e t h a n e s y s te m s , such as fo rm u la te d p ack ag es of iso c y a n a te s, polyols, flu o ro carb o n blowing a g e n ts, fire retardants, surfactants, and catalysts. TDI and pure MDI, or sp ecial liquid MDI products, are used to make elastomers, which are used in m a n u fa ctu rin g p rin tin g rolls, liners for m ine c h u te s and grain elevator ch u tes, c o a te d fab ric s, shoe soles, and automobile bumpers . MDI is also used in th e foundry in d u stry as part of a binding system for casting molds . The total consumption of MDI and partially polymerized MDI in 1975 was about 300 m illion pounds. TDI consumption totaled about 400 million pounds, and only a few million pounds of other diisocyanates were used in 1975 , W orkers w ith potential occupational exposure to diisocyanates include adhesive w orkers, insulation w orkers, d iiso c y an ate resin workers, lacquer workers, organic c h e m ic a l s y n th e s iz e r s , p ain t sp ray ers, p o ly u reth an e m a k ers, rubber w orkers, shipbuilders, textile processors, and wire-coating workers .
A NIOSH s u r v e y co n d u cted in 1972-1974 e s tim a te d th a t 50,000-100,000 em plo y ees in th e U n ited S ta te s w ere p o te n tia lly exposed to diisocyanates. This n u m b e r does not include o ccasio n al users of iso c y a n a te p re p a ra tio n s such as p o ly u reth an e varnish and m ay th e re fo re u n d e re s tim a te th e num ber of workers exposed.

# Historical Reports
Toluene d iiso c y an ate and h ex am eth y len e d iiso c y an ate (HDI) were the most w id e ly u sed d iis o c y a n a te s in th e early s ta g e s of th e in d u stry , acco rd in g to W illiam son  and Munn  .
C o n seq u en tly , the earliest reports of hazards from exposure to iso c y a n a te s usually involved th e se compounds. Both of these com pounds a re am ong th e m ore v o la tile diisocyanates, and respiratory and other h ealth problems associated with these compounds prompted the development of less v o la tile di isocyanates and derivatives, as well as improved handling techniques. As a re s u lt, although many new d iiso c y an ate p ro d u cts have been used in industrial applications more recently, the number of reports of toxic effects from exposure to diisocyanates has decreased.
In G erm any in 1941, G ross and Hellrung, according to Friebel and Luchtrath  , in v e stig a te d the toxicity of TDI in animal experiments. They exposed dogs, cats, rabbits, and guinea pigs to a commercial TDI preparation at 14-1,400 ppm and re p o rte d th a t, a t the low er c o n c e n tra tio n s stu d ied , irritation of the respiratory tr a c t o c cu rred , and, a t the higher c o n c e n tra tio n s , b ro n ch itis, pneum onia, and pulmonary edema resulted.
A ccording to Brugsch and Elkins , toxic effects of TDI had been observed in G erm an w orkers handling th e su b stan ce in w ar-related industries during World War II. However, the first published account of TDI toxicity in humans was a 1951 r e p o r t by Fuchs and Valade  , They d escrib ed nine c ases of p rogressive bronchial ir rita tio n in F ren ch w orkers exposed to TDI. On continued exposure, seven of th e a f f e c te d w orkers developed an a sth m a -lik e co n d itio n , w hich the authors suggested was allergic.
In 1953, R einl  reported a human fatality attributed to organoisocyanate exposure. This was 1 of 17 cases of respiratory illness in German workers exposed to TDI or other isocyanates. Thirteen of these illnesses were severe. Two workers developed pulm onary ed em a, w hich in one case was f a ta l, te rm in a tin g in cor pulm onale. In the same year, in Sweden, Swensson et al  described three cases of re s p ira to ry illness in painters who used lacquer containing isocyanates. Two of th e se w orkers had s p iro m e tric pulm onary fu n c tio n m e a su re m e n ts suggestive of emphysema.
In the 1950's many similar cases of isocyanate toxicity were reported in Europe , including an o th er f a ta lity  , and in th e United States . T hese o c c u rre d in w orkers exposed to TDI in manufacturing polyurethane foam or using TDI-or p o ly iso c y an ate -b ase d la cq u ers and glues. As many as 99 cases of respiratory illness were reported from a single US plant manufacturing polyurethane foam  . A 1962 review by Elkins et al  reported a total of 222 cases of respiratory illness attributed to TDI exposure in the literature through 1960.
G o ld b la tt and Goldblatt , in a 1956 report, described a case of a chemist exposed to th e vapor of h e a te d 1,5-naphthalene diisocyanate (NDI). The chemist developed a sev ere cough th a t recurred each time he returned to the laboratory. G erritsen  suggested in 1955 that an asthm atic condition in workers exposed to HDI was the result of an allergic mechanism.
M ost of th e e a r ly r e p o r ts of re s p ira to ry illn ess in w orkers exposed to d iiso c y an ate s described bronchial asthm a or chronic bronchitis, often considered by th e a u t h o r s to involve ev id en ce of se n s itiz a tio n . H ow ever, som e re s p ira to ry illn esses w ere a ttr ib u te d to d ire c t irrita tio n from TDI, usually as a result of acute accidental exposures 35].
Friebel and Luchtrath , in 1955, attem pted to dem onstrate sensitization to TDI in guinea pigs. They were not able to produce allergic asthm atic responses in animals exposed to TDI aerosol a t 120 ppm or TDI vapor at 50-80 ppm. Effects on th e anim als' lungs were attributed to primary toxic action by TDI. Zapp , in 1957, also reported only direct effects on the respiratory tra c t in rats, guinea pigs, dogs, and ra b b its exposed to TDI a t 1.5 ppm fo r about 80 exposures of 6 hours each.
Since 1960, ad d itio n al cases of occupational illness attributed to exposure to diisocyanates have been reported, but these have been less frequent and less severe as recognition of the hazard has increased. In 1973, NIOSH published criteria for a recom m end ed standard for occupational exposure to TDI . The studies of TDI to x ic ity on which NIOSH based its 1973 reco m m en d atio n s a re discussed in the follow ing s e c tio n s, as is in fo rm a tio n on TDI th a t has appeared in the literature more recently and data on other diisocyanates. Most studies on TDI in this chapter th at are dated prior to 1973 were discussed in the earlier document.

# Effects on Humans
Much of th e in v e stig a tio n of th e biologic effe c ts of diisocyanates has been d i r e c t e d to w ard d e term in in g th e e x te n t and n a tu re of s e n s itiz a tio n to th e se com pounds. In this document, sensitivity to diisocyanates denotes the tendency of so m e in d iv id u a ls to h a v e a r e s p ira to ry response when th ey a re exposed a t c o n c e n tra tio n s much low er th a n th o se th a t irritate the respiratory tra c t in most p e o p le . S e n s i t i z a t i o n m ay d e v e lo p gradually or suddenly a f te r exposure to diiso c y an ate s.
The usual response is an a s th m a tic re a c tio n , c h a ra c te riz e d by w heezing, dyspnea, and bronchial constriction. Use of these term s is not intended to im p lic ate any p a rtic u la r m echanism as the cause of the reaction. The term s "allergy" and "allergic," on the other hand, are reserved for conditions in which an immunologic response is implied. W orkers occu p atio n ally exposed to the diisocyanates in various industries have d e v e lo p e d a d v e r s e re s p ira to ry e ff e c ts ; re p o rts of skin d isease and evidence suggesting sy stem ic to x ic ity from such exp o su res have been far less numerous. Most of th e affected workers have been exposed in manufacturing diisocyanates, in using th e se com pounds to manufacture polyurethane products such as foam, and in painting or spraying polyurethane varnishes and paints. These activities also involve possible exposure to o th e r potentially harmful chemicals, including chlorobenzene, phosgene, sty ren e, and am in es, and little is known of how such mixed exposures may affect the toxicity of the diisocyanates.
Most of th e d a ta available on exposure to diisocyanates are on TDI. Several reports on MDI and a smaller number on other diisocyantes, including HDI and NDI, have also been published. In the following subsections, information on the biologic effects of TDI is discussed first, followed by data on MDI and other diisocyanates.

# (a) Respiratory Effects
The odor th resh o ld for TDI estim ated by Zapp  in 1957 was 400 ppb (2.8 m g /c u m) in 12 of 24 m en te s te d .
Five y ears la te r , H enschler e t al  e s tim a te d an odor threshold of 50 ppb (360 yg/cu m), using the analytical method of E rlich er and Pilz , which they found was more accurate and sensitive than the R a n ta m ethod used by Zapp. Eye irr ita tio n was experienced by three of six volunteers exposed at this concentration for 10 minutes and five of six exposed for 15 m inutes; one also had nasal irritation . At 100 ppb (700 yg/cu m), two of six com plained of th r o a t ir r ita tio n , and exposure a t 500 ppb (3,600 yg/cu m) produced eye, nose, and throat irritation in all volunteers.
Pulm onary fu n ctio n testing has been used in many studies of workers exposed to TDI and o th e r d iiso c y a n a te s to e v a lu a te changes in lung function. In 1964, seven fu rn itu re p lan t employees who sprayed, dipped, or painted with polyurethane varnish developed acute respiratory symptoms 0.5 hour to 3 weeks after their first known exposure  .
T h ree m e a su re m e n ts m ade a f te r some improvements in ventilation showed TDI at 80, 100, and 120 ppb (570-850 yg/cu m). All seven men coughed and had difficulty in breathing and four had blood-stained sputum. Five of the seven were tested for forced vital capacity (FVC) and forced expiratory volume a t 1 second (FEV 1) 2-3.5 months after exposure and had higher values than they did shortly after exposure. The responses to a questionnaire given 22 months after exposure after exposure suggested to the author that four of six who responded had become sensitized to TDI.
In 1965, W illia m s o n  d e s c r ib e d six w orkers exposed to TDI in a p o ly u reth an e foam p lan t who developed symptoms that were considered suggestive of s e n sitiz a tio n .
Four of th e se , from a workforce of 99, had become sensitized during 18 m onths of exposure to TDI a t c o n c e n tra tio n s usually below 20 ppb, ap p are n tly d eterm in e d by a re a m onitoring. The author believed th at sensitization had re su lte d from exposure at higher concentrations caused by spills. Immediately a fte r one spill, TDI at 200 ppb (1.4 mg/cu m) was found, but the concentration was less than 5 ppb (35 y g /c u m) 10 m in u tes la te r .
All six a ffe c te d workers had asth m a or b ro n ch itis w ith decreased ventilatory capacity (FVC and FEV 1) during th e se in c id en ts. Some of the subjects were also occasionally exposed to MDI, but always at concentrations below 20 ppb (204 yg/cu m).
In 1976, Charles et al  described a case of pneumonitis and three cases of chronic re s p ira to ry d isease in w orkers exposed to TDI or HDI. Pneumonitis was diagnosed in a 5 0 -y ear-o ld nonsmoker who had experienced difficulty in breathing, weight loss, and fever for 6 weeks at the time of examination. Prior to his 5 years of working in th e p o ly u reth an e foam in d u stry , he had been a coal miner for 11 years. C h est X -rays showed alveolar filling lesions in both the lungs. Two months la te r , pulm onary fu n c tio n te s ts showed reduced FEV 1, vital capacity, total lung c a p a c ity , and residual volum e of the lungs.
A bronchogram showed peripheral cy stic bronchiectasis in the right upper lobe. All immunologic tests for antibodies against TDI were negative. Microscopic examination of biopsy samples of lung tissue showed variations from normal architecture ranging from diffuse interstitial disease to a c u te in flam m atio n and end-stage interstitial fibrosis. The authors stated that the a re a s of filled alveoli resembled desquamative interstitial pneumonitis and that the w hole p ic tu re resem b led th a t of a pulmonary hypersensitivity response to an in h a le d a l le r g e n r a t h e r th a n c o a l-m in e rs' pneum oconiosis, but th ey did not demonstrate that this was related to TDI exposure.
Two o th er w orkers developed sev ere dyspnea after exposure to spills of TDI  .
Two to th r e e years after exposure, both workers had moderate obstruction of the airw ays, as in d ic a te d by FEV 1 measurements below predicted values; one also had a decreased vital capacity, and the other, although his vital capacity was normal, still experienced severe nonwheezing dyspnea after minimal exertion.
Sim ilar symptoms occurred in a 61-year-old man who had been a paint sprayer for 43 y ears with no previous history of respiratory illness; he developed wheezing, d y s p n e a , an d sw eatin g w ithin hours when he f ir s t used a p o ly u reth an e paint co n tain in g HDI  .
Whenever he was reexposed to the paint by casual contact w ith fum es from other spraying operations, he again developed symptoms. Testing 1 year a f te r exposure showed moderate obstruction of airways, and he complained of nonwheezing dyspnea after exertion. Pepys e t al  te s te d fo u r p a tie n ts w ith o ccu p a tio n a l a s th m a fo r TDI sen sitiv ity by simulating occupational exposures to a two-stage polyurethane varnish w ith TDI activ ato r. The subjects applied varnish with the TDI activator and, on a se p a ra te day, w ith o u t th e a c tiv a to r , to a surface in a small cubicle. When the a c tiv a to r was used, TDI concentrations in the air reached a maximum of almost 2 ppb (14 y g /c u m), as measured by the colorimetric method of Meddle et al . No TDI was d e te c te d when th e varnish alone was applied. All the subjects were e sse n tia lly a sy m p to m a tic a t the time of testing, and their FVC and FEV 1 values w ere not m ore than 10% below predicted values. None showed positive responses in skin te s ts with common allergens, and none had a family or personal history of allergies.
A 26-year-old boatbuilder, who had been using a two-stage polyurethane varnish system for 8 years, had cough and dyspnea at night , The attacks gradually b eca m e more severe and occurred earlier in the day, appearing only when the twos ta g e varnish was used. A nother man, 46 years old, had worked for 8 years as a m a in te n a n c e en g in eer whose d u ties included maintenance of a polyurethane foam m achine. He had chest tightness and shortness of breath, which disappeared within 20 m inu tes a f te r he le ft w ork. His sym ptom s also b eca m e progressively worse, developing into sev ere asth m a. Neither man had any known exposure to spills of TDI. In challenge testing, both reacted to the varnish only when the TDI activator was added. The boatbuilder developed a late asthm atic reaction that appeared at 1-2 hours and re a c h e d a m axim um a t 3-4 hours, while the maintenance engineer showed an immediate reaction.
T h e o th er tw o su b je c ts w ere w om en who w orked in a te le v isio n fa c to ry d e p a rtm e n t w here co a te d wires were soldered . The wire, coated with cured p o ly u r e t h a n e an d po ly v in y l b u ty ra l, w as dipped into a resin flux co n taining dim ethylam ine hydrochloride and then into multicore solder at 460 C. One woman, 44 y ears old, developed a chronic cough and, after 6 years, wheezing. The second w om an, a 5 4 -y ear-o ld sup erv iso r in the same departm ent, developed a productive cough, wheezing, and breathlessness, developing into severe bronchitis that kept her away from work for 5 weeks. Her symptoms recurred within 1 week of her return, and this p a tte r n was re p e a te d eac h tim e she attem pted to return to work. Both w o m en r e a c te d to th e varn ish w ith TDI a c tiv a to r .
The fir s t woman had an im m e d ia te re a c tio n th a t was reso lv ed in 2 hours but was follow ed by a la te re a c tio n a t 3-4 hours.
The second woman had only a late reaction at 3-4 hours. She was also te s te d w ith various com ponents used in th e soldering operation. This te s t p roduced a severe asthm atic reaction starting 30-60 minutes after exposure ended and continuing for 6 w eeks b efo re her FEV 1 re tu rn e d to p r e te s t levels. Blood tests on these four p a tie n ts showed no eosinophilia, but sputum collected from the 54-year-old woman contained eosinophils. This suggested to the authors a reagin-mediated reaction.
The se n sitiz e d individuals te s te d by Pepys and colleagues  had adverse re a c tio n s to TDI after exposures as brief as 10 minutes a t reported concentrations of a b o u t 2 ppb (14 u g /c u m). The au th o rs em p h asized th a t none of th e se sen sitized individuals had a known history of heavy TDI exposure, such as exposure to spills. Thus, it ap p ea rs th a t exposure to massive amounts of TDI, as from a spill, may not be necessary to produce sensitization.
The sam e technique of challenge exposure to polyurethane varnish was used by C a rro ll and co w o rk ers  to te s t four em p lo y ees who w orked in an o ffic e a d ja c e n t to a fa c to ry th a t used TDI. Three clerical workers and a security guard, am ong 47 w orkers in th e office block, had histories of asthm a-like symptoms, and in tw o cases these were clearly alleviated during periods away from work. It was discovered th a t the air inlet for the office building was located only 23 feet from th e v e n tila tio n outflow of the factory that used TDI, but actual air concentrations in the offices were not determined.
The p o ly u reth an e varnish m ixture used in the challenge testing was one-third TDI, and th e au th o rs  s ta te d th a t th e a tm o sp h e ric c o n c e n tra tio n of TDI c r e a te d by painting it on a surface in the test chamber was about 1 ppb (7 yg/cu m), but th e m ethod of d e te rm in a tio n was not described. Three of the patients reacted to TDI, one after a 15-minute exposure, one after 30 minutes, and one only a f te r a 6 0 -m in u te exposure.
Exposures to the varnish without the TDI activator produced no reactions.
The a u th o rs  also m en tio n ed th a t one ad d itio n al o ffic e w orker had a s th m a tic sym ptom s th a t w ere re lie v e d by removal from the environment. This suggests th a t 4 of th e 47 w orkers were sensitized to TDI, a sensitization rate of about 9%.
To e v a lu a te th e s p e c ific ity of TDI sensitivity, O'Brien et al  tested the responses of TDI workers to TDI, histamine, and exercise. The 63 men studied had been referred for investigation of possible work-related respiratory symptoms. A s u b je c t was considered sensitive to TDI if his fall in FEV 1 after exposure was 15% more than on the control day. TDI concentrations in the cubicle w ere m easu red by a continuous monitor; in 23 cases, breathing-zone sampling was also p erfo rm e d , and the results of the two measurements were found to be closely correlated (r = 0.95).
F ifty -tw o of th e workers were also tested by inhaling an aerosol of histamine acid pho sp h ate a t g rad ed c o n c e n tra tio n s up to 32 m g /m l for 30-second periods  .
A 20% fall in FEV 1 was considered evidence of bronchial hyperreactivity. F o rty -six su b jects p a r tic ip a te d in e x e rc ise te s tin g , co n sistin g of fre e running sufficient to increase the heart rate to 140 beats/m inute. A fall in FEV 1 of more than 9% was re g a rd e d as in d ic a tiv e of an asthm atic reaction.
All subjects were prick te s te d w ith 23 common respiratory allergens, and those who reacted to 1 or more were considered atopic.
T h i r ty -s e v e n of th e 63 w o rk ers w ere se n sitiv e to TDI as in d ic a te d by respiratory responses to challenge testing, which included 2 immediate, 17 late, and 18 dual reactions . Nine of these workers reacted to TDI at concentrations of less than 1 ppb (7 y g /c u m). When ch allen g ed w ith h istam in e, 17  H ow ever, in th e subgroup of sensitive workers who responded to TDI at less than 1 ppb, there were significantly more reactions to both histamine (P<0.005) and e x e rc ise (P<0.01) than in those who reacted only at higher TDI concentrations; this extrem ely sensitive group also had a singificantly higher incidence of exerciseinduced a sth m a th an th e group th a t did not react to TDI (P<0.025). Age, atopic s ta tu s , and h isto ry of rh in itis w ere sim ilar in the TDI sensitive and nonsensitive groups, but th e re was a higher incidence of asthm a prior to work with TDI and of a fam ily h isto ry of allerg y in th e n o n sen sitiv e group. There was no significant d iffe re n c e s betw een smokers, exsmokers, and nonsmokers on the TDI, histamine, or exercise tests.
In a fu rth e r stu d y , O 'B rien e t al  investigated cross-reactivity to TDI, MDI, and HDI in 24 d iiso cy an ate workers referred for investigation of respiratory sym ptom s.
All 24 m en had been exposed to TDI, 14 to MDI, and 6 to HDI; 5 of the latter group had been exposed to all 3 diisocyanates. All su b jects w ere ch allen g ed w ith TDI by the procedure previously described and w ith MDI over th e sam e ran g e of co n cen tratio n s (<1-20 ppb) by heating the m a te ria l in a closed cubicle . Nine, including the six with previous exposure to H D I, w e re a lso c h a l le n g e d by p a in tin g w ith an HDI v a r n is h , b u t air c o n c e n tra tio n s of HDI w ere not measured. All subjects were tested by histamine inhalation.
S ix teen of th e subjects were sensitive to TDI, and eight of these also reacted to MDI, including four who had no known previous exposure to MDI . Three of the nine w orkers te s te d with HDI showed positive responses; all three had also re a c te d to both TDI and MDI, and two of them had no previous exposure to HDI. H istam in e inhalation produced a positive reaction in five of the eight subjects who did not respond to challenge with diisocyanates, one of the eight who reacted only to TDI, and six of the eight who reacted to both TDI and MDI (including all three who also reacted to HDI). The authors reported that subjects who reacted to more than one d iiso c y an ate had a greater degree of histamine reactivity and reacted to TDI at lower concentrations than did those who reacted only to TDI. Among workers referred for respiratory symptoms, TDIsensitive individuals were no more likely to have nonspecific asthm atic responses to h istam in e or e x e rc ise than were those who did not react to TDI. However, those who showed e x tre m e se n s itiv ity to TDI, reacting at concentrations of less than 1 ppb, did have an increased incidence of nonspecific asthm atic responses, suggesting to the authors that specific sensitivity to TDI might be exacerbated by irritative or p h arm a co lo g ic h y p e rre a c tiv ity of th e airw ay s.
The e x iste n c e of such a dual m echanism in individuals extremely sensitive to diisocyanates was supported by the re su lts of cross-challenging with TDI, MDI, and HDI . The authors considered th a t im m unologic c ro s s -re a c tiv ity b etw ee n th e se th r e e compounds was unlikely because of th e ir s tr u c tu ra l d iffe re n c e s .
They concluded that their results were consistent with the existence of a specific mechanism of TDI sensitivity coupled, in e x tre m e ly sen sitiv e individuals, with a pharmacologic mechanism that also caused increased reactivity to other diisocyanates.
Occupational exposure to MDI has produced respiratory effects similar to those reported from TDI exposure. Longley , in 1964, described an incident in which 12 m en who w orked 60-120 f e e t from an MDI foarn-spraying operation developed sym ptom s, including a sth m atic breathing, retrosternal soreness, constriction of the c h e st, cough, retrobulbar pain, depression, headache, nasal discharge, and insomnia. All 12 workers developed symptoms within several hours after exposure to the mist. The w orkers actually spraying the MDI foam, who wore full protective clothing and air-supplied respirators, were unaffected. Munn co n clu d ed th a t MDI was a p o te n tia l respiratory irritant and that in rare instances it could cause sensitization.
In 1972, Lob  d escrib e d a reaction to MDI in a 50-year-old worker in a p o ly u reth an e fa c to ry who had no h isto ry of allergies, bronchitis, or asthma. He in te rm itte n tly e x p e rie n c e d m alaise acco m p an ied by fever, nausea, and coughing, usually a t th e end of th e day.
A fte r one such a tta c k , a thorough examination showed th a t he had a slightly decreased vital capacity. A fter another attack, he had an increased white blood cell count (WBC) of 12,650/cu mm.
To d e te rm in e th e fa c to rs producing th e se symptoms, Lob  exposed the worker for 3-4 minutes in a simulated operation where plastic belts were welded by h e a t. The au th o r s ta te d th a t MDI was d e te c te d in th e whitish fumes given off during th e w elding p ro cess, b u t th e c o n c e n tra tio n was not given; no TDI was d e te c te d . The worker's body tem perature increased to 39 C within 4-5 hours after he was exposed, and he had nausea and a severe cough. Vital capacity decreased slig h tly , WBC in c re ased , and he had c o n g este d conjunctiva, increased pulse, and decreased blood pressure. All these signs were normal the next day. Lob concluded t h a t th e o n s e t, s e v e rity , p e rs is te n c e , and re c u rre n c e of th e sym ptom s w ere suggestive of an allergic reaction to MDI.
In 1971, Lapp  described the effects of brief exposures to TDI and MDI on th re e men. One was a 3 8 -y ear-o ld w orker in a chemical plant who had worked w ith d iiso c y an ate s for 13 years. The other two were 25-and 23-year-old medical o ffic e rs w ith no previous exposure to diisocyanates. Each subject slowly inhaled TDI from a sn iff b o ttle . A fter at least 1 day without exposure, each subject was challenged w ith MDI in the same manner. Pulmonary function of each subject was determined before and after each exposure.
F ifte e n m in u tes a f te r TDI inhalation, the values for FVC, FEV 1, and forced e x p ira to ry flow b e tw e e n 25 and 75% of the FVC (FEF 25-75) in the worker who had previously been exposed to d iiso c y an ate s w ere 3.16, 2.79, and 3.62 liters, respectively, compared with corresponding preexposure values of 4.03, 3.68, and 5.92 liters. Airway resistance increased to 123% of the preexposure value at 15 minutes and 166% a t 30 m i n u te s .
T The e f f e c ts of MDI w ere re v e rs e d follow ing ad m in istra tio n of a bronchodilator. Approximately 4-6 hours later, the man again ex p erien ced c h e st tightness and wheezing and his tem perature increased to 100 F. All th e se sym ptom s had disappeared by the next morning. The other two subjects showed no loss of pulm onary fu n ctio n a f te r exposure to MDI. Minor changes in th e ir airway resistance and thoracic volume were probably due to chance, according to the author, though he noted that these might have been caused by irritation.
Lapp  co n clu d ed th a t th e ch anges o b serv ed in th e previously exposed individual who was ex p osed to TDI and MDI a t levels th a t did not cause such re a c tio n s in th e o th e r su b jects co n firm ed his re s p ira to ry s e n s itiv ity to th e se com pounds. Since the isocyanates to which this worker had previously been exposed w ere not id e n tifie d , this study does not provide ev id en ce on th e p o te n tia l of diisocyanates to produce cross-sensitization.

# (b) Immunologic Effects
The stu d ies discussed in th e preceding section indicate that some people are sen sitiv e to d iiso cy an ates, reacting to these substances in quantities much smaller than tho se th a t p roduce d ir e c t ir r ita tio n of th e lungs in most individuals. The m e c h a n is m of s e n s i t i z a t i o n to th e d iis o c y a n a te s has been in v e stig a te d in immunologic and pharmacodynamic studies on exposed workers.
A lle r g ic responses th a t re s u lt from c irc u la tin g an tib o d ies can be e ith e r im m ediate or late, or a combination of the two. Immediate responses occur within m inutes of exposure to th e a n tig en , and late reactions appear a few hours after exposure. Im m ed iate re a c tio n s to some substances are associated with atopy, an in n a te te n d e n c y to d e v e lo p a lle rg ie s , w hich may be r e la te d to high serum c o n c e n tra tio n s of re a g in -ty p e im m unoglobulin (IgE). Atopy is often judged to be p resen t if tw o or m ore skin te s ts with common inhalant allergens such as pollen and animal dander are positive.
Molecules with molecular weights of less than 10,000 are rarely antigenic; thus, im m unologic a c tiv ity of th e diisocyanates probably results from a reaction with a h ap ten com plex fo rm ed from a d iiso c y an ate and a naturally occurring antigenic s u b s t a n c e such as p ro te in or p o ly sacch arid e. B ecause iso c y a n a te s r e a c t w ith hydroxyl, am ino, su lfh y d ry l, or sim ilar groups, it is likely that hapten complexes may be fo rm ed .
Most in v e stig a to rs who have stu d ie d th e immune response to d iiso c y an ate s have a tte m p te d to duplicate this hapten complex by conjugating the iso cy an a te w ith a protein such as egg albumin or human serum albumin for use as an an tig en in im m unologic te s ts , using a modification of the method described in 1964 by Scheel et al Four of these five, but only 1 of 21 unsensitized workers, had a history of allergies before working with diisocyanates. These four sensitized subjects also had c le a rly p o sitiv e ly m p h o cy te tra n s fo rm a tio n te s ts , although all had been without exposure to diisocyanates for at least 6 months before testing. Neither unexposed nor u n sen sitized exposed w orkers gave p o sitiv e resp o n ses in this test. Passive cu tan eo u s anaphylaxis (PCA), Prausnitz-Kuestner (P-K), leukocyte histamine release, passive h em ag g lu tin atio n , and gel d iffusion precipitin tests were negative in all subjects and did not identify the sensitized workers. Subsequent studies by Nava et al  and B utcher e t al  have not confirmed the diagnostic value of the lymphocyte transformation test for diisocyanate sensitivity. B ruckner and co w o rk ers  noted that all five sensitized workers had been exposed to d iiso c y an ate s a t c o n ce n tratio n s above 20 ppb. They also pointed out that the development of sensitization in these workers occurred only after 2 months to 5 years of repetitive exposures, concluding that overt clinical sensitization might be avoided if workers who showed increasingly severe signs of respiratory irritation were removed from further exposure to diisocyanates.
In 1970, Taylor  attem p ted to detect circulating antibodies to TDI in 55 w orkers w ith sym ptom s su g g estiv e of TDI sensitivity. Their sera were compared w ith th o s e fro m 40 u n e x p o s e d t e x t i l e w orkers for an tib o d ies by te s ts for com plem en t fix atio n , PCA , and red-cell-linked antiglobulin. None of the control sera, but 23 of the te s t sera, gave p o sitiv e results in one or more tests. Five w ere positive in more than one test, but only one in all three tests. Six sera taken w ithin a few m onths of an unusually high exposure to TDI that produced severe sym ptom s all showed p o sitiv e te s t re su lts.
T here was no co rrelatio n between p o s itiv e antibody te s ts and eosinophilia as d e te rm in e d from blood or sputum sam ples. The au th o r su g g ested th a t th e lack of c o rre la tio n between the tests indicated that they detect antibodies of slightly different specificity or of different immunoglobulin classes.
In 1975, N ava e t al  d escrib ed im m unologic re s e a rc h on 182 clinical p a tie n ts , all but one of whom had respiratory symptoms, who had been exposed to d iiso c y an ate s in th e workplace. Ninety-six of these patients reacted positively to in tra d e rm a l te stin g w ith T D I-p ro tein conjugates. Thirty-seven of the 96 workers w ith positive tests and 6 of 86 with negative ones were atopic. However, in the 45 p a tie n ts w ith im m ed iate re a c tio n s , 60% were atopic. The authors concluded that atopy was not a f a c to r in TDI se n s itiz a tio n , since m o st p a tie n ts with positive reactions to TDI in intradermal tests were not atopic. However, their data suggest that atopy may be a predisposing factor. Nava and asso ciates  also performed pulmonary function testing on 45 of th e s e p a tie n ts who w ere exposed to TDI a t 100-130 y g /c u m (14-18 ppb) in ch allenge te s ts .
T h irty -fiv e p a tie n ts showed decreased pulmonary function after TDI challenge. An immediate or dual response occurred in 25, whereas 10 had only a la te response; in c o n tra s t, over half the positive reactions in intraderm al tests co n sisted of a la te response only. Tests with acetylcholine on 18 subjects showed th a t those who w ere h y p e rre a c tiv e to th is b ro n c h o c o n s tric to r te n d ed to have im m e d i a te b r o n c h ia l re a c tio n s to TDI. This su g g ests th a t a p h arm aco lo g ic mechanism, as well as an immunologic one, is involved in diisocyanate sensitivity.
In 1975, P o rte r e t al  published a retrospective study of sensitization in w orkers in a TDI manufacturing plant that had been in operation since 1956. The workforce exposed to TDI numbered about 200, remaining fairly constant throughout th e study period, and the turnover during the 17 years of the study was about 100 w orkers. The investigators examined medical records of the workers to determine th e r e la tio n s h ip of c l i n i c a l p r o b le m s to TDI c o n c e n tra tio n s in th e p la n t. Immunologic and lung function testing were performed on some workers. From 1956 to 1974, 30 of 300 workers at risk in the plant were judged on the basis of medical examinations to have become sensitized to TDI . At least six w orkers w ere h y p ersen sitiv e to TDI on first exposure, reacting at concentrations below 5 ppb (35 y g /c u m); in other workers, sensitization developed as late as 14 y ears a f te r in itia l exposure. The authors noted that, as individuals became more sensitized, they responded more quickly to TDI exposures and recovered more slowly a f te r rem oval from ex posure.
T able III-1 shows th e num ber of new c ases of s e n s itiz a tio n diagnosed eac h y ear in relation to the average air concentration of TDI. The d a ta in d ic a te th a t a d o se-resp o n se relationship for sensitization may ex ist. It is also clear, however, that the incidence of sensitization decreased with tim e during th e y ears b e fo re 1970 w hen th e re w ere no s ig n ific a n t changes in av era g e TDI c o n c e n tra tio n s . The au th o rs a ttr ib u te d th is not only to improved control of peak concentrations and increased employee understanding of TDI effects, but also to possible "hardening" of exposed workers.
It appears m ore likely th a t m ost p o te n tia lly s e n s itiz a b le w orkers became se n sitiz e d during th e ir e a rlie r y ears a t th e higher exposures. The authors  noted th a t sensitized workers were relocated out of the TDI handling area to other parts of the plant. These considerations preclude the assumption that 20 ppb can be reg ard ed as a no-effect level for sensitization on the basis of this study. The low tu rn o v er r a te im plies th a t only an average of 5-6 workers each year were newly exposed to TDI, so that most of the workers exposed during the last 3 years of the study already had several years of exposure at higher average concentrations. Some w orkers b eca m e sensitized after 14 years of exposure, indicating th at some of the s e n s i t i v i t y c a s e s r e p o r t e d in a b o u t 1970 d ev elo p ed when th e a v e ra g e TDI c o n c e n t r a t i o n s w ere ab o u t 60 ppb. It is u n clear w h eth er th e a u th o rs used a w eighting procedure in calculating the average concentrations, or perhaps, averaged a ll r e s u l t s .
F o r th is r e a s o n it is im p o s s ib le to co n c lu d e w h at th e TWA c o n c e n tra tio n s w ere in the plant, and thus impossible to ascertain a concentration sufficiently low to prevent sensitization. P o rte r e t al  also presented case studies and results of immunologic and pulm onary fu n ctio n te s tin g fo r 32 of th e w orkers in th is p lan t; some of these workers had signs of respiratory illness, according to medical diagnosis, while others w ere a sy m p to m a tic .
Sera from th e s e w orkers w ere te s te d for the presence of   an tib o d ies with the P-K test in monkeys and the PC A te st in guinea pigs, by using a te s t antigen of TDI conjugated with serum protein from the same animal species; this is th e only im m unologic study found on TDI th a t used antigens made with hom ologous p ro tein s in th e se te s ts . The P-K te s t was intended to identify IgE an tib o d ies, which th e au th o rs e x p e c te d to be a ss o c ia te d w ith h y p ersensitivity re a c tio n s, and th e PCA w as to id e n tify c irc u la tin g IgG antibodies, which they assum ed to confer immunologic protection. The workers' sera were similarly tested with a common pollen antigen.
In th e cases d escrib ed , there was no correlation between the presence of IgE or IgG an tib o d ies ag ain st TDI and e ith e r clin ical sym ptom s, lung function, or reactivity to pollen antigens. For example, apparent sensitivity to TDI accompanied by loss of lung fu n ctio n was re p o rte d in a worker who had a positive PCA test w ith TDI an tig en but not with pollen antigen and in one who gave a positive P-K te s t w ith pollen but show ed no antibodies against TDI; another sensitized worker had positiv e PCA to both TDI and pollen but refused pulmonary function testing. Two w orkers w ith s e n s itiz a tio n re a c tio n s to TDI had p o sitiv e results with TDI an tig en in th e P-K te s t , but no loss of lung function. Workers who showed no sig n s of se n s itiz a tio n to TDI included som e who gave n eg a tiv e re s u lts in all im m unologic te sts and others with positive reactions to TDI in the PCA, P-K test, or both. These re su lts do not support the authors' hypothesis regarding the roles of IgE and IgG an tib o d ies in TDI se n s itiz a tio n . The authors attributed the loss of lung fu n ctio n , which was a p p a re n tly in d ep en d en t of th e p resen ce of an tib o d ies, to b ronchoco n strictio n ; the reactions of these individuals occurred almost immediately upon exposure and w ere relieved by treatm en t with a bronchodilator. In contrast, clinical reactions in the two workers with positive immunologic tests but no loss of lung function had developed gradually after several years of exposure. The findings of th is s tu d y i n d i c a t e t h a t an im m unologic m echanism may be involved in diisocyanate sensitivity but that sensitivity in some individuals may also result from a nonimmunologic mechanism.
As part of a long-term study of workers exposed to TDI, described in detail in E pidem iologic Studies, Butcher and associates  reported in 1976 the results of im m unologic and in h a latio n ch allen g e studies of 167 employees who worked in a fa c to ry producing TDI. B efo re TDI p ro d u ctio n began and a t 6 and 18 months afterw ard, employees were prick-tested to determine their reactivity to a conjugate of TDI with human serum albumin (HSA) and to HSA alone. They were also prickte s te d w ith 15 common inhalant allergens. Using blood taken from the workers at th e s a m e t e s t in te r v a ls , th e in v e stig a to rs d e te rm in e d eosinophil counts and im m unoglobulin levels.
To identify TDI-specific antibodies, sera were tested with the TDI-HSA antigen by radioimmunoassay tests, the PCA test on guinea pigs, and Workers were subdivided into groups with constant, interm ittent, or no exposure . On initial testing, four workers had positive skin reactions to both TDI-HSA and HSA a lo n e ; h o w ev er, during th e th ird p lan t v isit 6 m onths la te r , th re e individuals r e a c te d p o sitiv ely to TDI-HSA but not to HSA. The authors did not in d icate the exposure groups of th e se persons, but they noted that none of the three showed clinical respiratory responses to TDI.
Both b efo re and after TDI production began, PCA, P-K, and radioimmunoassay te s ts for TDI an tib o d ies w ere negative in all subjects . Eosinophil counts did not d iffe r in exposed and unexposed groups. Immunoglobin levels were similar in all th re e exposure groups.
Six m onths after production began, both IgG and IgE had in c re ased sig n ifican tly over p reex p o su re values; however, this increase was ap p a re n t in all groups, and the IgE increase was greatest in the unexposed group. The au th o rs therefore concluded that the increase was not related to TDI exposure but probably reflected seasonal variation. H ow ever, th e au th o rs n o te d that the number of individuals tested was too small to indicate that antibody titer was proportional to exposure.
In a 1973 NIOSH h e a lth h azard ev alu atio n , V an dervort and Lucas  in v e stig a te d im m unologic resp on ses of 90 w orkers exposed to MDI a t average c o n c e n tra tio n s of up to 11 ppb (110 U g/cu m) in a plant manufacturing fibrous glass tan k s. PCA , P-K , and agglutination tests were carried out with a "specially prepared isocyanate antigen," not otherwise characterized. Of 12 men with positive P-K te s ts , 2 showed respiratory responses to MDI, and 1 had decreased pulmonary function; pulm onary fu n ctio n te stin g was recom m ended for 2 others to evaluate their status. The other seven showed no evidence of adverse reactions to MDI, and th e au th o rs co n sid ered th em "hardened" to its effects. Forty workers who gave positive results only in the PCA or agglutination tests were also asymptomatic. It is possible, as th e authors suggested, that certain workers giving positive tests for an tib o d ies w ere im m unologically "hardened" to th e effects of MDI and that the c irc u la tin g IgG an tib o d ies th a t m ight be in d ic a te d by positive PCA tests were involved in c o n ferrin g such im m unologic p ro te c tio n .
H ow ever, th e inadequate c h a ra c te r iz a tio n of the antigen used in testing makes it difficult to determine the validity of these results.
To evaluate whether the difficulty in detecting diisocyanate antibodies might be due to nonavailability of exposed hapten groups in the antigen, Karol e t al , in a 1978 study, used a c o n ju g ate of p -to ly l isocyanate with human serum albumin (TMI-HSA) as a te s t a n tig en . B ecause it contained only one isocyanate group on eac h m olecule, this monoisocyanate would not cross-link the protein component of th e an tig en , increasing the probability that the tolyl portion of the molecule would be ste ric a lly exposed. The authors tested 23 employees of a large TDI production fa c ility , 4 of whom w ere considered sensitized to TDI. Three of these had had a sen sitiv ity response, e ith e r bronchial or skin reac tio n , within 1 year before the study; the fourth had avoided exposure to TDI for at least 2 years. The remaining 19 w orkers w ere co n sid ered unsen sitized because they showed no adverse effects when exposed to TDI; in som e c a ses, this judgm ent was confirmed by negative results in challenge tests with TDI at 20 ppb (140 yg/cu m).
A radioimmunoassay for IgE bound to TMI-HSA showed that the 19 unsensitized w o rk e rs had antibody ti te r s sim ilar to th o se of 10 blood-blank donors  . H ow ever, th e se n sitiz e d group show ed a significantly elevated titer of anti-tolyl an tib o d ies (P<0.01). The th re e workers who had had TDI reactions within the last year had antibody titers higher than any of the unsensitized or control individuals. Serum -binding to th e an tig en was inhibited in the presence of nonisocyanate tolyl com pounds, suggesting to the authors that the antibodies were toly 1-specific. There was no co rrelation between the tolyl-specific IgE antibodies and the levels of total IgE in the sera. Incubating lym phocytes from sen sitiv e and nonsensitive workers with TDI in the absence of iso p ro te re n o l did not a f f e c t cy clic AMP levels. T h ere was a d o se-dependent inhibition of iso p ro teren o l-stim u lated cyclic AMP levels in lymphocytes from both sensitive and nonsensitive subjects; there was no significant difference in the ability of cells from these two groups to exhibit cyclic AMP stimulation.
In th e m echolyl ch allen g e stu d ie s, 6 of th e 10 clinically sensitive subjects showed a drop in FEV 1 of m ore th an 20% w ithin 1.5 m in u tes a f te r a single inh alatio n of mecholyl . Only 1 of the 10 nonsensitized subjects gave such a response, and this occurred 5 minutes after inhaling mecholyl four times.
This study  indicates that TDI is not a histamine releaser per se but that it does suppress stimulation of the beta-adrenergic system by isoproterenol. These resu lts a g re e w ith those of a similar study by Van Ert and Battigelli  on the e f f e c ts of TDI on h ista m in e release in vitro. Butcher et al  concluded that th e ir findings suggested that TDI may act as a beta-receptor blocking agent. This would produce increased reactivity to agents capable of causing bronchoconstriction, such as m echolyl. In a follow up re p o rte d in tw o 1978 abstracts , blood te stin g a f te r ch allen g e ex posures to TDI show ed that histamine levels increased a f te r a bronchial re a c tio n , w hile com plem ent components were not affected. In this study, all TDI r e a c to r s r e a c te d p o sitiv ely to m echolyl ch allen g e, and the au th o rs  n o ted that kinetic studies had revealed a strong indication that cells from TDI re a c to rs respond d iffe re n tly th an th o se of n o n re a c to rs to the betaadrenergic agonists isoproterenol and prostaglandin E, and to TDI added alone. These stu d ies  suggest that a pharmacologic mechanism is involved in r e s p i r a t o r y s e n s i t i v i t y to TDI, b ut th e re is no in d icatio n w h eth er m echolyl hyperreactivity is a preexisting factor or a result of TDI exposure.
(c) Skin Effects Some diisocyanates have been described as skin irritants , but there are few re p o rts in th e lite r a tu r e of skin effects from these compounds. Munn  has noted th a t, in several years of study, he has seen only two mild cases of skin irrita tio n from d iiso c y an ate s and no cases of skin sensitization. Bruckner et al  re p o rte d that 6 of 44 workers in a chemical plant experienced skin irritation a ttrib u te d to exposure to unspecified diisocyanates. These reactions consisted of e ry th e m a only on areas of skin that were in actual contact with the diisocyanates. One w orker who o fte n had d iiso c y an ate s on his hands n o ted th a t his skin had become hard and smooth, so that he had difficulty in turning pages.
Possible skin sensitization to TDI was described in two of the studies discussed in th e previous section. Nava et al  reported that a worker with eczematous d e rm a titis was 1 of 3 w orkers who reacted positively to TDI in a patch test, out of 182 workers tested. Karol e t al  found tolyl-specific IgE antibodies in two w orkers who displayed im m e d ia te skin reactions when exposed to TDI, apparently w ithout a bronchial response. These skin reactions were extensive and not confined to areas where TDI had contacted the skin.
Rothe , in 1976, described 20 cases of occupational skin disease in workers exposed to poly u reth an es. Clinical examinations, observation of the course of the disease, reex p o su re te s ts , and skin te s ts were carried out. Standard and special te s ts using a v ariety of isocyanates, amines, and additives were used to determine the specific sensitivity of the workers. R othe  found 12 cases of c o n ta c t e c z e m a c h a r a c te r iz e d by follicular papules in w orkers exposed to MDI or p artially polymerized MDI. Ten of these co n stitu ted more than half the total number of workers who had come into contact w ith a p o ly u reth an e sealing com pound a t one plant, and two were from another plan t.
S everal in sp ectio n s showed that there was very close contact between the w orkers' skin and th e sealing com pound.
Work c lo th e s were often soaked with resin. The workers had positive skin test reactions to the isocyanate component of th e sealing com pound.
T w en ty -fiv e unexposed persons with eczem a had negative r e s u lt s .
Five of seven w orkers w ith MDI a lle rg ie s e x h ib ite d ty p ical e c z e m a re a c tio n s to diaminodiphenyl methane (MDA). Only one of these had had previous contact with the MDA, which was not used at the plant. Skin disease disap p eared in all four persons se n sitiz e d to IPDI a f te r exposure was stopped. T hree of th e in v e stig a to rs tested themselves with undiluted IPDI and no reactions o ccu rred w ithin 4 days  . However, two of the three investigators developed fo llicu lar papules 10 days a f te r te stin g . Sensitization in these investigators was confirm ed in a la te r test with a 1% IPDI solution, which produced no reactions in six nonexposed subjects.
The o th e r four p a tie n ts with skin disease included two cases of eczem a from TDI exposure, one case with exposure mainly to TDI but also to MDI, and one case of eczem a probably related to exposure to triphenylmethane triisocyanate . In all 20 cases th e re was a pattern of brief exposure to the isocyanate, often caused by spills, with subsequent development of eczema. In most cases, sensitization was co n firm ed by sk in -te stin g with a dilute solution of the isocyanate suspected to be the agent.

# UU Other Effects
A lthough m ost re p o rts of diisocyanate toxicity have described effects on the resp ira to ry tr a c t or skin, some have noted other effects. These have included eye irritation, psychologic symptoms and CNS effects, and hematologic changes. Most of th e se e f f e c ts have o c c u rre d following mixed exposures to diisocyanates and other c h e m ic a ls , an d su c h e f f e c t s can n o t be c le a rly ascrib e d to th e d iiso c y an ate exposures.
S everal stu d ies have su g g ested th a t TDI, esp ecially a t very high exposure levels, may cause neu ro lo g ic or CNS e f f e c ts .
In th e firs t published report of occupational illness from TDI exposure, Fuchs and Valade  noted that insomnia was o fte n th e firs t co m p lain t of a f f e c te d w o rk ers, p reced in g any re sp ira to ry sym ptom s. They also m en tio n ed that three patients had a decrease of the kneejerk and A chilles re fle x e s . In one patient, who completely lacked these reflexes, th e cond itio n p e rsiste d for 2 months after he stopped working with TDI and then ab ru p tly re tu rn e d to no rm al. In th e ab sen ce of other signs of exposure-related nervous d iso rd ers, th e a u th o rs did not specifically im plicate TDI as the cause of this condition.
A 1964 USSR study  investigated the effects of TDI on electrical activity in th e human cerebral cortex. No experimental details were reported, but TDI was said to a f f e c t electroencephalographic (EEG) rhythms at a threshold concentration of 100 U g/cu m (14 ppb). This study was not included in th e 1973 c r ite r ia docum ent on TDI . Little can be made of these results in the absence of any inform atio n on experimental methods, but the implication of CNS effects at a such a low concentration suggests that such effects should be more carefully evaluated.
In 1965, a Canadian report  indicated that 12 of 24 maintenance workers d e v e lo p e d r e s p i r a t o r y s y m p to m s a f t e r th e y had c lean ed pipes and vessels c o n ta m in a te d w ith TDI. In ad d itio n , four of th e workers developed psychologic problems, including anxiety neuroses, psychosomatic complaints, depression, and even paranoid te n d en cie s. A year after exposure, they had not returned to work; some s till com plained of cough and d iffic u lty in b re a th in g , although their pulmonary fu n ctio n te s ts were normal. This report suggests the possibility th at TDI produces CNS e ff e c ts ; cleaning p ro cesses, how ever, involve th e use of solvents to which th e se CNS e f f e c ts m ight be attributed. This report did not detail the procedures or solvents used in cleaning the TDI-contaminated vessels.
B urton  , review ing O n tario w orkm en's co m p en sa tio n claim s in 1972, m entioned an in cid en t of TDI exp o su re in a rubber plant. One of three women em ployees who developed chronic obstructive lung disease after an acute exposure to TDI also had a "psychogenic problem," not otherwise described. N ev erth eless, it is not unequivocal that the effects reported were caused by TDI.
In a 1962 report, Filatova et al  described the effects of mixed exposures to TDI, ch lo ro b en zen e, phosgene, to lu en e diam ine, and HDI on 63 men and 17 w om en who had m anufactured diisocyanates for 1-2 years. These effects included irrita tio n of th e ey es, nose, and skin, coughing, difficulty in breathing, headaches, in s o m n ia , w eak n ess, tre m o rs , re fle x ch an g es, and c h e s t and abdom inal pain. H e m a to lo g ic te s ts show ed d e c re a se s in eosinophils and n eu tro p h ils, and some w orkers had slightly en larg ed liv ers w ith no functional impairment. The authors concluded th a t th e substances produced during diisocyanate production were toxic, but they could not a ttr ib u te th e sym ptom s to TDI alone, since other compounds that were present could have produced similar effects. O n ly th e HDI concentrations were said to be in excess of the MAC.
Thirty-two workers complained of headaches, 36 of increased perspiration, 20 of aches in th e a re a of the heart and under the right ribs, 13 of dream disturbances, 12 of difficulty in breathing, 19 of general weakness, and 6 of coughing . All w orkers re p o rte d th a t HDI vapor irritated their eyes and upper respiratory tract. N in eteen w orkers, who had w orked in th e p lan t for 7-13 y ears, had developed slightly en larg ed liv ers th a t w ere painful upon palpation. Duodenal sampling and blood bilirubin and cholesterol analyses revealed no hepatic lesions. Most of the 55 w orkers ex am in ed for liver abnorm alities showed hypocholesteremia, indicating to th e au th o rs an early sta g e of d istu rb a n ce of liv er function. Most workers also showed abnormalities in blood proteins and serum cholinesterase activity.
A pproxim ately 50% of the examined workers had developed chronic subatrophic pharyngitis w ith o u t any p ath o lo g ic changes in th e lungs  . Effects on the ca rd io v ascu lar system were seen in 47 workers, 27-40 years old, more than half of whom had sinus arh y th m ia , b ra d y c a rd ia , e x tra s y s to le , and slowing of endoatrial co n d u ctiv ity indicative of toxic myocardiodystrophy. Some workers had trem ors of the fingers and eyelids and increased muscular excitability. Filatova et al  concluded that the adverse effects on workers' health were produced by a m ix tu re of to x ic com pounds whose main component was HDI. No o th e r re p o rts of h e p a to to x ic ity or cardiovascular effects in diisocyanate workers have been found.
It should be noted that chlorobenzene is a hepatotoxin that has re p o rte d ly cau sed h e p a tic necrosis in animals at high doses  and produced an increase in liver weight in rats inhaling 1,150 mg/cu m for 6 months .

# Epidemiologic Studies
Studies of w orker p o pulations exposed to TDI have r e la te d environm ental exposure levels to th e incidence and severity of respiratory symptoms, changes in pulm onary function, and immunologic reactivity. Investigations of workers exposed to MDI and HDI have g en era lly provided less useful data because they involved mixed exposures to several other toxic chemicals.
In 1957, H am a e t al  re p o rte d th a t 12 workers exposed to isocyanates (TDI) a t 30-70 ppb (210-500 ug/cu m) for 1 week in an automobile plant had mild to sev ere re sp ira to ry symptoms including cold symptoms, continuous coughing, sore th ro at, dyspnea, fatigue, and nocturnal sweating. No symptoms had developed during th e previous m onth when isocyanate concentrations were below 10 ppb (70 Ug/cu m), and when concentrations were subsequently reduced to the 10-30 ppb range (70-210 u g /c u m), no fu rth e r co m p lain ts o c c u rre d in over 3 m onths.
A w ritte n co m m unicatio n from Hama (3une 1973) confirmed that the isocyanate was TDI and in d icate d th a t exp o su re concentration measurements were based on breathing-zone sam ples an aly zed by th e R a n ta m ethod. This m ethod is unable to distinguish b e tw e e n TDI and th e TDI u re a fo rm ed in th e p re se n c e of w a te r.
Thus, the concentrations of TDI in the area were probably less than the reported values.
A d e ta ile d 2 .5 -y ear study by W alw orth and Virchow  of a polyurethane foam p lan t was published in 1959. TDI concentrations ranged as high as 300 ppb (2,200 y g /c u m), but monthly averages were generally below 150 ppb (1,100 yg/cu m). E ig h ty -th re e cases of respiratory illness that required medical attention were a ttrib u te d to TDI ex posure; m ost of them occurred after 3-4 weeks of exposure. The to ta l num ber of w orkers a t risk was not reported. The authors noted that t h e r e w as l i t t l e c o r r e l a t i o n b etw ee n m easu red TDI c o n c e n tra tio n s and the app earan ce of respiratory symptoms. They attributed this largely to short exposures a t high c o n c e n tra tio n s not r e f le c te d in th e m easurem ents of average exposures. They added that once workers experienced adverse effects from TDI they could not tolerate even minute exposures.
In 1964, to x ic e ffe c ts from TDI in workers in three New Zealand plants were reported . At one plant, where usual TDI concentrations ranged from 3 to 120 ppb (20-850 y g /c u m), three cases of respiratory sensitization occurred in 1 year. In tw o of th e se w orkers, sym ptom s first appeared after 2-3 hours of pouring TDI inside a r e f r ig e ra te d van, w here unusually high concentrations were likely. The third w orker, whose sym ptom s developed gradually, could work 50-60 feet away from th e foaming operation, where TDI concentrations were about 5 ppb (35 yg/cu m), but he had a respiratory reaction when he worked within the foaming area. In a sim ilar p la n t, w here TDI co n cen tratio n s were usually below 20 ppb (140 yg/cu m), t h e r e w e re tw o c a s e s of mild cold sym ptom s and one case of possible s e n sitiz a tio n , all a ss o c ia te d w ith a foam ing o p e ra tio n in w hich concentrations reac h ed 100 ppb (700 y g /c u m). This p lan t also reported one case of a severe a s th m a tic a tta c k and co llap se in a worker exposed at a very high concentration. He subsequently re tu rn e d to work with no evidence of sensitization. In the third plan t, tw o w orkers exposed to TDI at 18 ppb (130 yg/cu m) wearing canister-type m asks e x p erien ced very mild cold symptoms at the end of the day when a double run was carried out. The total workforce at risk in these plants was not reported.
In 1962, Elkins et al  described experiences with TDI in 15 Massachusetts plants over a 5 -y ear period.
They e v a lu a te d th e c ases of re s p ira to ry illness o ccu rrin g in eac h of the plants and made environmental measurements, apparently from a re a sam ples.
Most of th e sam ples were analyzed by the Marcali method. The R a n ta m ethod was used for some of the early measurements and found to be less a c c u ra te , but the authors did not indicate which measurements were made by this method. Other methods used in a few plants reportedly gave results comparable to the Marcali method. The findings of Elkins and coworkers, as adapted by NIOSH to p r e s e n t w h a t w e re c o n s id e r e d to be re le v a n t d o se-resp o n se d a ta , w ere sum m arized in the 1973 TDI criteria document , and are shown in Table III-2. This ta b le om its data from plants where environmental levels were not determined or w here th e au th o rs considered that these measurements were not representative of exposure.
The numbers given for workers at risk are probably somewhat higher than th e a c tu a l num bers exposed to TDI, which could not be determined from the paper.
Elkins e t al  found a to ta l of established cases and 73 questionable cases of re s p ira to ry illness a s s o c ia te d with TDI exposure. Concentrations higher than 20 ppb (140 yg/cu m) were measured in only three plants. From the data in Table III-2, it can be seen that cases of respiratory illness were associated with all exposure co n cen tratio n s above 10 ppb (70 yg/cu m), but there were no cases at 7 ppb (50 y g /c u m) or low er.
At 9 ppb th e re w ere no established cases but one q u estio n ab le one; th e re w ere sev eral estab lish ed cases a t 8 ppb. The authors concluded that the environmental limit for TDI should be considerably less than 100 ppb (700 y g /c u m), and th ey su g g ested th a t 10 ppb (70 yg/cu m) was "not an unreasonable limit." E ight m en who had a positive reaction to histamine had a larg er daily decrease in FEV 1 than did nonreactors (0.310 vs 0.115 liter). Smoking status was not significantly related to the changes in FEV 1. It is therefore difficult to evaluate the significance of the changes reported.
The following year, Williamson  reported the results of pulmonary function te stin g over a 14-m onth period on 15 w orkers in an o p e ra tio n w here TDI was se p a ra te d from a so lv en t by d istilla tio n .
Frequent environmental measurements w ere m ade and th e se never show ed TDI concentrations above 20 ppb (140 Ug/cu m), but av era g e c o n c e n tra tio n s w ere not given. One major spill occurred during th e study, causing c o n c e n tra tio n s high enough to permit detection of odor, from w hich th e au th o r in fe rre d th a t th e c o n c e n tra tio n was at least 200 ppb, and the room was immediately cleared.
All the workers tested were free of respiratory symptoms . In four series of m easurem ents of FVC and FEV 1, the only significant change was a fall in FEV 1 a t the tim e of the second measurement (P<0.01), and subsequent tests showed no significant change from baseline FEV 1 values. There was little difference between Monday and Friday values; daily changes were not measured. Williamson  No sig n ific a n t d iffe re n c e in respiratory symptoms was found b etw een 76 currently employed men exposed to TDI and controls. Nine of 76 men in the co n tro l group had w heezing, co m p ared with only 1 of 76 men exposed to TDI.
In th e second p a rt of the study, Adams  exam ined men who had been rem oved from th e TDI p la n ts b ecau se of re s p ira to ry symptoms such as mild to severe bronchospasm and dyspnea.
A bout 15% of the men employed in the TDI p lant w ere rem oved from th e p lan ts in th e ir 1st year b eca u se th ey developed re s p ira to ry symptoms. In the 2nd year of employment, only 3.5% of the remaining w orkers developed re s p ira to ry sym ptom s, and th e rate gradually dropped to less than 2%/year after the 5th year, totaling about 20% of the original workforce over th e 9 years of the study. In form ation on symptoms in 46 men removed from the plan t, who had not been exposed to TDI for 2-11 years, was collected annually by respiratory questionnaire and compared with responses from 46 age-m atched workers not exposed to TDI. These results were correlated with the results of pulmonary fu n ctio n te s ts .
The d a ta w ere analyzed for statistical significance by chi-square test.
D ata from 46 co n tro ls and 46 m en previously exposed to TDI show ed no d i f f e r e n c e s in t h e i r sm o k in g h ab its  .
H ow ever, 17 of th e 46 w orkers previously exposed to TDI developed breathlessness after exertion, significantly more th a n th e 5 m en in th e c o n tro l group w ith this sym ptom (P<0.01). W heezing o cc u rre d in 17 w orkers but only in 7 controls (P<0.05). These findings indicated th a t re s p ira to ry sym ptom s p e rs is te d in som e subjects after exposure to TDI had ceased.
Pulmonary function data for 61 men who had had no contact with TDI for 2-11 years showed th a t th e ir av e ra g e FVC and FEV 1 values were slightly lower than control values after adjustment for age and height . Eleven of the 20 workers who had been rem o v ed from the plants because of sensitization to TDI and whose p reem p lo y m en t lung fu n ctio n records were available were asymptomatic after 3-8 years w ith o u t ex p osure, and 12 of these 20 had FEV 1 and FVC values unchanged from th e ir p reem p lo y m en t levels. Six had FEV 1 and FVC values between 90 and 100% of th e ir p reem p lo y m en t levels, and two had values of 80-90%. Those who had red u ced pulm onary fu n ctio n co m p lain ed of dyspnea on e x e rtio n , nocturnal dyspnea, and tightness in the chest.
Adams  concluded th a t exposure to TDI at about 20 ppb (140 Ug/cu m) for 5 y ears did not in c re a se respiratory symptoms or affect the lung function of w orkers who w ere not se n s itiz e d to the compound. However, sensitized workers, even when no longer exposed to TDI, had m ore re s p ira to ry symptoms than did unexposed controls, suggesting th at effects of TDI are, to some extent, irreversible. F or e n v iro n m en ta l m easu rem en ts, area samples, apparently collected at 6-month intervals, were analyzed by the Marcali method.
The initial study , made during December 1966, included 38 workers, 7 of them w om en, w ith an average age of 36.3 years (range 18-62 years), employed an av era g e of 104.6 w eeks (2-624 weeks). Environmental measurements taken during this period show ed TDI co n cen tratio n s ranging from 0.1 to 3.0 ppb (0.7-21 ug/cu m). Pulmonary function measurements on 34 workers showed a mean daily decrease in FEV 1 of 0.19 lite r (P<0.001). S ignificant daily decreases were also noted in FVC (P 0 .0 0 1 ), PFR (P<0.05), FR50% (P<0.01), and FR25% (P<0.05). From Monday m orning to F riday m orning, th e m ean FEV 1, FR 50% , and FR25% all showed significant decreases (P<0.001). Responses for smokers and nonsmokers were similar, but w orkers with respiratory symptoms had a significantly greater decrease in FEV 1 than those without symptoms (P<0.05). The authors noted that there appeared to be no rela tio n sh ip b e tw e e n pulm onary fu n ctio n changes and amount of exposure, which they judged from the distance between work stations and sources of TDI.
At th e 6-m onth followup , 28 of the 34 workers were still employed, and 6 new w orkers w ere added to th e study group. Environmental concentrations at th a t tim e ranged from undetectable to a high of 12.0 ppb (85 ug /cu m) in the TDI pouring a re a .
Monday p resh ift and postshift measurements of pulmonary function showed significant decreases (P<0.02) in both FVC and FEV 1; Tuesday morning tests sh o w e d e s s e n t i a l l y c o m p le te re c o v e ry in FVC, but FEV 1 valu es w ere s till significantly lower than on the previous morning.
When pulm onary fu n ctio n te s t re su lts w ere compared with those from tests done 6 m onths e a rlie r, sig n ific a n t decreases were found in FEV 1, the ratio FEV 1/FVC, and FR values at 75, 50, 25, and 10% of vital capacity . The authors noted th a t th e re was a high c o rre la tio n (r=0.72) between the 1-day and 6-month d e c r e a s e s in FEV 1.
T he only o th er v aria b le sig n ific a n tly c o r r e la te d w ith pulm onary fu n ctio n test results was lifetime smoking history, and when this factor was held constant, the 6-month changes in FEV 1 were still significantly correlated with diurnal changes (r=0.60).
The 12-m onth followup, made in December 1967, showed a much lower diurnal d ec re a se in FEV 1, 0.05 lite r  .
In th e 25 workers still available from the original 34, the decrease in FEV 1 over 1 year was still significant, but the entire d ec re a se was a c c o u n te d for by changes during the first 6 months. The authors noted th a t TDI concentrations measured at this time were very low; the maximum concentration detected was only 1.5 ppb (11 Ug/cu m). In itial m e asu re m en ts show ed a dose-related diurnal decrease in FEV 1 in the th re e groups . At the 2-year followup , only 63 members of the original w orkforce were still employed. Examination of records showed that 40 of those no longer em ployed had resig n ed v o lu n tarily and th a t th e se w orkers had shown a diurnal decrease in FEV 1 of 0.126 liter at the earlier testing, compared with 0.096 lite r in th o se who w ere still employed. While this difference was not significant, th e authors noted that it reflected a trend for self-selection based on health among TDI workers.
In g e n e ra l, work assig n m en ts had been stable over the 2 years, with workers averaging 20 months at a work station; workers were therefore assigned to exposure groups on the basis of their usual work station . Since 5 workers had variable exposures and could not be assigned to any group, final testing was performed on 57 w orkers; 20 of these in each of the high and low exposure groups and 17 were in th e m edium exposure group. The incidence of coughing and phlegm production in c re ased w ith higher ex p o su re; 15% of the 57-person study group had symptoms suggestive of chronic bronchitis, but these were not related to exposure level. The 2-year d e c re a se in FEV 1 a v e ra g e d 0.102 liter (SD = 0.204 liter) in the exposed w orkers; th e groups with low, medium, and high exposure had respective decreases of 0.012, 0.085, and 0.205 liter (SD = 0.204, 0.177, and 0.185 liter). The authors noted th a t th e d e c re a se in the high-exposure group was "clearly excessive," while th a t in th e low -exposure group was " c le a rly w ithin normal limits." The authors' analysis of v arian ce show ed th e d iffe re n c e in 2-year decrem ent in FEV 1 in the th re e groups to be significant at P<0.01. Age, length of employment, and smoking habits did not d iffe r significantly in the three groups. Since several factors that a f f e c t lung size, including sex, h eig h t, and race, differed among the groups, the au th o rs sta n d a rd iz e d fo r lung size by dividing the 2-year decrease by the initial FEV 1 m e a su re m e n t; th is standardized figure still showed a significant difference between exposure groups. T h ere was no significant difference in mean FEV 1 b etw ee n w orkers exposed for less th an 3 y ears and those exposed 10-25 y ears, although the m ean for sm okers was sig n ifican tly different from that for nonsm okers.
L ab o ra to ry te s ts in d ic a te d th e re w ere no alterations of peripheral blood values, hematopoietic system, or kidney function.
Weili e t al  and Butcher et al  have reported on the first 5 y ears of a lo n g itu d in al study of respiratory symptoms, pulmonary function, and im m u n e re sp o n se s in w orkers a t a T D I-m an u fac tu rin g p la n t.
The study was in itia te d in April 1973, before TDI production began at the plant, and is planned to extend through 1978. In the 1978 annual report on this study, Weill e t al  noted that only 88 of th e origin al 166 w orkers were still participating. To offset attrition, workers had been added during the first 3 years of the study, so that some data were available on a to ta l of 277 workers. The original exposure groups were no longer considered valid because of w orkers tra n s fe rrin g from one exposure c a te g o ry to another. P ersonal m onitoring d a ta c o lle c te d since 1975 w ere th erefo re used to estim ate cu m u lativ e ex p osures in ppm-months for each worker. Mean TWA exposures were calculated for each of six job categories, ranging from 2 to 6 ppb (14-40 Ug/cu m). TDI c o n c e n tra tio n s fo r jobs assigned to the control group were found to be below th e lim it of d e te c ta b ility of th e method (reported as 1.5 ppb) more than 99% of th e tim e , and th e author assigned these jobs a mean TWA concentration of 0 ppb. For each worker, time spent in each job category was multiplied by the mean TWA c o n c e n tra tio n for th a t job and re su lts w ere sum m ed to d e te rm in e cum ulative exposures.
Lung fu n ctio n te s t resu lts were statistically correlated with these cumulative exposures in cross-sectional and longitudinal analyses [ When re su lts w ere analyzed by sm oking and atopy categories, most of the increase in bronchitis was accounted for by nonatopic smokers in the exposed group. There was no significant d iffe re n c e betw een continuously and interm ittently exposed groups, but correlations with cumulative exposures were not made.
This study  is th e only study available on TDI workers that provides preex p o su re d a ta for all w o rk ers. In ad d itio n , because of the use of continuous personal monitoring, it provides realistic information on actual exposures. In a 1973 NIOSH h e a lth h azard e v alu atio n , V andervort and Sham a  in v e stig a te d re s p ira to ry sym ptom s and a c u te lung fu n c tio n ch an g es in workers exposed to TDI a t low c o n c e n tra tio n s a t a p lan t making polyurethane foam ice ch e sts and p icn ic jugs. During a preliminary visit, air samples were collected and analyzed for TDI by th e m odified M arcali m ethod of Grim and Linch . A q u estio n n aire to identify histories of respiratory symptoms was administered to all 290 em plo y ees of th e p la n t, about 200 of them exposed to TDI. The authors did not in d icate th e to ta l num ber of w orkers with respiratory symptoms or describe th e ir exposures to TDI. Twenty-nine of the 200 exposed workers were selected for fu rth e r study; 13 of these were experiencing respiratory symptoms, as indicated in responses to th e q u e stio n n a ire , and 16 were asymptomatic. These workers were subdivided into m o d e ra te and low exposure groups on the basis of environmental m e asu re m en ts m ade a t th e time of the initial visit. The four workers making up th e sym ptom atic low-exposure group were among 14 sensitized workers in the plant who had been transferred away from the immediate area of the foaming operation because of intolerance to TDI. Seven unexposed control employees, m atched to the study group for age, sex, and smoking habits, were selected as controls.
Two weeks after the initial visit, the investigators  performed preshift and p o stsh ift pulm onary fu n ctio n te stin g on the exposed and control workers selected for th e study. The TWA exposure concentration of each employee was determined for th e sh ift from breathing-zone samples. Short questionnaires were administered before and a f te r th e m o n ito red sh ift and again th e n ex t morning to determine whether the employees were experiencing symptoms. R esu lts of pulmonary function testing showed no significant difference between m orning and evening testing except in the symptomatic low-exposure group of four s e n sitiz e d w orkers who had been tran sferred out of the foaming area; this group also showed significantly greater decreases in FVC and FEV 1 than did the controls  .
The individual w ith the g r e a te s t d e c re a se , who had never smoked, was exposed a t a c o n c e n tra tio n of only 0.2 yg/cu m and thus was highly sensitive to TDI.
In th e asym ptom atic groups with both moderate and low exposure, all but two of th e w orkers re p o rte d m ild irritatio n of the mucous membranes, and three had re sp ira to ry sym ptom s such as coughing or chest tightness . All 13 workers in th e sy m p to m atic groups reported coughing, chest tightness, wheezing, or shortness of b reath .
T here was a considerable increase over preshift findings in the number of sym ptom s re p o rte d a t th e end of th e s h ift in both th e m oderate-and lowexposure symptomatic groups and some increase in the asymptomatic groups. However, the investigators noted that it could not be assum ed th a t w orkers had become sensitized at these low levels. Nine of the 13 sy m p to m atic em p lo y ees had been exposed to spills of TDI in the past, and 8 of th e se 9 developed sym ptom s a t the tim e of th e spill, so sensitization may have developed as a result of these exposures. The authors could not determine whether this was the first occasion on which they showed symptoms. Other studies found on populations of workers exposed to MDI have provided no quantitative information on exposure concentrations, but they do indicate that there is a rela tio n sh ip b etw ee n ad v erse e f f e c ts and exp o su re lev els or d u ratio n of exposure. For ex am p le, in 1971, Tanser et al  examined the effects of MDI exposure on 57 employees in a factory producing rigid polyurethane foam moldings. F o u rte e n of th e 57 w orkers re p o rte d th a t any contact with MDI vapor produced e f fe c ts ranging from a sore throat and wheezing to severe asthma and tightness in th e c h e s t. Spirometric analysis showed that 8 of the 57 employees had an FVC of less than 9096 of the predicted value or an FEV 1/FVC ratio below 75%; only 2 of these 8 reported symptoms of sensitivity to MDI.
The authors  reported that most of the symptoms appeared to be those of d ire c t irrita tio n and not of an allergic reaction. However, four workers who had c o n ta c t with MDI were diagnosed as having possible hypersensitivity; three of these had sev ere asth m a, and the fo u rth developed fever, headaches, aching limbs, and cough following exposure.
The 1976 stu d ie s of Saia e t al  and F ab b ri e t al  ex p lo red the rela tio n sh ip b etw ee n exp o su re to MDI and ch ro n ic n o n sp ecific lung disease in w orkers in an Italian r e f r ig e r a to r fa c to ry .
The total exposed workforce of 180 com prised 94 fu rn a c e w orkers (who removed polyurethane molds from the furnace and w ere e s tim a te d to have the highest exposures), 32 injectors, and 54 assembly line w orkers w ere also included.
The groups w ere sim ilar in average age and length of employment.
Responses to a questionnaire indicated that 85 of the workers in the plant had re sp ira to ry sym ptom s  .
The p rev alen ce of th e se sym ptom s was le a st in workers exposed less than years and greatest in those exposed more than 8 years; th e av era g e age in all th r e e groups was 37-38 years. Pulmonary function studies sh o w e d t h a t a b o u t h a lf of th e 180 w o rk e rs had v ital c a p a c ity and FEV 1 m easurem en ts below 90% of predicted values, and 15-20% had values below 80% of p red icted . The 85 workers with respiratory symptoms had pulmonary function m e a su re m e n ts sig n ifican tly low er th an the average for the 180 employees. These measurements decreased with length of exposure even when adjusted for smoking.
R esu lts w ere also analyzed by job function in 160 workers who had no history of previous occupational exposure to respiratory irritants . Furnace workers had sig n ifican tly low er pulm onary fu n ctio n values and a g r e a te r prevalence of respiratory symptoms than workers in other jobs.
Exposure d a ta w ere not re p o rte d and control groups were not used in these studies  , severely limiting their usefulness. The authors did not reveal the source of d a ta on p re d ic te d pulm onary fu n ctio n values, so it is im possible to determine the relevance of these data to the worker population studied.
Only one study, a 1975 NIOSH health hazard evaluation by Hervin and Thoburn  , has been found on w orkers exposed to HDI.
These w o rk ers, 18 spray p a in te rs in an airplane repair facility, were exposed to HDI at up to 300 ug/cu m (40 ppb); th ey w ere also exposed to trim e r ic biuret compounds of HDI at up to 3,800 y g /c u m and to a v a rie ty of organic solvents at concentrations above the F ed eral stan d ard s.
P ulm onary fu n ctio n m e asu re m en ts in spray painters and the d e c re m e n ts in th e se m e a su re m e n ts over the workshift did not differ significantly from values in 40 controls who worked during shifts when spray painting was never perfo rm e d . All the spray p a in te rs , who wore re s p ira to rs but no eye protective devices, co m p lain ed of eye irritation while painting, and about half complained of nose and th r o a t ir r ita tio n , cough, and c h e st discomfort. The authors mentioned th a t the re s p ira to r program was deficient in many respects. This report suggests th a t MDI produces symptoms similar to those from TDI and MDI. However, it does not provide any in d ic a tio n of th e c o n c e n tra tio n s of HDI that produce irritation, since th e re was sim u ltan eo u s exposure to organic solvents and to trim eric HDI at relatively high concentrations. All th e diisocyanates that have been studied caused irritation when applied directly to th e skin of rabbits or instilled into their eyes. Their potentials as skin and eye irritants, determined from these studies, are summarized in Table XI M icroscopic ex am in atio n s of tissu e se c tio n s showed tracheitis and bronchitis with sloughing of the superficial epithelium in animals exposed to TDI at 2 ppm and killed by the 4th day a f te r exposure. Lungs of animals killed 7 or more days after exposure did not d i f f e r sig n ifican tly fro m th o se of c o n tro ls, su g g estin g th a t th e e f f e c ts w ere reversible. In animals exposed at 5 or 10 ppm, damage was more severe and longlasting. T h ere w ere a re a s of co ag u latio n necro sis of the superficial epithelium surrounded by in fla m m a to ry cells, and a t points of deep ulceration, connective tissue had developed.

# Animal Toxicity
B ronchopneum onia developed in all species except mice. Since th e an im als w ere exposed only once, th is lung dam age was the result of irritation rather than an allergic reaction.
In an o th er 1962 stu d y , H enschler et al  exposed rats and guinea pigs to TDI repeatedly at concentrations of 0.1-10 ppm (0.7-70 mg/cu m). In rats, three 4hour exposures a t 10 ppm were lethal for all animals; four exposures at 5 ppm or 10 exposures a t 1 ppm w ere le th a l for most rats. At 0.5 ppm, adult rats could w ith stan d 24 exposures, but this exposure regimen killed about half the young rats exposed.
Most d eath s w ere due to severe peribronchitis and bronchial pneumonia. In surviving an im als, lung ch ang es w ere rev ersib le within several months. Rats e x p o s e d at 0.1 ppm fo r 40 exp o su res had no ch an g es in th e lungs th a t w ere attributable to TDI exposure, but they did gain less weight than controls. In guinea pigs, th e se au th o rs w ere unable to find any evidence of sensitization to TDI after 48 exposures at 0.5 ppm, which was lethal to most of the animals.
These results were qualitatively similar to those reported by Zapp  5 years e a rlie r, but H enschler e t al In 1965, Niew enhuis et al  described the effects on animals of repeated exposure to TDI a t a low c o n c e n tra tio n . They exposed rats, rabbits, and guinea pigs to TDI a t 0.1 ppm (0.7 mg/cu m), 6 hours/day for either 38 consecutive days or 5 day s/w eek fo r 58 exposures. Chamber concentrations were measured by the Marcali method.
Lung d am age in these animals generally increased in severity for several days a f te r exposure ended  .
A rabbit examined immediately after exposure had e sse n tia lly norm al lungs, but animals killed 3-10 days later had bronchopneumonia, bronchitis, perivasculitis, and lung abscesses. A rabbit killed after 20 days had only chronic bronchitis. R ats killed immediately had less inflammation than those killed la te r , but fibrous tissue had proliferated in the walls of the bronchioles in several ra ts .
At 3-24 days a f te r ex p o su re, in flam m atio n was marked, and animals had bronchopneumonia, extensive fibrous tissue proliferation, and polypoid hyperplasia of th e ep ith eliu m . All control rats had bronchiectasis, which the authors attributed to chronic m urine pneum onia.
In guinea pigs, there were localized accumulations of lym phocy tes, m acro p h ag es, and p lasm a cells th ro u g h o u t th e lungs and varying degrees of pneumonitis and bronchopneumonia. No abnormalities of the heart, liver, kidneys, lymph nodes, or spleen were found in any of the animals. R a ts exposed a t th e h ig h est c o n c e n tra tio n gained sig n ifican tly less w eight th an th o se a t the lo w est c o n c e n tra tio n (P<0.05). No sig n ifican t d iffe re n c e s b e tw e e n exposure groups were found in blood composition, liver fu n ctio n , urin aly sis, or kidney fu n ctio n , and no dam age to any organ was observed in m a cro sc o p ic exam inations. However, there was an increased lung-tobody w eig h t ra tio in the high-exposure group. Animals exposed at 1,370 ug/cu m had sig n ifican tly low er liver and spleen weights than those exposed at 250 ug/cu m. The author did not suggest an interpretation of these differences. R esu lts of th e ir 2-hour LC50 studies in mice showed th a t HDI w as 2.3 times as toxic as CHI. The threshold concentration for influence on th e CNS in m ice was 1 mg/cu m for HDI and 10 mg/cu m for CHI, although the th resh o ld c o n c e n tra tio n s for respiratory irritation were sim ilar~2.9 mg/cu m for HDI and 4.5 mg/cu m for CHI. Exposure to CHI caused only a nonsignificant decrease in weight gain.
A ccording to th e au th o rs  , adding chlorine to the molecule of an organic com pound would be e x p e c te d to in c re a se th e toxicity of the compound. Yet the resu lts of this series of experiments showed that HDI was substantially more toxic th an CHI. The f a c t th a t th e le th a lity of HDI was dose dependent may indicate th a t the com pound is abso rb ed sy ste m ic a lly , while the effects of CHI appear to result only from local irritation of the respiratory tract. Kondratyev and Mustayev  dem onstrated skin sensitizing effects of HDI in experim ental animals in 1974. Guinea pigs were sensitized by application of HDI in 50% solution in acetone to the skin for 2 days in a row. An initial irritant effect in th e fo rm o f h y p erem ia, ed em a, and itch in g was o b serv ed a t th e s ite s of ap p licatio n . A fter 21 days, the degree of sensitization was determined by applying HDI in various c o n c e n tra tio n s to previously unexposed skin. A specific allergic re a c tio n was seen in most animals at concentrations as much as 40 times less than th e p re v io u s ly d e t e r m in e d th r e s h o l d dose of 50% fo r skin ir r ita tio n .
The ep icu tan e o u s sensitization observed was also accompanied by changes in the bloodserum p ro tein fra c tio n s . This study su g g ests that skin contact with HDI in the workplace could lead to allergic derm atitis.
Kimmerle  found that IPDI produced moderate skin sensitization in guinea pigs. His e x p e rim e n ta l m eth o d s w ere not described but were said to follow the r e c o m m e n d a tio n s of th e Food and D rug A d m in istratio n .
IPDI, a d m in iste re d in tra d e rm a lly , produced a larger area of swelling on reinjection than it had in an earlier injection in all 15 guinea pigs tested.
A nim al e x p e rim e n ta tio n has been used in sev eral studies to investigate the m echanism of sensitization to diisocyanates. In 1964, Scheel et al  investigated the immunologic aspects of TDI sensitization. The authors produced TDI antigens by conjugatin g TDI with egg albumin; they attem pted to characterize the antigen, and th e ir m ethod of p re p a ra tio n , w ith m o d ificatio n s, became the standard for many subsequent immunologic studies on TDI. TDI-specific antibodies were demonstrated in ra b b its exposed to TDI by inhalation at 100 ppb (700 Ug/cu m) 6 days/week for 2-4 weeks. When a purified protein derivative of the tubercule bacillus was injected during TDI inhalation, a skin sensitivity response to TDI could also be demonstrated; a n im a ls so t r e a t e d r e a c t e d to 0.001 mg of TDI ap p lied to th e skin, while u n sen sitized anim als r e a c te d only to 0.2 mg. When the proportion of TDI in the an tig en was increased, the antigenicity of the protein was masked so that it would not re a c t w ith an tib o d ies to egg albumin. This dem onstrated that the circulating antibodies contained a reacting group specific for the TDI hapten.
Thom pson and Scheel , in 1968, investigated the effects of TDI on rats p re tre a te d with alloxan to suppress anaphylaxis or with insulin and pertussis vaccine to enhance the responses. R ats were exposed to TDI at 1 ppm (7 mg/cu m) for 10 hours. A lthough th e au th o rs found th a t pretreatm ent altered the effects of TDI e x p o s u r e on th e lu n g s in th e p r e d ic te d d ire c tio n , th ey concluded th a t the m echanism of lung damage was not immunologic. This interpretation was based on th e ir in ab ility to e lic it a re a c tio n to cutaneous or intravenous challenge and the f a c t th a t reex p o su re to TDI produced less response than the original exposure. In a d d itio n , m icro sco p ic findings in d ic a te d th a t th e lung e f f e c ts p roduced w ere co n siste n t with chemical damage rather than an immunologic process and that they occurred primarily in the first few days after exposure.
In 1970, S tevens and P alm er  stu d ie d sensitization in guinea pigs and rhesus m onkeys exposed to TDI a t 0.01-5 ppm fo r th re e 6-hour periods. Three w eeks la te r, th e se an im als and previously unexposed animals were exposed to TDI a t 20 ppb (140 u g /c u m). B reath in g p a tte rn s of the animals were measured by plethysmography to detect changes indicative of respiratory sensitivity. P a tc h te s ts showed skin se n s itiz a tio n to TDI, but serolog ic te s ts for sensitization were negative. Guinea pigs preexposed to TDI at 0.5 ppm did not show m easurable respiratory changes, suggesting that a threshold for se n s itiz a tio n e x iste d b e tw e e n 0.5 and 2.0 ppm.
T h ere was no evidence of se n sitiz a tio n in m onkeys a f te r reex p o su re, and th e re were no serologic changes in d icativ e of sen sitizatio n . The authors concluded that exposure to large amounts of TDI may produce se n s itiv ity to TDI in low er c o n c e n tra tio n s , b ut th a t this sen sitiv ity m ight not involve an allergic mechanism. However, they noted that the d iffic u lty in preparing a suitable antigenic system made it impossible to determine whether an immunologic mechanism was involved.
K arol e t al , in 1978, were able to dem onstrate the production of serum an tib o d ies sp e c ific for the tolyl portion of an isocyanate molecule. They exposed guinea pigs by in h a latio n to a conjugate of the monofunctional p-tolyl isocyanate w ith egg album in (EA). This antigen induced a respiratory response in the animals beginning ab o u t th e 8th day of exposure, and serum antibodies were detectable by gel diffusion and im m u n o electro p h o resis by the 14th day. The authors concluded th a t the antibodies were hapten-specific, since p-tolyl isocyanate that was bound to an o th e r p ro tein c a r r ie r , such as bovine serum albumin, elicited both respiratory re a c tio n s and serum an tib o d y resp o n ses in anim als previously sensitized to the iso cy an a te-E A a n tig e n . In addition, sensitivity to the EA carrier in the conjugate was not produced, suggesting to the authors that the conjugate contained sufficient iso cy an a te m o lecu les to e ffe c tiv e ly shield an tig en ic determinants in the protein m olecule. In a subsequent study, which has been described in Effects on Humans, K arol and her co lleag u es  used this antigen to dem onstrate IgE antibodies in the sera of workers who had sensitivity reactions to TDI. . The compounds were tested on Salmonella typhimurium s tra in s TA1535, TA1537, TA1538, TA98, and TA100, with and without a mammalian liver microsome activating system. MDI was mutagenic in strains TA98 and TA100 in th e p resen ce of the liver activating system. The other diisocyanates tested did n o t show m u t a g e n ic a c t i v i t y .
D e t a i l s of th e e x p e rim e n ta l p ro c e d u re and quantitative results were not provided.

# Correlation of Exposure and Effect
In th e e arly days of the industry, a large proportion of the workforce exposed to TDI dev elo p ed re s p ira to ry illn esses The adv erse e f f e c ts of TDI on th e lungs may re s u lt from direct irritation caused by exposure a t relatively high concentrations. An experiment on volunteers  showed th a t one of six subjects experienced irritation of the nose and throat during a 10-m inute exposure at 710 yg/cu m and that all experienced it at 3,600 y g /c u m; however, these subjects did not report chest symptoms. In an automobile p lan t, all 12 w orkers exposed to TDI developed severe respiratory symptoms when TDI c o n c e n tra tio n s w ere 30-70 ppb (210-500 y g /c u m)  . Their symptoms disappeared when concentrations remained below 30 ppb.
A cute and ch ro n ic re s p ira to ry e f f e c ts caused by exposure to TDI have been re p o rte d , but the results of such studies have been inconsistent. Results appear to d iffe r su b sta n tia lly depending on th e ty p e of operation or process in which TDI exposure o ccu rs. In a spraying operation, where TDI concentrations reached 6,400 y g /c u m, G andevia  found a significant decrease in FEV 1 during the course of a w orkday in 20 exposed men. This decrease was not fully reversed overnight or on the weekend and the cumulative decrease over 3 weeks was also significant.
In a TDI distilling operation where concentrations were generally less than 140 y g /c u m, Williamson Ll7] found no significant changes, compared with preexposure baseline values, in th e pulm onary fu n ctio n of 21 men over 14 months. He also reported little difference between Monday and Friday values.
In an o th er ty p e of exposure situation, a polyurethane foam plant, Peters et al  found sig n ific a n t daily, w eekly, and cumulative decreases over a 2-year period in workers exposed at concentrations below about 100 yg/cu m. This study did not include preexposure measurements, but the mean annual decrem ent in FEV 1 of 0.11 lite r /y e a r was con sid erab ly higher than those the authors found in the lite r a tu r e for norm al working and general populations, which ranged from 0.025 to 0.047 lite r /y e a r . A long-term study of workers in a TDI-manufacturing plant, conducted by Weill e t al  and B utcher e t al , showed no significant exposurere la te d changes in lung function. TDI concentrations in the plant generally ranged from 14 to 50 u g /c u m during th e 5.5-year study. The entire study population, which included controls from elsewhere in the chemical factory not exposed to TDI, had ex cessiv e d eclines in som e pulm onary function measurements compared with p re d ic te d values, but th e re w as no d iffe re n c e b e tw e e n groups w ith c o n s ta n t, in te r m itte n t, and no exposure, and decreases were not correlated with cumulative exposures. These findings are questionable on the basis that the control group may h a v e b e e n so a f f e c t e d by e x p o s u re to o th e r ch em ica ls th a t th e study was insensitive to possible effects of TDI exposure.
The d isa g re e m e n t of th e se findings with those obtained in polyurethane foam plants  may also r e f le c t d iffe re n c e s in exposure to other chemicals and fa ilu re to detect occasional excursions to much higher exposure concentrations than those usually prevailing. Both TDI manufacturing and polyurethane foam production involve mixed exposures, but in the latter process, exposures to other chemicals are likely to be much m ore closely c o rre la te d w ith exp o su res to TDI. Thus, the ap p a re n t dose-response relationship to TDI exposure in the polyurethane foam plant A t t e m p t s to d e te rm in e th e c o n c e n tra tio n s of TDI n ece ssary to produce sensitization have not been fruitful. Porter et al  reported that there were no new c a s e s o f s e n s i t i z a t i o n in a TDI p la n t in 2 y e a r s w h en a v e ra g e TDI concentrations were below 140 y g/cu m; during the previous 16 years of operation, when TDI concentrations had averaged 350-420 yg/cu m, from one to four cases of s e n s itiz a tio n had been diagnosed each year, the number gradually decreasing with increasin g len g th of o p e ra tio n .
Superficially, these data suggest an average TDI exposure, 140 y g /c u m, below which s e n s itiz a tio n does not o ccu r.
However, ex am in atio n of the data reveals that, even during the years when the average TDI c o n c e n tra tio n rem ain ed constant at 420 yg/cu m (1956-1969), there was a general decline in the number of cases of sensitization, suggesting that potentially sensitive individuals may have b ecom e sensitized and left the workforce during their early years of em p lo y m en t.
Thus, th e se findings do not rule out the possibility that s e n s itiz a tio n might develop in newly hired workers exposed at less than 140 yg/cu m for longer periods of time.

# S everal au th o rs have noted that workers often become sensitized during brief e x p o s u r e s a t h ig h c o n c e n t r a t i o n s r e s u l t i n g from spills, leaks, or spraying
H ow ever, sensitivity to TDI has been observed in workers with no known exposure to spills or sp raying operations . A NIOSH health hazard survey of a plant making polyurethane foam found respiratory symptoms in workers a t a foam ing o p e ra tio n w here no TDI c o n c e n tra tio n s of more than 35 yg/cu m w ere m easu red  , H ow ever, 9 of 13 workers who had been transferred away from th e foam ing operation because of severe symptoms were known to have been exposed previously to spills of TDI. In another NIOSH survey, none of the nine em ployees of a p o ly u reth an e foam p lan t where TDI concentrations averaged less than 7 y g /c u m and did not exceed 16 yg/cu m had respiratory symptoms , indicating that sensitization may be rare or nonexistent at such low concentrations. O th er stu d ie s sug g est th a t th e rate of sensitization may be som ew hat higher. F our of 47 workers (9%) in an office that received exhaust air fro m a nearby TDI p lan t b eca m e se n sitiz e d ; in 3 of th e se , se n s itiz a tio n was co n firm ed by bronchial responses in challenge tests, and the 4th improved when he was rem oved from exposure . Porter et al  reported that 30 of the 300 w orkers (10%) in a TDI plant were diagnosed as sensitive to TDI during 17 years of o p eratio n .
Adams  found that 15% of the workforce in one plant left during th e ir 1st y ear of em p lo y m en t because of effects on their health; 1-3.5% left for th e same reason during subsequent years, for a total of about 20%. A similar rate was suggested in a study by Bruckner et al , in which 5 of 26 workers exposed to u n sp ecified iso c y a n a te s w ere considered sensitized because they had asthm atic reactions at low concentrations. Some re p o rts have suggested that sensitization to TDI is related to a personal history of allerg y  or to atopy, as indicated by reactivity to prick tests with com m on in h a lan t allergens . However, most investigators report that there is no pattern of allergies or atopy in sensitized workers .
Several investigators have attem pted to dem onstrate an immunologic mechanism for TDI sensitivity. In 1964, Scheel e t al  dem onstrated circulating antibodies and positiv e skin reactions in guinea pigs sensitized to TDI by inhalation, but later w orkers w ere unable to co n firm th e se re su lts in guinea pigs, rats, and monkeys .
In hum ans, im m unologic te stin g has indicated the existence of both re a g in -ty p e an tib o d ies and c irc u la tin g IgG antibodies in some workers exposed to TDI  .
H ow ever, th e se te s t resu lts have generally correlated poorly with sym ptom s su g g estiv e of TDI sensitivity or with respiratory responses to challenges w ith TDI at low concentrations. Since the TDI molecule has been thought to be too sm all to be a n tig e n ic in itself, a central problem in immunologic testing has been th e d evelo p m en t of an appropriate test antigen (a conjugate of TDI with a carrier p ro tein ).
A re c e n t study by K arol e t al  , using a te s t antigen of p-tolyl (m ono)isocyanate, dem onstrated the presence of tolyl-specific antibodies in the sera of th re e of four TDI w orkers who had se n sitiv ity re a c tio n s to TDI; the fourth w orker had not been exposed to TDI for 5 y ears.
This study show ed that an immunologic mechanism may be involved in TDI sensitization.
S tu d ie s by B u tch er e t al  and Van E rt and B a ttig e lli  have suggested that a pharmacologic mechanism is also involved in respiratory sensitivity to TDI. These investigators showed that TDI inhibited the isoproterenol-stimulated cy clic AMP levels in human lymphocytes. The effect was greater in lymphocytes from individuals who w ere se n sitiv e to TDI F ar less in fo rm a tio n e x ists on exposure to the other diisocyanates, but their e f f e c ts ap p ear to be generally similar to those of TDI. Thirty-four of 35 workers, only 6 of whom w ere exposed to MDI a t c o n c e n tra tio n s above 150 U g/cu m, experienced irritation of the eyes, nose, and throat, and half of them had bronchial sym ptom s  .
W orkers ex posed to MDI a t 50-110 y g /c u m did not have a s ig n ific a n t decrease in FEV 1 during a workshift in which foaming was carried out, but 3 of 29 w orkers had respiratory symptoms . Workers exposed to MDI at unknown concentrations in an Italian refrigerator factory had reduced vital capacity and FEV 1, and 85 of 180 workers had respiratory symptoms . This study in d icate d th a t the e f f e c ts w ere d o s e -re la te d , since fu rn a c e workers, who were exposed to MDI a t th e h ig h est co n ce n tratio n s, had significantly lower pulmonary fu n ctio n values and a g r e a te r p rev alen ce of resp irato ry symptoms than workers elsew h ere in the plant. The incidence of respiratory symptoms also increased with years of employment at the plant. These au th o rs co n sid ered im m unologic cross se n sitiv ity unlikely because of the differences in structure between the compounds. The subjects who cross-reacted to other diisocyanates tended to react to extremely low c o n c e n tra tio n s of TDI (less than 1 ppb) and to be hyperreactive to histamine. The auth o rs suggested that extrem e sensitivity to TDI might be the result of both an immunologic mechanism and a nonspecific pharmacologic or irritative mechanism, w ith th e la tte r m echanism acc o u n tin g for th e cro ss-re actio n s to MDI and HDI. This is co m p atib le w ith th e reports of Butcher et al  th at TDI may block the b e ta-ad ren erg ic system and with the suggestive evidence obtained by Porter et al  th a t TDI sensitivity does not necessarily require the presence of anti-TDI an tib o d ies.
H ow ever, th e p o ssib ility of im m unologic c ro ss-se n sitiv ity between diisocyanates remains to be tested with a specific antigen system like that of Karol et al  and is at present only speculative. In th e ab sen ce of other data on mutagenicity, this single study is insufficient evidence that diisocyanates are likely to be mutagenic in humans.   During the startup procedures, the mean weekly TDI concentrations for the synthesis, finishing, and drummming areas were 5.6, 17. Both monitoring methods were used simultaneously during some period eac h day for 22 m onths.
When 8-hour TWA values w ere analyzed, no positive c o rre la tio n could be found between personal and area sampling. Area monitoring, then, did not seem to accurately reflect actual individual exposures.
H ervin and Thoburn  reported that concentrations of airborne TDI were below the TLV of 20 ppb (140 ug/cu m) in an aircraft overhauling facility where th e p a in te rs sprayed aircraft with polyurethane paints. Area and personal samples w ere analy zed by th e th in -la y e r ch ro m ato g rap h ic method of Keller et al . The c o n c e n tra tio n s of airb o rn e TDI n ear th e aircraft fin, near the wing, on the floor w here mixing was done, and on the floor midway between the two bays were <30, <20-30, 20, and <20 U g/cu m (<4, <3-4, 3, and <3 ppb), respectively. The corresponding concentrations of HDI were 40-100, <30-60, <20-300, and <20 Ug/cu m (6 -1 5 , <4-9, <3-45, and <3 ppb). T h irteen p ersonal sam p les ta k e n a t various o p eratio n s c o n tain ed TDI at concentrations of 40 ug/cu m or less. Corresponding HDI concentrations ranged from less than 30 to 300 Ug/cu m.
In an o p eratio n w here polyurethane foam lines were used to make automobile s e a t cusions, B utler and Taylor F itz p a tric k e t al  stated that most of the MDI detected in the air was c a rrie d by this particulate m atter in the reactive form. The reaction of MDI with o th er com ponents of th e foam w as co m p lete w ithin about a minute, or 60 feet downstream from the spraying operation.
Dharmarajan and Weill  found that approximately 90% of the MDI present in air during a foam spray operation was blocked by passage through glass fiber or Teflon filters (0.5 pm pore diameter). The percentage blocked was independent of MDI c o n c e n tra tio n in th e ran g e 20-550 p g /c u m, a finding th a t su p p o rts the c o n te n tio n th a t m ost airb o rn e MDI is present in particulate form. Furtherm ore, they found th a t a p p ro x im ate ly 50% of th e p a rtic le s w ere less th an 10 pm in d i a m e t e r .
A ssuming th a t all MDI in th e air is in th e form of aero so ls and assum ing an equal collection efficiency for simultaneous sampling of particulates on a f ilte r and MDI in an a b so rb er, th e au th o rs found th a t MDI constituted 3.03-20.34% of the mass of the airborne dust collected on a filter. No m e a su re a b le MDI co n ce n tratio n s were found in 10 s a m p le s from th e mixing o p e ra tio n and 12 from th e m olding o p e ra tio n ; both o p eratio n s are co n d u cted a t room tem perature. Ten samples from the torching or oven-drying operation also showed no MDI, and 17 mold-pouring samples showed less than 7 ppb (70 y g /c u m); these operations involve elevated tem peratures, and the author attributed the low concentrations to the brevity of the operations, which did not p erm it sig n ific a n t vapor concentrations to be generated. The primary objective of engineering controls for operations using diisocyanates m ust be to reduce the concentrations of airborne diisocyanates so that they are at or below th e reco m m en d ed en v iro n m en ta l lim its.
P ro cess equipment should be designed so th a t the sy stem is to ta lly en closed and operates, if possible, under n eg ativ e gage pressure  . When it is necessary to open a vessel or when leaks or spills are likely, local ex h au st v e n tila tio n systems should be provided. Unless o th er m eans can be used to control the concentrations of diisocyanates, the source should be f itte d w ith a local exhaust ventilation system  . If a process is too large for this type of enclosure, dilution ventilation may be necessary. N um erous polyurethane products exist, and the polyurethane may sometimes be form ed under circum stances that are not readily adaptable to conventional exhaust v en tila tio n p ro ced u res, eg, a p p lic a tio n of polyurethane foam to storage tanks to p rev en t co rrosion. Some operations, such as spraying, mixing, foaming, injecting, flushing, pouring in p lace, and painting, can occur either in fixed locations or in the field.
W orkers engaged in these operations may require additional protection, such as p o sitiv e p ressu re su p p lied -air re sp ira to rs  and additional protective clothing. Although many types of diisocyanates are used in urethane foam systems, many of th e se system s co n ta in po ly m eric iso cy an ates, which usually have lower  1 8 ] and Industrial Ventilation-Manual of Recommended P ractice, the 1976 edition  or a later edition.
The co n ce n tratio n of diisocyanates in the workplace may also be decreased by s u b s t i t u t i n g a co m p o u n d w ith a low er vapor p ressu re.
For ex am p le, w here fo rm u latio n c o n sid e ra tio n s p e rm it, MDI m ight be substituted for TDI . In spraying and certain foaming operations where the diisocyanate is present in aerosol form, this substitution may not be an effective means of controlling exposure.
When v e n tila tio n requirements for any diisocyanate work area are determined, and it is established that an exhaust ventilation system is necessary, care must be ta k en in the p la c e m e n t of in ta k e and ex h au st vents . Carroll et al  described re s p ira to ry sensitization from TDI in office workers as a result of TDIcontarninated air being drawn into the ventilation system of an office building from th e exhau st v ents of a neighboring factory using TDI. This report emphasizes the im p o rtan ce of d eterm in in g that intake air for the ventilation system is not drawn from a re a s in w hich o th e r d iiso c y an ate s are handled, and that exhaust vents be positioned to avoid exposure of other persons to the diisocyanate-contam inated air. For less chemically reactive diisocyanates such as HDI , hydrolysis would be e x p e c te d to occur at considerably slower rates. The authors  concluded th a t increased humidity reduces the concentration of atmospheric TDI, but n ot to a d eg ree that would prove useful as a routine control measure in the workplace. A decrease in apparent TDI concentrations due to humidity has also been observed by other investigators .

# Sampling and Analysis
V olatilized amines may also be presented in workroom air where diisocyanates are being manufactured or used. Toluene diamine, a synthetic precursor to TDI and a possible hydrolysis p ro d u c t, is known to in te r f e r e p o sitiv ely in th e M arcali d e te rm in a tio n of TDI . O th er prim ary arom atic amines would be e x p ec ted to be p o sitiv e interferences with any method in which diisocyanates are determined as secondary reaction products of their amine derivatives.
Meddle and Wood  developed a method for detecting arom atic isocyanates in air in th e p resen ce of p rim ary a ro m a tic amines. Individual air samples were bubbled through two different absorber solutions. A solution of dimethylformamide (DMF) and 1,6 -d iam in o h ex an e (DH) was used to trap the primary arom atic amine and inactivate the isocyanate in one air sample. The second air sample was drawn through a solution of DMF, DH, and hy d ro ch lo ric acid th a t tra p s th e primary a ro m a tic am ine and hydrolyzes th e iso cy an a te to its corresponding amine. The sam ples w ere th en diazotized and coupled, and the amount of amine or isocyanate p resen t was d e te rm in e d sp ectro p h o to m etrically using standard calibration curves. The color in th e DMF-DH ab so rb en t solution is produced by the primary amine alone, and th a t in the DMF-DH-hydrochloric acid absorbent solution is produced by both the am ine and th e isocyanate. The amount of isocyanate present in the air sampled was determined by subtracting the former value from the latter.
T e rtia ry am ines, such as triethylenediam ine (TEDA), which are often used as c a ta ly s ts in u re th a n e p o ly m eriza tio n s, have been shown to reduce the apparent c o n c e n tra tio n of a irb o rn e TDI . Smith and Henderson  were the firs t to re p o rt the n eg a tiv e interference of TEDA vapors in the determination of gaseous TDI by the Marcali and Reilly tape methods. The fraction of apparent TDI loss, when an aly zed by both m ethods, ranged from 49 to 88%. These results led th e au th o rs to question whether the tape and Marcali values were underestimating actual TDI exposure levels in polyurethane foaming operations. The reported degree of negative interference, however, appears independent of the TEDA concentrations. In additio n , th e ra tio s of TEDA to TDI exam ined, 17-262 , are 135-2,100 tim es th o se th a t m ight be e x p e c te d during actual foaming or spraying operations .
In a la te r a tte m p t to elucidate the mechanism of tertiary amine interference, Holland and Rooney  compared values obtained for TDI in mixed TDI-TEDA a tm o sp h eres by th re e analytical techniques: midget impinger sampling and analysis by th e M arcali m ethod, co n tin u o u s-ta p e m onotoring, and direct air-injection gas chromatography.
All m ethods gave similar values for TDI, and each showed similarly decreased v a lu e s fo r th e sam e TDI c o n c e n tra tio n in th e p resen ce of TEDA  .
In c o n tra s t to th e previous report , this study dem onstrated that the reduction in m easu rab le TDI exhibited some dependence on atmospheric amine concentration. A sum m ary of the data shows that, at TEDA-to-TDI ratios of 9.6-25, about 90% of the input TDI could be m easu red ; a t a TED A -to-TD I ratio of 105, only 21-25% could be m easu red .
Six o th e r catalysts used in polyurethane manufacturing were s a id to g iv e s im ila r r e s u l t s .
The e f f e c t of TEDA on m e asu ra b le TDI was significantly red u ced w hen glass co m p o n en ts of th e experimental apparatus were siliconized to d e c re a se su rfa c e ad so rp tio n .
The a u th o rs co m m en te d th a t gas ch ro m ato g rap h y did not detect any stable reaction interm ediates, including toluene diam ine, in th e m ixed gas stream . The only reaction product found proved to be the TDI u rea th a t had fo rm ed as a w hite pow der on the surface of the mixing sy stem . The au th o rs  concluded th a t all th re e a n a ly tic a l m ethods gave a c c u ra te m e asu re m en ts of atmospheric TDI in the presence or absence of tertiary am ine c a ta ly s ts and th a t th e o b serv ed n eg ativ e interference reflected an actual reduction in TDI concentration. Furtherm ore, the mechanism by which this reduction o ccu rred may have depended on surface effects, relative humidity, and constituent concentration and residence time.
The above re p o rts  su g g est th a t th e p re se n c e of te rtia ry amine vapors may c a ta ly z e th e hydrolysis of airb o rn e TDI to its urea. The reaction ap p ears to be f a c ilita te d by ab so rp tio n of one or m ore of th e re a c ta n ts to a su rfa c e  .
W hereas gas chromatography of the mixed gases failed to isolate any stab le re a c tio n in te rm e d ia te , th e e x iste n c e of short-lived, potentially toxic, r e a c t i v e c o m p le x e s in m in u te am ounts can n o t be d isco u n ted .
Both stu d ies  used concentrations of TDI that may be representative of actual working environm ents, 18-400 ppm; however, since the relative concentrations of amine used far ex ce ed ed re a lis tic le v els, th e re le v a n c e of th e se re s u lts to th e workplace situation remains questionable. The amine is diazotized and coupled with 1-naphthyl eth y len ed iam in e to produce a red d ish -b lu e color.
The intensity of this color is m easured spectrophotom etrically at 550 nm to provide an indication of the amount of TDI present. Marcali  reported that the method was capable of detecting 10 ppb (70 yg/cu m) of toluene-2,4-diisocyanate. He also determined that recovery of total TDI was apparently reduced when 35% toluene-2,6-diisocyanate was present. A similar reduction was reported by Meddle et al  for TDI mixtures containing 20 or 40% of th e 2,6-isom er. To increase the accuracy of measuring mixtures of TDI is o m e r s , both M arcali  and M eddle e t al  reco m m en d ed th a t standard curves be constructed with the appropriate isomer ratios. A portable field kit em ploying stab le color standards could easily detect TDI at 50 ppb (360 yg/cu m) and could be modified to detect TDI at 20 ppb (140 y g/cu m). The method does not d e te c t the TDI u re a , 3 ,3 '-d iiso cy an ato -4 ,4 '-d im eth y lcarb an ilid e, a hydrolysis product that is formed on reaction of TDI with water. The Ranta method, as described by Zapp  and Marcali  can measure both TDI and TDI urea with equal efficiency and cannot distinguish between them. The com pounds are collected by bubbling the air sample through a reagent solution of aqueous sodium n itr ite , ethylene glycol monoethyl ether (Cellosolve), and boric acid.
The in te n sity of th e resulting orange-yellow color, measured at 450 nm, is proportional to the concentration of either compound.
On th e basis of field and la b o ra to ry ev alu atio n s of th e se tw o m ethods, Skonieczny  concluded th a t the Marcali method was more suitable for field d e te rm in a tio n of peak c o n c e n tra tio n s and for d e te c tin g sm all amounts of TDI.
Because th e R a n ta m ethod req u ire s a sampling tim e of 10-30 minutes to collect su ffic ie n t am ounts of TDI under usual working conditions, Skonieczny noted that it might not detect momentarily high concentrations.
In The sensitivity of the method was said to be improved by in creasin g the length of the light path in the spectrophotom etric cells. If amounts of TDI g re a te r th an 70 ppb m ust be measured, the final reagent solution can be d iluted with absorber solution or a smaller air sample can be taken. Although MDI is detected by this method, the time required for complete color development under th e prescribed conditions is 1-2 hours, compared with 5 minutes for TDI . It is possible th a t TDI can be determined in the presence of MDI if the absorbance of the test solution is measured within 10 minutes after adding the coupling agent.
Various field te s t kits using th e p rin cip les of the Marcali or Ranta method have been developed.
These kits have simplified and standardized test procedures fo r o n -s ite m e a s u r e m e n t .
G rim an d Linch  d escrib ed a field kit for d eterm in in g c o n c e n tra tio n s of TDI. Air was sampled through the standard midget im pinger using a self-p o w ered , constant-rate air aspirator. The sensitivity of the field kit employing the Marcali method was improved to allow detection of TDI at 10 ppb (70 Ug/cu m) by co lle c tin g a la rg e r volum e of air and by reducing the volum e of th e reagent used. By increasing the coupling reagent concentration and adding sodium c a rb o n a te to the absorbing medium, the field kit could be used for d e t e r m i n a t i o n s o f a i r b o r n e MDI. The R a n ta m eth o d w as m odified to allow m easurem ent of TDI urea and TDI at concentrations as low as 10 ppb by increasing th e v o lu m e o f s a m p le c o lle c te d , reducing the volum e of re a g e n t used, and in creasin g th e le n g th of th e lig h t path in the colorimeter to 100 mm. To make the R a n ta m ethod su ita b le for field use, color standards that can be used with a portable visual com parator were developed and included in the kit.
Belisle  described a field kit suitable for measuring TDI in air. Air was sampled at a rate of 0.1 cu ft/m inute through an acidified absorber solution in a m odified m id g et im pinger co n tain in g in situ-generated glutaconic aldehyde and cation-exchange resin. This process converts TDI to its corresponding amine, which re a c ts w ith g lu ta c o n ic ald eh y d e to form an orange-red product. To measure the c o n c e n tra tio n of TDI, th e o ra n g e -re d color th a t appeared on the surface of the resin beads was m a tc h e d a g ain st a set of color s ta n d a rd s.
R esults reportedly ag reed closely w ith those obtained by the Marcali method. A major advantage of this m ethod is th a t th e color develops while th e air is being sam pled.
At a c o n c e n tr a ti o n of 10 ppb (70 U g/cu m) of TDI, sam pling and analysis can be c o m p lete d in 5 m in u tes.
The m ethod is capable of measuring TDI at 5 ppb (35 U g/cu m) in 0.5 cubic fo o t of air, and it may be m o d ified to m easu re other a ro m a tic iso c y a n a te s or a ro m a tic am in es by constructing appropriate calibration data.
Reilly  developed a field method for determining MDI in air. The sample was draw n th ro u g h an acid ab so rb er m edium in w hich MDI w as c o lle c te d and hydrolyzed to the corresponding amine. The amine was diazotized and coupled with 3 -h y d ro x y -2 -n ap h th an ilid e to form a pin k ish -o ran g e azo com pound.
This was e x tra c te d into ch lo ro fo rm and co m p ared visually w ith in o rg an ic color standard solutions. The method was capable of measuring MDI at 10-40 ppb (100-400 ug/cu m) w ith a 5 -lite r sam p le of air.
The eq u ip m en t req u ire d is p o rta b le , and a complete determination can be accomplished in 12-15 minutes.
M eddle e t al  ex te n d e d th e G rim and Linch a d a p ta tio n  of the M a rc a li m ethod to a g e n e ra l f ie ld -te s t p ro ced u re cap a b le of d e te c tin g o th e r aro m atic diisocyanates in air. Procedures were described that established maximum sampling and analytical conditions for TDI, MDI, NDI, dianisidine disocyanate, and a polym eric form of MDI, polym ethylene polyphenyl isocyanate. The authors noted th a t, w ith the ex ce p tio n of TDI, attem pts to generate dynamic vapor atmospheres by bubbling dry n itro g en th ro u g h liq u ified d iiso c y an ate s proved u n su ccessful. A irborne co n cen tratio n s produced by this method diminished rapidly indicating that th ese d iiso c y an ate s, w here p re se n t in air, would be in aero so l fo rm .
Similar o b serv atio n s w ere m ade by R eilly  in his work with MDI. Analysis of all te s te d d iiso c y an ate s was subsequently performed on generated aerosol atmospheres  .
A co n seq u en ce of th e aero so l n a tu re of these test atmospheres was the a d o p tio n of a s in te r e d dom e bubbler for air sam pling. To en su re c o m p lete reco v ery , aero so l p a rtic le s tra p p e d in th e s in te re d dom e during sampling were allowed time to dissolve in the absorber solution before coupling reagent was added. A 10-m inute digestion time was judged sufficient under these conditions. Impinger sam pling a t th e sam e flo w ra te of 1 lite r /m in u te w as only 53% as efficient as sam pling w ith the s in te re d dom e bubbler. For use in the field, permanent color standards for MDI, NDI, TDI, and polymethylene polyphenyl isocyanate are available for concentrations of 10-40 ppb.
The aerosol nature of MDI in air was further supported by results of a recent study by D h arm arajan and Weill . They found that MDI vapor generated by heating th e d iiso c y an ate to 110 C in a small enclosed room did not behave as a gas but ra th e r as an aero so l.
They co m p ared th e am ount of MDI collected in absorbers acco rd in g to th e standard NIOSH-recommended method  with and w ithout p re filte rs and found th a t 98% of th e airb o rn e MDI was collected on a Teflon f ilte r backed w ith a cellu lo se pad and 87% was c o lle c te d on the filter backed w ith a sta in le ss-ste e l pad. Since the collection efficiency of the absorber for MDI aero so l was unknown in this study, it is likely that the actual amount of MDI in sam ples was higher th a n th e am ount d e te c te d .
The percentage of the sample consisting of MDI aerosol could also have been underestimated. The authors also poin ted o ut th a t since th e m ajor p o rtio n of MDI in air is p re se n t as an aerosol, concentrations of this compound should be reported in mg/cu m rather than ppm.
(c) Tape Methods R eilly  dev elo p ed a test-paper method to measure the concentration of TDI in air.
A 5 -lite r air sam p le was draw n through a chemically treated filter paper a t a r a te of 1 lite r /m in u te .
A fter sam pling was c o m p le te d , stain was allow ed to develop on th e t e s t paper for 15 minutes. The intensity of the stain was then com pared with a set of color standards for TDI concentrations of 10, 20, 40, 60, and 100 ppb (70-700 u g /c u m). The method is specific for the arom atic d iiso c y an ate s, w ith no response o b ta in ed from th e diam ine derivatives. Several p re p a ra tio n s of te s t p ap er, exposed to TDI a t known co n cen tratio n s, showed a v aria tio n in color d ev elo p m en t of ab o u t 20%. Qualitative tests indicate that the m ethod m ay be adap ted to detect MDI and NDI, and it is reported to require less analytical skill to perform than other methods. , th e au th o rs discovered that two midget impingers in series were necessary to tra p airb o rn e TDI adequately. Although the 1973 NIOSH criteria document  s ta te d th a t a "single bubbler absorbs 95% of the diisocyanate if the concentration is below 2 ppm," Miller and Mueller determined that, at TDI concentrations ranging from 1 to 76 ppb (7-532 y g /c u m), the collection efficiency of the first bubbler was approximately 83%.
The D unlap/IC I m o n ito r has also been used to measure MDI under laboratory  and field  conditions. Development of tape color intensity in response to MDI, e ith e r as a vapor generated in toluene solution  or when spotted in known concentrations directly on the tape , was approximately 75% of the m axim um when re a d a t 15 m in u tes and th e re a c tio n was complete in 4 hours. Maximum color development with TDI, on the other hand, is complete at 15 minutes.
W here MDI may be found as a c o n s titu e n t of a re a c tiv e p a r tic u la te , the a c c u r a c y of th e m o n ito r may be fu rth e r red u ced .
In an in itia l t e s t of the applicability of the Dunlap/ICI area monitor in MDI systems, results obtained by the m onitor in foam and p ain t spraying o p eratio n s w ere 36% and 35%, respectively A fte r applying th e m a n u fa c tu re r's recom m en d ed c o rre c tio n factor, the authors found that the values obtained by the ta p e m on ito r a t readings ranging from 1 to 5 ppb (10-50 yg/cu m) were in good agreem ent with those obtained by the spectrophotometric method. D h arm arajan and Weill  assessed the performance of the TDI continuous ta p e m on ito r for an aly zin g both h e a t-g e n e ra te d and foam -spray-generated MDI aerosols. Eight-hour TWA concentrations of MDI in ppb determined by the monitors w ere com p ared w ith th o se o b tain ed by the standard NIOSH-recommended method  .
In th e range of 5-8 ppb as d e te rm in e d by the NIOSH method, the tape m onitors c o n siste n tly gave read in g s indicating concentrations two to three times higher. The authors  explained this difference by pointing out that, whereas th e filte r ta p e medium of the monitors could be expected to collect 99.9% of the MDI aero so l, an im pinger flo w ra te of 1 liter/m inute would select against certain p a rtic le size populations. The ab so rb er co lle c tio n e ffic ie n c y , however, was not d eterm in e d in this study. H aving em p h asized th e necessity for expressing MDI concentrations in units of mg/cu m, the authors devised a procedure for calibrating th e TDI ta p e m o n ito r for use in MDI aero so ls. C olor in te n sity developed during th is tim e could be correlated with the known concentration of MDI in mg/cu m. However, the authors  did not test the validity of this calibration method in the workplace.
In view of these findings , it is important that calibration curves for continuous ta p e monitors used to detect MDI be constructed to simulate as closely as possible the actual conditions under which the monitor will be used.
The phenom enon described by a number of investigators , th a t MDI is ra re ly , if e v e r, found as a gas a t a m b ien t tem peratures, has been shown to apply to NDI and dianisidine diisocyanate  and can be considered a general p ro p erty of o th e r diisocyanates that are solids or viscous liquids at room tem perature. The sam pling r a te was lim ited to 1 liter/m inute because at higher sampling rates the toluene in the impinger would bubble over into th e next im pinger in the series and because excessive evaporation of toluene could occur. The authors suggested that 0.1 ml should be the maximum allowable volume for ev ap o ra tio n for one im pinger.
This r a te of evaporation would introduce an additional 1% error into the cumulative error for the resultant concentration. The to ta l co lle c tio n e ffic ie n c y of this system was 98%, with the first impinger being 90% efficient.
The a n a ly tic a l sy stem co n sisted of a B arb er-C o lm an S eries 5000 Selectra System gas chromatograph equipped with a tritium -source electron-capture detector  .
A 4 -fo o t P yrex U-tube column (1/4-inch inner diameter) was packed with C hrom osorb G (60/80 mesh) solid support coated with a mixture of Epon 1001 and A piezon L. O x y g en -free n itro g en was used as th e c a rr ie r gas a t an optimum flo w ra te of 100 ml/minute at an inlet pressure of 15 psig. Operating tem peratures w ere 150 C for the colum n and in je c tio n port and 170 C for the detector bath. The liquid sam ple size for in jectio n was 5 y l  .
Calibration curves were p rep ared by seq u en tially dilu tin g TDI with chromatographic-grade toluene . T he c a l i b r a t i o n c u r v e s w e re th en ch eck ed a g ain st a p rim ary sta n d a rd (TDI p erm e a tio n tube). This p aire d system of sampling and analysis could accurately analyze TDI in a 1 0 -liter sam p le of dry air at 1.4 ppb (10 yg/cu m). When the system was tested using air that had not been previously dried, readings were lower th a n e x p e c te d .
A fter a p p ro p ria te c o rre c tio n s w ere m ade for th e e f f e c ts of humidity , the authors  obtained an overall efficiency of 97%.
A th in -la y e r ch ro m a to g ra p h ic (TLC) m ethod was developed by Keller et al  for isolation and quantitative determination of various isocyanate compounds. The m ethod is based on th e re a c tio n of iso c y a n a te s w ith N-4-nitrobenzyl-N-npropylam ine (nitro reagent) to form the corresponding ureas. The concentration of the u reas are then determined. The method is said to be capable of isolating and m easuring diisocyanate monomers in the presence of partially polymerized reaction p roducts.
C oncentrations of both monomer and free isocyanate-containing polymer can be determined.
Air in th e w orking en v iro n m en t is sam pled with two impingers containing a solution of th e n itro re a g e n t  .
The solutions in th e im pingers are then com bined and e v a p o ra te d to dryness, and the rem ain in g resid u e is dissolved in benzene. The benzene solution is chromatographically analyzed on thin-layer silicagel p la te s, and ureas are visualized by reducing the nitro groups to amines and by diazotizing the amines with nitrous fumes. After evaporation of the nitrous fumes, the thin-layer chromatographic plates are sprayed with N-l-naphthyl ethylenediamine and qu an titativ e determinations are made by visual comparison of the samples with stan d ard s.
Scanning d e n s ito m e try can be used for more accurate determinations. The low er limit for the determinations was found to be 80 yg/cu m for MDI, HDI, and TDI. The method, however, is time consuming and requires skilled attention to detail during the reduction and coupling steps. C h ro m a to g rap h ic s e p a ra tio n of th e u reas was accomplished on a pellicular silica HPLC colum n.
As w ith the TLC m ethod  , both a lip h a tic and aro m a tic iso cy an a tes can be analyzed. The HPLC method, however, extended the detection lim its to 5, 5, and 10 y g of TDI, MDI, and HDI, respectively. The values were based on a 20-,liter air sample and a 90-y l injection volume. The method cannot be used to an aly ze a tm o sp h e re s that can oxidize or reduce the nitro reagent used in the impingers during sampling. The report  cited the following reasons for failure: deterioration of silica gel colum ns cau sed by excess nitro reagent in samples; oxidation of the n itro re a g e n t a f te r sam pling; shipping and exposure problems posed by the use of toluen e in th e c o lle c tio n m edium . The time allotted for the study precluded an attem pt to resolve these problems.
Two of these difficulties have already been addressed by previous investigators .
To elim inate excess nitro reagent in samples, Vogt et al  added p -toly l iso c y a n a te to th e absorbing solution after the collected diisocyanates were allow ed tim e (about 1 hour) to r e a c t.
The resu ltin g m onourea derivative was o b s e r v e d to ru n w e ll ah ead of the d iureas.
A lte rn a tiv e ly , colum n life was p reserv ed from the effects of excess nitro reagent by daily flushing of the column with solvent. , how ever, ap p e a re d to be a result of insufficient p u rific a tio n of th e sy n th esiz ed n itro re a g e n t and of the grade of toluene used. N itro re a g e n t is now com m ercially available. When the nitro reagent is dissolved in c h ro m a to g ra p h ic -g ra d e to lu en e, absorber solution impurities should be minimal. Com pounds th a t will in te r e f e r e w ith this procedure are those that absorb in the u ltrav io let range and also have the same column retention time as the diisocyanate being investigated. Toluene rem ain s the solvent of choice for this method . Federal reg u latio n s (49 CFR 172) allow air transportation of toluene in quantities of up to 1 q u a rt/p a c k a g e .
W here p ersonal sam pling p ro ced u res may expose workers to toluen e vapor for ex te n d e d p eriods, air sam p ler outlets could be fitted with an appropriate scrubber.
A fter reviewing the currently available analytical methods, NIOSH recommends the HPLC procedure described above . This method is described in detail in Appendix I. Although the method may necessitate some initial experimentation b e f o r e r o u tin e m e a su re m e n ts can be m ade, it is th e m o st se n sitiv e m ethod. B ecause q u a n titie s of d iiso c y an ate s in th e nanogram range may be determined, re la tiv e ly sh o rt sam pling tim es are allow ed.
A nalysis of th e primary reaction produ ct of d iiso c y an ate and ab so rb er en su res d ire c t m e a su re m e n t of available iso cy an a te fu n ctio n al groups and p reclu d es in te rfe re n c e by o th e r diisocyanate re a c tio n p ro d u cts.
The re la tiv e ch em ical stability of the nitro-ureas  allows for possible elapsed time between air sampling and subsequent analysis. In a d d itio n , the p ro ced u re is cap ab le of se p a ra tin g and id e n tify in g m ix tu res of d iiso cy an ate m onom ers as w ell as mixtures of monomer and partially polymerized p roducts . The p ro ced u re has not been tested with diisocyanates other th an TDI, MDI, and HDI. It is reaso n ab le to assum e, how ever, that a method which can e ffe c tiv e ly s e p a ra te th e isom ers of TDI, as does the HPLC method,  can be used su ccessfu lly fo r m easuring o th e r diisocyanates. Where possible in te rfe re n c e from reducing or oxidizing atmospheres may be encountered, a lte r n a te sam pling and a n a ly tic a l m ethods should be calib rated with the HPLC procedure.
N um erous stu d ies have shown th a t ab so rb er c o lle c tio n efficiency may vary d ra m a tic a lly . It is therefore recommended that two serially c o n n e c te d im pingers be used for air sam pling u n til a re p ro d u cib le c o lle c tio n efficiency is established for any given operation, after which a single impinger may be used for ro u tin e monitoring. The recommended flow rate of 2 liters/m inute for 10 m inutes re p re s e n ts a co m pro m ise for e ff ic ie n t aero so l and vapor sampling . Diisocyanates are also skin irritants and sensitizers ; how ever, e f f e c ts on th e skin from these compounds do not appear to have been a m ajor problem in in d u stry  . Eye contact with liquid TDI and TDI vapor has produced irrita tio n and watering of the eyes , and it is likely that direct eye contact with other diisocyanates would produce similar effects. D iiso cy an ates en co m p assin g a wide ran g e of molecular weights and physical p ro p e rtie s (see Table X I-1) are av ailab le for use in industry. The potentials of th e se com pounds to ir r i ta te th e re s p ira to ry trac t, mucous membranes, eyes, and skin vary depending on the particular diisocyanate being considered. The potential for skin irritation and eye injury is generally higher for the lower molecular weight diisocyanates and the severity of these irritant responses is reduced with increasing molecular weight .
The potential respiratory hazards encountered during the use of diisocyanates in th e w orkplace are related to their vapor pressures . The lower molecular w e ig h t d iiso c y a n a te s te n d to be m ore read ily v o la tiliz e d into th e w orkplace atm o sp h ere th an th e higher m o lecu lar w eig h t d iiso c y a n a te s  . Figure XI-1 presents graphically the decrease in vapor pressure with increasing molecular weight for sev eral d iiso c y an ate s. The low er molecular weight diisocyanates, such as HDI and TDI, when handled w ith o u t special precautions, can release amounts of vapor su ffic ie n t to be e x tre m e ly irritatin g to the respiratory tra c t of workers . H igher m o lecu lar w eight com pounds such as NDI, IPDI, and MDI present a lesser vapor h aza rd when handled in well-ventilated areas at normal room tem peratures, ie, less than ap p ro x im ate ly 40 C (104 F) for MDI . Although th e vapor pressures of the higher molecular weight diisocyanates are relatively low, they may g en erate vapor concentrations sufficient to cause respiratory and mucous m em brane irrita tio n if th ey are handled in poorly ventilated areas. Air exhaust hoods may be n ecessary under such co n d itio n s  . High m o lecu lar w eight d iiso c y an ate s like MDI m ay also present significant vapor hazards when heated or used in exothermic production processes .
The physical s ta te of th e d iiso c y an ate being handled will also a f f e c t the p o te n tia l h aza rd s e n c o u n te re d during its use. MDI and NDI, which are normally solid m a te ria ls a t room tem perature, present less vapor inhalation or skin contact hazard as a re s u lt of sp lash es or spills th an th e low er molecular weight liquid d iiso cy an ates do  .
H ow ever, w orkers should be aware of the possibility of re sp ira to ry and mucous membrane irritation from the dusts of such compounds, and of c o n ta m in a tio n of th e ir clo th in g w ith the powdered diisocyanates. Operations involving the use of such compounds, such as weighing, should be performed with equipm en t incorporating a barrier between the worker and the diisocyanate. Local ex h au st v e n tila tio n m ay also be n ecessary .
C lothing c o n ta m in a te d w ith solid diiso cy an ate should be decontaminated and laundered as soon as possible to prevent fu rth e r exposure of th e w orker and to avoid contamination of other work areas. Spills involving th e se compounds should also be decontaminated and cleaned up as soon as possible.
The p ro cesses and o p e ra tio n s in which diisocyanates are used will affect the sev erity of th e h azard .
In d u strial p ro cesses involving e v a p o ra tio n from large su rfa c e areas or spraying operations may result in a greater potential vapor hazard than o p eratio n s involving p o u rin g -in -p lace or fro th in g techniques . Special h azard s may arise in spraying operations since the diisocyanate-containing aerosol cloud may drift to areas beyond the immediate spraying area. T he r a t e o f r e a c t i o n is v e ry slo w for TDI and MDI a t te m p e ra tu re s below 50 C.
As th e te m p e ra tu re increases, the reaction between th e se com pounds and w a te r becomes more vigorous. TDI and MDI will also react w ith bases, such as sodium hydroxide, am m onia, prim ary and secondary amines, acids, and alcohols.
This re a c tio n may be v io len t, producing enough h e a t to in c re ase th e ev o lu tio n of diisocyanate vapor and the generation of carbon dioxide. These re a c tio n s , like th e reactions with water, may lead to dangerously increased pressure in closed c o n ta in e rs  , Thus, containers of diisocyanates should be kept closed as much as possible to prevent water, atmospheric moisture, or other reactive compounds from entering and vapors or solids from escaping.
D iiso cy an ates should be transported or stored in sealed, intact containers. A "sealed co n tain er" is one that has been closed and kept closed to the extent that th e re is no re le a se of d iiso c y an ate s.
An " in ta c t container" is one that has not d e te r io r a te d or been dam ag ed to th e e x te n t th a t d iiso c y a n a te s a re rele ased . D iiso cy an ates in seale d , in ta c t c o n ta in e rs should pose no threat of exposure to em ployees; th e re fo re , it is not necessary to comply with required monitoring and m edical su rv eillan ce re q u ire m e n ts in o p eratio n s involving such containers. If, how ever, c o n ta in e rs a re opened or broken so that diisocyanates may be released, th en all provisions of the recommended standard should apply. Indoor storage areas should be dry, fire p ro o fe d (autom atic sprinkler systems should be considered), and well v e n tila te d ; te m p e r a tu r e e x tre m e s in these areas should be avoided . The sto ra g e a re a should have a firm floor m ade of some nonabsorbent material  .
If d iiso c y an ate s a re a c c id e n ta lly frozen during storage or while in transit, they may be th aw ed by storage in a warm area . Extreme caution must be used if h e a t is ap p lied , and a flame or similar localized heat source should never be used.
D iiso cy an ates are transported in drums, tank trucks, or tank cars. Containers should be properly labeled and shippers should be aware of precautions to be taken fo r tra n sp o rtin g , loading, and unloading th e p a rtic u la r c o n ta in e r and type of diiso cy an ate being tra n sp o rte d . Emergency measures to be taken in the event of an a c c id e n t or some type of damage to the container or tank en route should also be w orked o u t in ad vance by th e shipper and the supplier or producer  , The H a z a r d o u s M a te r i a ls R e g u la tio n s as p ro m u lg ated by th e US D e p a rtm e n t of Transportation in 49 CFR Subchapter C should be adhered to where applicable. W here bulk quantities of diisocyanates are handled, adequate ventilation should be provided and re s p ira to ry p ro te c tiv e eq u ip m en t should be read ily available. W orkers should wear chemical safety goggles when handling solid diisocyanates and chem ical sa fe ty goggles w ith face shields when using liquid diisocyanates. Local exhaust v e n tila tio n should be em ployed when opening containers of diisocyanates  .
Local ex h au st v e n tila tio n should also be used when performing laboratory operations involving diisocyanates.
Since th e flash p o in ts of m ost diisocyanates are high, the compounds are not flam m ab le under norm al circumstances, although they can burn if they are heated su ffic ie n tly .
B ecause of th e wide range of physical and chemical properties of d iiso c y an ate s (see T able XI-1), it is im portant to be aware of the potential fire hazard th a t may be a s s o c ia te d w ith a p a rtic u la r d iiso c y a n a te in the industrial se ttin g in which it is used or sto red .
Any diisocyanate involved in a fire may produce high concentrations of toxic vapors, and only trained and properly equipped personnel should be involved in firefig h tin g . All nonessential personnel should be e v a c u a te d from th e a re a during a fire. Suitable extinguishing media for fighting d iiso c y an ate -su p p o rted fire s a re dry ch em ica l pow der, carbon dioxide, or foam. W ater should be used only if la rg e q u a n titie s a re av ailab le, since the reaction b etw een w ater and a hot diisocyanate may be vigorous. A fter the fire is out, the a r e a should be in sp e c te d by p roperly p ro te c te d p erso n n el, and any su spected residues should be decontaminated before other workers are perm itted to return to the area. If splashes or c o n ta c t w ith aero so ls of d iiso c y an ate s a re likely to occur, em ployees should w ear rubber or polyvinyl chloride gloves and aprons and rubber boots; a p p ro p ria te r e s p ira to ry eq u ip m en t, as d escrib ed in T able 1-1, should be readily available. Where supplied-air respirators are used, the air supply must come from a source not c o n ta m in a te d w ith diisocyanates . For all workers near spray gun operations (within approximately 10 feet), an air-supplied hood, impervious gloves (rubber or polyvinyl chloride), tightly buttoned coveralls, and rubber galoshes or b o o ts a r e n e e d e d  .
W orkers w ith o u t this eq u ip m en t should not be p e rm itte d close enough to spraying operations performed outdoors to be exposed to d iiso c y an ate vapors or particulates. A minimum of 50 feet is recommended. For indoor spraying operations, the safe distance for unprotected workers will depend on th e ty p e an d e ffic ie n c y of th e v e n tila tio n provided   When leaks or spills of diisocyanates occur, only properly trained and equipped personnel w earing appropriate protective clothing should be perm itted to remain in the a re a  .
If major spills occur, air-supplied masks or self-contained breathing a p p a ra tu s as described in Table 1- Any existing reg u latio n s pertaining to the discharge of such m aterials into sewer lines should be s tric tly a d h ere d to. Since spills of diisocyanates may freeze during cold weather, water and ammonia will merely coat the solid m aterial with insoluble urea, stopping fu rth e r reactions. In cold weather, cleanup should be performed with a mixture of equal p a rts of isopropyl alcohol and e th y len e glycol  .
A supply of this mixture should be on hand and ready for immediate use in cold weather. B ecause of th e potential hazards of exposure to diisocyanates, the importance of good housekeeping should also be em p h asized .
Spills should be cleaned up pro m p tly , and all equipm ent used in the exposure areas, such as buckets, weighing c o n ta in e rs, and funnels, should be decontam inated and cleaned immediately after use.
Smoking and th e carry in g of smoking supplies should be prohibited in areas w here exposure to diisocyanates may occur, as should preparing, storing, dispensing (including vending m achines), and consum ing food and b e v e ra g e s.
E m ployees exposed to d iiso c y an ate s should be encouraged to wash their hands before eating, d rin k in g , or s m o k in g , an d b e f o r e an d a f te r using to ile t f a c ilitie s . The US D e p a rtm e n t of Labor regulations concerning general sanitation in the workplace as specified in 29 CFR 1910.141 should be adhered to.
Em ployees should be instructed on the health hazards of diisocyanates and the p reca u tio n s to be follow ed in handling th em .
They should be trained to report prom ptly to th e ir supervisors all leaks, suspected failures of equipment, exposures to d iiso c y an ate s, or sym ptom s of exposure.
The location of safety showers and eyew ash fo u n tain s should be c le a rly m arked, and ap p ro p riate warning signs and labels should be p ro m in en tly displayed in exposure a re a s and on containers of diiso c y an ate s. E m ergency ex its should be provided and be accessible at all times. All em erg en cy show er, eyew ash, p ro tectiv e, and firefighting equipment should be checked periodically to ensure its serviceability.   also recommended that this limit not be exceeded because respiratory irritation occurred in anim als exposed to TDI at concentrations of 1-2 ppm. He noted that TDI and sim ilar diisocyanates are strong irritants to the skin, eyes, and gastrointestinal and respiratory tracts and that they may cause asthma-like symptoms in workers.
In 1962, th e ACGIH red u ced the TLV for TDI to 0.02 ppm (0.14 mg/cu m) Isocyanates in general were reported to irritate the skin, eyes, and respiratory tra c t and to cau se re s p ira to ry s e n s itiz a tio n when sufficient vapor concentrations were p resen t even for a short time . Konzen et al  observed an immunologic response in w orkers exposed to MIDI a t approximately 1.3 ppm-minute but not in workers exposed at 0.9 ppm-minute. Bruckner et al  noted that workers might becom e se n sitiz e d to isocyanates when exposed at concentrations above 0.02 ppm. A ccording to the 1971 documentation , available data indicated that MDI was sim ilar to TDI in its ir r ita n t and sensitizing properties, suggesting that a similar ceiling value of 0.02 ppm (0.2 mg/cu m) was warranted.
In th e U nited S ta te s , o ccu p a tio n a l exposure standards for diisocyanates have been estab lish ed only fo r TDI and MDI. A ccording to th e International Labour O f f ic e  , o ccu p a tio n a l exposure lim its for TDI, MDI, and sev eral o th er d iiso c y an ate s have been s e t by foreign countries. These limits are summarized in Tables VI-1 and VI-2.
C u rre n t Federal standards (29 CFR 1910(29 CFR .1000  , who re p o rte d th a t w orkers had no sym ptom s at concentrations below 10 ppb but developed resp irato ry illness within 1 week when concentrations rose to 30-70 ppb; when co n ce n tratio n s were reduced to 10-30 ppb, there were no further complaints. The recom m en d ed ceiling was intended to protect against irritative effects of TDI in non sen sitized w orkers, but ev id en ce was insufficient to determ ine whether it would also protect against sensitization. The document noted that no evidence was available to point to a concentration of TDI that would be safe for workers already s e n sitiz e d to TDI. The present document reexamines the earlier recommendations for a TDI stan d ard , taking into account more recent information that has become available since 1973.   No th resh o ld concentration for such reactions has b e e n id e n tif ie d , but th e re is ev id en ce th a t, for som e individuals, it may be u nm easurably low ; th u s, it is not possible at this time to establish a level below which sensitized workers will not experience adverse respiratory effects from exposure to diisocyanates.

# Basis for the Recommended Standard
Several studies have shown that 5-20% of the workforce may become sensitized to d iiso c y an ate s . There is evidence, however, that the incidence of s e n sitiz a tio n can be red u ce d by co n tro llin g exposures. The data of Elkins et al  on 15 TDI plants showed that all plants where average exposures exceeded 70 y g /c u m had w orkers w ith T D I-re la te d re s p ira to ry illness, but no such illnesses w ere re p o rte d in p lan ts where average exposures were 50 yg/cu m or lower. On th e o th e r hand, Weill  reported instances of sensitization developing in a plant w here av era g e TDI ex posures ran g ed from 14 to 50 yg/cu m. These studies did not re p o rt th e frequency or magnitude of excursions above these averages, so that the more precise estim ates of exposure concentrations cannot be determined. Exposure to diisocyanates may also cause chronic respiratory effects measurable as lo n g -term decrem ent in pulmonary function, especially FEV 1, in excess of that expected from aging. It is not clear from existing data whether this change occurs only in se n sitiz e d w orkers or w h eth er it may also a f f e c t workers who show no clinical sym ptom s from diisocyanate exposure. The findings of Porter et al  in d ic a te th a t som e w orkers who are sen sitiv e to TDI and who have anti-T D I an tib o d ies may ex h ib it norm al pulm onary fu n ctio n , w hile o th e rs w ith clin ical sym ptom s of s e n s itiz a tio n but n eg ativ e re su lts on im m unologic tests may have sev erely im p aired pulm onary fu n ctio n .
In the study conducted by Wegman et al  , in w h ich w orkers exposed a t c o n c e n tra tio n s above 20 U g/cu m had a significantly greater decrease in FEV 1 than those exposed at lower concentrations, th e w ork fo rce studied included both sensitized and unsensitized individuals. In the plant studied by Weill and colleagues , where workers who showed symptoms of clin ica l sensitization were not included in the study population, the investigators found no sig n ifican t e f f e c ts on lung function related to TDI exposures at average c o n c e n tra tio n s of 14-50 ug/cu m. These findings indicate that the TWA limit of 5 ppb (35 U g/cu m) for TDI recommended by NIOSH in 1973 , which was based on th e findings of Elkins et al , provides adequate protection against chronic effects of TDI on pulmonary function of workers who are not sensitized. E nv iro n m en tal d a ta for the other diisocyanates are insufficient to establish a safe exposure lim it.
The diisocyanates commonly used in industry are respiratory irrita n ts  . In a plant where area samples showed MDI concentrations of 10-150 U g/cu m and breathing zone concentrations for 6 sprayers were 120-270 ug/cu m, 34 of 35 workers had eye, nose, or throat irritation, and nearly half had wheezing, sh o rtn ess of b re a th , and ch est tightness . In another plant, 3 of 29 workers exposed to MDI a t 50-110 ug/cu m had respiratory symptoms . Nine of 18 w orkers exposed to HDI a t less th a n 300 Ug/cu m and to an HDI trim er at less than 3,800 ug/cu m had irritatio n of the upper respiratory trac t, cough, or chest tightness [ 100 j.
L ik e TD I, o th e r d i i s o c y a n a t e s a r e likely to be re a c tiv e w ith biologic m acrom o lecu les, such as proteins, and thus are potential sensitizers. Some authors  have re p o rte d th a t MDI produces respiratory sensitization, since affected w orkers gave p o sitiv e re su lts in immunologic tests. The assumption of a common m echanism of a c tio n suggests that structurally similar diisocyanates might produce cross-sensitization; there is one report  of positive tests for antibodies against MDI in w orkers sen sitized to TDI, but the validity of these results is questionable because of th e lack of characterization of the test antigen used. A study of skin s e n s itiz a tio n  su g g ested th a t w orkers exposed to TDI and MDI were cross sen sitized to IPDI. In an o th e r study , some workers with previous exposure only to TDI had bronchial reactions to MDI and HDI as well. These workers were sig n ifican tly m ore h y p e rre a c tiv e to h ista m in e th a n workers who reacted to TDI only, suggesting th a t c ro s s -re a c tiv ity m ight involve a nonspecific pharmacologic mechanism.
The p re d ic te d r e a c tiv ity of the diisocyanates with biologic macromolecules is th e probable basis for th e ir im m unologic effects and perhaps for the respiratory sym ptom s and effects on pulmonary function produced at low concentrations. It is th e re fo re reasonable to expect that other diisocyanates react similarly to TDI on a molar basis. In th e absence of data indicating that any of the diisocyanates is substantially less to x ic th an TDI, th e exposure concentrations recommended in 1973 should be ex ten d ed to all diisocyanates. It is recommended that exposure to the diisocyanates be c o n tro lle d so th a t no em p lo y ee is exposed at concentrations in excess of the following environmental limits, equivalent, in the case of volatile diisocyanates that o c c u r as v a p o r s , to a TWA lim it of 5 ppb fo r a 10-hour w o rk sh ift, 40-hour workweek, and a ceiling limit of 20 ppb for a 10-minute sampling period:
TWA G e i1ing  The recom m ended method also permits separation of different diisocyanates in th e sam e sam ple.
It has not been tested with diisocyanates other than TDI, MDI, and HDI, b u t, w ith a p p ro p ria te m o d ificatio n s and so lv en t systems, it should be capable of detecting these compounds in the same range.
The reco m m en d ed m ethod fo r sam pling a irb o rn e d iiso c y a n a te s consists of draw ing air a t a r a te of 2 lite rs /m in u te for 10 m in u tes th ro u g h tw o serially co n n ec ted a ll-g la ss m idget impingers, each containing 15 ml of absorbing solution. The use of tw o im pingers in series is n ece ssary u n til a reproducible collection efficiency is established for any given operation, since absorber collection efficiency is highly variable . The diisocyanates react with the absorbing solution to form s p e c ific u re a d eriv ativ es which are then injected into the high speed liquid ch ro m a to g ra p h for an alysis. The m eth o d is described in detail in Appendix I. To p re v e n t d ev elo p m en t of serious re s p ira to ry sym ptom s, a medical su rv eillan ce program should provide for th e tim ely d e te c tio n of adverse health effects that develop from exposure to diisocyanates. E m ployees w ith a h isto ry of respiratory illness, especially asthma, and those exposed to o th e r re s p ira to ry ir r ita n ts , eg, smokers, may be at increased risk of developing ad v erse h e a lth effects from exposure to diisocyanates, and they should be counseled on this risk. All employees should be monitored so that work-related sym ptom s or loss of pulm onary fu n ctio n can be detected early. Employees who d e v e lo p s y m p to m s o f TDI s e n s itiz a tio n should be co u n seled on th e risks of continuing to work with TDI.
Each em p lo y ee should re c e iv e a thorough preplacement medical examination, which includes a h isto ry of exposure to diiso cy an ates, a smoking history, and a history of re s p ira to ry illnesses. Each employee should receive pulmonary function te s ts , including FEV 1 and FVC, and a chest X-ray before beginning work in any p lan t m a n u fa ctu rin g or using d iiso c y a n a te s. F o r em p lo y ees w ith occupational e x p o s u re to d iiso c y an ate s, physical ex am in atio n s should be re p e a te d a t le a st annually.
B ecause of seaso n al and diurnal variations in pulmonary function, the periodic e x am in atio n of an individual employee should be performed at about the sam e tim e ea c h y ear and at the same time of day, so that changes in respiratory function can be evaluated. Chest X-rays are not required at periodic examinations, and should be re p e a te d a t th e d isc re tio n of the examining physician. Records of m edical examinations should be kept for at least 30 years after the employee's last exposure to diisocyanates.
The previous NIOSH criteria document on TDI  recommended a leukocyte count w ith d iffe re n tia l as p a rt of th e p re p la c e m e n t m ed ical ex am in atio n and su g g ested p erio d ic eosinophil counts. However, there is no evidence at this time th a t blood findings a re a significant indicator of adverse effects of TDI exposure. This change in the recommendations for the medical examination is consistent with th e fa ilu re to find eosin o p h ila in T D I-sen sitized individuals in re c e n t stu d ies . W here liquid diisocyanates may be present on floors, protective shoe coverings should be worn.
If th e p o te n tia l e x ists for splashes or contact with aerosols of diisocyanates, em ployees should be provided w ith face shields (20-cm minimum) with goggles, rubber or polyvinyl ch lo rid e gloves and aprons, rubber b oots, and ap p ro p riate re s p ira to ry eq u ip m en t as d escrib ed in Table 1-1. Because diisocyanates have poor w arning properties , the use of chemical cartridge respirators or gas masks is not recommended. At present, air-purifying respirators with an end-of-service-life in d icato r a re not available for the diisocyanates. Demand-type (negative pressure) supplied-air respirators are not recommended because of the possibility of facepiece leakage. Workers within 10 feet of a unit spraying m aterial containing diisocyanates should w ear full-body p ro te c tiv e clo th in g and appropriate respiratory protective devices .
All protective clothing th at becomes contaminated with diisocyanates should be rep la ced or thoroughly decontaminated in a solution of 8% ammonia and 2% liquid d e te rg e n t in w ater and clean ed b efo re reu se.
L ockers should be provided for w orkers so th a t work and s tr e e t clothes can be stored separately. The employer should arran g e for laundering of all work clothes and ensure that laundry workers are aware of the hazards of exposure and appropriate safety precations.

# (e) Informing Employees of Hazards
At the beginning of em p lo y m en t, all em p lo y ees should be informed of the h azard s from exposure to diisocyanates. Brochures and pamphlets may be effective aids in informing employees of hazards. In addition, signs warning of the danger of exposure to diisocyanates should be posted in any area where occupational exposure to the diisocyanates is likely. Access to areas of potential high exposure should be re s tr ic te d to em p lo y ees equipped with appropriate protective gear. A continuing ed u ca tio n program, which includes training in the use of protective equipment such as respirators and information about the value of the periodic medical examinations, should be available to the employees. Employees exposed to diisocyanates should be inform ed th a t symptoms of exposure, such as nocturnal dyspnea, may occur several hours a f te r th e end of the workshift. Because of the possibility of sensitization to th e d iiso c y an ate s, em p lo y ees should be w arned th a t the im proper home use of po ly u reth an e p ro d u cts, such as foam kits and varnishes, that contain diisocyanates may in c re a se th e ir risk of developing w o rk -re la te d h e a lth problems. Employees should be in s tru c te d in th e ir own responsibility for following work practices and sa n ita tio n p ro ced u res to help p r o te c t th e h ealth and p rovide for the safety of themselves and their fellow employees. T hese sy stem s should be designed to p re v e n t th e a c c u m u la tio n or re c irc u la tio n of d iiso c y a n a te s in the w orkplace en v iro n m en t and to effectiv ely remove diisocyanate vapors or aerosols from th e b reath in g zone of th e em p lo y ees.
The v e n tila tio n systems should be periodically ch eck ed , including airflow measurements, to ensure that the systems are w orking p ro p erly .
Exhaust ventilation systems discharging to outside air must conform to ap p licab le lo cal, state, and Federal air pollution regulations and must not constitute a hazard to employees or to the general public. In ad d itio n, it is recom m en d ed th a t em ployees who work in areas that use diisocyanates wash their hands thoroughly b efo re e a tin g or using to ilet facilities. Smoking should not be perm itted in areas where diisocyanates are stored or used because of the possibility that smoking materials may become contaminated with diisocyanates.

# (g) Monitoring and Recordkeeping Requirements
In ad d itio n to a program of regular personal monitoring of air concentrations, continuous a re a m o n ito rin g is strongly recommended where aliphatic diisocyanates such as TDI and MDI are p re se n t.
This will p e rm it engineering controls to be m odified or im proved to keep the concentrations of diisocyanates at or below the recom m en d ed lim its.
M onitoring should also be perform ed whenever there is a c h a n g e in th e pro cess or m a te ria ls used th a t could in c re a se th e exposure of employees.
Em ployers should m onitor exposure of employees to diisocyanates by taking a s u ffic ie n t num ber of b reath in g -zo n e samples to adequately characterize exposures for every o p eratio n . In determining the sampling strategy for a particular worker, th e process and the job description of the worker should be considered, and those p ro cess cy cles in w hich p o te n tia l exposure is g r e a te s t should be given prim e consideration. R eco rd s should be kept for all sampling operations and should include the type of personal p ro te c tiv e d ev ices in use, if any, and th e sam pling and analytical m ethods used. Employees or their designated representatives should have access to records of their own environmental exposures. These records should be kept at least 30 years after the employee's last exposure to diisocyanates.

# VII. RESEARCH NEEDS
In fo rm atio n needed to develop a stan d ard for occupational exposure to the diisocyanates is incomplete in many respects. It has been necessary to recommend a stan d ard for th e d iiso c y a n a te s based on sim ila ritie s to TDI and MDI, since ad eq u a te in fo rm atio n is not av ailab le on other diisocyanates to dem onstrate that they differ appreciably in their toxicity. . These relationships could be studied in guinea pigs exposed to TDI, using the p-tolyl isocyanate antigen  to test for th e in d u ctio n of tolyl-specific antibodies. Sera from these animals should not be pooled, so that the standard deviation can be determined. Changes in respiratory response in exposed animals should also be evaluated to determine their correlation w ith th e ap p e a ra n c e of IgE or IgG antibodies. As a corollary experiment, animals should be exposed at the same total dose administered over varying tim e periods to sim u late the e f f e c ts of excursions while retaining the same 8-hour TWA exposure; eg, groups of anim als m ight be exposed a t 5 ppb fo r 8 hours, 160 ppb for 15 minutes, and 2,400 ppb for 1 minute.
To im prove p ro te c tio n of exposed w orkers, it is p a rtic u la rly desirable to d e te rm in e w h eth er th ere are intrinsic, predictable differences between sensitizable and nonsensitizable individuals. The studies of Butcher et al , showing that persons se n sitiz e d to TDI tend to be hyperreactive to bronchoconstrictors such as m echolyl, ap p ear to o ffe r prom ise in this reg ard .
It is necessary to determine w hether this h y p e rre a c tiv ity is a re su lt of exposure or a preexisting factor that may in d ic a te a p red isp o sitio n to become sensitized to diisocyanates. Methods of id en tify in g sensitized individuals before overt chronic symptoms develop should also be explored.
The value of m e asu re m en ts of eosinophilia and cyclic AMP and of pulm onary fu n ctio n stu d ies and immunologic testing as diagnostic tools should be c a re fu lly e v a lu a te d , since ex istin g re p o rts of their usefulness are contradictory. The p-to ly l iso c y a n a te te s t an tig e n developed by Karol and her colleagues  ap pears to be a p a rtic u la rly useful d iag n o stic tool for TDI se n s itiz a tio n , and analogous an tig en s should be developed for in v e stig a tin g sensitization to other diisocyanates.
B ecause th e d iiso cy an ates may be highly reactive biologically, it is important th a t th e ir p o te n tia l to cau se carcinogenic and mutagenic effects be investigated. M u tag en icity screen in g in m icro b ial te s ts should be c a rrie d o u t, using a te s t p ro to co l th at will decrease the likelihood of hydrolysis to possibly mutagenic amine in te rm e d ia te s .
D iiso cy an a tes, esp ecially those that are positive in mutagenicity te s ts , should also be te s te d for carcinogenicity in animal experiments. Studies of absorptio n , distribution, metabolism, and excretion of diisocyanates are also needed to elucidate the mechanism of their action.
The co n seq u en ces of ex p o su re to the aerosols produced in many diisocyanate ap p licatio n s, such as sp ray in g , should also be investigated. It has been assumed th a t re a c tiv e diisocyanates in aerosol form produce the same biologic consequences as d iiso c y an ate vapors a t eq u iv alen t c o n c e n tra tio n s. This assumption should be e x p e rim e n ta lly v e rifie d .
S im ilarily, m ost a p p lic a tio n s of diisocyanates involve sim u ltan eo u s exp o su re to o th e r to x ic ch em ica ls, and in a d e q u a te information is av ailab le on th e ro le of th e se ch em icals in producing observed health effects in diisocyanate workers and their possible additive or synergistic nature. R eliab le, se n sitiv e continuous monitoring methods should be developed for all th e diisocyanates. The paper-tape method developed by Reilly  is a valuable m ethod for continuous m onitoring of the arom atic diisocyanates, particularly TDI. C om parab le m ethods a re need ed for other diisocyanates to protect workers from dangerous ex cu rsio n s and to provide better information relating health effects to actual exposures. The following items of information that are applicable to a specific product or m a te ria l shall be provided in th e a p p ro p ria te block of the Material Safety Data Sheet (MSDS).
The product designation is inserted in the block in the upper left corner of the firs t page to facilitate filing and retrieval. Print in upper case letters as large as possible. It should be printed to read upright with the sheet turned sideways. The product designation is that name or code designation which appears on the label, or by w hich the p ro d u ct is sold or known by em p lo y ees.
The r e la tiv e numerical hazard ratings and key statem ents are those determined by the rules in Chapter V, P a rt B, of th e NIOSH p u b licatio n , An Id e n tific a tio n System for Occupationally Hazardous Materials. The company identification may be printed in the upper right corner if desired. C hem ical substances should be listed according to their complete name derived from a reco g n ized sy stem of nom enclature. Where possible, avoid using common nam es and g en era l class n am es such as " a ro m a tic am in e," " sa fe ty solvent," or "aliphatic hydrocarbon" when the specific name is known.
The "%M may be the ap p ro x im ate p e rc e n ta g e by weight or volume (indicate basis) th a t eac h h azardous ingredient of the mixture bears to the whole mixture. This may be in d ic a te d as a range or maximum amount, ie, "10-40% vol" or "10% max wt" to avoid disclosure of trade secrets.
Toxic hazard data shall be stated in term s of concentration, mode of exposure or test, and animal used, eg, "100 ppm LC50-rat," "25 mg/kg LD50-skin-rabbit," "75 ppm LC-man," or "p erm issib le exposure from 29 C FR 1910.1000," or, if not av ailab le, from o th er sources of publications such as the American Conference of Governmental Industrial Hygienists or the American National Standards Institute Inc. F lashpoin t, shock se n s itiv ity , or similar descriptive data may be used to indicate fiammability, reactivity, or similar hazardous properties of the material.

# (c)
Section III. Physical Data
The d a ta in Section III should be for the total mixture and should include the boiling point and melting point in degrees Fahrenheit (Celsius in parentheses); vapor p ressu re, in co nventional millimeters of mercury (mmHg); vapor density of gas or vapor (air = 1); so lubility in w a te r, in p a rts /h u n d re d parts of w ater by weight; sp ecific gravity (water = 1); percent volatiles (indicated if by weight or volume) at 70 F (21.1 C); e v a p o ra tio n r a te for liquids or sublimable solids, relative to butyl a c e ta te ; and ap p earan ce and odor. These data are useful for the control of toxic su b stan ces.
Boiling point, vapor d en sity , p e rc e n t volatiles, vapor pressure, and ev ap o ratio n are useful for designing proper ventilation equipment. This information is also useful for design and d eploym ent of adequate fire and spill containment eq u ip m en t. The ap p e a ra n c e and odor may facilitate identification of substances stored in improperly marked containers, or when spilled.

# (d)
Section IV. Fire and Explosion Data S ection IV should co n tain c o m p le te fire and explosion data for the product, including flash p o in t and autoignition tem perature in degrees Fahrenheit (Celsius in p aren th eses); flam m ab le lim its, in percent by volume in air; suitable extinguishing m edia or m a te ria ls; sp ecia l firefighting procedures; and unusual fire and explosion h azard in fo rm atio n .
If th e p ro d u ct p re se n ts no fire h aza rd , in se rt "NO FIRE HAZARD" on the line labeled "Extinguishing Media." (e) Section V. Health Hazard Information
The "Health Hazard Data" should be a combined estim ate of the hazard of the to ta l pro d u ct.
This can be ex p ressed as a TWA concentration, as a permissible exposure, or by som e o th e r indication of an acceptable standard. Other data are acceptable, such as lowest LD50 if multiple components are involved.
Under "R o u tes of Exposure," co m m en ts in eac h category should reflect the p o te n tia l h azard from ab so rp tio n by th e ro u te in q u estio n . C o m m en ts should indicate the severity of the effect and the basis for the statem ent if possible. The 124 basis might be animal studies, analogy with similar products, or human experiences. C om m ents such as "yes" or "possible" are not helpful. Typical com ments might be: Skin C ontact-single short contact, no adverse effects likely; prolonged or repeated contact, possibly mild irritation.
Eye C ontact-some pain and mild transient irritation; no corneal scarring.
"E m ergency and F irs t Aid Procedures" should be w ritten in lay language and should primarily represent first-aid treatm ent that could be provided by paramedical personnel or individuals trained in first aid.
In fo rm atio n in th e "N o tes to Physician" se c tio n should include any special m e d ic a l in fo rm a tio n w hich would be of a ssista n c e to an a tte n d in g physician, including required or recommended preplacement and periodic medical examinations, diagnostic procedures, and medical management of overexposed employees. It is p a rtic u la rly im p o rta n t to h ig h lig h t in s ta b ility or in c o m p atib ility to com m on su b stan ces or c irc u m s ta n c e s, such as w ater, direct sunlight, s te e l or co p p er piping, acid s, alk alies, etc. "Hazardous Decomposition P roducts" shall include those products released under fire conditions. It must also include dangerous p ro d u cts p roduced by aging, such as peroxides in the case of some ethers. Where applicable, shelf life should also be indicated.

# (g)
Section VII. Spill or Leak Procedures D etailed procedures for cleanup and disposal should be listed with emphasis on p reca u tio n s to be tak en to protect employees assigned to cleanup detail. Specific n e u tra liz in g c h em ica ls or p ro ced u res should be d escrib ed in d e ta il. D isposal m ethods should be ex p licit including proper labeling of containers holding residues and ultim ate disposal methods such as "sanitary landfill" or "incineration." Warnings such as "Comply with local, state, and Federal antipollution ordinances" are proper but not sufficient. Specific procedures shall be identified.

# (h)
Section VIII. Special Protection Information S ection VIII requires specific information. Statem ents such as "Yes," "No," or "If necessary " a re not informative. Ventilation requirements should be specific as to ty p e and p re fe rre d m eth o d s. R e sp ira to rs shall be sp e c ifie d as to type and NIOSH or US Mine S afety and H ealth Administration approval class, ie, "Supplied air," "O rganic vapor canister," etc. Protective equipment must be specified as to type and materials of construction.

# (i)
Section IX. Special Precautions " P re c a u tio n a ry S ta te m e n ts " shall consist of the label statem ents selected for use on the container or placard. Additional information on any aspect of safety or h e a lth not co v ered in o th e r sections should be inserted in Section IX. The lower block can contain references to published guides or in-house procedures for handling and sto rag e. D e p a rtm e n t of Transportation markings and classifications and other freight, handling, or storage requirements and environmental controls can be noted.

# IX. APPENDIX I SAMPLING AND ANALYTICAL METHOD FOR DIISOCYANATES IN AIR
The follow ing m ethod for sam pling and analysis of airborne diisocyanates is ad ap ted from NIOSH M ethod No. MR 240 (C la ssific a tio n E) . A Class E m ethod is defin ed by NIOSH as "Proposed: A new, unproven, or suggested method not previously used by industrial hygiene analysts but which gives promise of being suitable for the determination of a given substance."

# Principle of the Method
A known volum e of air is drawn at a flowrate of 2 liters/m inute through two m idget gas im p in g ers, c o n n e c te d in se rie s, containing the nitro reagent absorber solution. The recommended airflow is 2 liters/m inute, rather than 1 liter/m inute as in d i c a t e d in M eth o d N o. MR 240  , to en su re c o lle c tio n of p a rtic u la te diisocyanates. At the time of analysis, the two impinger solutions are initially kept s e p a ra te to allow d e te rm in a tio n of collection efficiency. The impinger solutions (s e p a ra te or com bined) are carefully rotary evaporated to dryness. The residue is then dissolved in 1.0 ml of m eth y len e ch lo rid e, CH2C12, containing an internal stan d ard .
An aliquot of the solution is injected into a liquid chromatograph. The a r e a of the re su ltin g peak is d e te rm in e d and co m p ared to a re a s o b ta in ed by injecting standard urea solutions of known concentration.

# Range and Sensitivity
The upper lim it of th e range of the method depends on the concentration of th e nitro reagent in the midget gas impingers. For a 10-liter air sample, the limit of d iiso c y an ate s th at can be absorbed is 0.0015 millimole/cu m using 15 ml of 0.2 mM nitro reagent solution.
T he m inim um d e te c ta b le lim it is 2 n g /in je c tio n fo r TDI and MDI and 5 n g /in jectio n for HDI. The advisable injection volume is 50 pi. Hence, for a 20lite r sam ple, th e usefu l range is 2-300 p g /c u m of to ta l d iiso c y a n a te s. If a p a rtic u la r atm o sp h e re is su sp e cted of containing a large amount of isocyanate, a smaller sampling volume should be taken.

# Interferences
Any com pound that reacts with nitro reagent and has the same retention time as th e a n aly te is an in te r e f e r e n c e . R e te n tio n tim e alone cannot be considered p ro o f of c h e m ic a l i d e n t i t y .
W hen th e p o s s i b ili ty of in te r f e r e n c e ex ists, 117 ch ro m a to g rap h ic conditions (eg, modes of gradient, concentration of mobile phases, packings) have to be changed to circumvent the problem.
Precision and Accuracy P recisio n and accuracy for the total analytical and sampling method have not been determ ined. However, the analytical method has been shown tc have relative stan d ard deviations within experimental error for peak areas and retention times of 2 .8 -1 6 .5 % and 0.6-4.1% , re s p e c tiv e ly , depending on th e c o n c e n tra tio n of the analytes.

# Advantages and Disadvantages of the Method
The sam p lin g d ev ice is p o rta b le .
The a n a ly tic a l m ethod is sp e c ific for i s o c y a n a t e s , an d i n t e r f e r e n c e s a re m inim al.
S im ultaneous analysis of five substances can be carried out routinely.
T he n i t r o re a g e n t m ust be p re p a re d a t ra th e r fre q u e n t in te rv a ls.
It is recommended that it not be stored for more than 3 weeks, and it should be kept in d arkness. Commercially available nitro reagent may prove more stable. The ureas f o r m e d in s o lu tio n a r e g e n e r a lly s t a b l e up to 7 d a y s .
D e g r a d a t io n or p o ly m e riz a tio n may occu r a f te r th is period.
E xcess n itro re a g e n t should be rem oved w ith p -to ly l iso c y a n a te or by som e o th e r means before the solution is in jecte d into the liquid chromatograph to maintain longer column life and precision.

# Apparatus (a)
An approved and calibrated personal sampling pump whose flowrate can be determined within 5% at the recommended flowrate. P re p a ra tio n of N itro R e a g e n t Solution: A typical procedure for the routine p re p a ra tio n of the n itro re a g e n t so lu tio n is as follow s.
A bout 120 mg (0.52 m illim ole) of the commercially available hydrochloride of nitro reagent is dissolved in 25 m l o f d is ti lle d w a te r.
T h irte e n m illilite rs of 1 N NaOH is added to p re c ip ita te th e fre e am in e.
The fre e amine is extracted with 50 ml of toluene. The to lu en e lay er is dried over anhydrous CaS04 (Drierite, WA Hammond Drierite Co, Xenia, Ohio), and the resulting solution is diluted to 250 ml to prepare a 2 mM solution and is sto re d in th e r e f r ig e ra to r .
The nitro reagent solution is further d iluted 10-fold w ith to u len e b efo re it is added to the impinger collecting tubes. Prepared nitro reagent should be examined periodically by HPLC for the appearance of additional peaks that indicate reagent degradation.
Flowrate: 2.0 ml/minute.
(2) G rad ien t elu tio n : 10% B/A to 100% B in 10 minutes (B = 9.1% isopropanol/CH2C12; A = 100% CH2C12).
(3) D etector: uv at 254 nm.
(4) Temperature: ordinary room.
(5) Recorder chart speed: 0.5 inch/minute. The peak area is measured by peak height times peak width at half the height or by an e le c tro n ic integrator such as a computing integrator. Preliminary results are read from a standard curve prepared as discussed below.

# Calibration and Standards (a)
A series of standards varying in concentration over the range of interest are prepared. Calibration curves are established prior to sample analysis each day. When an in te rn a l standard is used, the analyte concentration is plotted against the area ratio of the analyte to that of the internal standard. (1)
The follow ing w eights of th e isocyanates are dissolved in 4.0-ml portions of CH2C12: 2.12 mg MDI; 29.60 mg of TD1 (ie, 19.30 mg of 2,4-TDI and 10.30 mg of 2,6-TDI), 21.14 mg of HDI.
Then 755 y l of MDI, 83.1 y l of TDI, and 75.5 y l of HDI are m ixed and 1.017 ml CH2C12 is added to make a total of 2.00 ml (200 ng/liter of each). Then 1.0 ml nitro reagent (2.06 mg/ml in hexane) is added to 1.0 ml of the iso cy an a te m ix tu re.
The total isocyanate/nitro reagent mole ratio in this solution is 1:1. The re a c tio n m ix tu re is sto re d overnight. Dilutions are made from this s o lu tio n .
T he so lvent is e v a p o ra te d in a ro ta ry e v a p o ra to r and th e residue redissolved in 1 ml CH2C12. These solutions are used to establish the calibration curves, linear dynamic range, and minimum detectable amount in the 25-cm Partisil 10 column.
Calculations