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HHE Report No. HETA-87-0042-1869, Florida Department of ... Flipbook PDF
Individuals were designated as cases of dermatitis if they reported a rash (red, inflammed skin) or dryness and chapping
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This This Health Health Hazard Hazard Evaluation Evaluation (HHE) (HHE) report report and and any any recommendations recommendations made made herein herein are are for for the the specific specific facility facility evaluated evaluated and and may may not not be be universally universally applicable. Any Anyrecommendations recommendationsmade madeare arenot notto tobe beconsidered consideredas asfinal finalstatements statementsof ofNIOSH NIOSHpolicy policyor orof ofany anyagency agencyor orindividual individualinvolved. involved. applicable. applicable. Any recommendations made are not to be considered as final statements of NIOSH policy or of any agency or individual involved. Additional AdditionalHHE HHEreports reportsare areavailable availableat athttp://www.cdc.gov/niosh/hhe/reports http://www.cdc.gov/niosh/hhe/reports
HETA 87-042-1869
NIOSH Investigators:
This Health Hazard Evaluation (HHE) report and any recommendations made herein are for the specificA. facility evaluated Gregory Ornella, M.D.and may not be universally FEBRUARY 1988 applicable. Any recommendations made are not to be considered as final statements of NIOSH policy or of any agency or individual involved. C.G. Toby Mathias, M.D. FLORIDA DEPARTMENT OF HEALTH Additional HHE reports are available at http://www.cdc.gov/niosh/hhe/reports
AND REHABILITATIVE SERVICES JACKSONVILLE, FLORIDA I. SUMMARY
On October 21, 1986, the National Institute for Occupational Safety and Health (NIOSH) received a request from the State of Florida Department of Health and Rehabilitative Services (DHRS), to evaluate dermatologic conditions (red rashes, dryness and chapping) in public health laboratory workers processing Neisseria gonorrhoeae (GC) culture plates. To determine if the reported skin conditions in workers were related to occupational exposures, NIOSH investigators visited five of the seven state public health laboratories on January 12-23, 1987. A questionnaire was administered to all laboratory personnel present on the dates of visits to the individual laboratories. Ninety-nine (97%) of the 102 total laboratory personnel employed completed the self-administered questionnaire. Cases were defined as individuals with a red rash or excessive dryness and chapping on the hands or arms, lasting one or more days, and occurring within the past year. A total of 54 workers reported exposure to the oxidase reagents, used in the preliminary identification of Neisseria gonorrhoeae cultures. Twenty-four (44%) of those workers exposed to the oxidase reagents were identified as cases (Relative Risk (RR) = 2.0, Confidence Interval [CI] = l.l-3.6). The twenty-four oxidase-exposed cases were skin patch tested with the oxidase reagents; seven (29%) individuals had positive tests for allergic contact dermatitis. This represents a sensitization rate of at least 13% among all 54 workers exposed to the oxidase reagents. An association was also found between non-sensitized cases of dermatitis and the degree of exposure to the oxidase reagents. Workers with the greatest degree of exposure were at increased risk of becoming non-sensitized cases. Based upon the results of this investigation, the investigators concluded that there was a health hazard from exposure to oxidase compounds at public health laboratories of the Florida Department of Health and Rehabilitative Services. Recommendations for reducing exposure to oxidase reagents and reassigning sensitized workers are contained in Section VIII of this report. KEYWORDS: SIC 8071; P-phenylenediamine (CAS:l06-50-3); p-diaminobenzene (CAS:l06-50-3); 1,4 diaminobenzene (CAS:l06-50-3); ursol; oxidase; p-aminodimethylaniline oxalate (CAS:2463l-29-6); N,Ndimethyl-p-phenylenediamine (CAS:l05-l0-2); N,N- dimethyl-p-phenylenediamine monohydrochloride (CAS:2052-46-2) ; N,N- dimethyl-p-phenylenediamine dihydrochloride (CAS:536-46-9); N,N,N',N'tetramethyl-p-phenylenediamine dihydrochloride (CAS:637-0l-4); allergic contact dermatitis; skin rash.
II. INTRODUCTION In October 1986, NIOSH received a request for a health hazard evaluation from the Office of Laboratory Services at the Florida Department of Health and Rehabilitative Services. The request was initiated as a result of several reported cases of severe dermatitis in laboratory workers at five of the seven Florida State public health laboratories. Workers involved with Neisseria gonorrhoeae (GC) culture plate processing, and in particular having contact with oxidase reagents (used in the preliminary identification of Neisseria gonorrhoeae species) or residue from carbon dioxide generating tablets, were reported to have the most severe skin problems. NIOSH investigators conducted field evaluations of this problem during January 12-23, 1987. The preliminary findings of this investigation were presented by telephone on March l5 to the Office of Laboratory Services, and a written presentation of the initial results of the study was sent at that time. The preliminary results were presented to administrative staff and employees at the Florida DHRS, Miami laboratory on May l8, l987. III. BACKGROUND The Florida Department of Health and Rehabilitative Services is centered in Jacksonville, Florida, where administrative offices, as well as a public health laboratory are located. In addition, there are six regional laboratories located in Miami, Orlando, Pensacola, Tallahassee, Tampa, and West Palm Beach. At these public health facilities, the general public is offered testing for a number of communicable diseases. One of the busiest operations the laboratories are involved in is testing and screening for sexually transmitted diseases. The processing of Neisseria gonorrhoeae cultures comprises a large portion of that work. Screening and testing for GC begins with the collection of a urethral, vaginal, anal or pharyngeal swab, which is plated onto culture media at the time of collection, usually in area hospitals, clinics or emergency rooms. Plated specimens are then placed in individual plastic bags with a carbon dioxide (CO2) generating tablet, which reacts to create an anaerobic environment to support growth of GC during transport. Laboratory slips, which identify the patient, specimen source and type of test to be completed, are either placed inside the plastic bags with the culture plates or are attached to the outside of the bags. The bags are then transported to public health laboratories for processing. Once received at the laboratories, approximately 24-48 hours later, the bags are opened and laboratory slips are removed. Technicians apply a few drops of 1% oxidase reagent from a plastic squirt bottle onto thoseculture plates with positive growth (usually about 10%-15% of all plates received). Neisseria species turn a dark purple or black color within a few minutes. Untreated colonies are gram-stained and/or sub-cultured. Technicians then treat the entire surfaces of all plates without growth (about 85%-90% of all plates received) with a larger volume of oxidase reagent to detect micro-colonies that might not be visible to the unaided eye, a technique referred to as "plate flooding." All plates are then discarded. Initial telephone interviews conducted by NIOSH with all seven laboratory directors revealed that five of the laboratories had one or more employees with dermatitis. The five laboratories employ a total of 102 workers, and are located in the cities of Jacksonville, Miami, Orlando, Tallahassee, and Tampa. The investigation focused primarily upon employees at these five laboratories. IV. EVALUATION DESIGN AND METHODS Employees at the five public health laboratories were evaluated by use of a self-administered questionnaire (see Appendix). The questionnaire was designed to evaluate and characterize laboratory personnel by age, race, sex, occupational history and exposures, personal and family history of allergy, and the occurrence of skin conditions within the past year.
Individuals were designated as cases of dermatitis if they reported a rash (red, inflammed skin) or dryness and chapping of skin, occurring on the upper extremities, within the past year. Cases who worked in the processing of GC culture plates, (which includes plating, incubating, gram staining, transporting, applying oxidase reagent, handling GC laboratory slips, etc.) were given closed skin patch tests to evaluate sensitivities to work related exposures. The skin patches contained test substances consisting of three different oxidase reagents at concentrations of 1% by weight in petrolatum; they included: 1) p-aminodimethylaniline oxalate, Miami laboratory; 2) p-aminodimethylaniline oxalate, Jacksonville laboratory; 3) N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride, Orlando laboratory; 4) and N,N-dimethyl-p-phenylenediamine monohydrochloride, obtained from the Cincinnati Health Department laboratory (compounds l and 2 above are identical). Also included in the patch testing were paraphenylenediamine at a concentration of 1% by weight in petrolatum, the carbonate (CO2- generating) tablet at a concentration of 10% by weight in petrolatum, and a blank of petrolatum. Paraphenylenediamine and the fourstructurally related oxidase compounds were tested at concentrations as recommended for paraphenylenediamine by the North American Contact Dermatitis Group (NACDG) and the International Contact Dermatitis Research Group (ICDRG).1 Where indicated by their use in the individual laboratories, liquid hand soaps and laboratory countertop disinfectants were incorporated into the patch test at a strength of 5% dilution in distilled water, or at actual working concentrations if these were less than 5% of full strength. Stronger concentrations of soaps or disinfectants were also tested by the uncovered patch test method.2 Standard Finn chambers on Scanpor were used to apply the closed patch test.3,4 Patch tests were applied to the lateral aspect of the upper arm, removed at 48 hours, and interpreted at 72 hours after initial placement. The test was interpreted at 72 hours as: negative (-), indicating "no reaction"; doubtful reaction (?+); weak (1+), indicating a non-vesicular reaction; strong (2+), indicating an edematous or vesicular reaction; extreme (3+), indicating a bullous or ulcerative reaction; and IR, indicating an irritant reaction, rather than an allergic skin reaction. The above grading scale recommended by Wilkinson et. al.,5 is the most widely used interpretation scheme among dermatologists today. A standard Chi-square test was then used to compare cases to noncases with respect to race, sex, history of atopy, history of eczema, family history of allergy, degree of handwashing, use of laboratory countertop disinfectants, and exposure to oxidase reagent and/or the CO2-generating tablet. A Fisher's Exact Test was used to compute p-values when expected cell sizes were less than 5 in the 2 X 2 contingency tables.6 Further analyses examined subgroups of the cases (i.e. sensitized cases and non-sensitized cases) compared to noncases. Next, a series of 2 X 2 contingency tables were constructed to look at a possible effect modification between exposure to oxidase and other risk factors for dermatitis Only non-sensitized cases and noncases were used in the analysis. Sensitized individuals were excluded in the comparisons. The final analyses involved the use of Mantel's Chi-square test for trend(7) to incorporate duration and intensity of exposure into the analyses. Exposure variables were developed using the worker's length of employment in the laboratories, the number of years of their exposure to the oxidase reagents and CO2-generating tablets, and the average number of culture plates they applied oxidase reagent to(and/or plates handled and contained in plastic bags with the CO2-generating tablet) in an average week. For example, the exposure variable OXDOSE was calculated as the product of the average number of plates oxidaswas applied to in a typical workweek multiplied by the total number of weeks worked at this job. The exposure variable (OXDOSE) had a very high variance; therefore, Logl0 values of OXDOSE were used in the test for trend analyses. Five levels of exposure were used over the range of Logl0 OXDOSE values, and this was
done by two methods. Cases were compared to noncases using levels of exposure determined by equal increments of exposure over the dosage range, and then by an equal distribution of study subjects over the dosage intervals. These comparisons were repeated for non-sensitized cases and sensitized cases. In the test for trend using only sensitized cases and exposed noncases, two exposure categories were used. This was because the small number of sensitized cases did not allow at least one member of that group to be present in each dosage interval when greater than two intervals were used, and there were no sensitized cases in the zero exposure category. V. EVALUATION CRITERIA Di- and tetra-methyl-substituted paraphenylenediamine compounds and their mono- and dihydrochloride salts are currently used as oxidase reagents at public health, private and hospital based sexually transmitted disease laboratories and microbiology departments for the preliminary identification of Neisseria gonorrhoeae species in culture growths. These compounds are very similar to p-phenylenediamine (PPD) (FIGURE 1), which is used in permanent hair dyes, fur dyes, leather processing, rubber vulcanization, printing inks, photographic developing, x-ray fluids, lithography, and in the manufacture of azo dyes. l.
Human Health Effects Although there are no published reports of health hazards associated with di- and tetra-methyl-substituted paraphenylenediamine compounds (oxidase reagents), PPD and its derivatives are known to cause adverse health effects in other groups of workers and consumers. Several reports have linked the use of PPD in the fur-dyeing industry with cases of occupational contact dermatitis and asthma.8 Contact dermatitis has also been reported secondary to wearing furs dyed by PPD compounds9. Paraphenylenediamine and closely related chemical derivatives (especially isopropyl-aminodiphenylamine or IPPD) are used as accelerants in the vulcanization of rubber and as antioxidants in the final product. Rubber workers have been identified as a high risk group for contact dermatitis as a result of their close work with chemicals in general, and more specifically due to work with PPD related derivatives.l0,ll IPPD sensitivity has even been reported to develop in one purchaser of a new automobile, who, after several washings of the vehicle, developed allergic contact dermatitis to IPPD contained as an antioxidant in the car's tires and bumper guards.l2 The use of paraphenylenediamine as an antioxidant in the black rubber of eyelash curlers has resulted in contact dermatitis of the eyelids.l3,l4 PPD derivatives are used in the manufacture of azo and aniline dyes and inks. PPD has also been implicated as a cause of occupational dermatitis in a worker exposed to stamp pad ink.l5 The largest and most extensively studied group of workers exposed to PPD are hairdressers. These workers are commonly exposed to PPD contained in permanent hairdyes. Sensitization to PPD was reported to be 3l% among hairdressers with hand eczema in one study,l6 and as many as 45% of hairdresser patients in a more recent study were reported to have positive patch tests to PPD.l7 In addition to being a skin irritant, PPD is a potent skin sensitizer. Tests conducted in a normal, previously unexposed population produced sensitization in 53% of those individualsl8 (the standardized method of predictive testing used a modified Draize procedurel9 and employed 200 human subjects who were patch tested with l.0% concentrations of PPD). Human maximazation tests conducted by Kligman showed a l00% sensitization rate in 24 subjects.20 Another study suggests that PPD compounds alone are responsible for as much as 8% of all cases of occupational dermatitis in Sweden.2l Further evidence of the strong sensitizing ability of PPD may be supported by the FDA complaint file in l974, where as many as l.9% (639) of all consumer complaints were registered against oxidative hair
dyes that contain PPD or its close chemical derivatives.22 Hair-dye users are, in fact, cautioned to patch-test themselves behind the ear prior to each use of the dye. The use of PPD and its close chemical derivatives is widespread throughout industry, and cross-sensitization to the derivatives is known to occur. In addition, cross-reactions may occur in individuals secondary to cross-sensitization between PPD (as well as close chemical derivatives of PPD) and a number of other compounds and medications. For instance, PPD-sensitized individuals have had reported cross-reactions with azo and anthraquinone dyes, local anesthetics (procaine and benzocaine), sulfonamides, para-aminosalicylic acid, hydrochlorothiazide, carbutamide, pyrogallol and para-aminobenzoic acid (PABA)-based sunscreens.23 Individuals sensitive to PPD and its closely related chemical derivatives are at risk for cross-reaction with other compounds and medications, even though the risk for this is usually low. A number of epidemiologic studies have attempted to determine whether there is an association between the use of hair dyes and cancer.24-28 The findings have been equivocal and conflicting. One NIOSH study involving the analysis of 4l7,795 Social Security disability awards made to female workers between l969 and l972 showed elevated proportional morbidity ratios among cosmetologists and hairdressers for cancer of the digestive organs, respiratory system, trachea, bronchus and lung, breast and genital organs.29 Although such findings are consistent with the hypothesis that cosmetologists and hairdressers may be at risk of developing a neoplasm due to occupational exposures (e.g. to PPD and its chemical derivatives), these workers come into contact with a large variety of substances, only one of which is PPD. As such, it is not possible to attribute any excess incidence of cancer to hair dyes in general, or to any singular chemical contained in their formulations. 2.
Toxicity Data and Laboratory Studies Oxidase reagents currently in use in laboratories for the identification of N. gonorrhoeae species are the following: l) N,N-dimethyl-paraphenylenediamine and its mono- and dihydrochloride salts; 2) N,N-dimethyl-paraphenylenediamine oxalate (p-aminodimethylaniline oxalate); and 3) N,N,N'N'-tetramethyl-paraphenylenediamine dihydrochloride. Of the aforementioned compounds, very little or no data was found in the literature with respect to human or animal toxicity except for the compound N,N-dimethyl-paraphenylenediamine. The lowest published toxic dose for human skin of this latter compound was reported to be l4 mg/kg.30 The lowest lethal dose by oral ingestion (LDLo) in the rat for this compound was 50 mg/kg.3l The LDLo in rats for N,N-dimethyl-paraphenylenediamine monohydrochloride was l00 mg/kg.32 Although no toxicity data exists for N,N- dimethyl-paraphenylenediamine, N,N,N',N'tetramethyl-paraphenylenediamine dihydrochloride or para-aminodimethylaniline oxalate, some data does exist for very similar compounds. Paraphenylenediamine monohydrochloride has a reported LDLo of l00 mg/kg when administered orally to rats.33 PPD dihydrochloride was lethal to 50 percent (LD50) of rats when administered at a dose of l47 mg/kg.34 A review of studies concerning the carcinogenic risk of this chemical by the International Agency for Research on Cancer (IARC) in l978 deemed the data on PPD to be insufficient to make an evaluation regarding its carcinogenicity.35 A study completed the following year on the bioassay of this compound for possible carcinogenicity concluded "there was no convincing evidence that dietary administration of p-phenylenediamine dihydrochloride was carcinogenic in Fischer 344 rats or B6C3Fl mice."36 Tetramethyl-paraphenylenediamine has also undergone rudimentry testing for toxicity in rats. An oral LDLo for this chemical was reported at 500 mg/kg.37
The most extensive data on the toxicity of these compounds is found concerning paraphenylenediamine (PPD) itself. Mild skin irritation was shown when PPD was tested on skin at concentrations of 250 mg/24H in human subjects as well as dogs, rabbits, pigs and guinea pigs.38 The oral LD50 for rats exposed to PPD has been reported at 80 mg/kg and the LDLo was found to be at l00 mg/kg for cats and 250 mg/kg in rabbits.39-4l Hanzlik has reported an LDLo of l70 mg/kg in rats and 200 mg/kg by oral ingestion in cats.42 A TLV for PPD has been recommended at 0.l mg/m3 for skin as suggested by Goldblaat with regard to industrial exposure in Britain.43,44 VI. RESULTS Of the 102 workers employed at the five laboratories surveyed, 99 (97%) completed the self-administered questionnaire. The majority of respondents (68%) were female, almost half (46%) were white, and they ranged in age from 20 to 68 years, with a mean age of 42.6 years (TABLE 1). Thirty-four (34%) laboratory personnel reported a skin condition that met the case definition. When compared to noncases, cases did not differ significantly with respect to age, race or sex (TABLE 2). Furthermore, no association was seen between being a case and having a personal history of atopy, eczema or family history of allergy, the degree of handwashing or use of laboratory countertop disinfectants. The percentage of cases among laboratory workers using oxidase reagent was twice that of other workers, and this difference was unlikely to have been explained by chance (RR = 2.00, X2= 5.38, [CI] l.ll,3.60) (TABLE 2). This association was also noted for CO2-generating tablet exposure (RR = 2.25, X2= 7.67, [C.I.] l.30,4.82. Exposures to oxidase reagent and the CO2-generating tablet were very similar, and the following should be noted. Ten of the thirty-four cases of dermatitis had no exposure to the oxidase reagent and 8 had no exposure to the CO2-generating tablet. All cases exposed to oxidase (24) had simultaneous exposures to the CO2-generating tablets and only 2 of the 26 cases exposed to the CO2-generating tablet had exposure to that alone. Among the 65 noncases, thirty reported exposure to oxidase and 33 had exposure to the CO2-generating tablet. Again, all noncases exposed to oxidase reagent had simultaneous exposure to the CO2-generating tablet and only 3 noncases of the 33 exposed to the CO2-generating tablet had exposure to that substance alone. Thus, the close covariance of oxidase and CO2-generating tablet exposure did not permit assessment of a risk for dermatitis to either compound alone. Workers were skin patch tested if they satisfied the case definition for dermatitis and were exposed to some aspect of GC culture plate processing. Four cases were not patch tested since they did not meet the exposure criteria. Three other cases declined the skin patch test (two of whom had exposure to GC plate processing but not to oxidase reagent). Thus 27 of the 34 cases underwent patch testing. Seven (26%) of the 27 cases tested had positive reactions, all strong, to all 4 oxidase reagents (TABLE 3) and were considered sensitized to the oxidase reagents. The lowest possible sensitization rate among the 54 oxidase exposed workers was thus l3%, assuming all sensitized individuals were among those patch tested. Of the 24 cases reporting exposure to oxidase reagents, the sensitization rate was 29%. These individuals not only reacted to the specific oxidase reagent used in their respective laboratory, but also showed cross-sensitization to the other two chemically related reagents, which they had never worked with. Two of the seven oxidase-sensitized individuals exhibited a weak cross-sensitization to paraphenylenediamine. One of the seven individuals also showed sensitization to "Septisol," a laboratory countertop disinfectant solution. None of the individuals tested showed evidence of allergic skin reactions to CO2-generating tablets, or to liquid hand soaps. For purposes of further analysis, cases of dermatitis were sub-classified into sensitized (positive patch test) and non-sensitized cases to oxidase reagent. The group of non-sensitized cases is comprised of those workers with red rashes or dry chapped skin that were not found to have sensitivity to oxidase reagent on skin patch testing. Also included in this group are 3 cases who refused patch testing (none of whom had red, inflamed skin, and 2 who had no oxidase exposure), and four cases who had no exposure to any aspect of GC plate processing.
Only the exposures to the oxidase reagent and CO2-generating tablets were found to increase a subject's risk of sensitization (TABLES 4a & 4b). There were no statistically significant associations between any of the potential risk factors and non-sensitized case status. The next analysis examined the effect certain risk factors had on the risk of developing non-allergic (non-sensitized) dermatitis while controlling for oxidase exposure (TABLE 5). Workers exposed to oxidase reagent and certain other risk factors were not found to be at greater risk than workers exposed to oxidase reagent alone. However, for workers exposed to oxidase reagent, excessive handwashing was protective against non-allergic dermatitis. On the average, sensitized workers applied oxidase to three times as many culture plates as the oxidase exposed noncases (TABLE 6). Little difference was seen between non-sensitized cases and noncases with respect to oxidase exposure. The mean total culture plates to which oxidase was applied by a worker during their career (OXDOSE) for non-sensitized cases and oxidase exposed noncases was 256,990 and 253,6l3, respectively. With regard to the CO2 tablet exposure, exposed noncases handled l.4 times as many culture plates in plastic bags containing the CO2-generating tablet as did sensitized cases. Little difference was seen between non-sensitized cases and exposed noncases with regard to this exposure (the mean CO2 dose for non-sensitized cases and CO2 tablet exposed noncases was 2l8,667 and 2l7,3l5 total culture plates handled respectively). A general test for trend45 was computed employing the Log10 values of cumulative oxidase reagent exposure (OXDOSE). The relative risk for contact dermatitis (as defined by questionnaire) increased with increasing exposure to oxidase reagents (TABLES 7 and 8). A slight drop in the risk of dermatitis was noted in the group with greatest exposure, compared to the preceding group. The X2 tests for trend using equal dosage intervals and equal distribution of cases and noncases were both highly significant (X2= 7.94, p