Centers for Disease Control and Prevention

“ The disease control expert’s preliminary investigation suggested that some persons with cases of gastroenteritis had eaten at salad bars at restaurants in the community before becoming ill. One week later, on about September 24, the disease control expert learned that there were additional cases of illness in the community and that some affected persons had been hospitalized because of their illnesses. ”

“ However, laboratory studies also have limitations that undermine their usefulness for judging the causal relationship between CCP exposure and health effects. First, these studies are largely limited to the inclusion of healthy volunteers. A consequence of this approach is that persons with a history of allergy or irritation reaction might be less likely to volunteer than those with no symptoms, thus creating selection bias. Second, it is unclear whether the exposures in laboratory studies are representative of those actually experienced by workers in the field. ”

“ NIOSH reviewed all of the industry-sponsored laboratory studies in humans submitted to its docket as a result of the Federal Register notices in 1987 and 1997. Most of these studies were RIPT studies, which are summarized in Table 4–12. The RIPT is a test method designed to evaluate the potential of a material to induce and elicit type IV skin sensitization reactions (allergic contact dermatitis) in humans [ASTM 1999] . In general, these tests were performed by administering multiple potentially sensitizing doses of study material as occlusive patch tests over a several-week period. ”

“ In Canada, Harris [1983] reported that the symptoms directly associated with use of CCP (and shown to decrease outside of work or at other tasks) develop primarily in office workers who use CCP and less in those who make it. He stated that the symptoms (1) appear to be quickly reversible when exposure ceases, (2) are rarely caused by allergic reactions, and (3) vary greatly from office to office (which may depend on combinations of factors including the brand of CCP, the intensity of use, and office conditions such as ventilation and humidity) . ”

“ No pattern was observed to identify the CCP component responsible for the mild skin irritation reported in humans. A total of 271 substances were tested in the allergic contact dermatitis animal model, and 13 were positive. This result suggests that CCP infrequently causes allergic contact dermatitis in animals. Whether materials with positive toxicological outcomes were actually marketed is unclear; but the general rationale for toxicity testing is to prevent the marketing of materials that may harm users. ”

“ Studies in 80 office workers observed only eye and respiratory tract irritation caused by CCP. Norbäck et al. [1983b] found no correlations between airborne solvent concentrations from CCP and the occurrence of irritative symptoms. Formaldehyde, glutaraldehyde, and the organic solvents in which the color formers are dissolved were studied under standardized conditions. According to the authors, the emission of aldehydes from CCP was too low to cause the irritative symptoms. The highest airborne concentration was that of kerosene, which could not be related to symptoms. ”

“ Symptoms of kerosene exposure include eye, skin, nose, and throat irritation; burning sensation in the chest; headache; nausea; weakness; restlessness; incoordination; confusion, drowsiness; vomiting, diarrhea; dermatitis; and chemical pneumonia (if liquid kerosene is aspirated) . Airborne exposures at concentrations cited in the CCP studies are not likely to lead to eye or upper respiratory irritation. Quantitation of skin exposure to kerosene from CCP has not been reported. However, skin contact with CCP containing kerosene or its components could result in skin irritation. ”

“ Ventilation studies: Four types of paper were used to examine the effect of ventilation on the concentration of formaldehyde in the chamber air. For each test, 120 sheets of paper were placed inside the chamber. Page turning, ventilation, and sampling all began at time zero. Pages were turned at the rate of 4 sheets/min for 30 min and were left exposed in the chamber for the final 30 mins. Ventilation and sampling were continuous for the full hr. Ventilation was simulated by forcing compressed air into the chamber and allowing the air to flow out through a hole in the rear of the chamber. ”

“ A number of studies on indoor air quality have associated CCP exposure (and other factors) with workers’ symptoms (Table 4-3) . Three indoor air quality studies—Knave et al. [1985] , Reinikainen et al. [1990] , and Thompson [l996] —are not included in this review because they were judged to be largely uninformative with respect to potential health effects associated with CCP exposure. One common limitation of the studies described below is that they generally include only two or at most three categories of CCP exposure and thus provide a very limited assessment of exposure-response. ”

“ Lack of a comparison group is particularly problematic when the cases involve common diseases or symptoms and when the exposure is relatively common (which is clearly the case with these reports for CCP exposures) . In the absence of a comparison group, case reports and series can provide the first clues to the identification of new diseases or exposure effects, and they are potentially useful for formulating research questions; however, the evidence usually cannot be used to test hypotheses [Buring and Hennekens 1991] . ”

“ Airborne concentrations of total dust, dust-bound solvent, solvent in the vapor phase, and formaldehyde were also determined in a laboratory situation using a 34-m3 room with an air-exchange rate of 0.8 times/hr. Thirty sheets of each type of paper were handled in a standardized procedure for 60 min. Table 3-3 shows that airborne solvent concentrations are generally low, and they are considerably lower in the office environment than in the printing shop. Area samples were also consistently lower than personal samples, suggesting that manual handling generates airborne solvent. ”

“ Slight irritation occurred when testing 50% kerosene (1 of 59) and 50% isoparaffins (1 of 59) . Slight redness (1 of 1) occurred with 100% alkylated benzene, but no reaction occurred at repeat testing with a 50% concentration in 54 test subjects. Two of five D-inks produced primary irritation at 5% concentration: the first ink resulted in a slight redness in 43% of patients (19 of 44) ; and at 1% concentration, the second caused slight redness in 59% of those tested (26 of 44) . "Itch" tests assessing skin response to a nonantigenic stimulus (histamine) were performed. ”

“ Three industry-sponsored tests evaluating the irritation potential of CCP under simulated conditions of office use were submitted to the NIOSH docket in response to the 1987 and 1997 Federal Register notices.
Hill Top Research, Inc., conducted a double-blind placebo study in which subjects were provided with scissors and asked on 4 consecutive days to cut up samples of paper for 60 min under controlled temperature and humidity (Hilltop Research, Inc., Report 83–0965–70) . Three types of CCP and a control ("white") paper were tested in random order by two groups of 10 and 9 subjects. ”

“ A 27-year-old woman in the United States had an 8-year history of pruritus, eye and throat irritation, hoarseness, irregular heartbeat, headache, nausea, tightness of the chest, shortness of breath, and fatigue within 30 min of exposure to CCP [Marks et al. 1984; Trautlein et al. 1984] . For 10 years, she had worked in the same factory, which printed, cut, collated, and packaged CCP. She reported that her symptoms became progressively worse as she processed greater amounts of CCP in her job of removing and stacking forms from a collating machine. ”

“ Symptoms improved in all four workers when they avoided exposure to CCP. Two of the four workers became so sensitized that they could not be in the vicinity of CCP without being hoarse. Medical evaluations confirmed acute systemic reactions to CCP (laryngeal edema and sixfold increases in plasma histamine levels) after blinded, provocative, cutaneous challenges with alkylphenol novolac resin, a component of CCP. Subsequently, both workers developed hoarseness as a response to other chemicals such as paint, wall paper adhesives, and colognes. ”

“ NIOSH recognizes that it may occasionally be necessary to limit CCP exposure in certain workers through administrative controls (such as job rotation) . But in most cases, implementing normal precautions and recommendations for maintaining acceptable indoor air quality should be adequate to reduce or eliminate symptoms. Good industrial hygiene and work practices are likely to prevent symptoms from potent irritants (such as formaldehyde) that may be emitted from CCP. These include adequate ventilation, humidity, and temperature controls ”

“ Of the 35 workers who were skin-patch tested with CCP, none had positive reactions. Environmental factors such as high temperature, low humidity, and dust were thought to be contributing. The authors concluded that it was difficult to decide which symptoms could definitely be correlated with CCP. The prevalence of complaints was 4% of the 3,000 workers who came in contact with CCP; but if slight complaints of doubtful origin were ignored, the prevalence was 2.4%. Symptoms were more severe in those predisposed to allergy, but no allergy to CCP components was demonstrated. ”

“ This study did not consider the effect of high local concentrations of solvent on the epidermis when a microcapsule fractures. Also unresolved are the relative skin exposures for workers in offices and printing plants. Although printing plant workers process a far greater tonnage of paper than office workers, its not clear whether printing plant workers have more or even as much skin contact as CCP users in offices. ”

“ The populations studied had not been selected on the basis of prior complaints or concerns about CCP. The response rate to the questionnaire was 81%, representing a study population of 2,678 (1,119 men and 1,559 women) . Of these workers, 910 were exposed to CCP. The outcomes studied included the work-related symptoms often associated with sick building syndrome as well as chronic respiratory symptoms and respiratory infections. Multivariate analyses controlled for building ventilation type in addition to a number of demographic, psychosocial, and other environmental factors. ”

“ Vesicular eczema developed on both hands but cleared over a 3-month sick leave followed by vacation. Upon returning to work, the worker relapsed.
Skin-prick testing was negative for 20 common allergens and natural rubber latex. On skin-patch testing using a series of standard European allergens and CCP, both CCP and one of the chemicals used to produce the microcapsules of CCP provoked a strong (3+) allergic reaction. Analysis of the paper showed that it contained enough DETA to induce allergic contact dermatitis. ”

“ Thus connecting the test results from pure compounds to finished products was not possible. None of the mutagenicity studies were positive, but not all substances were tested for mutagenicity. Another NIOSH docket submission from Monsanto is a series of 44 toxicity reports conducted by various testing laboratories on papers and dyes that were tested during the years 1978 to 1986. Each report consists of one to six toxicity tests that include oral and dermal toxicity, skin and eye irritation assessment, mutagenicity testing, and skin sensitization testing in animals. ”

“ The second exposure group of 15 workers processed the 42,000 returned forms over a 2-week period, checking and entering information into computers (about 280 per day per worker) . The comparison group was selected from 122 employees who worked in the same large office building and had returned completed questionnaires about symptoms and exposure to CCP. These questionnaires were administered weekly during the exposure periods. They included questions about CCP exposure, work with computers and photocopying, and subjective symptoms of skin and respiratory irritation. ”

“ Crude prevalence rates showed a dose-response between frequency of CCP exposure and mucous membrane symptoms:
With multiple logistic regression analysis, handling CCP weekly or daily had a significant effect on mucosal irritation (odds ratio [OR] =1.3, 95% confidence interval [CI] =1.1–1.6) , and handling CCP was the only exposure with a significant effect on general symptoms (see above; OR=1.6, 95% CI=1.1–1.7) . Also the authors commented that these office workers handled relatively small quantities of CCP.
Zweers et al. 1992. Zweers et al. ”

“ The CB coating may be applied in a separate plant area to the paper as it passes through a series of dryers and is rewound on a roll.
The CF and CB coatings are prepared in the coater preparation area. The phenolic resins (1- to 10-μm or 1- to 3-μm size range is preferred [Mathiaparanam 1992] ) may be prepared by grinding the resins to specific-size particles, or they may be purchased already prepared. The already prepared resin reduces exposure to phenol among workers who handle the coating preparation and is the preferred option for today's technology. ”

“ Cullen [1987] proposed the most commonly referenced definition of MCS: an acquired disorder characterized by recurrent symptoms that (1) are referable to multiple organ systems, (2) occur in response to demonstrable exposure to many chemically unrelated compounds at doses far below those known to cause harmful effects in the general population, and (3) do not correlate with any single widely accepted test of physiological function. ”

“ He noted an absence of documented cases of skin disorders among workers in the manufacturing industry—despite the fact that workers in this industry would be expected to have much higher exposures than office workers. On the basis of both his review of the literature and his experiences as a consultant for a manufacturer of CCP, Murray concluded that although individual cases of sensitivity to CCP components would continue to be reported, a "negligible" threat is posed to the health of producers and users. ”

“ Exposed workers reported large decreases in most symptoms during the second period, when they handled the completed forms with broken microcapsules (280/day) rather than the fresh forms (1,200 per day) during the first period. These symptom decreases during the second period included a sixfold decrease in skin irritation and threefold decreases in eye irritation, pruritus, nasal congestion, nose-bleed, and cough. However, increases occurred in facial erythema, rash, and runny nose. Figure 4-2 shows the relationship between pruritus and increasing CCP exposure. ”

“ Two contained unknown solvents. Among the workers who handled only clay-based paper at the insurance office, the frequency of mucous membrane symptoms was approximately equal to that of the comparison group. The skin (hands and face) and eye symptoms were considered likely to be related to CCP exposure, since their frequency (21% among insurance workers versus 67% in laboratory workers) was much higher than that of the comparison group (5%) . ”

“ The authors concluded that it was probably the oily constituents of the papers that produced the observed irritation of the skin and mucosa of office workers. However, they also noted that the animal test results are probably more grave than those experienced by humans, since human exposures were limited to several hundred micrograms on the fingers at the end of a day of handling. ”

“ At the request of the management of the Defense Industrial Supply Center in Philadelphia, Pennsylvania, NIOSH evaluated possible excess cancer deaths and respiratory problems encountered among workers [Bennett and Chrostek 1986] . Measurements were taken for carbon dioxide, carbon monoxide, temperature, relative humidity, organic vapors, and airborne dust. Samples were taken of insulation, solvent cleaners, and CCP used at the facility. ”

“ Only a few cases of systemic reactions and allergic contact dermatitis have been reported in the United States or in Europe, which suggests that the risk of these serious outcomes is extremely low given the large number of people who have been exposed to CCP over a period of many years. ”

“ Selection bias is also a major concern--particularly in studies with a low participation rate, where subjects with symptoms may have been more likely to return the questionnaires. These studies may also have been biased toward observing no effects by (1) analyzing a mix of workers with high and low potential for CCP exposures and (2) including only active workers and thus excluding workers who may have left the workforce as a result of adverse health effects related to CCP exposure. ”