NIOSH Hazard Review: Carbonless Copy Paper/Executive Summary
In 1987, the Occupational Safety and Health Administration (OSHA) requested that the National Institute for Occupational Safety and Health (NIOSH) investigate the validity of reported adverse health effects in workers occupationally exposed to chemicals contained in or released from carbonless copy paper (CCP). Because of limited published information, NIOSH issued a Federal Register notice soliciting information about possible adverse health effects from CCP exposure [52 Fed. Reg. 22534 (1987)]. On the basis of information available at that time, no strong conclusion could be reached concerning a consistent link between CCP and major health effects. Between 1987 and 1997, additional reports involving health problems potentially related to CCP were identified. Therefore, in 1997 NIOSH issued a second Federal Register notice soliciting new information [62 Fed. Reg. 8023 (1997)]. This report contains a review of the published literature on CCP and the submissions to the NIOSH docket from the two Federal Register notices.
CCP was introduced in 1954 by the National Cash Register Company as no-carbon-required (NCR) paper—an alternative to separate sheets of carbon paper [Sandberg 1955; Green 1955; Miller and Phillips 1972; Calnan 1979; Buring and Hennekens 1991]. A given CCP can vary greatly as to its constituents, weight and types of paper coatings, paper color, dye colors and combinations of dyes used on coatings, solvents and solvent mixtures (including variations from different suppliers), physical form of the paper (rolls versus sheets), and final form of the product (i.e., bound with adhesives). Thus the product known as CCP is not a single product but includes thousands of different and often unique products [Mead Corporation 1997]. This fact needs to be considered when interpreting the findings from the scientific literature.
About 10 years after the introduction of CCP, medical complaints began to be reported by office workers [North Carolina Medical Journal 1982; Magnusson 1974; Göthe et al. 1981; Buring and Hennekens 1991]. Since 1965, various health effects associated with exposure to CCP have been reported in the literature appearing from Denmark, Finland, England, Sweden, Germany, the Netherlands, France, Italy, Belgium, Japan, Norway, and the United States.
NIOSH has reviewed the published and unpublished literature on CCP. The following paragraphs summarize the findings from this review regarding the primary health effects associated with CCP exposure.
Irritation of the Skin, Eyes, and Upper Respiratory Tract
The most common findings from the human studies are symptoms consistent with irritation of the skin, eyes, and upper respiratory system following exposure to some types of CCP. These symptoms have also been described in numerous case reports and case series of persons exposed to CCP, and associations between these symptoms and CCP exposure have been observed in several cross-sectional epidemiologic studies. A positive exposure-response relationship between these symptoms and CCP exposure has also been observed in those studies that examined this relationship.
The cross-sectional epidemiologic studies have several major methodologic limitations that make them difficult to interpret. One major potential source of bias in these studies is overreporting of symptoms by workers who are already aware of a potential association between CCP exposure and irritative symptoms. This form of bias is often referred to as "recall bias" and is well recognized to be a potentially important factor in epidemiologic studies in which symptoms or exposures are identified by questionnaires administered to the study subjects. 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.
The strongest evidence for an association between symptoms and CCP exposure comes from the studies of indoor air quality. These studies report a positive (and in several cases statistically significant) association between CCP exposure and symptoms of skin, eye, and upper respiratory tract irritation. Of the studies reviewed in this document, the indoor air quality studies are the least susceptible to recall bias because they were not conducted in workplaces where specific concerns about CCP or other indoor pollutants were heightened by previous complaints. None of these indoor air studies were designed primarily to address the CCP question, hence investigator bias is also less likely.
Other information supports the plausibility of the findings from the experimental studies in humans. The plausibility of signs and symptoms of irritation associated with CCP exposure is supported by the presence of several known irritants and allergens (e.g., formaldehyde, kerosene, phthalates, acrylates, glutaraldehyde, amines, and isocyanates) in some types of CCP and by similar effects in experimental studies of animals. For example, in seven studies of CCP and formaldehyde, nearly all exposure measurements exceeded the NIOSH REL (but not the OSHA PEL) for formaldehyde [Norbäck 1983b; Gockel et al. 1981; Hazelton Laboratories 1985; Apol and Thoburn 1986; Chovil et al. 1986; Omland et al. 1993; Zimmer and Hadwen 1993]. Finally, laboratory experiments in humans support the plausibility of the associations between irritative symptoms and exposure to CCP. Signs consistent with irritation of the skin and/or the upper respiratory tract have been noted in a few of the experimental laboratory studies in humans. However, most of these studies failed to demonstrate any effects or showed extremely mild reactions to CCP exposure. Inconsistencies in the findings of these studies might easily be explained by differences in study design and particularly by differences in the types of CCP tested.
Allergic Contact Dermatitis
Several authors have reported cases of allergic contact dermatitis that appear to have been associated with CCP or its components [Marks 1981; Kannerva et al. 1990a,b, 1993; Shehade 1987]. Development of sensitization to CCP or its components was also reported in a few persons in several industry-sponsored repeated insult patch test (RIPT) studies (Report 77-512-70 and Supplemental Report 79-512b-70, Report 77-896-71, and Report 79-0085-73, all from Hill Top Research, Inc.; and Project SH-72-4, dated April 18, 1972, performed by the Shelanski Holding Company, Conshohocken, Pennsylvania, for Monsanto Co., St. Louis, Missouri). In 8 of 217 test materials, study investigators indicated that skin sensitization occurred in some human subjects. However, these studies were mostly judged to be negative for irritation by the investigators. Thus in a small proportion of the population, CCP or its components appear capable of inducing cell-mediated (type IV) immune response and allergic contact dermatitis, particularly under the intensive exposures associated with RIPT protocols. Cases of allergic contact dermatitis were reported only in RIPT studies from the 1970s that were submitted to the 1987 NIOSH docket; no cases were reported in the studies submitted to the 1997 docket. This fact indicates that the CCP component(s) responsible for the allergic contact dermatitis observed in the early studies may have been removed from current formulations of CCP.
Three patients with systemic reactions clinically suggestive of mast cell and/or basophil degranulation after cutaneous challenge with CCP or its components have been reported in two published case reports [Marks et al. 1984; LaMarte 1988]. These reports suggest that some CCPs or their components can induce reactions clinically compatible with those caused by mast cell and/or basophil mediator release. Immunologic sensitization was not adequately evaluated in these studies, and thus it is unclear whether an immunologic mechanism underlies these reactions. However, no additional reports were located in the peer-reviewed literature over the last 12 years. Thus, even if the reported reactions were referable to CCP exposure, systemic reactions of this type appear to be exceedingly rare. Furthermore, the relevance of these reports to current CCP exposures is uncertain.
On the basis of a NIOSH review of the scientific literature and information submitted in response to its 1987 and 1997 Federal Register notices, NIOSH concludes the following:
- The weight of the evidence supports the conclusion that exposure to certain types of CCP or its components has, under some conditions, resulted in symptoms of irritation of the skin and of the mucosal membranes of the eyes and upper respiratory tract.
- This conclusion is based primarily on interpretation of the evidence from the epidemiologic studies. Although the magnitude of the effects observed in these studies was only weak to moderate, these studies were reasonably consistent in reporting an association and evidence of an exposure-response relationship between CCP exposure and irritative symptoms of the eyes, skin, and upper respiratory tract. The plausibility of the epidemiologic evidence is supported by the presence of known irritants in some types of CCP, toxicologic studies that demonstrate mild irritation in laboratory animals exposed to CCP, and the evidence for respiratory and skin irritation in some of the experimental laboratory studies in humans. Some of the epidemiologic studies may have been biased, particularly by overreporting from study subjects who were already concerned about the potential effects of CCP exposure (i.e., recall bias). However, it is unlikely that recall bias could explain the associations observed between CCP exposure and irritative symptoms of the eyes, skin, and upper respiratory tract in the indoor air quality studies, since these studies were not conducted in an atmosphere of concern regarding the health effects of CCP.
- Exposure to CCP or its components may rarely cause allergic contact dermatitis.
- This conclusion is based on published case reports of allergic contact sensitization and results reported in several industry-sponsored RIPT studies. Cases of allergic contact dermatitis were reported only in RIPT studies from the 1970s that were submitted to the 1987 NIOSH docket; no cases were reported in the studies submitted to the 1997 docket. This fact may indicate that the CCP component responsible for the allergic contact dermatitis observed in the early studies was removed from the more recent formulations of CCP.
- Systemic reactions have occurred in a few persons exposed to CCP.
- This conclusion is based on the finding that three such cases have been reported in the peer-reviewed medical literature. No cases have been reported in the last 7 years, and thus there is no evidence that current exposures to CCP present a risk for this health outcome.
- Data are insufficient to evaluate claims of other adverse health effects (such as neurologic effects and reports of multiple chemical sensitivity [MCS]) that have been suggested in some of the clinical reports submitted to the NIOSH docket.
In conclusion, although the weight of the evidence indicates that exposure to CCP in the past has resulted in adverse health effects, it is uncertain whether current formulations of CCP represent a significant risk to exposed workers. 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. Recently conducted experimental studies in humans (RIPT studies) suggest that the potential for skin irritation from exposure to current formulations of CCP is nonexistent, or at most slight. However, it is unclear how well these experimental studies simulate the exposures and potential responses of CCP users—particularly heavy users. Data from industry reporting systems suggest no widespread problem and in fact indicate a decrease in health-related complaints in recent years despite an increase in CCP production. However, these passive reporting systems are unlikely to capture all or even most cases of CCP-related health effects, and changes in publicity about CCP may have caused fluctuations in the reporting of cases. Since the 1980s, no epidemiologic studies have been conducted to determine irritative symptoms among U.S. workers exposed to CCP [Mendell et al. 1991]. A positive epidemiologic study was conducted in Finland in 1991 [Jaakkola and Jaakkola 1999]. However, the relevance of these findings for U.S. workers may be limited because of differences between the CCP products used in Europe and the United States. Thus information is lacking about the prevalence of irritation of the eyes, skin, and upper respiratory tract among workers currently handling CCP in the United States.
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; proper housekeeping; minimal hand-to-mouth and hand-to-eye contact; and periodic cleansing of hands.
In addition, NIOSH recommends the following:
- CCP manufacturers and their suppliers are encouraged to follow best practices, such as the Product Stewardship Code of Management Practices [American Chemistry Council 2000]; they should also consider enhancing their product guidance to reflect that published studies indicate that irritative symptoms appear to increase with increasing exposure to CCP.
- CCP manufacturers and their suppliers should also consider how human test procedures (e.g., RIPT) can be modified by the use of standardized protocols that include proper controls (e.g., bond paper), tests that mimic high-use situations, and meaningful criteria for scoring and interpreting these tests to assess safety from skin contact (e.g., ASTM D 6355-98) [ASTM 1999]. Current best practices in the field of product testing may not be sensitive enough to identify mild skin irritants.
- As part of ongoing surveillance, CCP manufacturers and their suppliers may want to evaluate the frequency and severity of irritation in workers using CCP.
- Federal Register. See Fed. Reg. in references.