NIOSH Hazard Review: Carbonless Copy Paper/Summary and Conclusions

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5 Summary and Conclusions

Overall, the toxicologic, epidemiologic, and experimental studies reviewed in this document indicate that exposure to CCP has been associated with the following adverse health effects: irritation of the skin and mucous membranes of the eyes and upper respiratory tract, allergic contact dermatitis (rarely), and some systemic reactions (rarely). The evidence regarding each of these possible health effects is summarized in this Chapter.

5.1 Irritation of the Skin, Eyes, and Upper Respiratory Tract

Evidence in the scientific literature indicates an association between exposure to some types of CCP and symptoms consistent with irritation of the skin, eyes, and upper respiratory tract. The primary evidence for an association comes from human studies. Irritative symptoms of the skin, eyes, and upper respiratory tract have been observed in numerous case reports and case series. Associations between irritative symptoms of the skin, eyes, and upper respiratory tract and CCP exposure have also been generally observed in cross-sectional epidemiologic studies of CCP-exposed workers.

A potential source of bias in the epidemiologic studies is overreporting of symptoms by workers who are already aware of a possible association between CCP exposure and irritative symptoms of the skin, eyes, and upper respiratory tract. This form of bias is often referred to as "recall bias" and is well recognized to be an important factor in epidemiologic studies in which symptoms or exposures are identified by

questionnaires administered to the study subjects. The potential for recall bias may have been exacerbated by the use of leading questions such as "Do you think the paper makes you itch?" (e.g., Menné et al. [1981]). A positive exposure-response relationship was observed between increasing CCP exposure and the prevalence of irritative symptoms of the skin, eyes, and upper respiratory tract in all of the studies that examined this issue; but the strength and statistical significance of the exposure-response relationship varied dramatically from report to report. The studies that examined an exposure-response are summarized in Table 5–1. Less potential exists for subjective report biases to influence a dose-response relationship than for such biases to influence an overall relationship with CCP. For subjective report biases to be important, study subjects with high CCP exposures would need to report symptoms more often than those with moderate or low CCP exposures. Though such a scenario is possible, it is less likely than for people with any CCP exposure to report symptoms more often than people with no exposure. Selection bias is also a major concern in the cross-sectional studies that had low participation rates, such as the study by Fristedt and Pettersson [1980]. It is possible that in these studies, subjects with symptoms would have been more likely to return the questionnaires than were subjects without symptoms.

Potential biases in the epidemiologic studies could also have led to an underestimation of
Table 5–1. Summary of studies that examined exposure-response relationships between CCP handling and irritative symptoms of the skin, eyes, or upper respiratory tract
Study Number of cases[1] Frequency of handling (sheets/time period) Reported irritative symptom prevalence (%)
Kolmodin-Hedman et al. 1981 20 0 10
145 NR[2] 32
12 1,000/day 92
Menné et al. 1981 NR 0–10/day 5
10–50/day 15
>50/day >20
Sondergard 1981 NR <100/day 57.6
100–150/day 66.7
250–1,000/day 93.5
>1,000/day 100
Kleinman and Horstman 1982 13 1–10/day 18.8
23 11–50/day 29.9
31 >50/day 41.3
Norbäck et al. 1983b NR CCP<150/day 26
CCP≥150/day 58
Messite and Baker 1984 NR Low exposure 0
Heavy exposure 30
Olson and Mørck 1985 26 0–5/day 0
26 6–20/day 0
28 21–75/day 32
25 76–250/day 56
24 251–2,000/day 71
Skov et al. 1989 1,648 Monthly or less 24
1,290 <25/week or day 32
183 >25/week or day 43
Omland et al. 1993 34[3] 0/day 20
10 100–750/day 40
10 >750/day 60
  1. Cases are individuals with irritation of the eyes, nose, upper respiratory tract, or skin.
  2. NR=not reported.
  3. Based on repeated measure in group of 18.
the health effects associated with CCP. In these cross-sectional studies, workers who reacted to CCP might have left the workforce and thus would not have been included. In addition, since many of the researchers did not classify their subjects by exposure level, the overall effect could have been diluted by the mix of workers with high and low potential for CCP exposure.

The strongest evidence for an association between symptoms and CCP exposure comes from the studies of indoor air quality [Skov et al. 1989; Mendell 1991; Zweers 1992; Jaakola and Jaakola 1999]. These studies report a positive (and in several cases a statistically significant) association between CCP exposure and symptoms of skin, eye, and upper respiratory tract irritation (Table 5–2). These are the least susceptible to recall bias because they were not conducted in workplaces where concerns about CCP or other indoor pollutants played a role in their selection for study. Also, none of the indoor air studies were designed primarily to address the CCP question; hence investigator bias is also less likely. These studies used the most rigorous epidemiologic study designs, and the investigators were able to control for a number of potentially confounding exposures when examining the association between symptoms and CCP exposure. Determining whether associations observed in epidemiologic studies are causal is frequently difficult given the observational nature of these studies and the possible influence of confounders and other sources of bias. Such is certainly the case with the epidemiologic CCP literature. Hill [1977] has developed useful criteria for evaluating causality using all of the available data. Epidemiologists have widely adopted these criteria for evaluating the evidence of causality in the epidemiologic literature. The criteria include (1) the strength of the association, (2) the consistency of the association,

Table 5–2. Elevated ORs for CCP exposure and irritation of the skin, eyes, nose, or respiratory system reported in the indoor air cross-sectional studies
Authors Health effect OR[1] 95% CI
Skov et al. 1989 Mucosal irritation 1.3 1.1–1.6
Zweers et al. 1992 Oronasal symptoms 1.18 1.0–1.39
Eye symptoms 1.13 0.96–1.33
Mendell 1991, Fisk et al. 1993 Eye, nose or throat symptoms 1.6 1.0–2.6
Chest tightness/difficulty breathing 2.3 1.1–4.9
Jaakkola and Jaakkola 1999 Eye symptoms 1.56 1.17–2.08
Nasal symptoms 1.49 1.19–1.88
Pharyngeal symptoms 1.89 1.27–2.62
Skin symptoms 1.68 1.19–2.39
Chronic bronchitis 1.79 1.31–2.45
Cough 1.43 1.14–1.78
  1. Abbreviations: CI=confidence interval; OR=odds ratio.
(3) specificity, (4) relationship in time (temporality), (5) biological gradient, (6) biological plausibility, (7) coherence, (8) experimental

evidence, and (9) reasoning by analogy. The following sections describe these criteria and use them to evaluate the reported associations between CCP exposure and irritation of the skin, eyes, nose, and upper respiratory tract.

5.1.1 Strength of the Association

Associations that are large in magnitude are considered more likely to be causal, since they are less likely to be explained by confounding or other forms of bias. In the cross-sectional studies, weak to moderate associations were observed between CCP exposure and irritation of the skin, eyes, and upper respiratory tract. The odds ratios (ORs) reported in the cross-sectional studies summarized in Table 5–2 were approximately between 1.1 (e.g., Zweers [1992]) and 2.3 (e.g., Mendell [1991]). The strength of association for rate (or odds) ratios that are 1.2 to 1.5 and 1.5 to 3.0 has been interpreted as being weak and moderate, respectively (see Monson [1980], p. 94). It should be recognized that the size of the odds ratios are limited by the relatively high background rates of the symptoms studied. Many of the other cross-sectional studies (i.e., non-indoor air studies) did not include an unexposed population, and thus it is difficult to judge the strength of association in these studies. It is noteworthy that the prevalence of symptoms among workers with extremely high CCP exposures (i.e., $1,000 sheets/day) was between 92% and 100% in two of the non-indoor air cross-sectional studies (Table 5–1), which suggests a strong association among highly exposed workers.

5.1.2 Consistency

Consistency refers to the repeated observation of similar findings in numerous study settings. The case studies and case series reports are consistent insofar as they report similar symptoms involving the skin and mucosal membranes of the eyes and upper respiratory tract. However, this apparent consistency might be partly a reporting bias that occurs because investigators have read previous case reports and are more likely to report findings that are similar to those previous reports. Perhaps more convincing is the fact that the cross-sectional epidemiologic studies were generally consistent (see Table 4–3) in associating skin, eye, and upper respiratory symptoms with exposure to CCP. Associations of CCP with other symptoms such as headache and fatigue have not been consistently observed in these studies. Overall, the epidemiologic studies are judged to be relatively consistent in reporting irritative symptoms of the skin, eyes, and upper respiratory tract.

5.1.3 Specificity

Specificity requires that an exposure be associated with a single specific effect. Furthermore, if a disease has no other major risk factors (e.g., asbestos and mesothelioma), the association is often very credible and the studies are the least susceptible to recall bias. The irritative symptoms of the eyes, skin, and upper respiratory tract reported in CCP studies are common effects with many risk factors. Ocular and upper respiratory tract irritative symptoms in particular can be triggered by many exposures encountered in the indoor environment and are quite prevalent in many office buildings. Thus the irritative symptoms of the eyes, skin, and upper respiratory tract that have been associated with CCP exposure are not specific to CCP. On the other hand, the studies have been relatively consistent in reporting an association between CCP exposure and irritative symptoms of the eyes, skin, and upper respiratory tract. These symptoms commonly occur together with exposures to an irritant and thus should probably be viewed as a single effect and consistent with the specificity criterion.

5.1.4 Relationship in Time (Temporality)

Temporality requires that the exposure precede the disease and that the effects follow a course in time that is physiologically plausible in relation to the exposure. In the epidemiologic studies, it can be reasonably assumed that the CCP exposures preceded the observed symptoms or signs. Furthermore, several of the case reports describe symptoms or signs of disease that subsided or disappeared after the subject left work or after the CCP exposure was removed. Thus these human studies meet the temporality criterion for the irritative symptoms of the eyes, skin, and upper respiratory tract associated with CCP exposure.

5.1.5 Biological Gradient

Biological gradient refers to evidence for a dose-response (or exposure-response) relationship. A dose-response relationship is viewed by most epidemiologists to be strong evidence for causality. A dose-response relationship is less likely to be explained by reporting bias or confounding than is an overall measure of association (i.e., a yes/no exposure). However, it is possible that such a dose-response relationship could be produced by confounding.

A positive dose-response relationship between the frequency of handling CCP and the prevalence of irritative symptoms of the eyes, skin, and upper respiratory tract was reported in the nine studies that examined this relationship (Table 5–1). Recall bias might explain these relationships in some studies. However, it is unlikely to explain the relationships observed in the study by Skov et al. [1989], which was one of the indoor air quality studies that was not conducted at a building with previous complaints related to CCP. Overall, these studies demonstrate a biological gradient by providing consistent evidence for an exposure-response relationship for irritative symptoms of the eyes, skin, and upper respiratory tract associated with exposure to CCP.

5.1.6 Biological Plausibility

Biological plausibility exists when an association is consistent with what is known about the biology of the disease. The biological plausibility of the symptoms associated with CCP exposure is supported by the presence of several well-known irritants in some formulations of CCP (e.g., formaldehyde, isocyanates, phthalates, acrylates, glutaraldehyde, amines, and kerosene). For example, in seven studies of CCP and formaldehyde, nearly all exposure measurements exceeded the NIOSH REL (but not the OSHA PEL) for formaldehyde [Chrostek and Moshell 1982; Gockel et al. 1981; Hazelton Laboratories 1985; Apol and Thoburn 1986; Chovil et al. 1986; Omland et al. 1993; Zimmer and Hadwen 1993]. The biological plausibility of the irritative effects is further supported by the similar effects observed in animal studies. Irritation of the skin or respiratory tract has been demonstrated in several studies of animals exposed to CCP or its components (e.g., see Certin and Zissu [1983]; Wolkoff et al. [1988]; Anderson [1992]). Irritation of the skin was reported in a number of the industry-sponsored toxicologic studies reported to the NIOSH docket, although these reactions did not indicate primary skin irritation according to the regulatory criteria established by FDA. In addition, the positive reactions observed in these studies were generally due to exposures to CCP components in liquid form. Users of CCP are not exposed to these substances in liquid form, and it is therefore unlikely that they would experience such high levels of exposure.

Understanding the mechanism by which an exposure causes a health effect adds credence to a causal association. The mechanisms involved in the irritative symptoms of the eyes, skin, and upper respiratory tract associated with CCP exposure have not been established. In fact, it is unclear which of the CCP components might be responsible for these symptoms, although (as mentioned above) chemicals in some types of CCP are known irritants. Few studies have included ordinary bond paper as a control for mechanical abrasion from handling paper or for exposure to chemicals (such as formaldehyde) that are contained in ordinary paper. However, in the few studies that compared CCP with ordinary bond, the irritative effects were clearly greater for CCP (i.e., Nilzen [1975], Norbäck et al. [1983b], Morgan and Camp [1988], and Koenig [1988]). An understanding of the mechanism should not be required for inferring causality. As Hill [1977] suggested, "What is biologically plausible depends upon the biological knowledge of the day." In numerous examples, causal associations have been identified well before the underlying biological mechanisms were understood (e.g., smoking and lung cancer). Overall, reasonably supportive evidence exists for the biological plausibility of the association between CCP exposure and the irritative symptoms of the eyes, skin, and upper respiratory tract observed in the epidemiologic studies.

5.1.7 Coherence

Coherence requires that the observed association not conflict with what is known about the natural history and biology of the disease. The distinction between this criterion and biological plausibility is a fine one. An example given by Hill [1977] is that the association between lung cancer and smoking is coherent with the temporal rise that has taken place in both variables over the last century. The reports in the literature of an association between exposure to CCP and irritative symptoms of the eyes, skin, and upper respiratory tract are not in conflict with current knowlege of the biology of these health effects. One apparently contradictory fact is that health-related inquiries to CCP manufacturers have reportedly decreased from 1987 to 1996, dropping from approximately 130 to 50 inquiries per year [letter to the NIOSH docket from Robert Tardiff, October 6, 1998]. This decrease has occurred despite increases in the production of CCP from approximately 85,000 to 100,000 tons/year over the same period. However, increases in production would not necessarily lead to increased exposures in offices and other situations where CCP is used.

Thus it is unclear whether the number of people exposed and the level of exposure have dropped or increased during this period. Changes in the formulation of CCP during this period could also explain the decrease in complaints. Therefore, the coherence criterion contributes little to determining causality for the irritative symptoms of the eyes, skin, and upper respiratory tract associated with CCP exposure.

5.1.8 Experimental Evidence

Experiments can provide the strongest evidence for causality, but such information is rarely available for toxic effects in workers. In the case of CCP, a few experimental studies in humans have demonstrated irritative symptoms and signs with exposure to some types or components of CCP. Nilzen [1975] reported weak to moderate signs of skin irritation among atopic persons exposed to CCP with skin-prick testing, but the same reactions were observed with exposure to ordinary bond paper. Nilzen [1975] also reported symptoms consistent with nasal irritation in subjects exposed to vapors from CCP or bond paper, but the CCP caused a stronger reaction. Another study measuring the effects of CCP on nasal passages reported signs consistent with nasal irritation and congestion [Morgan and Camp 1986; Koenig 1988]. In an industry-sponsored study, a high percentage of subjects (40%) demonstrated irritation of the eyes, skin, or nose when they used scissors to cut one particular type of CCP (Hill Top Research, Inc., Report 83–0965–70), but not when they cut bond paper. Signs of dermal irritation (e.g. Hill Top Research, Inc., Report 79–0085–73) were observed in some of the RIPT studies that were submitted to the 1987 docket. However, the use of the products tested in these studies has generally been discontinued. Only very mild signs of skin irritation were observed among subjects in the more recent RIPT studies that tested CCP materials in current use and that were submitted to the NIOSH docket in 1997. Generally less than 2% of subjects demonstrated very mild skin irritation in these studies, but higher percentages (e.g., >10%) were reported for some of the materials tested in two of the more recent studies submitted to the docket (Hill Top Research, Inc., 1998 and 1999). However, these two studies were not considered by the investigators to be positive for irritation. These experimental studies are not subject to the potential recall bias of the epidemiologic studies, since they used objective tests. Also, it is very unlikely that the positive findings in some of these studies could be explained by other forms of biases or chance. The inconsistency between the findings in these studies may be explained by differences in the types of CCP tested or other differences in study design. It is unclear how relevant these experimental models are, since the exposure from patch testing is quite different from exposures among workers who use CCP in offices and elsewhere. These studies also have the potential for a negative selection bias, since they generally involved healthy volunteers and could thus have excluded sensitive persons.

5.1.9 Reasoning by Analogy

Reasoning by analogy refers to making an analogy with the known health effects for a similar exposure. For example, the fact that a drug has characteristics similar to Thalidomide (a known teratogen) provides support for a causal relationship between this drug and birth defects. No useful analogies exist for CCP; thus this criterion is not useful for judging causality in this case.

5.1.10 Summary

In summary, the Hill criteria for consistency, specificity, temporality, biological gradient (dose-response), biological plausibility, and experimental evidence support a casual association between CCP exposure and irritative symptoms of the skin, eyes, and upper respiratory tract. Because the associations observed in the epidemiologic studies were generally weak to moderate, the evidence does not fully satisfy the criterion for the strength of association. Although not all of the criteria are fully met, Hill [1977] points out that none of the criteria can provide absolute proof of a cause-and-effect relationship, and none should be used as an absolute requirement for proof of a cause-and-effect relationship. Furthermore, not all of these criteria are equally important. The dose-response relationship observed and the experimental evidence reported for some CCP exposures and irritative symptoms of the eyes, skin, and upper respiratory tract provide the strongest evidence for a causal association.

5.2 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 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 shown in Table 4–12, 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 the more recent formulations of CCP.

5.3 Systemic Reactions

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]. One patient challenged by CCP handling became symptomatic approximately 15 to 20 min after exposure and experienced swelling of the exposed hand, hives on the neck, changes in both the inspiratory and expiratory limbs of the flow-volume loop (suggesting upper airways obstruction), and elevated circulating levels of several arachidonic acid metabolites. Skin-prick testing with CCP dust was reported to be negative [Marks et al. 1984]. One patient who was challenged by rubbing 1% alkylphenol novolac resin dispersion onto the forearm became symptomatic approximately 15 min after exposure and developed hoarseness, wheezing, and angioedema of both arms. A subsequent challenge with this material was followed by hoarseness, wheezing, and angioedema at the challenge site. Video endoscopy of the larynx was interpreted as showing diffuse swelling and marked edema of the true vocal cords. Plasma histamine levels obtained at the onset and peak of symptoms were sixfold higher than the prechallenge level [LaMarte 1988]. Finally, one patient who was challenged by rubbing 1% alkylphenol novolac resin onto one arm was reported to have angioedema of the arm and hoarseness 30 min after challenge [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.

5.4 Conclusions

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 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.