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Gulf War and Health: Volume 2: Insecticides and Solvents (2003)

Chapter: 9. Additional Health Effects

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Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

9
ADDITIONAL HEALTH EFFECTS

This chapter reviews the evidence concerning long-term, nonmalignant health outcomes that persist after cessation of exposure to insecticides or solvents. The immediate health effects of exposure to those agents are described in Chapters 3 and 4. In this chapter, a number of health outcomes are discussed with background information presented before the descriptions of epidemiologic studies. The committee considers case studies and case series for the health outcomes described in this chapter, because some of these outcomes may be difficult to investigate epidemiologically due to their rare occurrence or lack of reporting mechanisms (such as disease registries). For some health outcomes discussed in this chapter, such as renal effects, there is a body of literature only on exposure to solvents.

APLASTIC ANEMIA

Aplastic anemia is a disorder of hematopoiesis that occurs when the bone-marrow stem cells fail to produce mature blood cells. Some patients with aplastic anemia progress into myelodysplastic syndromes. Although aplastic anemia can occur at any age, it is most common in young adults and the elderly. About 1000 new cases are diagnosed each year in the United States (Castro-Malaspina and O’Reilly, 1998). The disease is more prevalent in Asia than it is in Europe or North America. In a small percentage of cases, aplastic anemia is an inherited condition (such as Fanconi’s anemia). Risk factors for acquired aplastic anemia include exposure to certain drugs (such as chloramphenicol or sulfonamides), industrial chemicals (such as benzene), high doses of radiation, chemotherapy treatments, viral infections (such as Epstein-Barr virus), and immune diseases. However, for more than half the reported cases a cause cannot be determined.

Epidemiologic Studies of Aplastic Anemia and Exposure to Insecticides

Several studies have examined the risk factors for aplastic anemia in relation to exposure to insecticides and pesticides. In response to concerns about possible high rates of aplastic anemia in Thailand, a population-based, case-control study began in Bangkok in 1989 and was expanded in 1991 to include two rural regions of Thailand (Issaragrisil et al., 1996). Patients and control subjects were interviewed about medical and occupational histories, drug and pesticide use, and chemical and radiation exposures. Issaragrisil and colleagues (1997) examined grain farming and pesticide use in a study of 81 cases of aplastic anemia in Khonkaen, a rural region in Thailand. That study involved 295 control subjects selected from the same medical institutions where the cases had been identified. The researchers reported an increased risk associated with occupational pesticide exposure

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

(relative risk [RR]=2.7, 95% confidence interval [CI]=1.1–6.6). For a subset (n=10) exposed to organophosphate insecticides, there was an elevated but equivocal increase in risk (RR=1.9, 95% CI=0.6–5.9). The authors state that selection bias is improbable as an explanation for the associations because of the low refusal rate, but they do not discuss the limitation of hospital-based case-control studies in selecting control patients or the possibility of recall basis.

A companion study examined recent household insecticide use in the entire group of cases (n=253) and controls (n=1174) in Bangkok and in two rural regions of Thailand (Kaufman et al., 1997). Risk estimates were calculated for use of specific insecticides and for groups of insecticides, and multiple logistic regression analyses were used to control for confounding by concomitant use of more than one insecticide and for demographic variables. A moderate increase in risk was seen in the comparison of cases (n=32) and controls (n=117) that reported any exposure to an insecticide product that combined dichlorvos, propoxur, and cyfluthrin (a pyrethroid) (RR=1.7, 95% CI=1.1–2.8). However, for subsets of this exposure group, associations were increased but not statistically precise: regular use (RR=1.6, 95% CI=0.9–2.9) and application by the subject (RR=1.8, 95% CI =0.8–4.1). Evaluation of exposure to the classes of insecticides showed no trend with increasing exposure for the subsets that reported any exposure to carbamates (n=36) (RR=2.1, 95% CI=1.2–3.7), regular use of carbamates (n=19) (RR=2.0, 95% CI=1.0–4.1), or carbamates applied by the subject (n=11) (RR=2.3, 95% CI=0.8–6.5). No important increases were seen in the analyses that examined exposure to classes of insecticides (organophosphates, pyrethrins, or organochlorines). The authors acknowledge that the few positive associations could have occurred by chance in the course of conducting multiple comparisons.

A case-control study of cases identified from the French national aplastic-anemia registry used interviews with 98 patients, 181 hospitalized control subjects, and 72 neighbor control subjects (Guiguet et al., 1995). Detailed information was collected about occupational history, including tasks, exposures, environmental conditions, and protection. Risk of aplastic anemia was not consistently elevated for occupational exposure to insecticides (n=18) compared with hospitalized controls (odds ratio [OR]=1.6, 95% CI=0.8–3.0) or with neighbors (OR=0.4, 95% CI=0.1–1.3).

A case-control study in North Carolina evaluated the relationship between occupational pesticide exposure and fatal cases of aplastic anemia (Wang and Grufferman, 1981). Sixty deaths attributable to aplastic anemia were identified from state records; two controls that died in the same year were selected for each case. No relationship was found between deaths in cases with occupations that might have involved exposure to pesticides and the occurrence of aplastic anemia (RR=0.67, 95% CI=0.26–1.7). Unlike the studies from Thailand, subjects for this study were identified from death certificates rather than from a hospital-case registry, and occupations recorded on death certificates, rather than questionnaires, were used to evaluate potential exposure. The authors reported no relationship between trends in the use of organochlorine insecticides (including lindane) and the incidence of aplastic anemia.

A number of studies have examined the relationship between hematologic parameters and exposure to insecticides. Those studies have the potential to provide evidence to support conclusions on aplastic anemia; however, because they generally examined workers with continuing exposures, they do not provide information about

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

persistent or long-term effects. For example, Bhatnagar and colleagues (1980) studied workers at a pesticide-formulation factory in Agra, India. They compared blood samples from 42 employees who manufactured DDT, aldrin, lindane, malathion, parathion, and carbaryl with blood samples from 15 healthy subjects chosen as controls. The pesticide-exposed workers had lower hemoglobin (11 g/dL vs 14.48 g/dL). No attempt was made to control for dietary iron intake, age, sex, or other medical conditions that could have been confounding factors. It also could not be ascertained whether the observed changes were short- or long-term effects. The committee reviewed many other hematologic studies, but they did not provide information on persistent long-term health effects (e.g., Khan and Ali, 1993; Milby and Samuels, 1971; Morgan and Lin, 1978; Queiroz et al., 1999; Rosenberg et al., 1999; Straube et al., 1999; Traczyk and Rudowski, 1979; Vine et al., 2000).

Summary and Conclusion

A small number of case-control studies have examined exposure to insecticides in relation to aplastic anemia (Table 9.1). One study showed increased risk associated with exposure to a mixture of dichlorvos, propoxur, and a pyrethroid. Other studies have not shown substantially increased risks for insecticide exposure.

The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to the insecticides under review and aplastic anemia.

TABLE 9.1 Selected Epidemiologic Studies: Aplastic Anemia and Exposure to Insecticides

Reference

Population

Exposed Cases

Estimated Relative Risk (95% CI)

Case-control Studies

Issaragrisil et al., 1997

Residents of rural Thailand

 

Organophosphate exposure

10

1.9 (0.6–5.9)

Kaufman et al., 1997

Residents of Thailand

 

 

Dichlorvos, propoxur, cyfluthrin

 

 

Any exposure

32

1.7 (1.1–2.8)

 

Regular use

17

1.6 (0.9–2.9)

 

Applied by subject

8

1.8 (0.8–4.1)

 

Carbamates

 

Any exposure

36

2.1 (1.2–3.7)

 

Regular use

19

2.0 (1.0–4.1)

 

Applied by subject

11

2.3 (0.8–6.5)

Wang and Grufferman, 1981

Residents of North Carolina in pesticide-exposed occupations

60

0.67 (0.26–1.7)

Guiguet et al., 1995

Residents of France and insecticide exposure

 

 

Hospital control comparison

18

1.6 (0.8–3.0)

 

Neighbor control comparison

4

0.4 (0.1–1.3)

Epidemiologic Studies of Aplastic Anemia and Exposure to Organic Solvents

Most of the relevant research on aplastic anemia has focused on exposure to benzene; a few studies have examined other specific solvents or solvent mixtures.

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×
Benzene

Exposure to benzene at high doses is hematotoxic and can result in destruction of bone-marrow precursor cells and, in turn, in a decrease in white-cell, red-cell, and platelet counts (Goldstein, 1988). The hematotoxicity and carcinogenicity of benzene have been extensively reviewed (e.g., ATSDR, 1997; IARC, 1987), and a brief overview of the toxicologic information is provided in Chapter 4. The metabolism of benzene, which occurs in the liver and to a lesser extent in the bone marrow, plays an important role in its toxicity. Benzene is metabolized to benzene oxide, an epoxide, through an oxidation reaction catalyzed primarily by cytochrome P450 2E1. Cytochrome P450 2E11/6 also participates in benzene biotransformation. Benzene oxide can then be metabolized to various compounds, including o-benzoquinone and p-benzoquinone, which are thought to be the two main metabolites that mediate the toxicity of benzene. Data from laboratory animals and humans show that benzene affects the bone marrow in a dose-dependent manner, causing anemia, leukopenia, and thrombocytopenia; continued exposure causes aplasia and pancytopenia1 (Bruckner and Warren, 2001). Benzene also has carcinogenic properties. In experimental animals, an increased incidence of malignant lymphomas and some solid tumors have been seen after exposure to high doses of benzene. As discussed in Chapter 6, benzene has also been associated with some types of leukemia in humans.

Most of the human evidence associating benzene exposure with aplastic anemia comes from case studies (many published in the early to middle 1900s). Although exposure characterization methods were poor, it is estimated that benzene concentrations often exceeded 100 ppm2 (as summarized in Smith, 1996). The hypothesis of an association with benzene exposure raised by the case reports has been confirmed by several epidemiologic studies, although most of the population-based studies have focused on the relationship between exposure to benzene and hematopoietic cancers (see Chapter 6).

As early as 1897, the deaths of four workers at a Swedish bicycle-tire factory were attributed to aplastic anemia associated with exposure to high concentrations of benzene (cited in Aksoy, 1985). A retrospective cohort study by Paci and colleagues (1989) examined exposures to potentially high concentrations of benzene among shoe-factory workers in Florence, Italy. During the period from 1953 to 1960, glues—estimated to be as much as 70% benzene by weight—were used in shoe manufacturing. When the researchers compared mortality rates for the 1950–1984 cohort of workers with national rates, they found increases for aplastic anemia in women (one case versus 0.2 expected) and in men (six cases versus 0.38 expected). The Italian national mortality rates combined all blood diseases, and the analysis resulted in standardized mortality ratios (SMRs) of 4.16 (95% CI not provided) for women and 15.66 (95% CI=5.47–32.64) for men.

A retrospective cohort study examined hematopoietic malignancies and related disorders in a group of 74,828 workers in China who were employed in 1972–1987 in benzene-exposed departments of 672 factories (Dosemeci et al., 1994; Travis et al., 1994; Yin et al., 1996a,b). Mortality and morbidity data on this cohort were compared with data on 35,805 nonexposed workers employed during the same period. Physician investigators blinded to exposure information reviewed histopathologic information, pathology reports,

1  

Pancytopenia is a nonfatal condition with below normal values of red cells, white cells, and platelets.

2  

The allowable occupational-health standard for benzene has steadily decreased in the United States. In 1987, the permissible exposure limit (PEL) set by the Occupational Safety and Health Administration was reduced from 10 ppm to 1 ppm TWA (time-weighted average).

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

and medical records of workers who developed hematologic neoplasms and related disorders. Yin and colleagues (1996a) reported nine cases of aplastic anemia in the benzene-exposed cohort as compared with no cases in the nonexposed population. Because the study used such a large population, it was possible to detect differences in relatively infrequent outcomes. Furthermore, there was a careful review of medical records to confirm the diagnoses. However, there is a possibility that the results were confounded by other occupational exposures.

Potential risk factors for aplastic anemia were examined in a case-control study in Baltimore, Maryland. Linet and colleagues (1989) compared 59 cases of aplastic anemia diagnosed in 1975–1982 with 59 controls matched for age, sex, race, and geographic area and selected by random-digit dialing. An increased risk of aplastic anemia was associated with self-reported benzene exposure (OR=3.1, 95% CI=1.0–9.2). However, for the purposes of this review, the inferences from the study are limited by the fact that 41% of the patients with aplastic anemia were under 20 years old at diagnosis and would not have had substantial occupational exposures.

Two other studies provide information on the relationship between benzene and aplastic anemia. In a case series from Turkey, Aksoy and colleagues (1984) reported that about 23% of patients with aplastic anemia had reported exposure to benzene. The study examined potential risk factors but did not have a comparison population. Ott and colleagues (1978) reviewed the deaths (1938–1970) of 594 workers chronically exposed to benzene at concentrations of 1 ppm to over 30 ppm at a Dow Chemical plant. One death from aplastic anemia was reported, whereas only 0.1 would have been expected.

The relationship between changes in hematologic parameters and exposure to low concentrations of benzene has been extensively studied. However, the studies generally are cross-sectional and do not provide substantial information about persistent or long-term effects of interest in this review, and they generally have had inconsistent findings. When changes were seen in hematologic measures at low exposure, the differences (such as in hematocrit, hemoglobin, white-cell count and platelet count) often were not internally consistent with other measures (for example, an elevated mean red-cell volume would be expected but decreased mean corpuscular hemoglobin concentration would not). Changes in hematologic or immunologic parameters are not necessarily stages in the development of a pathologic process. For example, the finding of gradually lower numbers of blood cells does not mean that continued exposure would lead to the development of aplastic anemia.

Examples of studies of hematologic parameters include the studies by Kipen and colleagues (Cody et al., 1993; Kipen et al., 1988, 1990) who followed a cohort of rubber workers exposed to varying concentrations of benzene. Studies of this cohort are described in Chapter 6 regarding cancer outcomes, particularly leukemia (Rinsky et al., 1981, 1987). During the period from 1940–1948, as benzene exposures gradually dropped from 137 ppm to 32 ppm, white-cell counts rose (from 6200 to 9591), red-cell counts rose (from 4.67 to 5.13), and hemoglobin rose (from 97.0 to 108.0) (Kipen et al., 1988). Those findings indicate that exposure to relatively high concentrations of benzene depressed the production of blood cells. In the years after 1948, when benzene exposure was much reduced, the values for white- and red-cell counts were within the normal ranges (although a nonexposed comparison group was not studied in the same period).

A study by Collins and colleagues (1991) compared hematologic parameters of 200 workers at a chemical factory who were exposed to low concentrations of benzene (0.01–1.4

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

ppm) with those of 268 nonexposed workers from the same factory. The study found no abnormalities in white-cell count, red-cell count, hemoglobin concentration, platelet count, or mean red-cell volume. The study did find that smoking affected many hematologic parameters, underlining the importance of controlling for confounding. Many other studies of the effects of benzene exposure on hematologic parameters that were reviewed provided no information on persistent long-term health effects (e.g., Aksoy et al., 1971; Bogadi-Sare et al., 1995, 1997; Collins et al., 1997; Khuder et al., 1999; Rothman et al., 1996; Tsai et al., 1983; Ward et al., 1996).

Solvents

Only a few studies have examined aplastic anemia in relation to exposure to other specific solvents or to solvents in general. Several of the insecticide-exposure studies described above also examined exposure to solvents. The population-based, case-control study in Thailand (Issaragrisil et al., 1996) compared 284 cases of aplastic anemia identified in 40 hospitals in Bangkok and 15 hospitals in rural areas. The study enrolled four hospital controls of similar age and sex for each case. Two hematologists confirmed the diagnoses of aplastic anemia. Using interviews with the case and control subjects, the researchers examined several risk factors for aplastic anemia. For the cases and controls drawn from Bangkok hospitals, there was a strong association with a history of solvent exposure (RR=4.6, 95% CI=2.5–8.7). About 40% of the total cases came from rural hospitals, and no association was noted when those cases were compared with their controls. The study reported positive associations for other risk factors (such as grain farming, hepatitis A, and low socioeconomic status) and multivariate analyses adjusted for the many possible confounders. However, the study presents little information on exposure-assessment methods, participation rates, or the conduct of the interviews. Also, such hospital-based case-control studies are vulnerable to selection and recall bias.

Using the French national register of aplastic anemia, Guiguet and colleagues (1995) studied 98 patients with aplastic anemia (recorded in the register in 1985–1988) and two groups of controls: 181 selected from the same hospital as the cases and 72 referred by case patients from among neighbors. Interviews were conducted to determine occupational and medical histories, and a toxicologist coded the occupational exposures (any exposure or a “large level of exposure”). The study reported no association between aplastic anemia and exposure to all types of solvents compared with hospital controls (OR=0.9, 95% CI=0.5–1.7) or neighbor controls (OR=0.6, 95% CI=0.3–1.4). Analysis of exposure to various classes of solvents revealed no consistently increased risk; for example, for higher exposure to halogenated solvents, the OR was 1.3 (95% CI=0.6–2.7) compared with hospital controls. Although the study was limited by a 50% participation rate, interviews were conducted at diagnosis, and the investigators found no evidence of participation bias in the case group.

The case-control study in Baltimore, Maryland, described above (Linet et al., 1989) found an association of aplastic anemia with self-reported exposure to paint (OR=6.1, 95% CI=1.2–29.7), but there was no association with the occupation of painter. The study reported a slightly elevated risk for aplastic anemia and exposure to any solvents (OR=1.1, 95% CI=0.5–2.7). However, as noted above, the inferences from this study are limited by the fact that 41% of the patients with aplastic anemia were under 20 years old at diagnosis and would not have experienced substantial occupational exposure.

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Although a number of studies of the effects of exposure to solvents, particularly ethylene glycol ethers, on hematologic parameters were reviewed, the studies did not provide information on the persistent, long-term health effects of concern in this report (e.g., Cardoso et al., 1999; Cook et al., 1982; Cullen et al., 1983, 1992; Kyvik et al., 1992; Shamy et al., 1994; Shih et al., 2000; Welch and Cullen, 1988).

Summary and Conclusion

The hematotoxicity of benzene’s metabolites has been well characterized in animal studies with strong evidence of a dose-response relationship. For more than a century, case studies have reported a direct association between chronic high-level exposure to benzene and aplastic anemia in humans. This association has been confirmed in studies of workers exposed to potentially high concentrations of benzene that found consistently increased risks of aplastic anemia (Table 9.2). The effects of low-level benzene exposure, however, have not been studied as fully, and there have been inconsistent findings regarding changes in hematologic parameters in studies of low level occupational exposure to benzene. Studies of exposure to solvent mixtures have not revealed consistent increased associations with aplastic anemia.

Results are for cases with higher exposure as compared with hospital controls. The committee concludes, from its assessment of the epidemiologic and experimental literature, that there is sufficient evidence of a causal relationship between chronic exposure to benzene and aplastic anemia.

There is inadequate/insufficient evidence to determine whether an association does or does not exist between exposure to other specific organic solvents under review or solvent mixtures and aplastic anemia.

TABLE 9.2 Selected Epidemiologic Studies: Aplastic Anemia and Exposure to Organic Solvents

Reference

Population

Exposed Cases

Estimated Relative Risk (95% CI)

Benzene

Cohort Studies

Paci et al., 1989

Shoe-manufacturing workers in Florence, Italy

 

 

Females

1

4.16a

 

Males

6

15.66 (5.47–32.64)a

Yin et al., 1996

Workers in China

9

Indeterminateb

Linet et al., 1989

Residents of Baltimore, Maryland

13

3.1 (1.0–9.2)

Solvents

Case-control Studies

Issaragrisil et al., 1996

Residents of Thailand

 

 

Bangkok residents

NA

4.6 (2.5–8.7)

Guiguet et al., 1995

Residents of France

 

 

All types of solvents

27

0.9 (0.5–1.7)c

 

Halogenated solvents

16

1.3 (0.6–2.7)c

 

Hydrocarbon solvents

19

1.2 (0.6–2.3)c

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Population

Exposed Cases

Estimated Relative Risk (95% CI)

Linet et al., 1989

Residents of Baltimore, Maryland

 

 

Any solvents

12

1.1 (0.5–2.7)

NOTE: NA=not available.

aSMR was calculated for bloodborne diseases as a group.

bStudy reported no nonexposed workers with aplastic anemia.

CARDIOVASCULAR EFFECTS

Cardiovascular disease is among the most common causes of death, chronic illness, and disability among adults in the United States. Most of the risk factors are related to lifestyle and family history, but occupational and environmental risk factors have been suggested for several cardiovascular outcomes. A potential for increased risk of ischemic heart disease is attributable to chronic exposure to carbon disulfide used in rayon manufacturing, and risk of cardiac arrhythmia is attributable to acute exposure to high concentrations of solvents (Fine, 1992; Kurppa et al., 1984). Exposure to some heavy metals, such as lead, also has been associated with the potential for intermediate cardiovascular outcomes, such as hypertension (Kristensen, 1989).

Epidemiologic Studies of Cardiovascular Effects and Exposure to Insecticides

The cardiac effects of the insecticides and insect repellents examined in this report have been discussed in the literature primarily in the context of acute poisoning (Roth et al., 1993; Saadeh et al., 1997). However, the insecticide literature is sparse regarding long-term cardiovascular health outcomes.

Two studies examined hypertension in relation to exposure to insecticides and other pesticides. A study in Oregon reported no difference in average blood pressure between control subjects and workers who formulated phenoxy herbicides or other unspecified pesticides (Morton et al., 1975); it was limited by a lack of information about the degree of exposure among the participating workers. Sandifer and colleagues (1972) reported increased systolic blood pressure among pesticide formulators and pest-control operators but not among farmers, manufacturing workers, workers designated as peripherally exposed, and control subjects. Both studies examined workers currently exposed to pesticides, so it was not possible to separate long-term and short-term health effects.

Evaluation of the long-term cardiovascular effects of exposure to insecticides was limited to data from mortality studies done primarily for purposes of assessing cancer risk. Many studies focused on pesticides in general and provided sparse exposure information. Most studies showed decreased cardiovascular mortality or no association but did not control for confounding by risk factors, such as smoking, family history of cardiac disease, and diet. The studies also were potentially limited by a selection bias known as the healthy-worker effect (see Chapter 2). For example, a study of 32,600 employees at a lawn-care service that used insecticides (including diazinon, carbaryl, and malathion), herbicides, and fungicides reported 17 deaths from arteriosclerotic heart disease (including congestive heart disease) (Zahm, 1997). Comparable US population mortality rates would project an expected 33.1 deaths (SMR=0.51, 95% CI=0.30–0.82). The cohort was generally young

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

and had been employed for only a short period (mean=1.6 years). Pesatori and colleagues (1994) reported similar results for mortality in a cohort of 4411 structural pest-control workers in Florida. For deaths from arteriosclerotic heart disease, the SMR was 0.9 (95% CI =0.5–1.1).

Summary and Conclusion

Although a well-recognized complex of short-term, reversible cardiac effects is associated with some pesticide poisonings, there are few data on long-term cardiovascular outcomes. Data from cross-sectional studies of workers who have continuing exposure to insecticides do not offer insights into the long-term nature of the effects. Mortality studies of pesticide-exposed workers show no increased risk; however, the healthy-worker effect and other study limitations make it difficult to evaluate long-term outcomes.

The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to the insecticides under review and irreversible cardiovascular outcomes.

Epidemiologic Studies of Cardiovascular Effects and Exposure to Organic Solvents

The literature on cardiovascular effects of solvent exposure is primarily on the short-term consequences of acute exposure. For some solvents, short-term cardiovascular effects are known to occur following acute exposure (reviewed in Kristensen, 1989; Wilcosky and Simonsen, 1991). For example, a body of medical literature, primarily case reports, exists regarding the metabolism of methylene chloride to carbon monoxide and the later development of angina pectoris in susceptible persons as a result of increases in carboxyhemoglobin. Case reports also discuss cardiac sensitization and arrhythmia attendant on acute exposure to chlorofluorocarbons and, to a smaller degree, to chlorinated solvents. Since these effects are considered short-term and they occur soon after exposure, they would not be considered relevant for the time frame being considered for Gulf War veterans.

The committee examined many cohort mortality studies that assessed excess mortality (usually with a focus on discerning elevations in cancer) among workers known to have been occupationally exposed to a variety of solvents. For the most part, the studies showed no effect or a decrease in cardiovascular diseases among the workers. Because of their study design, those studies do not control for the healthy-worker effect or for confounding attributable to cigarette smoking or other confounding factors. Due to the limitations in this type of study design for the purposes of this review, the studies are not reviewed in detail here. A meta-analysis by Chen and Seaton (1996) assessed 52 published mortality studies of occupational solvent exposure and calculated a pooled SMR of 0.87 (95% CI=0.86–0.88) for all circulatory disease. Although the committee did not include meta-analyses in the body of evidence it used for making a conclusion, that study provides an indication of the extent to which the healthy worker effect pervades the evidence related to cardiovascular outcomes.

In a cross-sectional study, Kotseva and Popov (1998) examined cardiovascular effects attributable to occupational exposure to solvents (including benzene, xylene, and phenol) in a Bulgarian petrochemical factory. The study identified 345 workers and 345 age-

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

and sex-matched control subjects and divided them into three categories: highest benzene, toluene, and gasoline exposures; high xylene and lower toluene, benzene, and gasoline exposures; and exposure primarily to phenol. Meaningfully higher prevalences of electrocardiographic abnormalities and higher mean systolic and diastolic blood pressure as compared to the controls were found among the exposed members of the first two groups, but not among those exposed primarily to phenol. Given the study design, the workers were being exposed to solvents occupationally at the time of the study and so were not considered exposure-free for the evaluation of persistent effects.

A retrospective cohort mortality study of workers at a cellulose-fiber plant examined ischemic heart disease (IHD) in 1271 workers exposed to methylene chloride (Ott et al., 1983). The study did not report an increase in IHD mortality among workers compared with the general population, nor when the duration of exposure and followup interval for IHD were assessed. A study of male workers exposed to methylene chloride in the production of cellulose triacetate photographic-film base also did not find an increased risk of IHD (Hearne et al., 1990).

Suadicani and colleagues (1995, 1997) reported on the Copenhagen Male Study, which began in 1970 as a prospective cardiovascular cohort study of 2974 men who were free of IHD at the study’s outset. At the time of the analysis, 184 men had had at least one IHD event; 258 members of the cohort reported occupational exposure to organic solvents. The adjusted RR comparing men exposed to solvents with unexposed men was 1.7 (95% CI =1.1–2.7). The occupational exposure assessment in this study was based on self-assessment of lifetime occupational exposure, which could lead to recall and misclassification bias. No information is provided about the timing of exposure and the development of myocardial infarction.

Wilcosky and Tyroler (1983) examined mortality from heart disease among workers exposed to solvents in a rubber and tire manufacturing plant in Akron, Ohio. They identified 1282 white male, hourly-wage workers who were employed at the plant or had retired after at least 10 years of exposure. Exposure estimates were obtained from annual solvent-use charts prepared for major processing areas of the plant for 25 solvents. Each subject was identified as having been exposed to specific solvents through a review of which jobs he had held in the company and through a review of the list of solvents authorized for use in specific areas, according to the annual-use charts. Until 1967, the plant had authorized the use of carbon disulfide, known to be associated with atherosclerosis (and not among the solvents sent to the Gulf War). Most workers were exposed to more than one solvent, and several solvents were often used concurrently in the process areas. Several solvents showed associations with IHD mortality, but the associations were inconsistent when adjusted for age and other solvent exposures. The age-adjusted rate ratio for workers exposed to ethanol but not to carbon disulfide or phenol was 1.8; for workers exposed to phenol but not carbon disulfide or ethanol, it was also 1.8. The study did not control for confounding by other known cardiovascular risk factors, and misclassification of exposures probably occurred. The authors pointed out that “solvent authorization” did not necessarily guarantee solvent use.

As a part of the Stockholm Heart Epidemiology Program, Gustavsson and colleagues (2001) identified 1335 persons surviving for at least 28 days after a first myocardial infarction. Control subjects were selected from a population registry and were sex-, age- and catchment-area-matched with the case subjects. Subjects were asked to complete

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

questionnaires on lifetime occupational history, including descriptions and duration of work. An industrial hygienist assigned exposure levels on the basis of probability and intensity. Adjusting for age, sex, smoking, hypertension, weight, diabetes mellitus, and physical activity, the authors reported a RR estimate for organic solvent exposure of 1.26 (95% CI=1.02–1.55) for those with low exposure, 1.05 (95% CI=0.76–1.47) for medium exposure, and 1.49 (95% CI=0.94–2.35) for the highest category of exposure compared with the unexposed subjects. The analysis of exposure and duration showed no trend with increasing exposure (lowest exposure, RR=1.50, 95% CI=1.14–1.96; moderate exposure, RR=1.00, 95% CI=0.74–1.34; and highest exposure, RR=1.20, 95% CI=0.92–1.58). The authors performed additional analyses to account for latency periods and lag in the calculation of dose, but the models gave no closer fit to the data. Variations of exposure within similar jobs and errors in work-history information could have contributed to exposure misclassification.

Summary and Conclusion

Only a few studies on solvent exposure have examined long-term cardiovascular effects, and they show inconsistent results and no trend of increased risk with increasing estimated exposure. Cohort mortality studies have generally demonstrated decreases in cardiovascular disease, but do not account for the healthy-worker effect. Other occupational cohort and case-control studies are fraught with the difficulties of assigning subjects in a retrospective exposure assessment and of controlling for lifestyle and other risk factors.

The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to the specific organic solvents under review or solvent mixtures and irreversible cardiovascular outcomes.

RESPIRATORY EFFECTS

Many compounds that are used in industry or have been identified as environmental contaminants have been associated with the development of nonmalignant lung disease. Examples are chronic bronchitis and emphysema associated with cigarette smoking, asthma associated with toluene diisocyanate exposure, and pulmonary edema associated with exposure to chlorine gas. The major confounding factor in most occupational studies of respiratory outcomes is smoking. Exposure to dusts and various chemical compounds also must be considered. For example, although some agriculture-related respiratory diseases have a known etiology (such as silo filler’s disease, which results from inhalation of nitrogen dioxide in unventilated farm silos), it has not been possible to pinpoint the etiology of many respiratory effects from among the numerous agricultural exposures of concern, including dusts, fungi, pesticides, and fertilizers (do Pico, 1992).

The literature on respiratory effects includes cross-sectional studies that examined lung function in relation to insecticide or solvent exposure. Often, the subjects were employed at the time lung function was assessed and so had ongoing exposures to the compounds of concern. Thus, it was often not possible to assess the persistence of changes in lung function after exposure had ended.

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Case-control and cross-sectional studies of Gulf War veterans have reported a high prevalence of respiratory symptoms (Cherry et al., 2001; Gray et al., 1999; Proctor et al., 1998; Richards et al., 1993), asthma (Gray et al., 2000), airflow obstruction and chronic laryngotracheitis (Das et al., 1999), and sleep apnea (Peacock et al., 1997) (see Appendix A). Those studies did not examine the association between the outcomes and specific Gulf War exposures to insecticides or solvents.

Epidemiologic Studies of Respiratory Effects and Exposure to Insecticides

A small number of studies have examined the persistent, long-term respiratory effects of exposure to insecticides. Acute high-level exposures to organophosphate compounds can result in an acute cholinergic syndrome involving bronchospasms (see Chapter 3). However, few studies have examined long-term respiratory outcomes related to insecticide exposures. Kossmann and colleagues (1997) conducted a cross-sectional study of 37 male and 17 female workers in the division of a chemical plant that produced liquid and dust pesticides. Those workers were exposed to multiple compounds, including organophosphate insecticides (such as dichlorvos), pyrethroids, triazines, carbamates, and dithiocarbamates. A control group of 22 men and 15 women, residents of the same region, were not occupationally exposed to chemical agents. The chemical-plant workers showed a 50% prevalence of chronic bronchitis, but this outcome was not assessed in the controls. Spirometry tests revealed obstructive impairment of pulmonary function in 11% of the chemical-plant workers. Peak expiratory flow was diminished in 41% of females and 27% of males. A strong correlation between decreased peak expiratory flow and the force of expiratory muscles was observed that could have been the result of muscle weakening caused by exposure to organophosphate compounds. The study was limited for the purposes of this review by its cross-sectional design and by the continuing exposure of the subjects to insecticides and pesticides. An attempt was made to control for the effect of smoking, but the group was too small to control for the confounding effect of multiple exposures.

A cross-sectional study of farmers in Saskatchewan described the prevalence of self-reported asthma and its possible association with the use of insecticides and herbicides (Senthilselvan et al., 1992). An internal comparison group of nonexposed farmers was compared with pesticide-exposed members of the cohort, controlling for age, smoking pack-years, and nasal allergies. Of 2375 farmers who were contacted, 1939 (81.6%) responded to a questionnaire and completed a pulmonary-function test (PFT). The validity of the self-reported diagnosis was supported by the finding that self-identified asthmatics had lower mean values of PFT variables than did self-identified non-asthmatics. An increased prevalence of asthma was associated with the use of carbamate insecticides (including methomyl and carbaryl) (adjusted OR=1.8, 95% CI=1.1–3.1). The study was limited by its partial reliance on subjective questionnaire data, by possible selection bias, and by confounding by noninsecticidal occupational exposures.

Other cross-sectional studies have reported positive associations between respiratory symptoms or impairment and exposure to insecticides (Al-Shatti et al., 1997; Rastogi et al., 1989; Sprince et al., 2000; Zuskin et al., 1997b), but they did not examine the persistence of outcomes after exposure had ended.

Cohort mortality studies have generally not reported an increase in nonmalignant respiratory disease mortality in cohorts of workers in pesticide-related occupations. Considerations regarding these studies include the healthy-worker effect, difficulties in

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

using death certificates to account for nonmalignant respiratory disease, and the overwhelming effects of smoking, which are difficult to control for adequately. Other workplace respiratory hazards also could confound results. A study of 2384 workers at a pesticide-manufacturing plant in Colorado that produced dichlorvos, aldrin, and other pesticides reported that the overall rate of deaths attributable to nonmalignant respiratory disease was not elevated over that of the state’s general population (SMR=1.07, 95% CI=0.78–1.43) (Amoateng-Adjepong et al., 1995). There was an increase in deaths from pneumonia (20 compared with 13 expected), which the authors hypothesized could have resulted from exposure to respiratory irritants (such as chlorine and bromine) at the plant. Zahm (1997) studied mortality in pesticide applicators and other employees of a lawn-care company who handled herbicides, fungicides, and insecticides (including malathion, chlorpyrifos, carbaryl, and diazinon). The SMR for nonmalignant respiratory disease was 0.67 (based on eight deaths). Other mortality studies of pesticide applicators and workers exposed to insecticides (and other pesticides and chemicals) showed no increase in deaths from nonmalignant respiratory disease (Alavanja et al., 1987, 1990; Blair et al., 1983; Fleming et al., 1999; Littorin et al., 1993; MacMahon et al., 1988; Pesatori et al., 1994; Wang and MacMahon, 1979).

Summary and Conclusion

The body of evidence on nonmalignant respiratory outcomes and insecticide exposures consists primarily of cross-sectional studies on lung function that did not examine long-term persistent outcomes after cessation of exposure. Furthermore, many studies did not control for confounding by smoking and other common causes of lung disease.

The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to the insecticides under review and persistent respiratory symptoms or impairment after cessation of exposure.

Epidemiologic Studies of Respiratory Effects and Exposure to Organic Solvents

Acute solvent exposure is generally recognized as causing acute mucosal irritation of the eyes, nose, and upper airways and symptoms of eye irritation, cough, and dyspnea that improve after exposure ends (reviewed in De Raeve and Nemery, 1999; Schenker and Jacobs, 1996). Rare case reports have described acute pulmonary edema or chemical pneumonitis after (frequently accidental) acute exposure to a small number of solvents, including formaldehyde, xylene, and styrene. Persistent nonspecific airway hyperreactivity or reactive-airway dysfunction syndrome (RADS) has been reported after exposure to high concentrations of a few organic solvents in a small number of case reports (Boulet, 1988; Brooks et al., 1985; reviewed in De Raeve and Nemery, 1999). In those cases, the subjects became acutely symptomatic within hours of the high level exposure. Symptoms and airway hyperresponsiveness usually resolve after the exposure ends, but they can persist for months to years. The delayed development of respiratory symptoms or the worsening of lung function months or longer after exposure has not been reported. The acute effects of exposure to lower occupational concentrations of solvents are less clear. A few studies have shown small decrements in lung function during the work shift or in exposure chambers;

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

other studies have shown no acute effects. Solvents in general are not considered sensitizing agents and so are not considered a cause of immune-mediated asthma. The limited number of chamber studies with asthmatic volunteers generally has not shown acute effects of solvent exposure on lung function in those with underlying asthma (reviewed in De Raeve and Nemery, 1999; Schenker and Jacobs, 1996).

Cross-sectional studies have investigated the effects of solvent exposure on upper respiratory symptoms, comparing solvent-exposed workers with various control groups. Those studies have involved mixed solvent exposures in conjunction with exposures to substances that are known to cause respiratory effects, including reactive and irritant chemicals, metal fumes, agricultural products, and mineral dusts. More than half have shown a higher prevalence of respiratory symptoms—such as cough, wheezing, or dyspnea—in exposed workers than in control subjects (e.g., Kilburn, 1999; Lebowitz, 1977; McCurdy et al., 1995; Sabroe and Olsen, 1979; Talini et al., 1998; Zuskin et al., 1997a). However, almost all the studies involved workers with continuous exposure, so it was difficult to isolate persistent respiratory symptoms after the cessation of exposure.

A smaller number of cross-sectional studies of exposed workers have reported spirometry findings. Most did not reported differences between solvent-exposed workers and control subjects (e.g., Akbar-Khanzadeh and Rivas, 1996; Angerer et al., 1991; Lee et al., 1997; Talini et al., 1998). A few studies have reported reduced lung function in terms of forced expiratory volume or forced vital capacity (FEV1, FVC, or FEV1-FVC) in solvent-exposed workers when compared with a control group (Oleru and Onyekwere, 1992; White and Baker, 1988). However, solvent exposures generally occurred in conjunction with other, better-recognized respiratory hazards (metals, other chemical compounds, and irritants), and the control groups generally were not comparable. Also, those studies did not distinguish between acute and chronic exposure. No longitudinal followup studies of workers after cessation of exposure were identified.

Several community-population-based studies have investigated the association between exposure to occupational solvents and increased prevalence of respiratory symptoms, respiratory disease, or decreased lung function (Le Moual et al., 1995; Lebowitz, 1977; Post et al., 1994). During the 25-year followup of a group of male residents of the town of Zutphen in the Netherlands, the cohort received several medical examinations, and the morbidity and mortality of the cohort were followed. Post and colleagues (1994) examined chronic nonspecific lung disease in the cohort and found an increased risk with occupational solvent exposure (RR=1.66, 95% CI=1.14–2.41). A community population study of men in Tucson, Arizona, reported an increased prevalence of respiratory symptoms and reduced lung function in those exposed to solvents, smoke, and other substances (Lebowitz, 1977). Similar studies of asthma patients and of twins who had asthma have shown an increased risk of asthma with solvent exposures (Antti-Poika et al., 1992; Toren et al., 1999). However, the exposure assessments in those studies relied on self-reported occupational histories, and concurrent non-solvent exposures were common.

Mortality studies generally have not reported increases in nonmalignant respiratory disease mortality among solvent-exposed workers, and many have actually found reduced SMRs, which is probably a consequence of the healthy-worker effect (e.g., Hearne and Pifer, 1999; Lanes et al., 1990; Spirtas et al., 1991; Svensson et al., 1990; Walker et al., 1993). Other limitations of those mortality studies include difficulties in using death

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

certificates to ascertain nonmalignant respiratory diseases, the overwhelming effects of smoking, and potential confounding by exposure to other non-solvent respiratory hazards.

Sleep apnea or nocturnal oxygen desaturation also has been examined in solvent-exposed workers (Edling et al., 1993; Laire et al., 1997; Monstad et al., 1987, 1992). Known risk factors for sleep apnea include obesity and alcohol and medication use. All the studies reported an increased prevalence of oxygen desaturation or sleep apnea in solvent-exposed workers. However, the control groups were rarely comparable, and known risk factors, such as obesity, were not often adequately addressed. One study (Monstad et al., 1992) found less sleep apnea when the subjects were retested 2 weeks after exposure; this suggests that the effect is more acute than chronic, which is similar to the effect of alcohol use on sleep apnea.

Summary and Conclusion

A few clinical and epidemiologic studies have evaluated associations between solvent exposure and respiratory symptoms, lung function (determined primarily with spirometry), nonmalignant respiratory diseases, and sleep apnea. Most have investigated the effects of acute exposure and generally have not differentiated persistent effects of exposure from short-term effects. Population-community-based studies have been hampered by basing exposure assessments on self-reports of occupational history. Occupational mortality studies of solvent-exposed workers, designed primarily to investigate cancer outcomes, are markedly limited in their ability to investigate nonmalignant respiratory outcomes because they use death certificates to ascribe respiratory mortality and morbidity. Furthermore, those studies are not able to control adequately for confounding by smoking or non-solvent occupational respiratory exposures. The healthy-worker effect may also limit the findings of the studies for the purposes of this report. Most studies involved mixed-solvent exposures, frequently in conjunction with other, better-known respiratory hazards, such as exposure to reactive and irritant chemical compounds, metal fumes, agricultural products, or mineral dusts. Although solvent exposure has only rarely been linked to RADS, it is conceivable that RADS resulting from acute, high-concentration exposure to solvents could persist for years after exposure. It is important to note that symptoms would appear at the time of exposure or shortly after.

The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between high-level exposure to mixtures of organic solvents and reactive airways dysfunction syndrome, which would be evident with exposure and could persist for months or years.

There is inadequate/insufficient evidence to determine whether an association exists between exposure to the specific organic solvents under review or solvent mixtures and persistent respiratory symptoms or impairment after cessation of exposure.

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

HEPATIC EFFECTS

The liver is the major site for the metabolism of exogenous substances, such as drugs and other chemical compounds. This section examines three hepatic effects: changes in liver function, fatty liver (steatosis), and cirrhosis. Many blood tests are available for evaluating hepatotoxicity and liver disease; measures of the hepatic enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are often used because these enzymes are present at increased concentrations after acute liver injury or in hepatitis attendant to viral infection, chemical exposure, alcohol use, or use of some medications. The magnitude and pattern of transaminase increase can be helpful in distinguishing alcohol-induced injury from other causes of hepatotoxic effects, such as exposure to solvents. The AST:ALT ratio is almost always over 1 in alcohol-related injury; other toxicant- or virus-induced hepatic injuries usually result in an AST:ALT under 1 (Guzelian et al., 1988; Podolsky and Isselbacher, 1998; Redlich et al., 1990; Upfal et al., 1992). Additional serum markers include alkaline phosphatase, γ-glutamyl transpeptidase (GGT), and bilirubin. However, the sensitivity and specificity of the enzymes for liver disease vary. Biochemical tests (such as for fasting serum bile acids) can be used to assess various functions of the liver, although the clinical significance of the findings can be equivocal. Furthermore, liver disease (particularly chronic liver injury) can be present despite normal results of liver-function tests. Abnormal test results can be caused by alcohol or medication use, viral infection, diabetes, and nonhepatic disease. Despite those limitations, liver-function tests are the best noninvasive means of detecting liver injury and disease.

Fatty change in the liver, or steatosis, occurs in association with several clinical conditions, including alcohol-related liver disease, diabetes mellitus, hypertriglyceridemia, and obesity. It is also associated with the use of various medications, and it can be a normal variant. Some degree of steatosis accompanies acute liver injury and hepatic necrosis, and more marked steatosis commonly is seen in chronic toxin-induced liver injury. The difficulty of documenting steatosis greatly hinders epidemiologic studies. Patients are usually asymptomatic, and results of liver-function tests can be normal. Noninvasive evaluation of the liver with ultrasonography and computed tomography (CT) can suggest hepatic steatosis, but definitive diagnosis depends on histopathologic examination of a liver biopsy specimen. It is not clear how often steatosis progresses to cirrhosis (Neuschwander-Tetri and Bacon, 1996).

Cirrhosis, or end-stage liver disease, is a chronic, irreversible condition in which the normal lobular architecture is replaced with fibrous tissue and regenerating liver nodules. Common causes of cirrhosis are alcohol-related liver disease and viral infection.

Epidemiologic Studies of Hepatic Effects and Exposure to Organic Solvents

As discussed in this section, studies on exposure to solvents and hepatic outcomes were limited for the purposes of this review. Some solvents (particularly carbon tetrachloride) that are not topics of this report have known effects on the liver, but few studies on other solvents have examined long-term hepatic outcomes after exposure has ended.

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×
Liver Function

Case reports and case series have documented that high (frequently accidental) acute and subchronic exposure to some solvents—including 1,1,1-trichloroethane, tetrachloroethylene, and methylene chloride—can cause acute hepatotoxicity (chemical hepatitis), typically with increased aminotransferases, that improves when the exposure ends (reviewed in Baker, 1994). Aminotransferase concentrations usually return to normal (reviewed in Redlich et al., 1990). Chronic sequelae of such acute and subchronic exposures are not well documented.

The effects of subchronic and chronic exposure to typically lower concentrations of solvents have been harder to evaluate. Clinical and cross-sectional studies have reported the results of various liver-function tests in chronically exposed workers (such as painters and dry-cleaning workers), most of whom are exposed to mixtures of solvents and other chemicals. Most of those studies have demonstrated normal aminotransferases (Cai et al., 1991; Chia et al., 1987; Franco et al., 1986; Kurppa and Husman, 1982; Lundberg and Hakansson, 1985; Rees et al., 1993).

Mildly elevated GGT or aminotransferase concentrations in association with solvent exposure have been reported in a few cross-sectional studies (Chen et al., 1991; Guzelian et al., 1988; Tomei et al., 1999; Upfal, 1992). However, the studies do not differentiate past from current, continuous solvent exposure, so it is difficult to distinguish long- and short-term effects. The differences in liver-function tests between the exposed and control groups in the studies were small, and the increased values usually were within normal limits. The studies generally used small groups, and many had few details regarding the exposure. Further, there are few data to determine whether abnormal liver transaminases persist after removal from subchronic or chronic exposure, although some clinical reports suggest improvement (Cotrim et al., 1999).

Hepatic Steatosis

It is known that acute high exposure to solvents (particularly chlorinated hydrocarbons such as chloroform and carbon tetrachloride3) can result in hepatic injury, including necrosis (Bruckner and Warren, 2001). A limited number of case reports and case series suggest that chronic exposure to chlorinated solvents, such as 1,1,1-trichloroethane (Hodgson et al., 1989); to nonchlorinated solvents, such as toluene (Guzelian et al., 1988) and dimethylformamide (Redlich et al., 1990); and to mixed solvents (Dossing et al., 1983) can result in hepatic steatosis, which can persist after exposure ends (Dossing et al., 1983; Redlich et al., 1990).

Larger clinical studies also suggest that chronic solvent exposure is associated with hepatic steatosis. Cotrim and colleagues (1999) screened 1500 asymptomatic petrochemical workers in Brazil. The workers were exposed to a number of solvents, including benzene, toluene, xylene, and methanol. Workers with obesity, alcohol use, and other risk factors for steatosis were excluded. Liver biopsies were performed on 32 workers who met diagnostic criteria, including multiple test results of elevated liver enzymes. Twenty of the biopsied workers were diagnosed with nonalcoholic steatohepatitis. Eight to 12 months after the

3  

Because carbon tetrachloride was not among the solvents sent to the Gulf War, it is not reviewed in this report.

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

exposure ended, the steatosis had improved in some, but not all, of those removed from exposure.

Brodkin and colleagues (1995) compared hepatic parenchymal echogenicity on ultrasonography and serum transaminase concentrations in 20 dry-cleaning operators exposed to tetrachloroethylene and in a control group of 29 nonexposed laundry workers. They reported that changes seen in ultrasonography consistent with steatosis were most strongly associated with high tetrachloroethylene exposure from the use of older dry-cleaning equipment and processes (OR=4.2, 95% CI=1.1–15.3). Mean ALT, AST, and GGT concentrations were somewhat higher in dry cleaners than in laundry workers. A case-control study in Sweden (Lundqvist et al., 1999) compared the occupational exposures of 30 men with steatosis with those of 120 control subjects in the same age range. Exposure to solvents was determined by questionnaire, and occupational-medicine physicians categorized the exposures. The study reported an OR of 4.3 (95% CI=1.2–15) for mixed-solvent exposure and an increased risk for intense solvent exposure of 7.7 (95% CI=1.7–48) for those who had been exposed for more than 1 year (in the preceding 15 years). A review of medical records ruled out confounding by alcohol use and other exposures.

Cirrhosis

There have been isolated often not well-documented case reports of cirrhosis associated with repeated exposure to several of the solvents reviewed in this report, including 1,1,1-trichloroethane and trichloroethylene (Thiele et al., 1982).4 Increased mortality due to cirrhosis has been noted in several cohorts of workers with mixed solvent and other exposures, including highway and other maintenance workers (Maizlish et al., 1988), automobile mechanics (Schwartz, 1987), newspaper pressworkers (Paganini-Hill et al., 1980), and metal workers (Mur et al., 1987; Teta and Ott, 1988). The studies did not adequately account for possible confounding factors, such as alcohol use, viral hepatitis, and other non-solvent exposures.

Summary and Conclusion

Case reports have examined acute hepatotoxicity after high exposure that typically improved when the exposure ended. Clinical and cross-sectional studies have reported inconsistent findings from various liver-function tests in workers chronically exposed to solvents, many of whom likely had continuous solvent exposure. There are few data on the persistence of abnormal liver transaminases after subjects were removed from subchronic or chronic exposure. There is more-consistent evidence from clinical and case-control studies of an association between chronic solvent exposure and steatosis (Table 9.3). In most of those studies, the exposures occurred in industrial settings and involved exposures to mixed solvents over periods of years. Information on the relationship between cirrhosis and solvent exposure is limited to mortality studies, many of which were designed to examine multiple cancer outcomes and most of which did not account for alcohol use, exposures to substances other than solvents, and other potential confounders.

The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between chronic exposure to specific organic solvents under

4  

Other solvents, particularly carbon tetrachloride, have also been associated with cirrhosis.

 

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

review or solvent mixtures and cirrhosis or persistent alterations in liver function tests after cessation of exposure.

There is limited/suggestive evidence of an association between chronic exposure to solvents and hepatic steatosis that could persist after cessation of exposure.

TABLE 9.3 Selected Epidemiologic Studies: Hepatic Steatosis and Exposure to Organic Solvents

Reference

Population

Exposed Cases

Estimated Relative Risk (95% CI)

Brodkin et al., 1995

Dry-cleaning workers in Seattle

 

 

Hepatic parenchymal changes and tetrachloroethylene exposure

 

 

Crude exposure

NA

2.5 (0.6–10.1)a

 

Old dry- or wet-transfer operation

NA

4.2 (1.1–15.3)a

 

Cumulative

 

 

<10 process-adjusted years

NA

5.1 (0.8–33.1)a

 

≥10 process-adjusted years

NA

1.2 (0.2–7.2)a

Lundqvist et al., 1999

Male steatosis patients in Sweden

 

 

Intense exposure to solvents at anytime

6b

6.7 (1.4–30)

 

in 1 year of preceding 15 years

6b

7.7 (1.7–48)

 

in >5 years of preceding 15 years

6b

29.7 (3.2–218)

NOTE: NA=not available.

aAdjusted for age, alcohol consumption, body-mass index, sex, and serologic evidence of hepatitis.

bData are for the highest exposure group as determined from type of job, title, and questionnaire exposure information.

GASTROINTESTINAL EFFECTS

Several gastrointestinal effects have been examined with regard to a potential relationship to solvent exposure. Pancreatitis occurs when inflammation in and around the pancreas disrupts its exocrine and endocrine functions. Autodigestion (during which digestive enzymes that are normally secreted in an inactive form become activated in the pancreas and begin to digest the pancreatic tissue) is one theory of the pathogenesis of pancreatitis (Greenberger et al., 1998). Chronic pancreatitis is a persistent inflammation that can result in extensive damage. Most of the estimated 50,000–80,000 cases of acute pancreatitis annually in the United States are caused by alcohol abuse or gallstones (NIDDK, 2001). Because chronic alcohol consumption is a known risk factor in the development of pancreatitis, researchers have theorized that occupational-solvent exposure, particularly to alcohol-based solvents, could cause chronic pancreatitis.

Epidemiologic Studies of Gastrointestinal Effects and Exposure to Organic Solvents

There are few epidemiologic data on the potential gastrointestinal effects of exposure to solvents.

Yamaguchi and colleagues (1985; Sato et al., 1987) examined the association between trichloroethylene exposure and pneumatosis cystoides coli, a benign condition of the large intestine involving formation of multiple gas-filled cysts. The cases (n=13) and

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

control subjects (n=65) in the studies were identified from hospital records in Japan. The study found that 12 of 13 patients with pneumatosis cystoides intestinalis reported trichloroethylene exposure, whereas only five of 65 control subjects reported the exposure (p <0.001). The authors, however, reported almost complete spontaneous disappearance of the condition after discontinuation of exposure to trichloroethylene in several patients who were followed longitudinally, indicating that this condition, although rare, is a short-term consequence of exposure.

Hotz and colleagues (1990) examined the effects of exposure to hydrocarbons in a cross-sectional study of 230 men working in various occupations (such as floor layers or printers). The study included 21 “formerly exposed” workers with a median time since last exposure of 4.2 years (range 0.2–27.9 years). There were no differences in serum amylase and lipase concentrations between men in solvent- or hydrocarbon-related occupations and controls. Serum amylase and lipase concentrations are nonspecific, insensitive measures that can be used in diagnosing pancreatitis. Each of the worker subgroups was small; this, with the healthy-worker effect, could account for the findings.

Concerns about the association between hydrocarbon-related occupations and chronic pancreatitis prompted McNamee and colleagues (1994) to conduct a case-control study in Manchester, England. The occupational exposures of 102 patients who met the diagnostic criteria for chronic pancreatitis were compared with those of 204 age- and sex-matched controls. Two occupational hygienists and two occupational physicians blinded to individual disease status developed a lifetime cumulative hydrocarbon-exposure score from a structured interview and questionnaire. Confounding—attributable to alcohol use, cigarette-smoking, dietary intake of antioxidants, and social class—was considered in the statistical analyses. Increased risks were found to be associated with higher cumulative hydrocarbon exposure scores (OR=2.67, 90% CI=1.22–5.87) and lower cumulative exposure (OR=1.20, 90% CI=0.61–2.35) after adjustment for a number of factors. For solvent exposures, an increased in pancreatitis was associated with high cumulative exposures to chlorinated solvents (OR=4.41, 90% CI=0.69–28.19), but there was a small depression with exposure to paint solvents (OR=0.87, 90% CI=0.31–2.52). Because the study was cross-sectional, it is not possible to determine whether the disease developed after an exposure-free period.

Summary and Conclusion

There is little information on the persistent or latent effects of solvent exposure on the gastrointestinal system. The few studies that have examined pancreatic outcomes had inconsistent results and a lack of specific exposure measures.

The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to the specific organic solvents under review or solvent mixtures and chronic pancreatitis or other persistent gastrointestinal outcomes.

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

RENAL EFFECTS

The kidneys metabolize waste, regulate acid-base concentrations, maintain electrolyte balance, and control fluid levels in the body. That work is accomplished in more than 1 million nephrons, each made up of a glomerulus—a cluster of looping blood vessels in a capsule (Bowman’s space)—and a fluid-collecting tubule. Because the glomerulus filters blood, it is particularly susceptible to autoimmune, infectious, metabolic, and chemical insults (including hyperglycemia, mercury, and cadmium) (Brady and Brenner, 1998).

Glomerulonephritis describes a variety of inflammatory conditions in which the glomeruli are damaged and can gradually be destroyed. End-stage renal disease and acute renal failure are possible long-term sequelae. Glomerulonephritis can result from a primary kidney condition or as a manifestation of systemic diseases (such as diabetes), inherited conditions, viral infections (such as hepatitis B or hepatitis C), medication use, or environmental exposures. Most glomerular diseases are immune-mediated and can result in granular or immune complex deposits in the glomeruli. Although most cases of primary glomerulonephritis are related to problems with the immune system, the precise etiology of individual cases can be difficult to identify. In about one-fourth of people with chronic glomerulonephritis, there is no history of kidney disease, and the disorder appears first as chronic renal failure (NLM, 2002).

Epidemiologic Studies of Renal Effects and Exposure to Organic Solvents

A number of studies have examined both the short- and long-term effects on the kidney of exposure to solvents. Acute tubular necrosis has been associated with exposure to a number of solvents. This condition is a reaction to high-dose solvent exposures. It is clinically apparent within a week of exposure. Renal changes are confined to the tubules, and the glomeruli remain intact. The lesions can progress to hemorrhagic cortical necrosis and in some cases to acute or chronic renal failure. Numerous studies have examined markers of glomerular and tubular function associated with solvent exposure, including glomerular filtration rates, 24-hour proteinuria, microalbuminuria, β-2-microglobulin, and N-acetyl-β-glucosaminidase (e.g., Brogren et al., 1986; Cai et al., 1991; Krusell et al., 1985; Laitinen et al., 1995; Nagaya et al., 1989; Stevenson et al., 1995). Most studies have been cross-sectional, and they report inconsistent results with various degrees of exposure assessment (Hotz, 1994). Although the committee’s primary focus was on epidemiologic studies that used defined health outcomes, these studies of renal function were considered to corroborate the committee’s conclusions.

Several case reports associate solvent exposures with Goodpasture’s syndrome (autoimmune glomerulonephritis indicated by the production of antiglomerular basement membrane antibodies). In 1972, Beirne and Brennan reported on eight patients with antiglomerular basement membrane antibody-mediated glomerulonephritis from whom extensive exposure histories were obtained by personal interview. The investigators found that six of the eight had extensive exposure to solvents.

One hypothesis regarding the etiology of renal disease has focused on hydrocarbon-related occupational exposures. Several early epidemiologic studies of renal disease reported that occupational exposures to hydrocarbon compounds were higher or more frequent than

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

generally seen in control populations (Finn et al., 1980; Lagrue et al., 1976, 1977; Zimmerman et al., 1975). Asal and colleagues (1996) examined hydrocarbons in the development of idiopathic chronic glomerulopathy. The study of 321 matched pairs found an elevated risk for hydrocarbon exposure of 100 ppm or higher (OR=1.39, 95% CI=0.94–2.04). A study of Belgian renal patients reported increased risk of chronic renal failure with exposure to oxygenated hydrocarbons (OR=5.45, 95% CI=1.84–16.2) on the basis of 25 exposed cases (Nuyts et al., 1995). Yaqoob and colleagues (1992) reported increased risk of primary glomerulonephritis associated with exposure to petroleum products (RR=15.5, p <0.001), to greasing and degreasing agents (RR=5.3, p<0.01), and to paints and glue (RR =2.0, p<0.05) in a case-control study of 55 patients with end-stage renal disease attributed to primary glomerulonephritis. A study by Ravnskov (1986) followed up on patients with glomerulonephritis to examine whether discontinuation of hydrocarbon exposure affected the course of disease. The study reported that patients with subnormal glomerular filtration rates who were no longer exposed to hydrocarbons had a more favorable course than did those who continued to be exposed, despite initially lower mean glomerular filtration rates. Although those studies are informative for this review, the category of “hydrocarbon compounds” often is used more broadly than is “solvents,” and it can encompass many non-solvent compounds, including glues, hairsprays, and fuels.

Case-control studies have focused more specifically on solvent exposures. A study in Sweden developed an exposure questionnaire and an exposure measure that also were used by later studies to examine the relationship between renal disease and exposure to solvents (Ravnskov et al., 1979). Ravnskov and colleagues interviewed 50 patients with biopsy-proven glomerulonephritis and 100 sex- and age-matched control subjects (50 patients with nonglomerular renal disease and 50 with acute appendicitis). Solvent exposures were categorized by multiplying the duration of exposure (hours per week multiplied by years of exposure) by an intensity factor (0.5, 1, or 2) determined from the nature of the exposure, the amount of protective equipment used, and the setting. In a discordant-triplet analysis, the point-estimate rate ratio for glomerulonephritis and solvent exposure was 3.9 (95% CI=1.9–8.1). When the exposure scores were used, there was a trend of increased risk with increased exposure: exposure score less than 1, RR=1.0; 1–10, RR=0.6; 11–50, RR=2.9; and over 50, RR=4.2 (no other statistical calculations were presented).

Later case-control studies using similar exposure measurement methods reported inconsistent findings. In the Netherlands, van der Laan (1980) identified 50 patients with chronic glomerulonephritis and 50 control subjects from outpatient departments of internal medicine at the same hospitals where the cases were treated. All the cases were newly diagnosed with biopsy. The study reported no differences in solvent exposure between cases and controls (RR=1.1, 95% CI=0.4–3.1). The cases in the study were in the early stages of disease, and the group appeared to include fewer highly exposed people than did the group studied by Ravnskov and colleagues (1979).

A study by Franchini and colleagues (1984) reported similar findings. No relationship was found between solvent exposure and chronic glomerulonephritis in comparing the exposures of 116 cases of chronic glomerulonephritis with hospital controls. Solvent exposure was somewhat elevated in the subset of patients with membranous nephropathy.

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

As with the preceding studies, a study by Bell and colleagues (1985) assigned a solvent-exposure score based on the responses of 50 patients with biopsy-proven proliferative glomerulonephritis and compared them with the responses of 100 age-, sex-, and social-class-matched controls chosen from acute admissions to two hospitals. The mean solvent-exposure score was greater in the glomerulonephritis group (score =13,186) than in the control group (score=3030) (p<0.01).

Occupational and nonoccupational exposures to solvents were examined by Porro and colleagues (1992), who compared 60 patients with biopsy-proven nonsystemic chronic glomerulonephritis and 120 age- and sex-matched control subjects. Comparisons of the exposure scores, estimated in a fashion similar to that used in the preceding studies, revealed a total solvent-exposure score larger in the glomerulonephritis group than in the control group (OR=3.50, 95% CI=1.18–12.18). Similar results were reported for the occupational solvent-exposure score (OR=4.25, 95% CI=1.18–16.36), but not for the nonoccupational exposure score (OR=1.71, 95% CI=0.57–4.94). Logistic regression analyses revealed a trend in occupational-solvent exposure (no exposure, OR=1.0; lower exposure, OR=2.12, 95% CI=0.81–5.57; higher exposure, OR=5.42, 95% CI: 2.01–14.59; p for linear trend=0.0002); no similar response to dose was observed for nonoccupational exposures.

Other case-control studies have examined the relationship between glomerular disease and exposure to solvents. Among the largest was a study by Stengel and colleagues (1995) that focused on three subtypes of glomerular nephropathies. Cases (n=298) were diagnosed at one of five hospitals in France and were age- and sex-matched to 298 controls selected from each hospital. Solvent exposure was assessed with a standard questionnaire; two industrial hygienists grouped responses into five categories of solvents (chlorinated, oxygenated, aromatic, aliphatic, and solvent mixtures) and three intensities of exposure (none, low, and high). Analyses were performed only on male patients (64% of the cases), and the study did not report an association between solvent exposure and glomerulonephritis either at low exposure (OR=1.0, 95% CI=0.6–1.6) or at high exposure (OR=1.2, 95% CI =0.7–2.1). There were no noteworthy associations between any of the categories of solvents and either all cases of the disease or any of the subtypes. When the investigators divided the cases into those with chronic renal failure and those without, they found that chronic renal failure was associated with high exposures to all solvents (OR=7.7, 95% CI=1.4–41.6), as it was for patients with minimal-change nephropathy and for those with IgA nephropathy (OR=3.5, 95% CI=1.0–11.8). A linear trend was seen for both end points in an evaluation for duration of exposure (p=0.03 and p=0.02, respectively). The detailed analyses could only be performed on small subgroups of the entire study population.

A study in the West Midlands, United Kingdom, enrolled 50 case subjects with glomerulonephritis. The subjects were identified prospectively from people who had renal biopsies (Harrington et al., 1989). Age-, sex-, and ethnic-group-matched controls were selected from within the same practice of the physicians who referred each case. Participants were asked to fill out questionnaires on health and lifetime occupational history. The surveys were assessed in a blinded fashion by an experienced chemist-occupational hygienist. Exposures were categorized as none, low, medium, and high and assigned values of 0, 1, 10, and 100, respectively, for the analysis. The analysis of glomerulonephritis and total solvent exposure (exposed versus nonexposed) found an OR of 1.0 (95% CI=0.16–6.3). The limitations of this approach include the possibility of overmatching of controls to cases and the arbitrary assignment of values and cutoff points for exposure assessment.

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Sesso and colleagues (1990) investigated rapidly progressive renal failure with biopsy-proven crescentic glomerulonephritis by comparing 17 patients with 34 controls selected at random from patients admitted to the surgical wards of hospitals in Sao Paulo, Brazil. All participants were interviewed by a nurse who was blinded to their status and who used a questionnaire developed by the US National Institute for Occupational Safety and Health that had been translated into Portuguese. Exposures were categorized as “regular” if they included 1 hour or more direct contact per week for at least 3 consecutive months. The RR for rapidly progressive glomerulonephritis with regular exposure to organic solvents was 5.0 (95% CI=1.14–22.00).

A large, well-designed case-control study that examined the outcome of end-stage renal disease included cases of glomerulonephritis, hypertensive kidney disease, and interstitial kidney disease (Steenland et al., 1990). The investigators identified 325 men with advanced end-stage renal disease from the Michigan Kidney Registry. Control subjects were chosen by using random-digit dialing and matched by age, sex, and residential area. Participants were interviewed over the telephone by persons who were not blinded to case-control status. The information about exposures was reviewed in a blinded fashion by industrial hygienists and then categorized and quantified. When the subjects were analyzed as ever-exposed versus never-exposed, the OR for exposure to all solvents was 1.51 (95% CI=1.03–2.22). The OR for solvents used in paints and glues was 1.01 (95% CI=0.58–1.74), for solvents used as cleaning agents or degreasers 2.50 (95% CI=1.56–3.95), and for solvents used in other processes 1.05 (95% CI=0.44–2.48). The interviewers’ awareness of each subject’s case or control status is of concern, but there is no suggestion that they influenced the respondents’ recall.

Summary and Conclusion

There has long been interest in exploring the relationship of hydrocarbon exposure and renal disease—with inconsistent results. The relationship between renal disease, particularly glomerulonephritis, and exposure to solvents has been well studied. Animal studies have shown increased tubular cysts and acute tubular degeneration with exposure to toluene, xylene, and other solvents. However, only a few animal studies have reported evidence of glomerular damage (Hotz, 1994). Many of the experimental studies have been conducted with carbon tetrachloride, which is not reviewed in this report.

Most of the human epidemiologic studies used similar methods and a semiquantitative approach to exposure assessment based on self-reporting, which is common in case-control studies (Table 9.4). To overcome the potential for recall bias, many investigators included hospitalized controls. All the studies reviewed included survivors, as opposed to proxies; this can affect results if survivor exposure histories differ from those who have succumbed to chronic renal failure. The results of several case-control studies showed an increased risk of glomerulonephritis with exposure to solvents. One study showed a trend of increased risk with increasing occupational solvent exposure.

The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between chronic exposure to solvent mixtures and chronic glomerulonephritis.

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 9.4 Selected Epidemiologic Studies: Renal Disease and Exposure to Organic Solvents

Reference

Population

Exposed Cases

Estimated Relative Risk (95% CI)

Glomerulonephritis

Solvents

Case-Control Studies

Ravnskov et al., 1979

Patients in Sweden

50 total cases

3.9 (1.9–8.1)

van der Laan, 1980

Patients in the Netherlands

50 total cases

1.1 (0.4–3.1)

Stengel et al., 1995

Male patients in France

298 total cases

 

 

Low solvent exposure

21%a

1.0 (0.6–1.6)

 

High solvent exposure

18%a

1.2 (0.7–2.1)

 

Chlorinated solvents

4%a

0.6 (0.2–1.5)

 

Oxygenated solvents

6%a

1.2 (0.5–3.0)

 

Aliphatics

10%a

2.0 (0.9–4.3)

 

Aromatics

5%a

1.6 (0.5–4.6)

 

Solvent mixtures

8%a

0.8 (0.4–1.7)

Harrington et al., 1989

Patients in the United Kingdom

50 total cases

1.0 (0.16–6.3)

Sesso et al., 1990

Patients in Brazil

17 total cases

 

 

Organic solvents

52.9%a

5.0 (1.14–22.00)

 

Overall hydrocarbons

58.5%a

2.8 (0.71–11.07)

Porro et al., 1992

Patients in Italy

60 total cases

 

 

Total solvent exposures

NA

3.50 (1.18–12.18)

 

Occupational

NA

4.25 (1.18–16.36)

 

Nonoccupational

NA

1.71 (0.57–4.94)

Hydrocarbons

Case-Control Studies

Asal et al., 1996

Patients in Oklahoma

 

 

Hydrocarbon exposure

(<100 ppm vs ≥100 ppm)

132

1.39 (0.94–2.04)

Yaqoob et al., 1992

Patients in the United Kingdom

 

 

Greasing, degreasing agents

NA

5.3b (p<0.01)

End-Stage Renal Disease

Solvents

Case-Control Studies

Steenland et al., 1990

Patients in Michigan

 

 

All solvents

124

1.51 (1.03–2.22)

 

Solvents used in paints and glues

38

1.01 (0.58–1.74)

 

Solvents used as cleaning agents or degreasers

94

2.50 (1.56–3.95)

 

Solvents used in other processes

17

1.05 (0.44–2.48)

Chronic Renal Failure

Hydrocarbons

Case-Control Studies

Nuyts et al., 1995

Patients in Belgium

 

 

Oxygenated hydrocarbons

25

5.45 (1.84–16.2)

NOTE: NA=not available.

aPercentage of total cases.

bRelative risk

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

DERMATITIS

Dermatitis is an inflammation of the skin with visible changes that can include scaling, crusting, redness, and swelling. In chronic dermatitis, the skin can remain rough and thickened. There are a number of types of dermatitis, including atopic dermatitis, a cutaneous condition frequently associated with asthma or hay fever. Environmental factors often trigger or exacerbate symptoms of atopic dermatitis. Contact dermatitis is a direct result of exposure to an exogenous compound. Irritant contact dermatitis is a direct toxic effect on the skin that is most often seen on the hands and often can be prevented with skin-protection measures, such as gloves or ointments. A number of compounds—including soaps, cleansers, and harsh chemicals—can cause irritant contact dermatitis, and there is wide variability in individual susceptibility to cutaneous irritants.

Allergic contact dermatitis is a delayed hypersensitivity response that results from an immune reaction to an external substance (Whitmore and Nethercott, 1994). Once sensitivity to a compound is established, exposure to even a small amount can produce a severe reaction (Niland, 1994). Common sensitizers include nickel, fragrances, poison ivy, and preservatives.

Patch testing often is used to distinguish between irritant and allergic contact dermatitis. Diluted antigens (1% for most insecticides) are placed on test strips and applied to the upper back for 48 hours. The patches are read at 48 and 96 hours for evidence of erythema, edema, or vesiculation (Abrams et al., 1991). Patch testing has become highly standardized; the concentrations of the potential allergens are below the irritant threshold, so they do not cause false-positive reactions when applied to the skin of nonsensitized subjects who serve as controls (Adams, 1997; Mathias, 1994).

Epidemiologic Studies of Dermatitis and Exposure to Insecticides

This section reviews the literature on exposure to insecticides and allergic or irritant contact dermatitis. The primary route of human exposure to most pesticides is the skin (Moses, 1989). Although agricultural workers are believed to have a much higher risk of contracting skin disease than workers in industrial occupations, it is difficult to pinpoint the cause of disease from among the many potential agriculture-related exposures, including herbicides, fertilizers, insecticides, and the crop itself (Moses, 1989). The cutaneous hazards of pesticide exposure depend not only on the toxicity of the insecticide formulation but also on the method of application, environmental conditions, the extent of skin protection, and the use of personal-hygiene measures. Reports on the dermatologic effects of insecticide exposure do not always differentiate between irritant and allergic dermatitis and focus primarily on short-term dermatologic outcomes that occur soon after exposure.

Allergic Contact Dermatitis

Dermal-sensitization tests in animals are conducted before insecticide products are registered with the US Environmental Protection Agency, and insecticide labels indicate whether products are potential sensitizers. Several insecticides and insect repellents reviewed in this report have been found to be potentially weak sensitizing agents (such as DEET [N,N,-diethyl-3-methylbenzamide], dichlorvos, and malathion), although the sensitizing potential can depend on the formulation (Abrams et al., 1991; Penagos et al.,

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

2001). Carbamates and organophosphates in general are not strong irritants or sensitizers (Penagos et al., 2001). The sensitization potential of individual insecticides has been examined in studies of patch testing (e.g., Guo et al., 1996; Sharma and Kaur, 1990).

A cross-sectional study of 122 Taiwanese fruit farmers examined dermal outcomes and skin sensitization (Guo et al., 1996). Skin diseases experienced by the farmers were assessed by a dermatologist through physical examination and questionnaire. Patch tests were conducted on the farmers and on a control group of 63 printing-press workers with no known exposure to pesticides. The farmers reported frequent use of pesticides, including organophosphate insecticides (such as malathion and parathion), pyrethroids, carbamates (such as carbaryl), herbicides, and miticides. Of the 122 farmers, 112 reported that they themselves prepared the pesticides for application; most said they regularly used hats, boots, and masks but not gloves or goggles. That could potentially result in high skin exposure to the frequently used pesticides. Hand dermatitis was exhibited in 30% of the pesticide-exposed subjects (rates of dermatitis in the control group were not provided). It was not possible to determine how long the farmers had experienced dermatitis. Patch testing of a standard series of antigens revealed similar rates of sensitivity to common skin allergens between the groups, and about twice as many farmers (40%) as controls were sensitive to one or more of the pesticides included in the series. One of the farmers had an allergic reaction to malathion as compared with no positive reactions in the controls. Patch testing with carbaryl did not result in positive reactions in farmers or controls.

A study by Sharma and Kaur (1990) examined contact sensitization to 13 insecticides by comparing the patch-testing results of 30 farmers who had previously been treated for contact dermatitis with 20 control subjects. The investigators found that 11 farmers had allergic reactions to one or more of the insecticides, fungicides, or herbicides, including two allergic reactions to malathion, one to carbaryl, and one to lindane. No allergic reactions to dichlorvos were seen. In comparison, there were no allergic reactions in the control subjects. The study is limited by the small number of patch-test participants.

As reviewed by Penagos and colleagues (2001), the literature regarding allergic contact dermatitis and insecticides consists primarily of animal dermal-sensitization data, human case reports, and a few studies of human patch testing generally involving few patients and often lacking an adequate control population. However, the potential for some of the insecticides reviewed in this report to result in sensitization reactions has been demonstrated.

Irritant Contact Dermatitis and Other Skin Disorders

Several studies have looked at dermatitis and occupational exposures; however, the extent to which the studies specifically differentiate between irritant and allergic contact dermatitis varies. A cross-sectional study in the Netherlands studied male agricultural and horticultural workers and pesticide formulators to determine the effects of exposure to various pesticides, including organophosphates, pyrethrins, chlorinated hydrocarbons, carbamates, and fungicides (Ensberg et al., 1974). Attempts were made to estimate the exposure to pesticides on the basis of the type and length of work and the amount of pesticides applied per year (85 workers were in the moderate-to-intensive exposure group, 64 in the slight-to-moderate group). The workers completed a questionnaire and had a physical examination that included blood and urine tests. Control subjects (matched for sex, locality, age, and socioeconomic status) were examined at about the same time. The number

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

of subjects with subjective symptoms of dermal sensitivity, itching, or eczema was increased with increased estimated time of exposure. Physical examination confirmed the presence of more skin disease in more highly exposed workers, but patch tests were not performed to differentiate allergic from irritant reactions. The study did not provide details about the effects that were included in the term skin disease, and it is not possible to determine how long the dermal effects were present in the workers.

Risk factors for farm-related dermatitis were examined in a cross-sectional study of male farmers in Iowa (n=382) and the wives of farmers (n=256), who completed a health and exposure questionnaire (Park et al., 2001). Among the men, the risk of dermatitis during the previous year was not increased with application of insecticides on field crops (OR=0.63, 95% CI=0.25–1.56) or with application of insecticides to livestock (OR=1.29, 95% CI=0.66–2.50). A history of allergy was the only risk factor meaningfully associated with dermatitis. The study was population-based, but the authors acknowledge a low response rate.

Gamsky and colleagues (1992) studied dermatitis in California farm workers and compared grape, citrus, and tomato workers. The study identified a wide array of pesticides used, including elemental sulfur in the vineyards. Grape workers experienced the highest prevalence of dermatitis, but their exposures were not well characterized, and there were many possible confounders. Other studies have examined dermatologic effects of pesticides with similar problems of multiple confounders and poorly characterized exposure (Cellini and Offidani, 1994; Cole et al., 1997; Matsushita et al., 1980).

One study of Gulf War veterans examined the potential dermatologic effects of pesticide exposure during the war in concert with other symptoms and exposures. Proctor and colleagues (1998) studied the symptom experience of a stratified random sample of two cohorts of Gulf War veterans from Massachusetts (Ft. Devens) (n=220) and New Orleans (n=71), both consisting of active-duty, reserve, and National Guard troops deployed to the Gulf War area. The control group (n=50) consisted of veterans who had been deployed to Germany during the Gulf War. Subjects completed symptom checklists, exposure questionnaires, other tests, and interviews. The greatest differences between case subjects and the control group were in dermatologic symptoms (such as skin rash, eczema, and skin allergy), neuropsychologic symptoms (such as difficulty in concentrating and in learning new material), and gastrointestinal symptoms (such as stomach cramps and excessive gas). With multiple regression and adjustment for other exposures, pesticide exposure was associated with neurologic symptoms and musculoskeletal symptoms but was not found to be related to dermatologic, gastrointestinal, neuropsychologic, or psychologic symptoms.

Summary and Conclusion

Many of the studies on dermatitis and insecticide exposure examined workers with continuing exposures to insecticides, so it is not possible to determine whether the dermatitis was a short- or long-term health effect of insecticide exposure. In addition, those studies examined agricultural workers who experienced multiple confounding exposures that are not always subject to control. Although case studies and review articles discuss an increased incidence of short-term dermatitis after handling pesticides, there is a limited amount of information about the long-term dermatologic effects of insecticide exposure. Several of the insecticides reviewed in this report have been found to be potential sensitizers, and reexposure to those agents could result in allergic contact dermatitis in sensitized persons.

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

However, there are few epidemiologic studies of exposure to insecticides and allergic contact dermatitis, and studies conducted to date have focused on a variety of insecticides and have involved small study populations.

The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between exposure to some of the insecticides under review and allergic contact dermatitis that results from sensitization to the compounds and subsequent reexposure.

There is inadequate/insufficient evidence to determine whether an association exists between exposure to the insecticides under review and chronic irritant contact dermatitis after cessation of exposure.

Epidemiologic Studies of Dermatitis and Exposure to Organic Solvents

Many solvents are irritants to the skin and cause acute dermatitis. Solvents alter the chemical and physical barriers of the epidermis, remove the lipid film on the surface and thus diminish the protective capacity of the skin. Acute dermatitis can occur after a single exposure or as a cumulative effect after repeated insults by low-grade irritants over a long period. Dryness and cracking of the skin are often the initial features of irritant contact dermatitis with redness, scaling, papules, vesicles and a gradual thickening of the skin developing over time. Irritant contact dermatitis can persist if untreated soon after the initial appearance. Even when the dermatitis appears to be healed, the protective capacity of the skin is still impaired for a period (Andersen, 1986).

Allergic Contact Dermatitis

Numerous case reports and case series have been included in the medical literature regarding allergic contact dermatitis and exposure to propylene glycol, a solvent widely used in foods, drugs, and cosmetics. Patch testing, used to confirm the diagnosis of allergic contact dermatitis, may have positive results for only a fraction of study participants because not everyone is sensitized to the compound. It has been noted that, because many solvents are irritants, it is difficult to test their potential for allerginicity with standard patch-test techniques (Wahlberg and Adams, 1999).

Using 100% propylene glycol, Andersen and Storrs (1982) patch-tested 84 dermatitis patients and reported that five of 12 patch-test-positive patients had allergic reactions; seven had irritant reactions. In followup tests, 248 eczema patients were patch-tested with propylene glycol at 100%, 20%, and 2% concentrations. Two of five patients with positive reactions to the patch tests developed an eczematous eruption after oral provocation with 15 mL of propylene glycol, confirming its potential as a sensitizer. The authors state that positive patch test reactions to propylene glycol are difficult to interpret and that allergic reactions can be confirmed by clinical relevance, repeated local skin provocation, or oral provocation.

Angelini and Meneghini (1981) conducted patch testing on 400 subjects with 20% propylene glycol in water and six of them developed an allergic contact dermatitis. Hannuksela and colleagues (1975) subjected 1556 eczema patients to a chamber test with propylene glycol, ethylene glycol, and polyethylene glycol. They reported 12.5% positive

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

reactions to propylene glycol, 30% of which were allergic in appearance. Not all studies determined a diagnosis of allergic contact dermatitis with exposure to propylene glycol. For example, at a skin clinic, Nater and colleagues (1977) conducted patch tests on 98 outpatients with eczema with propylene glycol. Eleven had positive patch-test reactions after a 48-hour application. However, because none of the study’s subjects gave a history consistent with possible allergic contact dermatitis related to propylene glycol, the authors concluded that all the reactions were irritant effects.

Wolf and colleagues (1994, 1996) evaluated the hand dermatitis of Israeli soldiers with occupational dermatitis. Cases and controls were patch-tested with a standard battery of contact sensitizers and five additional reagents: gun oil, hydraulic oil, automotive lubricant oil, white spirits, and gasoline. Olive oil was used as a control. In the exposed group, 31 patients (29%) had at least one positive skin reaction to the oil series, and 30 had reactions to the standard patch-test arrays. None of the 20 soldiers exposed to fuels and oils, but without dermatitis, had a positive test in the oil series. This study provides some indication that exposure to some oils, white spirits, and fuels can result in allergic contact dermatitis. However, no data are provided about clearing of the dermatitis after cessation of exposure.

Irritant Contact Dermatitis and Other Skin Disorders

Many of the studies of contact dermatitis involve workers who continue to be exposed to the substances of concern, so it is difficult to determine long-term effects after exposure ceases. Several descriptive studies reported a high prevalence of skin problems, including dermatitis, in workers exposed to solvents (e.g., Atav and Spencer, 1995; Cherry et al., 2000; Goon and Goh, 2000). However, those studies did not have control groups for comparison.

Yakes and colleagues (1991) conducted a cross-sectional study of newspaper pressroom workers. They obtained responses to a comprehensive health questionnaire and performed a skin examination of 212 pressroom workers. The results were compared with results in 33 compositors. On the questionnaire, pressroom workers were more likely to complain of dryness or cracked skin, itching, acne, and redness than were compositors (p values were all <0.05). Dermatitis was correlated with more frequent use of type 1 solvent (mineral spirits and naphtha blend), Cleansall (aliphatic hydrocarbons, pine oil, and surfactants), and isopropyl alcohol (p values were all <0.05). Participation rates in the study were high (over 90%), but only continuous exposure and disease were measured.

Svendsen and Hilt (1997) compared skin disorders in ships’ engineers exposed to mineral oil and solvents in the engine room with disorders in other seamen. On a questionnaire, engineers were more likely than were control subjects to report eczema, acne, dry skin, and any dermatitis. Use of Stoddard solvent was found to be positively associated with acne (OR=2.2, 95% CI=0.86–5.46), and there was a weaker association with hand dermatitis (OR=1.1, 95% CI=0.60–2.11).

Burg and Gist (1999) analyzed data from the trichloroethylene subregistry of the Agency for Toxic Substances and Disease Registry (ATSDR). Registrants were exposed to trichloroethylene-contaminated water and also might have been exposed to trichloroethane, tetrachloroethylene, dichloroethane, and dichloroethene. The study categorized the 4041 living members on the registry into four groups by amount and duration of exposure and examined the groups for possible relationships with 25 health outcomes. Using a cumulative trichloroethylene exposure index of parts-per-billion-years (ppb-yr) adjusted for age and

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

sex, risks for skin rashes were estimated (in comparison to the 0–49 ppb-yr group) for exposures of 50–499 ppb-yr (OR=1.02), 500–4999 ppb-yr (OR=1.29), and 5000 or more ppb-yr (OR=1.20), which all had confidence intervals overlapping 1.0. This study uses the term skin rashes to include rashes, eczema, and other skin allergies. In addition to bias associated with health outcomes being self-reported, bias might arise from the self-selection of people choosing to be enrolled in a registry. The use of the lowest exposure category as the referent group could bias the risk estimates towards the null, since these subjects might be experiencing some level of response greater than that of a strictly unexposed control group.

Health effects in semiconductor-industry workers were examined by McCurdy and colleagues (1995), who performed a cross-sectional survey of workers in eight locations. Participants reported outcomes on a questionnaire, and the responses were analyzed by comparing fabrication workers with nonfabrication workers; fabrication workers were subdivided into work groups. Reporting dermatitis within the preceding year was more common in fabrication workers than in nonfabrication workers (OR=1.19, 95% CI=1.04–1.35). The authors reported a weak relationship between dermatitis and intensity of exposure to methanol and isopropanol, with RRs in the highest-exposure categories for those solvents of 1.37 (95% CI=1.08–1.70) and 1.24 (95% CI=1.02–1.48), respectively. Limitations of this study include multiple continuous exposures associated with the outcomes of interest.

Summary and Conclusion

Many solvents are skin irritants. Irritant contact dermatitis is evident soon after exposure, but usually dissipates within a short time of removal of the irritant. In some cases, however, irritation might persist for months, or rarely longer, after exposure ceases.

Because allergic contact dermatitis results from sensitization to an external substance, the underlying sensitization to the allergens can persist indefinitely after the exposure has ceased. As discussed above, there are a number of case reports and some epidemiologic evidence that propylene glycol is an allergic sensitizer. Those sensitized to the compound may experience allergic contact dermatitis on reexposure to the sensitizing agent.

The committee concludes, from its assessment of the epidemiologic literature, that there is sufficient evidence of an association between exposure to propylene glycol and allergic contact dermatitis that results from sensitization to the compound and subsequent reexposure.

MULTIPLE CHEMICAL SENSITIVITY

Multiple chemical sensitivity (MCS)5 is a controversial condition marked by sensitivity to low chemical exposures. It is not formally recognized in ICD-10 (International Classification of Diseases, 10th revision) or by major medical associations as a discrete syndrome. Research criteria for MCS often specify symptoms of fatigue, cognitive impairment, respiratory inflammation, headaches, and other symptoms. The etiology of MCS is unknown, but may involve neuronal sensitization of mesolimbic pathways after

5  

Also called idiopathic environmental intolerances.

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

chemical exposure (Graveling et al., 1999). Because symptoms associated with MCS are frequently reported by Gulf War veterans, researchers have sought to establish whether veterans meet research criteria for MCS and whether self-reported insecticide or solvent exposures during the Gulf War are associated with onset.

For the purposes of this report, the committee sought to evaluate studies related to MCS that examined populations with known exposure to the relevant insecticides or organic solvents. Furthermore, studies were sought that evaluated participants (compared with a control or comparison group) after an exposure-free interval to identify long-term, rather than short-term, effects. The committee was not able to identify any occupational studies that met those criteria. Several studies of Gulf War veterans and MCS are described below. However, there is not a sufficient body of epidemiologic evidence with information on exposure to the relevant insecticides or solvents to support conclusions on this outcome.

Three studies addressed the possibility of an association between MCS and pesticide exposures during the Gulf War. They varied widely in their methods, samples of veterans, and definitions of exposures and of MCS. In the most methodologically rigorous of the three studies, Reid and colleagues (2001) further analyzed a population-based, random sample of British Gulf War veterans assembled by Unwin and colleagues (1999). MCS cases were defined by criteria used by Simon and colleagues (1993). The criteria required self-reported symptoms for at least 3 months related to at least three organ systems (including the central nervous system) and sensitivity to four or more of 11 substances that were included in the Unwin exposure questionnaire (the Simon criteria had a list of 14). Reid and colleagues (2001) set aside the two comparison cohorts developed by Unwin and colleagues (1999), thus restricting their analysis to responses from the Gulf War veteran cohort. About 1% of the Gulf War cohort matched the Simon criteria for MCS, and 0.8% indicated that they thought they had MCS. But there was little overlap between the two groups. Veterans who met the MCS criteria were much more likely (OR=14.6, 95% CI=7.2–26.6) to meet criteria for posttraumatic stress disorder (PTSD). Exposures to any of 23 Gulf War exposures were compared in veterans who met the MCS criteria and those who did not; the researchers used a logistic regression analysis that adjusted for sex, age, marital status, education, rank, and employment status at followup. The risk estimates of criteria-defined MCS were increased for most of the chemical exposures. For “personal pesticides” (OR=10.9, 95% CI=2.6–45.8) and “pesticides on clothing or bedding” (OR=12.3, 95% CI=5.1–30.0), the estimated risks were the highest found in the study. The adjusted OR for “POW exposure” (which could involve exposure to lindane, a delousing agent) was 4.0 (95% CI=1.8–8.9). The authors concluded that, “the relationship between MCS and pesticide exposure deserves further exploration.” The limitations of the study were self-reported symptoms and exposures and the potential for recall bias.

In the second study on Gulf War veterans, Bell and colleagues (1998) compared rates of self-perceived chemical intolerance in random samples of deployed and nondeployed veterans from the Tucson Veterans Affairs Medical Center and reported on perceived exposures to chemical agents during the Gulf War. A 15-minute telephone interview collected data on the veterans’ self-perceptions of their health (at the time of the interview, 6 months before, and just before entering and after leaving military service), plus self-reports of the diagnosis of PTSD and of intolerance to chemical odors of 17 substances. Self-reports regarding six exposures in the Gulf War were also solicited, and degree of exposure to each agent was rated on a 10-point scale. From an initial random sample of 100

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

veterans, the investigators contacted 28 Gulf War and 20 Gulf War era veterans (military personnel who were not deployed to the Gulf War but served during the same time period); 24 Gulf War and 17 Gulf War era veterans agreed to participate. Female veterans were oversampled in both groups because of early reports of higher rates of chemical sensitivity in women. For purposes of analysis, Gulf War veterans were first dichotomized into “healthy” and “ill” on the basis of changes in their self-reports of health status between the time preceding enlistment and the time of the survey. Veterans designated as “ill” in this analysis were further dichotomized into groups with and without deterioration in their tolerance to chemical odors since entry into the service. The comparison of ill and healthy Gulf War veterans resulted in ORs of 5.6 (95% CI=0.81–38.5) for pesticide exposure and 5.5 (95% CI=0.91–33.2) for insect-repellent exposure. Although not statistically precise, the risk estimates for associations with pesticide exposure were larger than those for other exposures. When ill Gulf War veterans whose self-perception of chemical sensitivity had increased since deployment were compared with healthy veterans, the associations with exposure to both pesticides (OR=12, 95% CI=1.3–111.3) and insect repellents (OR=12, 95% CI=1.1–136.8) were elevated. The researchers considered the findings preliminary. The study’s limitations included a nonrepresentative sample drawn from the patient population of the Veterans Affairs Medical Center and self-reported exposures and symptoms.

In the third study of MCS, Miller and Prihoda (1999) recruited a group of 72 Gulf War veterans with advertisements in MCS patient-group newsletters and word of mouth. No attempt was made to identify individual veterans who met the criteria for MCS, but the sample of veterans obtained had symptoms and symptom severity scores that were comparable with those of patients with MCS who were included in the same study. No attempt was made to determine actual exposures, but veterans were asked to identify exposures that they thought had led to their symptoms. Of the Gulf War veterans, two (3%) identified pesticide exposure during the Gulf War as a cause of their symptoms. However, this study is limited by the self-selected nature of the veteran sample and was not constructed to test hypotheses of causality.

Summary

Only one of the studies addressing MCS in Gulf War veterans can be considered a high-quality study. It is notable for its rigorous methods, random sample of British Gulf War veterans, and use of a definition of MCS that had been used in earlier studies; but there did not seem to be a unique association between pesticides and MCS, inasmuch as most of the exposures assessed resulted in positive associations with the symptom criteria for MCS. A second study used a very small, and possibly nonrepresentative, sample; and a third used a nonrepresentative sample and made no attempts to assess actual exposures. All three studies used self-reports of exposures, raising the possibility of recall bias. Because of the lack of other epidemiologic studies of MCS specifically addressing solvent or insecticide exposure, the committee did not form a conclusion on this outcome. Of course, studies of MCS necessarily examine exposure to a multiplicity of chemicals.

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

SYSTEMIC RHEUMATIC DISEASES

Epidemiologic Studies of Exposure to Organic Solvents

Scleroderma

Scleroderma encompasses disorders that involve abnormal growth of connective tissue resulting in a variety of clinical manifestations, from thickening and tightening skin to problems with blood vessels or internal organs. Although the etiology of the disease is not known, it is thought to be an autoimmune disease in which stimulated fibroblast cells produce excess collagen. Systemic scleroderma, or systemic sclerosis, is estimated to affect 40,000–165,000 people in the United States, with a female-to-male ratio of 3:1 (Medsger, 1994; NIAMS, 2001). Research suggests that environmental exposure (such as to viral infections and some adhesives) can trigger scleroderma in people who are genetically predisposed (NIAMS, 2001).

Several studies have examined the relationship between solvent exposure and scleroderma. Scleroderma is a rare disease, and most studies involve small numbers of cases. Lundberg and colleagues (1994) conducted a population-based study of 375,035 men and 140,139 women in Sweden, using census data linked to hospital-discharge data. In all, 47 men and 24 women had been treated for systemic sclerosis. By using a job-exposure matrix, they categorized occupations as exposed or not exposed to several chemicals. The study found an increased association for systemic sclerosis in men exposed to aliphatic hydrocarbons (RR=2.1, 95% CI=0.8–5.5). Risk estimates for systemic sclerosis and solvent exposure in women were not reported.

In a case-control study of male scleroderma patients in the United Kingdom, Silman and Jones (1992) mailed questionnaires about occupational exposures to the 56 case patients, 56 control subjects referred by the patients’ physicians, and 41 control subjects who were friends of the patients. Job descriptions and histories were blinded and assessed by an occupational hygienist. The study revealed positive associations for self-reported exposure to organic solvents when 18 exposed cases were compared with the physicians’ controls (OR=1.7, 95% CI=0.7–4.1) or with friend controls (OR=2.3, 95% CI=0.9–6.2). Duration of exposure (none, 0–9 years, 10–19 years, 20 years or more) did not correlate with a trend of increasing risk in comparison with either control group.

Nietert and colleagues conducted two studies (1998, 1999) of 178 systemic sclerosis patients at a rheumatology clinic in South Carolina. They assigned 200 control subjects with other rheumatologic diseases from the same referral practice. All participants were interviewed to determine residential, occupational, and medical histories. Laboratory tests were used to determine the presence of Scl70 autoantibodies, which are associated with some types of the disease. The 1998 study focused on occupational exposures to solvents and used a job-exposure matrix to categorize occupational histories by intensity of exposure (none, low, medium, or high). That study reported increased risk of systemic sclerosis for males with high cumulative intensity of “any solvent exposure” (OR=2.9, 95% CI=1.1–7.6; 60 exposed cases), maximal intensity of “any solvent exposure” (OR=2.9, 95% CI=1.2–7.1; 57 exposed cases), or maximal intensity of exposure to trichloroethylene (OR=3.3, 95% CI=1.0–10.3). No such positive associations were found for men in relation to exposure to benzene, carbon tetrachloride, and trichloroethane or for females with respect to

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

any intensity of solvent exposure or exposure to the four specific solvents. This study adjusted only for age at onset of disease.

Another study of this population examined exposure to solvents through hobbies (Nietert et al., 1999). The study found that the association between systemic sclerosis and solvent exposure from hobbies was only moderately increased for the group as a whole (OR =1.1, 95% CI=0.7–1.9). High cumulative solvent-oriented hobby exposure was greater in patients who were positive for the blood test Scl70 than for those with negative test results (OR=2.9, 95% CI=1.1–7.9), and it was greater when compared with controls (OR=2.5, 95% CI=1.1–5.9). The study design did control for potential confounders, including age at disease onset, sex, and intensity of occupational exposure.

Bovenzi and colleagues (1995) conducted a small case-control study in Trento, Italy, that interviewed 21 case subjects with scleroderma and 42 age- and sex-matched referents identified from hospital records. On the basis of only four cases exposed to solvents, the study reported an OR of 9.28 (95% CI=1.08–243.8).

Goldman (1996) conducted a questionnaire survey of patients in a rheumatology practice and reported an increase in exposure to organic solvents in a subset of patients with scleroderma (12 of 33 scleroderma patients) compared with patients with other rheumatologic diseases (22 of 246 patients, p=0.00001). However, the survey did not control for potentially confounding exposures.

Czirjak and colleagues (1989) reported that 28% of 61 patients with systemic sclerosis had prior exposure to chemicals, primarily solvents. The study did not, however, report the exposure rate in the control group.

Other Rheumatologic Diseases

A few epidemiologic studies have been conducted on other rheumatologic diseases in connection with exposure to solvents. Kilburn and Warshaw (1992) studied patients with systemic lupus erythematosus (SLE), a chronic inflammatory disease of unknown etiology. A group of 362 residents of Tucson, Arizona, had laboratory tests and participated in occupational- and medical-history interviews. The group was identified as possibly having been exposed to water contaminated with trichloroethylene, trichloroethane, inorganic chromium, and other substances. A group of 158 Phoenix residents served as a regional comparison population. SLE symptoms were reported considerably more often by the exposed group. Blood tests showed increased concentrations of antinuclear antibodies (associated with SLE) more often in females in the exposed group than in the comparison population, but notable differences were not seen in blood-test results of exposed and control males.

Rheumatoid arthritis was the primary focus of a large population-based study (described above) by Lundberg and colleagues (1994). By linking Swedish census data and hospital-discharge data, the study identified 896 males and 629 females who had been treated for rheumatoid arthritis in 1981–1983. The study reported an increased risk of rheumatoid arthritis in male spray painters and lacquer workers (RR=2.4, 95% CI=1.1–5.4). Female launderers and dry-cleaning workers had an increased relative risk on the basis of seven cases. In the analysis, which was based on a job-exposure matrix of occupational use of solvents, the study reported an increase for males with substantial use of organic solvents (RR=1.2, 95% CI=1.0–1.6), but the results for women in the same exposure category did not suggest increased risk (RR=0.9, 95% CI=0.3–2.8), although there were

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

only four exposed cases. The authors noted that there were only small differences in the risk of rheumatoid arthritis among the different occupations. The jobs studied often involved manual labor. It is possible that people with rheumatoid arthritis are less likely to seek such jobs (because of pain or deformity of their hands) and that the study therefore underestimated the association. Conversely, it is possible that rheumatoid arthritis was more likely to be diagnosed in people whose work required the use of their hands and that the study therefore overestimated the association.

Undifferentiated connective-tissue disorder (UCTD) is the term used to describe a condition with nonspecific rheumatic symptoms that do not meet the criteria for any specific rheumatic disease. Lacey and colleagues (1999) conducted a case-control study involving 205 females with UCTD, compared with 2095 population-based female control subjects identified by random-digit dialing. Interviews were conducted to assess occupational exposures to solvent-containing products and to specific solvents. The study reported an elevated risk of UCTD with painting or paint manufacturing (OR=2.87, 95% CI=1.06–7.76) and with some solvents and solvent products. Of 32 patients reporting exposure to paint thinners or paint removers, the OR was 2.73 (95% CI=1.80–4.16). For 18 patients exposed to mineral spirits, naphtha, or white spirits, the OR was 1.81 (95% CI=1.09–3.02). Analyses for trichloroethylene, toluene, and other specific solvents involved few exposed cases and did not show consistent increases in risk. Control for confounding included adjustments for age at diagnosis and year of birth. The study was subject to strong recall bias.

Summary and Conclusion

The studies reviewed by the committee have reported inconsistent results for an association between systemic rheumatic diseases and exposure to solvents (Table 9.5). As with studies of other health effects, the exposures lack specificity and their assessments involve the use of job categories with wide variations in exposure. Although there is an indication of elevated risks in several studies of scleroderma and exposure to solvents, additional studies using control groups could clarify the nature of this association.

The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between chronic exposure to specific organic solvents under review or solvent mixtures and the systemic rheumatic diseases: scleroderma, rheumatoid arthritis, undifferentiated connective tissue disorders, and systemic lupus erythematosus.

TABLE 9.5 Selected Epidemiologic Studies: Systemic Rheumatic Diseases and Exposure to Organic Solvents

Reference

Population

Exposed Cases

Estimated Relative Risk (95% CI)

Scleroderma

Case-Control Studies

Lundberg et al., 1994

Swedish residents with systemic sclerosis

 

 

Aliphatic hydrocarbon exposure

6

2.1 (0.8–5.5)

Silman et al., 1992

Scleroderma cases in the United Kingdom

18

 

 

Organic solvent exposure

 

 

Compared with general practitioner controls

 

1.7 (0.7–4.1)

 

Compared with friend controls

 

2.3 (0.9–6.2)

Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Population

Exposed Cases

Estimated Relative Risk (95% CI)

Nietert et al., 1998

Systemic sclerosis patients in South Carolina, occupational exposure

 

Males

 

Solvents, maximal intensity

57

2.9 (1.2–7.1)

Trichloroethylene, maximal intensity

10

3.3 (1.0–10.3)

Females

 

Solvents, maximal intensity

4

0.6 (0.2–1.9)

Trichloroethylene, maximal intensity

6

0.9 (0.3–2.3)

Nietert et al., 1999

Systemic sclerosis patients in South Carolina, hobby exposure

178

1.1 (0.7–1.9)

Bovenzi et al., 1995

Occupational exposures in scleroderma cases, Trento, Italy

4

9.28 (1.08–243.8)

Rheumatoid arthritis

Case-Control Studies

Lundberg et al., 1994

Swedish registry cases of rheumatoid arthritis

 

 

Males

 

 

Substantial use of organic solvents

68

1.2 (1.0–1.6)

 

Spray painters and lacquer workers

6

2.4 (1.1–5.4)

 

Females

 

 

Substantial use of organic solvents

4

0.9 (0.3–2.8)

 

Launderers and dry-cleaning workers

7

1.5 (0.7–3.2)

Undifferentiated connective-tissue disorder

Case-Control Studies

Lacey et al., 1999

Cases of undifferentiated connective-tissue disorder

 

Painting or paint manufacturing

5

2.87 (1.06–7.76)

Paint thinners or removers

32

2.73 (1.80–4.16)

Mineral spirits, naphtha, white spirits

18

1.81 (1.09–3.02)

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Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"9. Additional Health Effects." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Next: Appendix A: Overview of Illnesses in Gulf War Veterens »
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Gulf War and Health, Volume 2, is the second in a series of congressionally-mandated studies by the Institute of Medicine that provides a comprehensive assessment of the available scientific literature on potential health effects of exposure to certain biological, chemical, and environmental agents associated with the Gulf War. In this second study, the committee evaluated the published, peer-reviewed literature on exposure to insecticides and solvents thought to have been present during the 1990-1991 war.

Because little information exists on actual exposure levels – a critical factor when assessing health effects – the committee could not draw specific conclusions about the health problems of Gulf War veterans. However, the study found some evidence, although usually limited, to link specific long-term health outcomes with exposure to certain insecticides and solvents.

The next phase of the series will examine the literature on potential health effects associated with exposure to selected environmental pollutants and particulates, such as oil-well fires and jet fuels.

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