6
CANCER AND EXPOSURE TO SOLVENTS
INTRODUCTION
The associations between exposure to organic solvents and the incidence of and mortality from cancer have been investigated extensively in a number of industries and occupations, including dry-cleaning, painting, printing, and rubber and shoe manufacturing. As a result, the body of evidence on exposure to organic solvents and cancer reviewed by the committee is quite large compared with that on other health effects. To help the reader become more familiar with the studies on exposure to solvents and cancer, this chapter is organized differently from Chapter 5.
Following this general introduction is a description of the major occupational cohort studies that are cited throughout the chapter; these studies provide findings for multiple cancer outcomes. The committee describes the essential study design characteristics and pertinent information for each of these cohorts organized by the type of solvent exposure.
The occupational cohort studies examined populations with known or suspected exposure to the solvents under review. Many of them have been updated and expanded to include more cohort members, longer periods of assessment, and other estimates of exposure. All of the various studies that follow a particular cohort, such as the NIOSH Pliofilm cohort, are described together in Table 6.1. The committee reviewed all the papers related to each major cohort in drawing its conclusions of association, but it is usually the findings from the most recent papers that are provided in the data-analysis tables at the end of the section on each cancer site. In some cases, results from the earlier papers were never reproduced, so the committee used the earlier results in its analysis.
A description of key case-control studies at the beginning of each section is followed by a table that outlines the studies’ characteristics and design elements and is similar to the table of cohort studies at the beginning of the chapter. Discussions of strengths and limitations of the studies that formed the basis of the committee’s conclusions are presented in the sections on the specific outcomes.
Background information on the types of cancer or cancer in general is provided in Chapter 5, and the reader is referred to those sections for that information. A review of the pertinent toxicology and findings from other organizations charged with evaluating the carcinogenicity of organic solvents is provided at the end of this introduction.
As in Chapter 5, the cancer outcomes are presented in the order of the ninth revision of the International Classification of Disease (ICD-9).
The Literature on Exposure to Organic Solvents
The literature on exposure to organic solvents and cancer outcomes provides information on specific solvent exposures (for example, benzene, trichloroethylene, and
tetrachloroethylene), on mixtures of specific organic solvents, or on mixtures of unspecified solvents. In many studies, exposure to solvents was not assessed specifically; rather, surrogates of exposure were used, such as job title, industry type, or occupation.
As is discussed in Chapter 2, a study’s ability to determine exposure accurately and specifically is critical in evaluating its overall quality. For the purposes of this report, the committee used studies that assessed exposure to specific organic solvents or to solvent mixtures as the primary evidence for its conclusions. The committee also included surrogates of exposure in drawing its conclusions, but it viewed those studies as supportive or supplemental evidence. Those studies included exposure of painters, printers, aircraft maintenance and manufacturing workers, service-station attendants, and shoe and boot manufacturers. All those studies are included in the data-analysis tables that accompany discussions of each cancer outcome.
The committee found most of the cancer literature focused on the following compounds: benzene, trichloroethylene, tetrachloroethylene, methylene chloride, and mixtures of unspecified organic solvents. Therefore, most of the committee’s conclusions on cancer outcomes are focused on exposure to those compounds. A smaller number of studies analyzed associations between cancer outcomes and toluene, xylene, isopropyl alcohol, methyl ethyl ketone, phenol, and other individual solvents, but for most agents, there was insufficient evidence for the committee to draw conclusions.
For exposure to tetrachloroethylene, the committee included studies of dry-cleaning and laundry workers as part of the primary evidence in drawing conclusions of associations. As a result, the conclusions related to exposure to tetrachloroethylene are also related to exposure to “dry-cleaning solvents.” The committee acknowledges that dry cleaners and launderers are likely exposed to other organic solvents and chemicals, including naphtha, Stoddard solvent, carbon tetrachloride, trichloroethylene, and 1,1,1-trichloroethane (IARC, 1995). As a result, the committee decided to consider studies of both tetrachloroethylene and dry-cleaning solvents in forming their conclusions, thereby including the possibility that one of the other solvents used in that industry contributed to the risks observed in some of the studies on dry cleaners and launderers.
The committee based its review of cancer outcomes only on studies of humans that had a comparison or control group (cohort and case-control studies). Case reports, case series, review articles, and meta-analyses related to cancer were excluded from the committee’s review. Although the committee reviewed ecologic, cross-sectional, proportionate mortality ratio (PMR), and mortality odds ratio studies, it did not consider them critical to its decision and excluded them from the discussions. Chapter 2 describes their specific limitations.
Toxicity and Determination of Carcinogenicity
Excess incidence of cancer has been observed in animals exposed to the specific organic solvents reviewed by the committee. Benzene, perhaps the most thoroughly investigated solvent, is a well-established carcinogen and has repeatedly been shown to induce hematopoietic cancers and cancers of the ovaries, mammary glands, pancreas, and liver (ATSDR, 1997a). The International Agency for Research on Cancer (IARC) has determined that benzene is “carcinogenic to humans” as determined in studies of both humans and animals. IARC bases its determination of benzene’s carcinogenicity on evidence from human studies that is considered “sufficient,” whereas the available animal
data are considered “limited.” Most of the human studies cited by IARC involve the increased risk of leukemia and other lymphatic and hematopoietic cancers (IARC, 1987). The National Toxicology Program (NTP) has also classified benzene as “known to be a human carcinogen” in its most recent report on carcinogens on the basis of animal and human studies (NTP, 2001).
On the basis of animal studies, trichloroethylene has been associated with liver cancer in one strain of one species (mouse) (ATSDR, 1997b). Liver and renal cell cancers and mononuclear cell leukemia have typically been seen after exposure to tetrachloroethylene. According to the Agency for Toxic Substance and Disease Registry (ATSDR, 1997c), the relevance to humans of rodent toxicology studies on trichloroethylene and tetrachloroethylene is unclear, given that some mechanisms of action differ. However, a great deal of research has been conducted over the last decade, and some mechanisms of action appear to be similar in rodents and humans such as genotoxic and cytotoxic actions of mercapturic acid derivatives of both trichloroethylene and tetrachloroethylene in the kidney (see Chapter 4 for more information). IARC has also reviewed trichloroethylene and tetrachloroethylene and determined that both are “probably carcinogenic to humans.” The evidence from animal studies is stronger and considered to be “sufficient,” whereas the evidence from human studies is considered “limited” (IARC, 1995). In addition, the NTP has identified both trichloroethylene and tetrachloroethylene as “reasonably anticipated to be human carcinogens” (NTP, 2001).
Exposure to methylene chloride in some rodent species has consistently produced excess numbers of cancers of the liver and lung and benign mammary tumors (ATSDR, 2000). IARC has determined that exposure to methylene chloride is “possibly carcinogenic to humans,” and the NTP concluded that it is “reasonably anticipated to be a human carcinogen” (IARC, 1999; NTP, 2001). IARC has determined that toluene and xylene are “not classifiable as to their carcinogenicity to humans” in that there was inadequate evidence from studies of humans and animals (IARC, 1999).
Chloroform has produced liver and kidney tumors in a strain-, sex-, species-, and dose-dependent manner and, on the basis of sufficient evidence from animal studies, is “reasonably anticipated to be a human carcinogen” according to the NTP (ATSDR, 1997d; NTP, 2001). Chloroform was once used as an anesthetic, but its association with cancer in nonmedical exposures in humans has not been investigated extensively. The committee did not review studies on the efficacy of solvents as therapeutic agents (see Chapter 2). Chapter 4 provides details on the adverse effects of chloroform as observed in experimental studies.
In addition to evaluating the carcinogenicity of specific chemical agents, IARC has analyzed whether particular occupations pose a greater risk for exposure to carcinogenic agents. In fact, IARC has determined that working in the rubber industry and in boot and shoe manufacturing and repair pose such a risk (IARC, 1987), and it determined that there is “sufficient evidence for the carcinogenicity of occupational exposure as a painter” (IARC, 1989). Although IARC identifies exposures of concerns and specific cancer outcomes that demonstrate an increased risk, its overall charge is to determine whether a specific agent or occupation is carcinogenic, not whether an agent causes a specific cancer outcome. It is important to distinguish the objectives of IARC’s program and the charge of the present committee. The purpose of the IARC program is to determine whether agents or occupational exposures are carcinogenic, whereas this committee is charged with determining whether there is an association between exposure to a specific agent and
chronic human illnesses. As discussed earlier in this report, the committee uses experimental evidence only when it is required by the definitions of the categories of association. Only the category of “Sufficient Evidence of a Causal Association” requires support from experimental evidence. For each conclusion of causality, the animal data that provides a plausible mechanism for the outcome being discussed are described—as in the section on chronic exposure to benzene and acute leukemia. Additional information on the toxicology and available experimental data on a number of solvents reviewed in this report can be found in Chapter 4.
DESCRIPTION OF THE COHORT STUDIES
In reviewing the published epidemiologic literature on exposure to organic solvents, the committee examined a number of occupational cohort studies that provided information on the association between cancer mortality or incidence and exposure to specific organic solvents or to mixtures of organic solvents. Deaths or incident cases of cancer in the cohort studies were recorded, exposed populations were followed over time, and the relationship between rates of cancer and exposure was assessed with statistical methods. Because the cohort studies played an important role in the committee’s conclusions and are referred to throughout this chapter, they are described here according to the solvents they examined. Table 6.1 presents for each study a description of the population, the followup period, the number of subjects, the relevant exposures, the methods used to assess exposure to organic solvents, the statistical methods, and the adjustment for potential confounding variables. Similar tables for case-control studies are found in the sections on each type of cancer.
Studies of Workers Exposed to Benzene
Benzene is used in chemical processes often as an intermediate in the manufacture of other chemicals and end products. Occupational exposure to benzene has been studied primarily in industrial workers, including rubber, chemical, and petroleum and gasoline workers. On the basis of human studies of those occupational groups and animal studies over the last 60 years, 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 (OSHA) was reduced from 10 parts per million (ppm) to a time weighted average over 8 hours (8-hr TWA) of 1 ppm (NIOSH, 1997).
TABLE 6.1 Description of Cohort Studies Related to Exposure to Organic Solvents
Reference |
Description |
Study Group (N) |
Comparison Group (N) |
Exposure Assessment and Other Relevant Exposures |
Analysis and Adjustment for Potential Confounders |
Benzene |
|||||
NIOSH Pliofilm Cohort |
|||||
Infante et al., 1977 |
Mortality experience (1940–1975) of white male Pliofilm workers (at least 1 day in 1940–1949) at three Goodyear facilities in Ohio |
748 |
(1) US white male population |
Employment in a benzene-exposed occupation as verified through historical air exposure measurements |
SMR Age, time period |
(2) 1447 white, male fibrous-glass construction workers in Ohio |
|||||
Rinsky et al., 1981 |
Mortality experience (1940–1975) of |
|
US white male population |
Employment in a benzene-exposed occupation as verified through historical air exposure measurements |
SMR Age, sex, time period |
(1) the original cohort and |
(1) 748 |
||||
(2) a second group of white male Pliofilm workers (at least 1 day in 1950–1959) |
(2) 258 |
||||
at three Goodyear facilities in Ohio |
|||||
Rinsky et al., 1987 |
Mortality experience (1940–1981) of white male Pliofilm workers (at least 1 day in 1940–1965) at three Goodyear facilities in Ohio |
1165 |
US white male population |
Employment in a benzene-exposed occupation as verified through historical air exposure measurements, with cumulative exposure indexes |
SMR Age, time period |
Paxton et al., 1994a, 1996 |
Mortality experience (1940–1987) of white male Pliofilm workers (at least 1 day in 1940–1965) at three Goodyear facilities in Ohio |
1212 |
US white male population |
Employment in a benzene-exposed occupation as verified through modified historical air exposure measurements, with cumulative exposure indexes |
SMR Age, time period |
Paxton et al., 1994b |
Mortality experience (1940–1987) of white male Pliofilm workers (at least 1 day in 1940–1965) at three Goodyear facilities in Ohio |
1868 |
US white male population |
Employment in a benzene-exposed occupation as verified through modified historical air exposure measurements, with cumulative exposure indexes |
SMR, Cox proportional hazards model Age, sex, location, time of first Pliofilm employment |
Reference |
Description |
Study Group (N) |
Comparison Group (N) |
Exposure Assessment and Other Relevant Exposures |
Analysis and Adjustment for Potential Confounders |
Crump, 1994, 1996 |
Mortality experience (1940–1987) of white male Pliofilm workers (at least 1 day in 1940–1965) at three Goodyear facilities in Ohio |
1717 |
US white male population |
Employment in a benzene-exposed occupation as verified through modified historical air exposure measurements, with cumulative exposure indexes |
Life-table analysis Age, sex |
Wong, 1995 |
Mortality experience (1940–1987) of white male Pliofilm workers (at least 1 day in 1940–1965) at three Goodyear facilities in Ohio |
1868 |
US general population |
Employment in a benzene-exposed occupation as verified through historical air exposure measurements, with cumulative exposure indexes |
SMR Age |
Chinese Workers Cohort |
|||||
Yin et al., 1987 |
Mortality experience (1972–1981) of benzene-exposed workers (at least 6 months) in China |
28,460 total 15,643 men 12,817 women |
28,257 unexposed |
Employment in a benzene-exposed occupation as verified through historical air exposure measurements from factory records |
RR, SMR Age, sex |
Yin et al., 1989 |
Mortality experience (1972–1981) of benzene-exposed workers (at least 6 months) in China |
28,460 total 15,643 men 12,817 women |
28,257 unexposed |
Employment in a benzene-exposed occupation as verified through historical air exposure measurements from factory records |
RR, SMR Age, sex, smoking |
Yin et al., 1994 |
Incidence and mortality experience (1972–1981) of benzene-exposed workers (at least 6 months) in China |
28,460 total 15,643 men 12,817 women |
28,257 unexposed |
Employment in a benzene-exposed occupation as verified through historical air exposure measurements from factory records |
SMR, Poisson Age, sex, time of first employment |
Li et al., 1994 |
Incidence and mortality experience (1972–1987) of benzene-exposed workers (at least 1 day) in China |
74,828 total 38,833 men 35,995 women |
35,805 unexposed |
Employment in a benzene-exposed occupation |
RR Sex |
Reference |
Description |
Study Group (N) |
Comparison Group (N) |
Exposure Assessment and Other Relevant Exposures |
Analysis and Adjustment for Potential Confounders |
Yin et al., 1996a,b |
Incidence and mortality experience (1972–1987) of benzene-exposed workers (at least 1 day) in China |
74,828 total 38,833 men 35,995 women |
35,805 unexposed |
Employment in a benzene-exposed occupation as verified through historical air exposure measurements from factory records |
RR Age, sex |
Hayes et al., 1996 |
Mortality experience (1972–1987) of benzene-exposed workers (at least 1 day) in China |
74,828 total 38,833 men 35,995 women |
35,805 unexposed |
Employment in a benzene-exposed occupation with cumulative exposure assigned by industrial hygienist from historical records |
RR (Poisson), trend analysis Age, sex |
Hayes et al., 1997 |
Incidence (1972–1987) in benzene-exposed workers (at least 1 day) in China |
74,828 total 38,833 men 35,995 women |
35,805 unexposed |
Employment in a benzene-exposed occupation with cumulative and average exposure assigned by industrial hygienist from historical records |
RR (Poisson) Age, sex |
Other Cohort Studies |
|||||
McMichael et al., 1976 |
Mortality experience (1964–1973) of male rubber workers (at least 1 day) in four plants in Ohio and Wisconsin |
18,903 |
1968 US male population |
Employment at one of four rubber-manufacturing plants |
SMR Age, race |
Wilcosky et al., 1984 |
Cases, age 40–84 years, selected retrospectively from a cohort of active and retired male rubber workers in a plant in Akron, Ohio, in 1964–1973; an age-stratified, 20% random sample from the original cohort served as the control group |
NA |
1336 (20% of 6678) |
Linkage of worker histories to plant solvent-use records; work in process area with known solvent use equates to exposure |
Race-specific ORs Age |
|
Other exposures: trichloroethylene, tetrachloroethylene, toluene, xylenes, naphthas, ethanol, acetone, phenol |
|
Reference |
Description |
Study Group (N) |
Comparison Group (N) |
Exposure Assessment and Other Relevant Exposures |
Analysis and Adjustment for Potential Confounders |
Pippard and Acheson, 1985 |
Mortality experience (1939–1982) of male boot and shoe manufacturers (in 1939) in three tow ns in Great Britain |
5017 |
County general populations |
Job title |
SMR Age, time period |
|
Other exposures: trichloroethylene, solvents |
||||
Wong, 1987a |
Mortality experience (1946–1977) of male chemical workers (at least 6 months) in seven US plants |
7676 |
US general population |
Job title and employment duration |
SMR, Mantel-Haenszel RR Age, race |
Wong, 1987b |
Mortality experience (1946–1977) of male chemical workers (at least 6 months) in seven US plants |
7676 |
US general population |
Job title and employment duration |
SMR, Mantel-Haenszel RR Age, race |
Paci et al., 1989 |
Mortality experience (1939–1984) of shoe workers (at least 1 day) in Florence, Italy |
2013 total 1008 men 1005 women |
Italy general population |
Plant production records and work histories |
SMR Age, sex, calendar year |
Walker et al., 1993 |
Mortality experience (1940–1982) of shoe-manufacturing workers (at least 1 month in 1940–1979) in Ohio |
7814 total 2529 men 5285 women |
US general population |
Employment at one of two plants |
SMR Age, sex, race, time period |
|
Other exposures: MEK, acetone, naphtha, isopropyl alcohol, methanol, ethylene glycol monoethyl ether, xylene |
|
|||
Greenland et al., 1994 |
White, male cases of cancer (multiple sites; died in 1969–1984) and controls in a cohort of transformer-assembly workers in Massachusetts |
1821 cases 1202 controls |
Internal comparison |
Job titles rated for exposure by industrial hygienist |
Logistic OR (nested case-control) |
|
Other exposures: trichloroethylene, solvents |
Age, death year, covariates that altered an estimate >20% |
|||
Lagorio et al., 1994 |
Mortality experience (1981–1992) of self-employed gas-station attendants (in 1980) in Italy |
2665 total 2308 men 357 women |
Latium region, Italy general population |
Environmental survey and duration of employment |
SMR Age, sex |
Reference |
Description |
Study Group (N) |
Comparison Group (N) |
Exposure Assessment and Other Relevant Exposures |
Analysis and Adjustment for Potential Confounders |
Heineman et al., 1995 |
Brain tumor incidence in women (1980–1984) in Shanghai, China |
276 |
Shanghai general population |
Job title |
SIR Age |
Fu et al., 1996 |
Mortality experience (1939–1991) of shoe-manufacturing workers in England (1939) and Italy (1950–1984) |
6223 total 5220 men 1003 women |
England and Italy general populations |
Job title |
SMR Age, sex, time period |
Schnatter et al., 1996a,b |
Cases of lymphohematopoietic cancers (died in 1964–1983) and controls in a cohort of Canadian petroleum-distribution workers |
29 cases, matched 1:4 |
Internal comparison |
Industrial hygienist review based on work histories, site characterizations, surveys |
Mantel-Haenszel OR (nested case-control) Smoking, family cancer history, x-ray history |
Ireland et al., 1997 |
Mortality experience (1940–1991) of male US chemical-plant workers (at least 1 day in 1940–1977) in Monsanto company plant in Sauget, IL |
4172 |
Illinois general population |
Industrial hygienist exposure estimates based on work records |
SMR |
Lynge et al., 1997 |
Incidence experience (1970–1991) in service-station workers (1970) in Denmark and Scandinavia |
18,969 total 16,524 men 2445 women |
Nation general populations |
Job title |
SMR Age, sex |
Rushton and Romaniuk, 1997 |
Cases of leukemia and controls in a cohort of petroleum-distribution workers (1975–1992) in UK |
91 cases, matched 1:4 |
Internal comparison |
Measurements factored in occupational hygiene estimates, work histories, job descriptions, fuel compositions |
OR (nested case-control), logistic regression Age, smoking, date of hire, employment duration, socioeconomic status |
Reference |
Description |
Study Group (N) |
Comparison Group (N) |
Exposure Assessment and Other Relevant Exposures |
Analysis and Adjustment for Potential Confounders |
Trichloroethylene |
|||||
Aircraft and Aerospace Workers |
|||||
Garabrant et al., 1988 |
Mortality experience (1958–1982) of aircraft-manufacturing workers (at least 1 day) at an aircraft-manufacturing facility in San Diego County, California (with at least 4 years of cumulative company employment) |
14,067 total 11,898 men 2169 women |
US general population |
Employment determined through company work records and interviews |
SMR Age, sex, race, calendar year, duration of employment, year of death |
Spirtas et al., 1991 |
Mortality experience (1952–1982) of aircraft-maintenance workers (at least 1 year in 1952–1956) at Hill Air Force Base in Utah |
14,457 total 10,730 men 3727 women |
Utah white population |
Industrial hygienist assessment from interviews, surveys, hygiene files, position descriptions |
SMR, trend analysis Age, sex, calendar period |
|
Other exposures: Stoddard solvent, isopropyl alcohol, trichloroethane, acetone, toluene, MEK, methylene chloride |
|
|||
Blair et al., 1998 |
Incidence and mortality experience (1952–1990) of aircraft-maintenance workers (at least 1 year in 1952–1956) at Hill Air Force Base in Utah |
14,457 total 10,730 men 3727 women |
Utah white population |
Industrial hygienist assessment from interviews, surveys, hygiene files, position descriptions |
SMR, RR (Poisson) Age, sex, calendar period |
|
Other exposures: Stoddard solvent, isopropyl alcohol, trichloroethane, acetone, toluene, MEK, methylene chloride |
|
|||
Morgan et al., 1998 |
Mortality experience (1950–1993) of aerospace workers (at least 6 months) Hughes Aircraft plant in Arizona |
20,508 total (4733 exposed) 13,742 men 6766 women |
US general population |
Exposure matrixes generated by employees and industrial hygienists |
SMR, Cox proportional hazards model Age, sex |
Reference |
Description |
Study Group (N) |
Comparison Group (N) |
Exposure Assessment and Other Relevant Exposures |
Analysis and Adjustment for Potential Confounders |
Boice et al., 1999 |
Mortality experience (1960–1996) of aircraft-manufacturing workers (at least 1 year) Lockheed Martin facility in California |
77,965 total 62,477 men 15,488 women |
General California population of white workers |
Abstracted from walkthrough surveys, hygiene files, job descriptions |
SMR, RR (Poisson) Age, sex, race, dates of first and last employment |
|
Other exposures: tetrachloroethylene, solvents |
||||
Other Cohort Studies |
|||||
Axelson et al., 1978 |
Mortality experience (1955–1975) of Swedish men occupationally exposed during the 1950s and 1960s |
518 |
Sweden general population |
Biologic monitoring for U-TCA |
RR Age |
Axelson et al., 1994 |
Mortality experience (1955–1986) of Swedish workers occupationally exposed during the 1950s and 1960s |
1670 total 1421 men 249 women |
Sweden general population |
Biologic monitoring for U-TCA |
SMR, SIR (Poisson) Age, sex, time period |
Anttila et al., 1995 |
Incidence experience (1967–1992) of workers biologically monitored for occupational exposure to halogenated solvents (1965–1983) at the Finnish Institute of Occupational Health |
3974 total 2050 men 1924 women |
Finland general population |
Biologic monitoring for U-TCA, and blood metabolites of tetrachloroethylene and trichloroethane |
SIR Age, sex, time period |
|
Other exposures: trichloroethane, tetrachloroethylene |
|
|||
Ritz, 1999 |
Mortality experience (1951–1989) of male uranium-processing plant workers (at least 3 years, with first hire in 1951–1972) in Ohio |
3814 |
(1) External comparison with US general population (2) Internal comparison among workers monitored for exposure |
Exposure matrixes generated by employees and industrial hygienists |
SMR, RR (conditional logistic regression) Age, calendar year, time since first hired, pay type, radiation dose |
Reference |
Description |
Study Group (N) |
Comparison Group (N) |
Exposure Assessment and Other Relevant Exposures |
Analysis and Adjustment for Potential Confounders |
Hansen et al., 2001 |
Incidence experience (1968–1996) in Danish workers (1947–1989) occupationally exposed |
803 total 658 men 145 women |
Denmark general population |
Biologic monitoring for U-TCA |
SIR Age, sex, calendar year, period of first employment, employment duration |
Tetrachloroethylene |
|||||
Dry-cleaning Cohorts |
|||||
Brown and Kaplan, 1987 |
Mortality experience (1960–1982) of dry cleaners (at least 1 year, before 1960) in four US labor unions |
1690 |
US general population |
Employment in dry-cleaning shops using tetrachloroethylene or other solvents |
SMR Age, time period |
Ruder et al., 1994 |
Mortality experience (1960–1990) of dry cleaners (at least 1 year, before 1960) in four US labor unions |
1701 total 592 men 1109 women |
SMRs calculated with modified life-table analysis system of NIOSH |
Employment in dry-cleaning shops using tetrachloroethylene or other solvents |
SMR Age, sex, time period |
Ruder et al., 2001 |
Mortality experience (1960–1996) of dry cleaners (at least 1 year, before 1960) in four US labor unions |
1701 total 592 men 1109 women |
SMRs calculated with modified life-table analysis system of NIOSH |
Employment in dry-cleaning shops using tetrachloroethylene or other solvents |
SMR Age, sex, time period |
Blair et al., 1990 |
Mortality experience (1948–1978) of members of a dry-cleaning union in St. Louis |
5365 total 1319 men 4046 women |
US general population |
Exposure index created from job title and length of union membership |
SMR, trend analysis Age, sex, calendar year, race |
Other Cohort Studies |
|||||
Lynge and Thygesen, 1990 |
Incidence experience (1970–1980) of Danish laundry and dry-cleaning workers (in 1970) |
10,600 total 2033 men 8567 women |
Denmark general population |
Dry-cleaning, job title |
SIR Age |
|
Other exposures: trichloroethylene, 1,1,2-trichloro-1,2,2-trifluoroethane |
|
Reference |
Description |
Study Group (N) |
Comparison Group (N) |
Exposure Assessment and Other Relevant Exposures |
Analysis and Adjustment for Potential Confounders |
Anttila et al., 1995 |
Incidence experience (1967–1992) of workers biologically monitored for occupational exposure to halogenated solvents (1965–1983) at the Finnish Institute of Occupational Health |
3974 total 2050 men 1924 women |
Finland general population |
Biologic monitoring |
SIR Age, sex, time period |
|
Other exposures: trichloroethane, trichloroethylene |
|
|||
Boice et al., 1999 |
Mortality experience (1960–1996) of aircraft-manufacturing workers (at least 1 year) at Lockheed Martin facility in California |
77,965 total 62,477 men 15,488 women |
General California population of white workers |
Abstracted from walkthrough surveys, hygiene files, job descriptions |
SMR, RR (Poisson) Age, sex, race, dates of first and last employment |
|
Other exposures: trichloroethylene, solvents |
||||
Methylene Chloride |
|||||
Kodak Park Cohort |
|||||
Friedlander et al., 1978 |
PMR of former or current exposed workers (1956–1976) at Kodak Park |
334 |
Deaths of former or current unexposed workers (1956–1976) at Kodak Park |
Employment in methylene chloride area |
PMR, SMR Age, sex |
Mortality experience (1964–1976) of hourly-wage male workers (in 1964) at Kodak Park |
751 |
Hourly-wage male workers at Kodak Park and in New York state (excluding New York City) men |
|
||
Hearne and Friedlander, 1981 |
Mortality experience (1964–1980) of hourly-wage male workers (in 1964) at Kodak Park |
750 |
Hourly-wage male workers at Kodak Park and in New York state (excluding New York City) men |
Employment in methylene chloride area |
SMR Age, sex |
Reference |
Description |
Study Group (N) |
Comparison Group (N) |
Exposure Assessment and Other Relevant Exposures |
Analysis and Adjustment for Potential Confounders |
Hearne et al., 1987 |
Mortality experience (1964–1984) of hourly-wage male workers (in 1964) at Kodak Park |
1013 |
(1) New York state (excluding New York City) men (1945–1990) (2) Over 40,000 Rochester-based Kodak workers |
Employment in roll-coating division, cumulative exposure assigned by industrial hygienist from historical records |
SMR Age, sex, time period |
Hearne et al., 1990 |
Mortality experience (1964–1988) of hourly-wage male workers (in 1964) at Kodak Park |
1013 |
(1) New York state (excluding New York City) men (1945–1990) (2) Over 40,000 Rochester-based Kodak workers |
Employment in roll-coating division, cumulative exposure assigned by industrial hygienist from historical records |
SMR, trend analysis Age, sex, time period |
Hearne and Pifer, 1999 |
Mortality experience (1946–1994) of two overlapping cohorts of exposed male workers (at least 1 year in 1946–1970; any employment in 1964–1970) at Kodak Park |
(1) 1311 (2) 1013 |
New York state (excluding New York City) men (1945–1990) |
Employment in methylene chloride area, cumulative exposure assigned by industrial hygienist from historical records |
SMR, trend analysis Age, sex, time period |
Cellulose-Fiber Production Cohort |
|||||
Ott et al., 1983 |
Mortality experience (1954–1977) of cellulose-fiber production plant workers (at least 3 months) in Rock Hill, SC |
1271 total 551 men 720 women |
York County, SC, general population |
Employment in plant, comprehensive industrial hygienist survey |
SMR, conditional risk, Cox regression Age, sex, race, year of first exposure |
|
Other exposures: acetone, methanol |
||||
Lanes et al., 1990 |
Mortality experience (1954–1986) of cellulose-fiber production plant workers (at least 3 months in 1954–1977) in Rock Hill, SC |
1271 total 551 men 720 women |
York County, SC, general population |
Employment in plant, comprehensive industrial hygienist survey |
SMR Age, sex, race |
|
Other exposures: acetone, methanol |
|
Reference |
Description |
Study Group (N) |
Comparison Group (N) |
Exposure Assessment and Other Relevant Exposures |
Analysis and Adjustment for Potential Confounders |
Lanes et al., 1993 |
Mortality experience (1954–1990) of cellulose-fiber production plant workers (at least 3 months in 1954–1977) in Rock Hill, SC |
1271 total 551 men 720 women |
York County, SC, general population |
Employment in plant and comprehensive industrial hygienist survey |
SMR Age, sex, race |
|
Other exposures: acetone, methanol |
|
|||
Other Cohort Studies |
|||||
Gibbs et al., 1996 |
Mortality experience (1970–1989) of cellulosefiber production workers (at least 3 months) in Cumberland, MD |
3211 total 2187 men 1024 women |
Allegheny County, MD, general population |
Workplace monitoring data, job title |
SMR Age, sex, race, time period |
Tomenson et al., 1997 |
Mortality experience (1946–1994) of male cellulose triacetate film-base workers (any employment in 1946–1988) in Brantham, UK |
1785 |
England and Wales mortality rates |
Workplace monitoring |
SMR, trend analysis Age, time period |
Toluene and Xylene |
|||||
Swedish Paint Industry Cohort |
|||||
Lundberg, 1986 |
Incidence and mortality experience (1955–1981) of male, Swedish paint-industry workers (at least 5 years in 1955–1975) with long-term exposure to organic solvents |
416 |
Sweden general population |
Industry employment, historical air exposure measurements |
SMR Sex, time period |
Lundberg and MilatouSmith, 1998 |
Incidence and mortality experience (1955–1994) of male, Swedish paint-industry workers (at least 5 years in 1955–1975) with long-term exposure to organic solvents |
411 |
Sweden general population |
Industry employment, historical air exposure measurements |
SMR, SIR Age, sex, time period |
Other Cohort Studies |
|||||
Anttila et al., 1998 |
Incidence experience (1973–1992) in workers biologically monitored for occupational exposure to aromatic hydrocarbons (1973–1983) at the Finnish Institute of Occupational Health |
5301 total 3922 men 1379 women |
Finland general population |
Biologic monitoring |
SIR Age, sex, time period |
Reference |
Description |
Study Group (N) |
Comparison Group (N) |
Exposure Assessment and Other Relevant Exposures |
Analysis and Adjustment for Potential Confounders |
Svensson et al., 1990 |
Incidence and mortality experience (1925–1985) of Swedish male rotogravure workers (at least 3 months) |
1020 |
Population-specific rates for geographic area around factory |
Exposures evaluated through plant visits, biologic monitoring, workplace measurements, historical documents, interviews |
SMR, SIR Age, sex, calendar year, location |
|
Other exposures: benzene, solvents |
|
|||
Solvents |
|||||
UK Rubber Worker Cohort |
|||||
Parkes et al., 1982 |
Mortality experience (1946–1975) of UK male rubber workers (at least 1 year in 1946–1960) |
33,815 |
UK general population |
Industry employment |
SMR Age, sex |
Sorahan et al., 1986 |
Mortality experience (1946–1980) of UK male rubber workers (at least 1 year in 1946–1960) |
36,445 |
UK general population |
Industry employment |
SMR, regression models and life tables Age, sex, age at hire, entry cohort, location, work sector |
Sorahan and Cathcart, 1989 |
Mortality experience (1946–1985) of UK male rubber workers (at least 1 year in 1946–1960) |
36,691 |
UK general population |
Industry employment |
SMR, regression models and life tables Age at hire, entry cohort, location, work sector, duration of employment |
Reference |
Description |
Study Group (N) |
Comparison Group (N) |
Exposure Assessment and Other Relevant Exposures |
Analysis and Adjustment for Potential Confounders |
Other Cohort Studies |
|||||
Costantini et al., 1989 |
Mortality experience (1950–1983) of male workers at tanneries (at least 6 months) in Tuscany, Italy |
2926 |
Italy general population |
6 months of employment |
SMR Age, time period |
Guberan et al., 1989 |
Incidence and mortality experience (1970–1984) of painters and electricians (in 1970) in the Canton of Geneva |
1916 painters 1948 electricians |
Switzerland regional population |
Job title |
SMR, SIR Age |
Acquavella et al., 1993 |
Mortality experience (1950–1987) of workers hired at a metal components manufacturing facility (at least 6 months in 1950–1967) in Iowa |
3630 total 2664 men 966 women |
Iowa general population |
Occupational titles, departments |
SMR, RR Age, sex, time period |
Berlin et al., 1995 |
Incidence and mortality experience (1967–1987) of Swedish workers occupationally exposed to solvents |
5791 total 5283 men 508 women |
Sweden general population |
Patients with solvent-related disorders |
SMR, SIR Age, sex |
Lynge et al., 1995 |
Incidence experience (1970–1987) in Danish printing workers (in 1970) |
19,127 total 15,534 men 3593 women |
Economically active people in Denmark |
Job title |
SIR Age, alcohol and tobacco use |
Steenland and Palu, 1999 |
Mortality experience (through 1994) of members of US painters unions (at least 1 year of membership; born before 1940) in four states |
42,170 |
US general population, nonpainter cohort |
Union membership |
SMR, SRR Age, time period |
Other Specific Solvents |
|||||
Isopropyl Alcohol and Methyl Ethyl Ketone |
|||||
Alderson and Rattan, 1980 |
Mortality experience (1935–1975) of workers in Shell MEK dewaxing or isopropyl alcohol plants (at least 1 year) in Britain |
262 IAP 446 MEK |
US general population |
Employment in one of two plants |
SMR Age, time period |
Phenol |
|||||
Dosemeci et al., 1991 |
Mortality experience (1966–1979) of white male workers (employed before 1966) employed at five facilities producing or using phenol and formaldehyde |
14,861 |
US general population |
Employment at one of five facilities |
SMR Age, time period |
Although the association between benzene and cancer was assessed in a number of cohort studies, two studies provide the most comprehensive data. The first was designed to investigate mortality in three Ohio rubber-manufacturing plants, referred to as the “Pliofilm” cohort (Crump, 1994, 1996; Infante et al., 1977; Paxton, 1996; Paxton et al., 1994a,b; Rinsky et al., 1987; Wong, 1995). Benzene was used in the production of rubber hydrochloride, a natural rubber cast film used primarily for wrapping foods and marketed under the trade name Pliofilm. The plants were chosen because of the relatively high exposure to benzene and the lack of other toxic chemicals in use. In 1975, after a report of several leukemia cases, the National Institute for Occupational Safety and Health conducted a retrospective study of 748 Pliofilm workers who were exposed to benzene (Infante et al., 1977). Rinsky and colleagues (1981, 1987) expanded on the work of Infante and colleagues by increasing the size of the cohort to 1006 workers, extending the years of observation, and collecting additional exposure data from the plants’ processes, company records, and air-sampling data (Rinsky et al., 1981), thereby providing estimates of exposure for each job in the various areas of the plant (Rinsky et al., 1987). The retrospective exposure assessment was further modified by Crump and Allen (1984) and Paustenbach and colleagues (1992). Crump and Allen (1984) developed an exposure matrix based on the concept that the benzene levels in the workplace may have improved over time, whereas the exposure matrix developed by Paustenbach and colleagues (1992) incorporated more detailed information from monitoring devices, the changing length of the workweek over the years, the impact of World War II on production, engineering controls, and other available and experimental data to assess exposure to benzene. Considerable controversy surrounds the assessments of exposure (Wong, 1995). Different authors have used the different exposure assessments in their analyses: the Rinsky exposure assessment (Paxton et al., 1994a,b; Rinsky et al., 1981, 1987), the Crump assessment (Paxton et al., 1994a,b), and the Paustenbach assessment (Crump, 1994; Paxton et al., 1994a,b). The differences in the exposure assessments lead to differences in the estimates of relative risks for various sites of cancer according to exposure to benzene. The differences in relative risk are important in setting regulatory standards but were not sufficiently different to affect the committee’s determination of the magnitude of association.
The second key study of occupational exposure to benzene was conducted in China. After conducting a nationwide benzene-monitoring survey in China during 1979–1981, Yin and colleagues at the Chinese Academy of Preventive Medicine identified a cohort of about 30,000 workers who were occupationally exposed to benzene or mixtures containing benzene (Yin et al., 1987). Subjects were selected from painting, shoe-making, rubber synthesis, leather, and adhesive and organic-chemical synthesis factories. A sample of 28,257 workers employed in machine production, textile, and cloth factories was taken to represent an unexposed comparison population. Later studies expanded the original cohort to 74,828 benzene-exposed and 35,805 nonexposed workers and included a detailed assessment of exposure to benzene. Those studies were conducted in collaboration with the US National Cancer Institute (Hayes et al., 1996, 1997; Li et al., 1994; Yin et al., 1987, 1989, 1994, 1996a,b). Like the Pliofilm study, studies of the cohort yielded valuable information regarding the risk of developing or dying from cancer in relation to exposure to benzene.
Other important cohort studies of benzene-exposed workers include those of American chemical workers (Ireland et al., 1997; Wong, 1987a,b), female workers in China
(Heineman et al., 1995), other rubber-plant workers (McMichael et al., 1976; Wilcosky et al., 1984), shoe-manufacturing workers (Fu et al., 1996; Paci et al., 1989; Pippard and Acheson, 1985; Walker et al., 1993), transformer-assembly workers (Greenland et al., 1994), filling and service-station attendants (Lagorio et al., 1994, Lynge et al., 1997), and petroleum distributors (Rushton and Romaniuk, 1997; Schnatter et al., 1996a,b). These studies differed substantially from the two preceding studies in that exposure was much lower. For example, levels in the Pliofilm cohort ranged from 7.2 to 24.9 ppm (Rinsky et al., 1981, 1987), whereas levels in the cohort of petroleum workers ranged from 0.01 to 6.2 ppm (Ireland et al., 1997; McMichael et al., 1976; Rushton and Romaniuk, 1997; Schnatter et al., 1996a,b).
Studies of Workers Exposed to Trichloroethylene
The most important use of trichloroethylene has been in the removal of greases, tars, and oils from metal parts. It has also been used by the textile industry to scour cotton, wool, and other fabrics and as a solvent in waterless dying and finishing operations (ATSDR, 1997b). The regulatory limit set by OSHA is a 8-hr TWA of 100 ppm (NIOSH, 1997).
Mortality in relation to exposure to trichloroethylene has been examined in four large cohort studies of aircraft and aerospace manufacturing and maintenance workers (Blair et al., 1998; Boice et al., 1999; Garabrant et al., 1988; Morgan et al., 1998). In general, industrial hygienists reviewed information obtained from walkthrough surveys, interviews of long-term employees, and historical information on job titles and tasks, operations, and worksites to classify workers by duration and intensity of exposure. The first study was conducted to evaluate mortality rates among 14,457 aircraft maintenance workers at Hill Air Force Base, Utah, in response to concerns expressed by workers in the middle-1970s about potential health effects of chemical exposure (Spirtas et al., 1991). Trichloroethylene was used as a vapor degreaser until 1978, when it was replaced with 1,1,1-trichloroethane. It was also used to clean small electric parts at work benches until 1968 (Blair et al., 1998). Other solvents used at the base were primarily other chlorinated hydrocarbons, aromatic hydrocarbons, and carbon tetrachloride. Blair and co-workers (1998) extended the followup of the cohort assembled by Spirtas and colleagues (1991) by 8 years. The estimates of exposure developed for the initial cohort study (Stewart et al., 1991) were also used in the extended followup study.
Two additional large cohort studies evaluated mortality in aircraft manufacturing facilities where trichloroethylene was commonly used as a degreaser. Boice and colleagues (1999) investigated 77,965 workers at Lockheed Martin’s Burbank California factories, and Morgan and co-workers (1998) reported on 20,508 employees at a Hughes Aircraft manufacturing facility in Arizona.
Other important but smaller cohort studies of workers exposed to trichloroethylene are those of Swedish trichloroethylene production workers (Axelson et al., 1978, 1994), US uranium processing-plant workers (Ritz, 1999), and other workers occupationally exposed to trichloroethylene in Finland (Anttila et al., 1995) and Denmark (Hansen et al., 2001). Exposure-response analyses in the Scandinavian studies were based on biologic monitoring of urinary-trichloroacetic acid (U-TCA, a metabolite of trichloroethylene) measured in urine samples from workers (Anttila et al., 1995; Axelson et al., 1978, 1994; Hansen et al., 2001). Hansen and colleagues (2001) also used data on levels of trichloroethylene in the breathing
zone of workers. The US study used semiquantitative exposure estimates based on expert review (Ritz, 1999).
Studies of Workers Exposed to Tetrachloroethylene and Dry-cleaning Solvents
Tetrachloroethylene has been used for metal cleaning and vapor degreasing and for dry-cleaning and textile processing. The PEL set by OSHA is a 8-hr TWA of 100 ppm (NIOSH, 1997).
Occupational exposure to tetrachloroethylene has been studied primarily in dry-cleaning workers because of its widespread use. Dry-cleaning workers are extensively exposed to organic solvents, which are integral to the dry-cleaning process. The evolution of the dry-cleaning process has seen the use of a variety of solvents. Most of the early dry-cleaning solvents were petroleum-based and included naphtha and Stoddard solvent. The petroleum-based solvents were replaced in the 1930s largely with carbon tetrachloride, a less expensive alternative (IARC, 1995). Information about the toxicity and corrosiveness of carbon tetrachloride led to its replacement in the 1950s with chlorinated hydrocarbons. Today, tetrachloroethylene is the most commonly used dry-cleaning solvent in the United States. Other solvents and chemicals used in dry-cleaning include 1,1,2-trichloro-1,2,2-trifluoroethane, and 1,1,1-trichloroethane (IARC, 1995).
An important study examined a cohort of 1708 US dry-cleaning workers drawn from four labor unions, first reported by Brown and Kaplan (1987), and updated by Ruder and colleagues (1994, 2001). The original study investigated mortality through 1982, the first update extended the followup through 1990 (Ruder et al., 1994), and the most recent study updated mortality through 1996 (Ruder et al., 2001). In the updates, two subcohorts were evaluated on the basis of employment in shops where tetrachloroethylene was the cleaning solvent (625 workers) or in shops where tetrachloroethylene use could not be confirmed or another solvent was used as the cleaning solvent (1083 workers).
Another study, of 5365 members of a dry-cleaning union in Missouri, assessed mortality in relation to estimated levels of exposure to dry-cleaning solvents (Blair et al., 1990). Exposure indexes were based on job title and type of establishment. Information on the type of solvent used was not available so workers who specifically used tetrachloroethylene could not be identified.
Other studies of exposure to tetrachloroethylene and cancer include a US study of aircraft manufacturing workers (Boice et al., 1999) and a Finnish study of workers occupationally exposed to three halogenated hydrocarbons, including tetrachloroethylene (Anttila et al., 1995). The exposure assessment of the US study was based on expert review of walkthrough surveys and historical documents and other approaches (Boice et al., 1999), whereas the Finnish study estimated level of exposure from biologic monitoring (Anttila et al., 1995). Another study examined Danish laundry and dry-cleaning workers whose chemical exposure was inferred from their occupations, as specified by census industry codes (Lynge and Thygesen, 1990).
Studies of Workers Exposed to Methylene Chloride
Methylene chloride (dichloromethane) has been used in degreasing, in paint stripping, as an aerosol propellant, and in the manufacture of textiles, plastics, and photographic film. A large proportion of workers exposed to methylene chloride are
involved in metal cleaning, industrial paint stripping, and using ink solvents (ATSDR, 2000). The regulatory limits have decreased as information on toxicity has accumulated (ATSDR, 2000). The current PEL set by OSHA is a 8-hr TWA of 25 ppm (NIOSH, 1997).
The key occupational cohort study of exposure to methylene chloride was an incidence and mortality study of workers in an Eastman Kodak plant (Friedlander et al., 1978; Hearne and Friedlander, 1981; Hearne and Pifer, 1999; Hearne et al., 1987, 1990). The workers, ranging in number from 750–1311, were exposed chronically to methylene chloride in the manufacturing of cellulose triacetate, a photographic film base, as confirmed by study personnel who used air sampling and gas chromatography. In the most recent update, Hearne and Pifer (1999) followed the mortality experience through 1994 for two groups of workers: 1311 workers who first worked in film-support manufacturing and related operations in 1946–1970 and the Roll Coating Cohort (1964–1970) of 1013 employees that was previously studied (Hearne et al., 1987, 1990). Exposure to methylene chloride was estimated by combining air-monitoring data with information on work histories.
Other important studies include a study of workers employed at a plant that produced cellulose triacetate film base in the UK (Tomenson et al., 1997), and studies of workers in the production of cellulose fiber at a Hoechst manufacturing plant in South Carolina (Lanes et al., 1990, 1993; Ott et al., 1983) and a Hoechst plant in Maryland (Gibbs et al., 1996). Estimates of exposure in the UK cohort were derived from area-monitoring results, work histories, and historical information on production processes (Tomenson et al., 1997). Some exposure-monitoring data were obtained on the South Carolina cohort in the 1970s (Ott et al., 1983), but exposure estimates were unavailable for most of the study period. Exposure measurements were not used in the mortality analysis of the South Carolina cohort (Lanes et al., 1990, 1993), but Gibbs and co-workers (1996) used the available exposure data to determine high and low exposure ranges.
Studies of Workers Exposed to Other Specific Solvents
Three studies of solvent-production plants were used to evaluate mortality in relation to exposure to specific solvents: isopropanol (Alderson and Rattan, 1980; Teta et al., 1992), methyl ethyl ketone (Alderson and Rattan, 1980), phenol (Dosemeci et al., 1991), and toluene, xylene, and styrene (Anttila et al., 1998). The main uses of isopropanol are as a chemical intermediate and in applications in medicine and industry (Logsdon and Loke, 1996). The PEL is a 8-hr TWA of 400 ppm (NIOSH, 1997). Methyl ethyl ketone is used primarily as a solvent in industry. The regulatory limit set by OSHA is 200 ppm (NIOSH, 1997). Phenol is commonly used in the production of epoxy resins and polycarbonates, phenolic resins and molding compounds, caprolactam, aniline alkylphenols, and xylenols; as a fungicide or disinfectant; and in a variety of medications (ATSDR, 1998; Wallace, 1996). The occupational exposure limit set by OSHA is a 8-hr TWA of 5 ppm (NIOSH, 1997). Toluene and xylene are used in the manufacture of a variety of chemicals and as solvents for paints, lacquers, gums, printing inks, and resins. Styrene is used in the production of polystyrene plastics and resins and as an intermediate in the production of such copolymers as styrene-acrylonitrile, acrylonitrile-butadiene-styrene, and styrene-butadiene rubber. The occupational regulatory limit for toluene is a 8-hr TWA of 200 ppm (NIOSH, 1997), and the PEL for xylene and styrene is a 8-hr TWA of 100 ppm (NIOSH, 1997).
The key studies for evaluating risks posed by those solvents include the following. Alderson and Rattan (1980) evaluated mortality in 262 male workers employed in isopropanol plant and 446 male employees of two methyl ethyl ketone dewaxing plants, using the type of plant as an indicator of exposure. Teta and colleagues (1992) conducted a cohort mortality study of 1031 workers employed at two facilities that produced ethanol and isopropanol. Employment in an isopropanol strong-acid production unit was used as an exposure surrogate for isopropanol. Dosemeci and co-workers (1991) conducted a mortality followup of 14,861 workers employed in five plants that manufactured or used phenol and formaldehyde. Estimates of exposure to phenol were derived from expert review of information obtained from walkthrough survey reports, historical monitoring results, and other workplace information. Anttila and colleagues (1998) investigated 3922 male and 1379 female Finnish workers occupationally exposed to toluene, xylene, and styrene; level of exposure was determined from biologic monitoring (Anttila et al., 1995).
Studies of Workers Exposed to Unspecified Mixtures of Organic Solvents
Solvents are used in numerous occupations, so the committee examined cancer mortality and incidence in workers in a number of occupations that may have involved exposure to organic solvents. It is important to note that workers in the occupations in question have potential exposure to numerous chemicals in addition to solvents.
Painters have the potential for frequent and high level exposure to many types of organic solvents. Organic solvents, such as, toluene, xylene, glycols, and methylene chloride, have been used over the years in the composition of paint, paint thinners, cleaners, and strippers. Painters are exposed to numerous other chemical and environmental agents, including pigments, dusts, resins, and silicates. In most instances, it was not possible to identify which solvents were used, and the committee referred to them as unspecified mixtures of organic solvents. Lundberg and Milatou-Smith (1998) evaluated cancer mortality and incidence in a cohort of 411 male workers who had been employed for more than 5 years in 1955–1975 in the Swedish paint-manufacturing industry (followup of Lundberg, 1986). Guberan and colleagues (1989) studied cancer mortality and incidence in 1916 painters in Geneva, Switzerland, who were identified from the 1970 census. The largest cohort study of painters was conducted by Steenland and Palu (1999), who evaluated mortality patterns in a cohort of 42,170 painters who were members of the Painters Union for 1 year or more before 1979.
Other cohorts exposed to unspecified chemical mixtures involve printers (Lynge et al., 1995; Svensson et al., 1990); workers in solvent-production plants (Berlin et al., 1995); metal workers (Acquavella et al., 1993); rubber workers (Parkes et al., 1982; Sorahan and Cathcart, 1989; Sorahan et al., 1986); workers in tanneries (Costantini et al., 1989); and shoemakers (Fu et al., 1996; Paci et al., 1989; Pippard and Acheson, 1985; Walker et al., 1993). In the past, some shoemaking cohorts would have had considerable exposure to benzene (e.g., Fu et al., 1996; Paci et al., 1989). However, because the composition of glues has changed, benzene being replaced with other solvents, and because there were no precise estimates of exposure, the committee classified those cohorts as being exposed to unspecified mixtures of organic solvents.
ORAL, NASAL, AND LARYNGEAL CANCER
Description of Case-Control Studies
Two case-control studies reviewed by the committee that included oral, nasal, or laryngeal cancers are described in Table 6.2. One population-based case-control study examined the risk of nasal and nasopharyngeal cancer associated with occupational exposure to organic solvents (Hardell et al., 1982), and a second examined the risk of oral cavity and laryngeal cancers associated with work in the dry-cleaning industry (Vaughan et al., 1997). Both included interviews with study subjects concerning occupational history. In the former study, exposure to organic solvents was self-reported; in the latter, levels of exposure to tetrachloroethylene in cleaning jobs were assigned by an industrial hygienist.
Epidemiologic Studies of Exposure to Organic Solvents and Oral Cancer
Three cohort studies and one case-control study failed to provide strong evidence of an association between tetrachloroethylene and dry-cleaning solvents and oral cancer. Ruder and colleagues (2001) found a strong, increased risk of cancer of the tongue (standardized mortality ratio [SMR]=9.03, 95% confidence interval [CI]=1.86–26.39) in the subcohort exposed only to tetrachloroethylene. In another cohort of dry cleaners, Blair and colleagues (1990) found no increased risk of cancers of the buccal cavity and pharynx (SMR=1.0, 95% CI=0.3–2.2).
The case-control study undertaken by Vaughan and colleagues (1997) found little evidence of an increased risk of oral cancer in dry-cleaning workers (odds ratio [OR]possible exposure=1.2, 95% CI=0.3–4.6; ORprobable exposure=1.5, 95% CI=0.2–9.5). The relative risks increased with increasing cumulative exposure but not with duration of employment, although there was considerable statistical uncertainty in the trend.
In only one study was the risk of cancers of the mouth and throat evaluated among workers exposed to phenol (Dosemeci et al., 1991); no increased risk was found (SMR=0.8, 95% CI=0.4–1.5).
The risk of oral cancer in industries exposed to solvents was estimated in cohorts of workers in cellulose-fiber production (Lanes et al., 1990), shoe manufacture (Walker et al., 1993), methyl ethyl ketone dewaxing (Alderson and Rattan, 1980), and ethanol and isopropanol production (Teta et al., 1992). Although specific solvents were used in most of those occupations, many other solvents were also used, and specific solvents were not evaluated in any of the studies. There was no evidence of positive associations in any of these studies.
TABLE 6.2 Description of Case-Control Studies of Oral, Nasal, and Laryngeal Cancer and Exposure to Organic Solvents
Summary and Conclusion
There was little consistent evidence of an association between oral cancer and exposure to tetrachloroethylene and dry-cleaning solvents. Although there were several positive studies, most were based on small numbers of exposed cases and did not have sufficient statistical power. For exposure to phenol, only one study was identified and a risk of oral cancer was not found. No risk was also found among the occupational studies on solvent mixtures. Table 6.3 identifies the studies reviewed on oral cancer. Unless indicated in the table, the study populations include both men and women.
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 solvents under review and oral cancer.
TABLE 6.3 Selected Epidemiologic Studies—Oral Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Specific and Unspecified Mixtures of Organic Solvents |
|||
Cohort Studies—Mortality |
|||
Ruder et al., 2001 |
Dry-cleaning union workers exposed to tetrachloroethylene |
|
|
|
Cancer of the tongue |
3 |
9.03 (1.86–26.39) |
Walker et al., 1993 |
Ohio shoe-manufacturing employees |
|
|
|
Males and females |
5 |
0.67 (0.22–1.59) |
Teta et al., 1992 |
Male workers at ethanol/isopropanol production plants |
|
|
|
South Charleston |
2 |
1.3 (0.2–4.8)a |
|
Texas City |
1 |
1.4 (0.0–8.4)a |
Dosemeci et al., 1991 |
Male industrial workers exposed to phenol |
11 |
0.8 (0.4–1.5) |
Blair et al., 1990 |
St. Louis, MO, dry-cleaning workers |
5 |
1.0 (0.3–2.2) |
Lanes et al., 1990 |
Cellulose-fiber production workers |
2 |
2.31 (0.39–7.60) |
Alderson and Rattan, 1980 |
Male British workers at two methyl ethyl ketone dewaxing plants |
2 |
15.38 (1.86–55.54)a |
Case-Control Study |
|||
Vaughan et al., 1997 |
Oral cancer among dry-cleaning workers |
|
|
|
Possible exposure to tetrachloroethylene |
7 |
1.2 (0.3–4.6) |
|
Probable exposure to tetrachloroethylene |
4 |
1.5 (0.2–9.5) |
|
Cumulative exposure to tetrachloroethylene (ppm-years) |
|
|
|
1–29 ppm-years |
3 |
1.0 (0.1–7.0) |
|
30+ ppm-years |
4 |
1.4 (0.2–8.7) |
|
Duration of employment |
|
|
|
1–9 years |
6 |
1.4 (0.3–5.7) |
|
10+ years |
1 |
0.4 (0.0–31.6) |
aRisk estimate and 95% CI calculated by the committee using standard methods from the observed and expected numbers presented in the original study. |
Epidemiologic Studies of Exposure to Organic Solvents and Nasal Cancer
Few studies with sufficient numbers of cases to assess the relationship between exposure to benzene and oral cancer were available. The cohort study by Yin and colleagues (1996a) of
benzene-exposed workers in China showed an increased risk of nasopharyngeal cancer among male workers (relative risk [RR]=2.1, 95% CI=0.7–9.3). The RR was 2.4 (95% CI=0.8–10.5).
A cancer mortality study of shoe-manufacturing workers by Fu and colleagues (1996) analyzed the risk associated with exposure to solvents (found mostly in glues) and leather dusts in two cohorts of shoemakers in England and Florence, Italy. Risk of nasal cancer from occupational exposures was strongly increased (SMR=7.41, 95% CI=3.83–12.94) in the English cohort (only one death from nasal cancer was found in the Florence cohort). Exposure was assessed by using job titles, and no specific exposures were identified. It is not clear whether solvents, leather dust, or other agents contributed to the increased risk of nasal cancer.
Hardell and colleagues (1982) conducted a case-control study of nasal and nasopharyngeal cancers and exposure to various agents, including solvents. Although they provided no estimates of relative risk, the committee calculated relative risks and CIs from the raw data provided and found weak associations with exposure to high-grade organic solvents (nasal: OR=1.24, 95% CI=0.51–2.91; nasopharyngeal: OR=1.27, 95% CI=0.47–3.68).
Summary and Conclusion
The only study on exposure to benzene and risk of nasal cancer had a highly imprecise estimate of effect. Other studies are needed to determine whether an association exists. For exposure to solvent mixtures, the English shoemaker study showed a strong association. However, the Swedish case-control study (Hardell et al., 1982) did not corroborate those findings. Table 6.4 identifies the studies reviewed by the committee on nasal cancer. Unless indicated in the table, the study populations include both men and women.
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 solvents under review and nasal cancer.
TABLE 6.4 Selected Epidemiologic Studies—Nasal Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Specific and Unspecified Mixtures of Organic Solvents |
|||
Cohort Studies—Mortality |
|||
Yin et al., 1996a |
Chinese workers exposed to benzene |
|
|
|
Male |
12 |
2.1 (0.7–9.3) |
|
Total |
14 |
2.4 (0.8–10.5) |
Fu et al., 1996 |
Shoemakers in England and Florence |
|
|
|
English cohort |
12 |
7.41 (3.83–12.94) |
|
Florence cohort |
1 |
9.09 (0.23–50.65) |
Alderson and Rattan, 1980 |
Male British workers at an isopropyl alcohol plant |
1 |
50.0 (1.3–278.5)a |
Case-Control Study |
|||
Hardell et al., 1982 |
Male cases exposed to high-grade organic solvents |
|
|
|
Nasal |
8 |
1.24 (0.51–2.91)a |
|
Nasopharyngeal |
5 |
1.27 (0.47–3.68)a |
aRisk estimate and 95% CI calculated by the committee using standard methods from the observed and expected numbers presented in the original study. |
Epidemiologic Studies of Exposure to Organic Solvents and Laryngeal Cancer
In a cohort of dry cleaners, Blair and colleagues (1990) found 60% excess mortality from laryngeal cancers (SMR=1.6, 95% CI=0.3–4.7). In a case-control study of laryngeal cancer, Vaughan and colleagues (1997) found an association with possible exposure to tetrachloroethylene among dry cleaners (OR=2.3; 95% CI=0.5–10.2) but not among those probably exposed (OR=0.9, 95% CI=0.1–12.9). Risk increased with duration of employment in the dry-cleaning industry but not with increasing cumulative exposure.
Cohorts of workers in ethanol and isopropanol production (Teta et al., 1992) and shoe manufacture (Walker et al., 1993) were evaluated for their cancer mortality, and there was little evidence of an association (total of three exposed deaths).
Summary and Conclusion
For exposure to tetrachloroethylene and dry-cleaning solvents and risk of laryngeal cancer, both studies’ findings were based on very few exposed cases, and this resulted in imprecise estimates of relative risk. Similarly, the studies on solvent mixtures were limited by the small number of exposed cases and lack of positive findings. As a result, there was insufficient evidence to conclude that there were associations between exposure to specific solvents or solvent mixtures and laryngeal cancer. The studies reviewed by the committee are identified in Table 6.5. Unless indicated in the table, the study populations include both men and women.
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 solvents under review and laryngeal cancer.
TABLE 6.5 Selected Epidemiologic Studies—Laryngeal Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Specific and Unspecified Mixtures of Organic Solvents |
|||
Cohort Studies—Mortality |
|||
Walker et al., 1993 |
Ohio shoe manufacturing employees |
|
|
|
Females |
2 |
3.34 (0.40–12.09) |
Teta et al., 1992 |
Male workers at ethanol/isopropanol production plants |
|
|
|
South Charleston |
1 |
1.4 (0.0–8.0)a |
|
Texas City |
1 |
3.3 (0.1–18.6)a |
Blair et al., 1990 |
St. Louis, MO, dry-cleaning workers |
3 |
1.6 (0.3–4.7) |
Case-Control Study |
|||
Vaughan et al., 1997 |
Laryngeal cancer among dry-cleaning workers |
|
|
|
Possible exposure to tetrachloroethylene |
4 |
2.3 (0.5–10.2) |
|
Probable exposure to tetrachloroethylene |
1 |
0.9 (0.1–12.9) |
|
Cumulative exposure to tetrachloroethylene (ppm-years) |
|
|
|
1–29 ppm-years |
2 |
2.0 (0.2–17.9) |
|
30+ ppm-years |
2 |
2.5 (0.3–19.1) |
|
Duration of employment |
|
|
|
1–9 years |
3 |
1.9 (0.3–10.2) |
|
10+ years |
2 |
5.5 (0.4–75.0) |
aRisk estimate and 95% CI calculated by the committee with standard methods from the observed and expected numbers presented in the original study. |
GASTROINTESTINAL TRACT TUMORS
Description of Case-Control Studies
Several case-control studies were used to evaluate the risks of cancer at gastrointestinal sites in relation to occupational exposures (Table 6.6), and one study was used to assess the risk of colorectal and pancreatic cancers posed by exposure to tetrachloroethylene in drinking water (Paulu et al., 1999).
All the studies but one used interviews with subjects to assess occupational history and in some cases occupational exposures; one study used self-administered questionnaires of next of kin (Kauppinen et al., 1995). The response rates in the latter study were 50% or less, so the results were unlikely to be representative of the entire study population. There were four reports (Dumas et al., 2000; Gérin et al., 1998; Goldberg et al., 2001; Parent et al., 2000) of one multisite case-control study conducted in Montreal in the 1980s. The novel features of the study include use of a mixed control population (cancer and population controls), in-depth interviews to obtain details of each job of each subject, translation of the interviews by a team of industrial hygienists and chemists into semiquantitative indexes of exposure to about 300 physical and chemical agents, and good information on potential confounding factors. Ekstrom and colleagues (1999) investigated gastric cancer and also used experts to attribute exposure on the basis of questionnaires. The study by Paulu and colleagues (1999) of colorectal and pancreatic cancers used estimates of exposure to tetrachloroethylene in drinking water.
Alcohol is a risk factor for esophageal cancer, and this requires consideration in evaluating the association between solvent exposure and esophageal cancer. Two studies (Parent et al., 2000; Vaughan et al., 1997) considered this confounding variable, and one did not (Gérin et al., 1998). Risk factors for other gastrointestinal cancers are less well defined.
Epidemiologic Studies of Exposure to Organic Solvents and Esophageal Cancer
The risk of esophageal cancer was increased in Danish workers who were biologically monitored for a urinary metabolite of trichloroethylene (standardized incidence ratio [SIR]=4.2, 95% CI=1.5–9.2) (Hansen et al., 2001). There was no gradient in risk with cumulative exposure although fairly high relative risks were found for long duration of employment (SIR=6.6, 95% CI=1.8–17). An equivalent risk estimate and 95% CI were also found among workers with high cumulative exposure. Blair and colleagues (1998) reported an excess risk of esophageal cancer mortality among white male aircraft-maintenance workers exposed to trichloroethylene (SMR=5.6, 95% CI=0.7–44.5). In a cohort of aircraft-manufacturing workers in California, Boice and colleagues (1999) found no association between esophageal cancer and potential exposure to trichloroethylene (SMR=0.83, 95% CI=0.34–1.72).
TABLE 6.6 Description of Case-Control Studies of Gastrointestinal Tract Tumors and Exposure to Organic Solvents
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Canadian studies |
|||||||
Gérin et al., 1998 |
Male cases and controls, age 35–70 years, diagnosed in 19 large Montreal-area hospitals in 1979–1985 and histologically confirmed for one of 19 anatomic cancer sites; frequency matched by approximate age, population-based controls were also chosen from electoral lists and with random-digit dialing (see also Dumas et al., 2000; Goldberg et al., 2001; Parent et al., 2000) |
99 esophageal 251 stomach 497 colon 257 rectal 116 pancreas |
1,066 subjects for each site, consisting of 533 population controls and 533 randomly selected subjects from the eligible cancer control group |
Benzene Toluene Xylene |
In-person interviews with specific questions on details of each job subject had; analyzed and coded by a team of chemists and industrial hygienists (about 300 exposures) on semiquantitative scales |
Unconditional logistic regression |
Age, family income, ethnicity, cigarette smoking, respondent status |
Response rates: 82% of all cases, 71% of population controls |
|||||||
Dumas et al., 2000 |
Same as above (see also Gérin et al., 1998; Goldberg et al., 2001; Parent et al., 2000) |
257 rectal |
1,295 cancer 533 population |
Toluene Xylene Methylene chloride Trichloroethylene Acetone |
See above |
See above |
Age, education respondent status, cigarette smoking, beer consumption body mass index |
Response rates: 84.5% of cases, 72% of population |
|
|
|||||
Parent et al., 2000 |
Same as above (see also Dumas et al., 2000; Gérin et al., 1998; Goldberg et al., 2001) |
99 esophageal |
2,299 cancer 533 poulation |
Toluene Solvents |
See above |
See above |
Age, respondent status, birthplace, educational level, beer consumption, spirits consumption, β-carotene index, cigarette smoking (length and pattern) |
Response rates: 75% of cases, 71% of population controls |
|
||||||
Goldberg et al., 2001 |
Same as above (see also Dumas et al., 2000; Gérin et al., 1998; Parent et al., 2000) |
497 colon |
1,514 cancer 533 population |
Benzene Xylene Toluene |
See above |
See above |
Age, respondent status, ethnicity, nonoccupational factors (such as cigarette smoking, alcohol consumption) |
Response rates: 82% of cases, 72% of population controls |
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
US studies |
|||||||
Vaughan et al., 1997 |
Cases, age 20–74 years when diagnosed, identified from a cancer-surveillance system covering 13 counties in western Washington; cases lived in one of the three largest counties and were diagnosed in 1983–1990; population-based controls, frequency-matched by age and sex, identified through RDD |
404 esophageal and gastric cardia |
724 |
Tetrachloroethylene Dry-cleaning work |
In-person interviews on occupational history (job titles; including duration, exposure probability, cumulative exposure calculations) |
Conditional logistic regression |
Age, sex, education, study period, alcohol consumption, cigarette smoking, race |
Response rates: 82.9% of cases, 80.3% of controls |
|||||||
Paulu et al., 1999 |
Cases reported to the Massachusetts Cancer Registry, diagnosed in 1983–1986 among residents of five upper Cape Cod towns; living controls were selected from the records of HCFA and through RDD; deceased controls identified by the state Department of Vital Statistics and Research files |
311 colon-rectum 36 pancreas |
1,158 (colon-rectum) 622 (pancreas) |
Tetrachloroethylene |
Calculated relative delivered dose accounting for location and years of residence, water flow, pipe characteristics |
Multiple logistic regression |
Age at diagnosis, vital status, sex, occupational exposure to solvents; specific cancer risk factors controlled in respective analyses |
Response rates: 79% of cases, 76% of HCFA controls, 74% of RDD controls, 79% of next of kin of deceased controls |
|||||||
European studies |
|||||||
Fredriksson et al., 1989 |
Cases age 30–75 years identified through the Swedish Cancer Registry among patients diagnosed in 1980–1983; cases residents of the Umea region and alive during the study’s data collection; randomly selected population controls from the National Population Register were frequency-matched on age and sex |
329 colon |
658 |
Trichloroethylene Organic solvents Dry-cleaning work Painter |
Mailed questionnaire assessing occupational history (job titles); telephone interviews followed if necessary; solvent exposures independently coded by two physicians and one hygienist |
Mantel-Haenszel |
Age, sex, physical activity |
Kauppinen et al., 1995 |
Deceased cases as of April 1990, age 40–74 years at diagnosis in 1984–1987; identified cases and controls from the Finnish Cancer Registry; controls of similar age and period of diagnosis selected from deceased cases of stomach, colon, or rectal cancer |
595 pancreatic |
1,622 |
Solvents |
Mailed questionnaire to next of kin assessing lifetime work history (job titles); assignment of exposures by industrial hygienist and use of a job-exposure matrix |
Unconditional logistic regression |
Age, sex, tobacco smoking, diabetes mellitus, alcohol consumption |
Response rates: 47% of cases, 50% of controls |
Three cohort studies of workers in the dry-cleaning industry and in aircraft manufacture reported positive associations with esophageal cancer. In a cohort of dry-cleaning union members, Ruder and colleagues (2001) observed associations between esophageal cancer and exposure to tetrachloroethylene (SMR=2.47, 95% CI=1.35–4.14) and between esophageal cancer and long-term exposure to tetrachloroethylene (SMR=5.03, 95% CI=2.41–9.47). The risk of esophageal cancer observed in workers exposed solely to tetrachloroethylene (SMR=2.65, 95% CI=0.85–6.20) was similar to the risk observed in workers exposed to tetrachloroethylene and other dry-cleaning solvents (SMR=2.40, 95% CI=1.10–4.56). Blair and colleagues (1990) found an increased risk of esophageal cancer (SMR=2.1, 95% CI=1.1–3.6) in another cohort of dry-cleaning union workers; the risk among those with high exposure to dry-cleaning solvents was slightly higher (SRR=1.3) than the risk in the referent group with medium exposure. An increased risk associated with potential exposure to tetrachloroethylene was found in a cohort of aircraft-manufacturing workers (SMR=1.47, 95% CI=0.54–3.21) (Boice et al., 1999). However, no exposure-response pattern was apparent.
Vaughan and colleagues (1997) identified cases of several types of cancer, including two morphologic types of esophageal cancer, in examining the risks from occupational exposure. The risk of esophageal squamous cell carcinoma was increased for possible exposure to tetrachloroethylene (OR=3.6, 95% CI=0.5–27.0) and probable exposure (OR=6.4, 95% CI=0.6–68.9). Increases in risk of esophageal adenocarcinoma were found to be associated with possible exposure to tetrachloroethylene but not with probable exposure.
Gérin and colleagues (1998) reported no association between medium or high exposure to benzene and risk of esophageal cancer (OR=0.9, 95% CI=0.3–2.4). In the large cohort of Chinese benzene-exposed factory workers, increased rates of mortality from esophageal cancer were found (RR=1.8, 95% CI=0.8–4.5) (Yin et al., 1996a). The cohort was examined further, including information on cumulative exposure to benzene (Hayes et al., 1996). However, when the cumulative exposure data were categorized, the relative risks did not increase with increasing exposure. The analyses did not adjust for alcohol use, an important risk factor for esophageal cancer and a potential confounder.
Gérin and colleagues (1998) found an increased risk of esophageal cancer with exposure to xylene (OR=1.4, 95% CI=0.5–3.8) or toluene (OR=1.9, 95% CI=0.9–4.2) in the medium or high exposure category. The risk estimates in the low exposure category for those substances were around unity. In a more comprehensive analysis of the same study, Parent and colleagues (2000) found a similar risk associated with “substantial” exposure to toluene (OR=1.5, 95% CI =0.6–3.7). The risk was further increased when the analysis was restricted to cases with squamous cell carcinoma (OR=2.4, 95% CI=0.9–6.4).
The only study of methylene chloride was the comprehensive cohort study of Kodak employees (Hearne and Pifer, 1999; Hearne et al., 1987, 1990). The most recent followup of the cohort included two cases of esophageal cancer in the group exposed to methylene chloride and no excess risk was observed.
A cohort study of workers in US chemical plants evaluated the association between exposure to phenol and esophageal cancer risk (Dosemeci et al., 1991). Although a slightly increased risk was associated with “any” exposure to phenol (SMR=1.6, 95% CI=0.9–2.6), other studies of unspecified mixtures of solvents yielded no increased risks of esophageal cancer (Anttila et al., 1995: SIR=0.41, 95% CI=0.01–2.29; Garabrant et al., 1988: SIR=1.14, 95% CI=0.62–1.92; Parent et al., 2000: OR=1.1, 95% CI=0.7–1.7).
Summary and Conclusion
Although almost all the studies of esophageal cancer and exposure to tetrachloroethylene and dry-cleaning solvents showed positive associations, the small number of studies (four) and the lack of increased risk with increased exposure led some committee members to favor the inadequate/insufficient category of association. In addition, some committee members expressed concern over the lack of control or adjustment for tobacco and alcohol use (known risk factors for esophageal cancer) (see Chapter 2 and Appendix E for information on smoking as a potential confounder), whereas others believed that the lack of increased risk of lung and bladder cancer in the same studies constituted evidence that confounding alone could not account for the observed increase in esophageal cancer. As a result, several committee members believed that the evidence was inadequate/insufficient to determine whether an association exists between esophageal cancer and exposure to tetrachloroethylene or dry-cleaning solvents, and others felt that the evidence was limited/suggestive of an association. After extensive discussion and deliberation, the committee decided that it could not reach a consensus on the association. Future committees may re-examine this literature and any new studies that are conducted in the interim to clarify the association between exposure to tetrachloroethylene or dry-cleaning solvents and the risk of esophageal cancer.
In cohort studies of workers exposed to trichloroethylene, most risk estimates for esophageal cancer were increased but highly variable (because there were few exposed subjects), and the estimates of risk were not adjusted for known risk factors, including alcohol consumption. For exposure to benzene, xylene, toluene, methylene chloride, phenol, and solvent mixtures, some of the studies provided positive findings while others did not. Most were not statistically precise. The key studies reviewed by the committee on esophageal cancer are identified in Table 6.7. Unless indicated in the table, the study populations include both men and women.
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 solvents under review, other than tetrachloroethylene and dry-cleanings solvents, and esophageal cancer.
TABLE 6.7 Selected Epidemiologic Studies—Esophageal Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Study—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored Danish workers |
|
|
|
Any exposure |
6 |
4.2 (1.5–9.2) |
|
>75 months |
4 |
6.6 (1.8–17) |
|
Low cumulative exposure |
3 |
6.5 (1.3–19) |
|
High cumulative exposure |
3 |
4.2 (1.5–9.2) |
|
Low mean exposure |
5 |
8.0 (2.6–19) |
|
High mean exposure |
1 |
1.3 (0.02–7.0) |
|
Low employment duration |
2 |
4.4 (0.5–16) |
|
High employment duration |
4 |
6.6 (1.8–17) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
7 |
0.83 (0.34–1.72) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah, ever exposed |
10 |
5.6 (0.7–44.5) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Studies—Mortality |
|||
Ruder et al., 2001 |
Dry-cleaning union workers |
14 |
2.47 (1.35–4.14) |
|
Long-term exposurea |
10 |
5.03 (2.41–9.47) |
|
Tetrachloroethylene-only |
5 |
2.65 (0.85–6.20) |
|
Tetrachloroethylene-plus other solvents |
9 |
2.40 (1.10–4.56) |
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
Potential routine exposure |
6 |
1.47 (0.54–3.21) |
|
≥5 years routine or intermittent |
3 |
0.91 (0.13–1.60) |
Blair et al., 1990 |
Dry-cleaning union members in St. Louis, MO |
|
|
|
Dry-cleaning solvents |
13 |
2.1 (1.1–3.6)b |
|
Medium exposure (white males) |
1 |
2.9 (0.1–18.6)b |
|
Medium exposure (black males) |
7 |
3.6 (1.5–7.6)b |
|
High exposure (white males) |
0 |
— |
|
High exposure (black males) |
1 |
2.0 (0.1–11.1)b |
Case-Control Study |
|||
Vaughan et al., 1997 |
Cases from the dry-cleaning industry |
|
|
Squamous cell (possible exposure) |
2 |
3.6 (0.5–27.0) |
|
|
Squamous cell (probable) |
2 |
6.4 (0.6–68.9) |
|
Adenocarcinoma (possible) |
2 |
1.1 (0.2–5.7) |
|
Adenocarcinoma (probable) |
1 |
0.9 (0.1–10.0) |
Benzene |
|||
Cohort Studies—Mortality |
|||
Gérin et al., 1998 |
Male residents of Montreal, Canada |
|
|
|
Medium or high exposure |
5 |
0.9 (0.3–2.4) |
Yin et al., 1996a |
Chinese factory workers ever exposed to benzene |
27 |
1.8 (0.8–4.5) |
|
Males |
25 |
2.0 (0.9–5.4) |
|
Females |
2 |
0.8 (0.1–16.7) |
Hayes et al., 1996 |
Chinese factory workers (cumulative exposure to benzene) |
|
|
|
None |
7 |
1.0 |
|
<10 ppm-years |
5 |
3.5 |
|
10–39 ppm-years |
1 |
0.5 |
|
40–99 ppm-years |
3 |
1.3 |
|
100–400 ppm-years |
5 |
1.1 |
|
>400 ppm-years |
13 |
3.2 |
|
|
|
p-trend=0.09 |
Xylene and Toluene |
|||
Case-Control Studies |
|||
Parent et al., 2000 |
Male residents of Montreal, Canada |
|
|
|
Esophageal |
|
|
|
Any toluene |
16 |
1.2 (0.7–2.2) |
|
Substantial toluene |
7 |
1.5 (0.6–3.7) |
|
Squamous cell |
|
|
|
Any toluene |
15 |
2.0 (1.0–3.9) |
|
Substantial toluene |
6 |
2.4 (0.9–6.4) |
Gérin et al., 1998 |
Male residents of Montreal, Canada |
|
|
|
Medium or high exposure, xylene |
5 |
1.4 (0.5–3.8) |
|
Medium or high exposure, toluene |
9 |
1.9 (0.9–4.2) |
Methylene Chloride |
|||
Cohort Study—Mortality |
|||
Hearne and Pifer, 1999 |
Male Kodak workers in New York state, employed >1 year |
|
|
Methylene chloride cohort |
2 |
0.63 (0.07–2.28) |
|
|
Roll-coating division (external control) |
4 |
1.42 (0.38–3.65) |
|
Roll-coating division (internal control) |
4 |
1.40 (0.38–3.58) |
Epidemiologic Studies of Exposure to Organic Solvents and Stomach Cancer
The risk of stomach cancer was not increased in a cohort of Danish workers biologically monitored for a metabolite of trichloroethylene (Hansen et al., 2001). Another Scandinavian cohort, also of workers biologically monitored for trichloroethylene metabolites, showed an increased risk of stomach cancer (SIR=1.28, 95% CI=0.75–2.04), but higher concentrations of the metabolite were not associated with greater risks (Anttila et al., 1995). Blair and colleagues (1998) reported increased stomach cancer incidence with exposure greater than 5 years (SIR=3.1, 95% CI=0.8–12.1 for 5–25 unit-years of exposure), but the risks did not increase with increasing unit-years of exposure. No increased risk of stomach cancer mortality was reported in the study (SMR=0.9, 95% CI=0.4–1.9). A cohort study of aircraft-manufacturing workers in California had increased mortality (SMR=1.32, 95% CI=0.77–2.12), but an exposure-response analysis was not presented (Boice et al., 1999). A nested case-control study of rubber workers in Ohio showed no increased risks (Wilcosky et al., 1984).
Two cohort studies of workers in the dry-cleaning industry suggested no association between occupational dry-cleaning solvent exposure and stomach cancer (Blair et al., 1990; Ruder et al., 1994). Boice and co-workers (1999) found an increased risk of stomach cancer in the California cohort of aircraft- manufacturing workers (SMR=1.42, 95% CI=0.57–2.93).
No associations were found in the large cohort of Chinese benzene-exposed workers (Hayes et al., 1996; Yin et al., 1996b). In the Montreal case-control study (Gérin et al., 1998), the risk of stomach cancer was associated with medium exposure to benzene (OR=1.5, 95% CI =0.8–3.2) and high exposure (OR=1.3, 95% CI=0.5–3.2). A slightly increased risk was seen in rubber workers potentially exposed to benzene (Wilcosky et al., 1984).
In a cohort study of rotogravure workers exposed primarily to toluene, Svensson and colleagues (1990) reported an increased risk of stomach cancer mortality (SMR=2.72, 95% CI
=1.09–5.61). Similar risk estimates were reported among subjects with 5 years of exposure or more and at least a 10-year latency period. The cancer incidence results were similar. In the Montreal case-control study (Gérin et al., 1998), the risk of stomach cancer was increased with high exposure to toluene (OR=1.7, 95% CI=0.6–4.8), and a similar risk estimate was reported for exposure to xylene (OR=1.8, 95% CI=0.3–9.5).
In the Finnish study of workers biologically monitored for aromatic hydrocarbon exposures (xylene, toluene, and styrene), Anttila and colleagues (1998) found increased stomach cancer incidence (SIR=1.18, 95% CI=0.54–2.23). In a study of rubber workers potentially exposed to xylene or toluene, no excess risks of stomach cancer were found (Wilcosky et al., 1984).
Two cohort studies of workers exposed to methylene chloride found no persuasive evidence of associations between stomach cancer and exposure (Hearne and Pifer, 1999; Tomenson et al., 1997). Stomach cancer risk was somewhat increased in the Kodak cohort (Hearne and Pifer, 1999), but Tomenson and co-workers (1997) found no association in the cohort of cellulose triacetate workers they followed.
Dosemeci and colleagues (1991) examined stomach cancer associated with exposure to phenol in a cohort of workers at five US chemical plants. No increased risk was found to be associated with “any” exposure (SMR=0.8, 95% CI=0.5–1.3) or with categories of increasing exposure. The case-control study conducted among rubber workers included results for several specific solvents (naphthas, ethanol, acetone, isopropanol, and toluene mixture) and stomach cancer risk (Table 6.8). Risk was slightly increased with some exposures but not others (Wilcosky et al., 1984).
In several cohort studies (Acquavella et al., 1993; Anttila et al., 1995; Berlin et al., 1995; Costantini et al., 1989; Fu et al., 1996; Garabrant et al., 1988) and one case-control study (Ekstrom et al., 1999), the association between stomach cancer and exposure to mixed solvents was examined. Except for the Florence cohort of shoemakers (Fu et al., 1996), the studies showed no association with stomach cancer risk. Fu and colleagues (1996) reported a 92% excess risk of stomach cancer associated with solvents used by shoemakers.
Summary and Conclusion
With only one study showing a highly variable positive association, the committee concluded that the data were insufficient to determine whether an association exists between the risk of stomach cancer and exposure to trichloroethylene. For exposure to tetrachloroethylene and dry-cleaning solvents, benzene, xylene, toluene, methylene chloride, phenol, other specific solvents, and solvent mixtures, the results were mixed. Table 6.8 identifies the data points considered by the committee in making its conclusion regarding association for stomach cancer. Unless indicated in the table, the populations cited include both men and women.
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 solvents under review and stomach cancer.
TABLE 6.8 Selected Epidemiologic Studies—Stomach Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Studies—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored Danish workers |
3 |
0.8 (0.2–2.3) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
|
|
No trichloroethylene exposure |
6 |
1.5 (0.4–6.0) |
|
<5 unit-years |
1 |
0.3 (0.1–2.6) |
|
5–25 unit-years |
7 |
3.1 (0.8–12.1) |
|
>25 unit-years |
6 |
2.0 (0.5–8.1) |
Anttila et al., 1995 |
Finnish workers biologically monitored for exposure |
|
|
|
Years since first measurement |
|
|
|
0–9 years |
6 |
1.32 (0.48–2.87) |
|
10–19 years |
4 |
0.63 (0.17–1.60) |
|
20+ years |
7 |
2.98 (1.20–6.13) |
|
Whole period |
17 |
1.28 (0.75–2.04) |
|
Mean personal U-TCA level |
|
|
|
<100 µmol/L |
12 |
1.65 (0.98–1.39) |
|
100+ µmol/L |
4 |
0.91 (0.25–2.32) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
17 |
1.32 (0.77–2.12) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah, employed >1 year |
23 |
0.9 (0.4–1.9) |
Wilcosky et al., 1984 |
Male rubber workers in Ohio, exposed >1 year |
5 |
1.0 |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
7 |
1.42 (0.57–2.93) |
Ruder et al., 1994 |
Dry-cleaning labor-union workers |
5 |
0.61 (0.20–1.43) |
|
Males |
2 |
0.43 (0.05–1.54) |
|
Females |
3 |
0.86 (0.18–2.53) |
Blair et al., 1990 |
Dry-cleaning union members in St. Louis, MO |
|
|
|
Dry-cleaning solvents |
11 |
0.8 (0.4–1.4) |
Benzene |
|||
Cohort Studies—Incidence |
|||
Yin et al., 1996a |
Chinese factory workers ever exposed to benzene |
85 |
0.9 (0.7–1.4) |
|
Males |
71 |
0.9 (0.6–1.4) |
|
Females |
14 |
1.0 (0.4–2.8) |
Hayes et al., 1996 |
Chinese factory workers (cumulative exposure to benzene) |
|
|
|
None |
43 |
1.0 |
|
<10 ppm-years |
6 |
0.6 |
|
10–39 ppm-years |
13 |
1.0 |
|
40–99 ppm-years |
12 |
0.9 |
|
100–400 ppm-years |
25 |
1.0 |
|
400+ ppm-years |
27 |
1.2 |
|
|
|
p-trend=0.63 |
Case-Control Study |
|||
Gérin et al., 1998 |
Male residents of Montreal, Canada |
|
|
|
Benzene, medium exposure |
11 |
1.5 (0.8–3.2) |
|
Benzene, high exposure |
6 |
1.3 (0.5–3.2) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Ris (95% CI) |
Xylene and Toluene |
|||
Cohort Studies—Incidence |
|||
Anttila et al., 1998 |
Finnish workers biologically monitored for exposure to aromatic hydrocarbons (styrene, toluene, xylene) |
9 |
1.18 (0.54–2.23) |
Svensson et al., 1990 |
Male rotogravure workers in Sweden |
7 |
2.34 (0.94–4.82) |
≥5 years exposure with ≥10 years latency (primarily to toluene) |
5 |
2.18 (0.71–5.09) |
|
Cohort Studies—Mortality |
|||
Svensson et al., 1990 |
Male rotogravure workers in Sweden |
7 |
2.72 (1.09–5.61) |
≥5 years exposure with ≥10 years latency (primarily to toluene) |
5 |
2.53 (0.82–5.91) |
|
Wilcosky et al., 1984 |
Male rubber workers in Ohio, exposed >1 year |
|
|
Xylenes |
3 |
0.53 |
|
|
Toluene |
1 |
— |
|
Benzene |
12 |
1.3 |
Case-Control Study |
|||
Gérin et al., 1998 |
Male residents of Montreal, Canada |
|
|
|
Xylene, medium exposure |
7 |
1.0 (0.4–2.3) |
|
Xylene, high exposure |
2 |
1.8 (0.3–9.5) |
|
Toluene, medium exposure |
7 |
1.0 (0.4–2.2) |
|
Toluene, high exposure |
5 |
1.7 (0.6–4.8) |
Methylene Chloride |
|||
Cohort Studies—Mortality |
|||
Hearne and Pifer, 1999 |
Male Kodak workers in New York state, employed >1 year |
|
|
Methylene chloride cohort |
6 |
1.40 (0.51–3.04) |
|
|
Roll-coating division (external control) |
5 |
1.25 (0.40–2.91) |
|
Roll-coating division (internal control) |
5 |
1.26 (0.41–2.93) |
Tomenson et al., 1997 |
Male cellulose triacetate film workers in Brantham, UK, ever employed |
6 |
0.63 (0.23–1.37) |
Other Organic Solvents |
|||
Cohort Studies—Mortality |
|||
Dosemeci et al., 1991 |
Male workers in five US chemical plants |
|
|
Phenol |
|
||
|
No exposure |
10 |
1.1 |
|
Any exposure |
18 |
0.8 (0.5–1.3) |
|
Low exposure |
11 |
1.0 |
|
Medium exposure |
5 |
0.5 |
|
High exposure |
2 |
1.1 |
Wilcosky et al., 1984 |
Male rubber workers in Ohio, exposed >1 year |
|
|
Specialty naphthas |
18 |
1.1 |
|
|
Ethanol |
8 |
1.1 |
|
Acetone |
1 |
— |
|
Isopropanol |
14 |
1.4 |
|
Phenol |
6 |
1.4 |
|
VM&P naphtha |
3 |
1.1 |
|
Solvent “A” (toluene mixture) |
15 |
1.4 |
Unspecified Mixtures of Organic Solvents |
|||
Cohort Studies—Incidence |
|||
Anttila et al., 1995 |
Finnish workers biologically monitored for exposure to halogenated hydrocarbons (trichloroethylene, tetrachloroethylene, 1,1,1-trichloroethane) |
19 |
1.28 (0.77–1.99) |
Berlin et al., 1995 |
Swedish patients with acute solvent-related disorders |
2 |
0.5 (0.1–1.9) |
Epidemiologic Studies of Exposure to Organic Solvents and Colon Cancer
In a study conducted in Sweden (Fredriksson et al., 1989), a 640% excess risk of colon cancer (OR=7.4, 95% CI=1.1–47.0) was found with exposure to trichloroethylene among dry cleaners. Two cohort studies of aircraft workers did not show increased mortality from colon cancer (Blair et al., 1998; Boice et al., 1999). However, the incidence of colon cancer was increased in the cohort of aircraft-maintenance workers in Utah (Blair et al., 1998). Incidence increased with increasing unit-years of exposure (Table 6.9). Colon cancer risk was not increased in two cohorts biologically monitored for exposure to trichloroethylene (Anttila et al., 1995; Hansen et al., 2001). Anttila and co-workers found no increased risk associated with number of years since first measurement, which represents an approach to account for latency.
A case-control study of colon cancer in Sweden conducted by Fredriksson and colleagues (1989) reported an increased risk of colon cancer among female dry cleaners (OR=2.0, 95% CI=0.5–7.1). Paulu and colleagues (1999) conducted a case-control study of residents of Cape Cod that showed an increased risk of colorectal cancers with tetrachloroethylene exposure in drinking water (OR11 year latency=2.0, 95% CI=0.6–5.8) for exposures less than the 50th percentile, whereas the risk was somewhat lower when exposure equal to or greater than the 50th percentile was considered (OR11 year latency=1.5, 95% CI=0.4–4.4). A cohort of dry-cleaning workers experienced an increased risk of intestinal (excluding rectal) cancer (SMR=1.48, 95% CI=1.01–2.09), and findings were similar in a subcohort exposed to both tetrachloroethylene and other solvents; however, the risk was not similarly increased among those exposed only to tetrachloroethylene (Ruder et al., 2001). Because the analysis was based on cases of “intestinal” cancer, the findings are difficult to interpret; different classes of intestinal tract cancers, including cancers of the small and large intestines, are derived from distinct cells and may have different etiology. Real effects may be masked when diseases with different
etiology are investigated as one disease. Furthermore, when exposure was restricted to tetrachloroethylene, no increase risk was apparent.
Goldberg and colleagues (2001) reported an increased colon cancer risk with exposure to benzene at “substantial,” “medium,” and “high” levels; and risks increased by about 10% for every 10 years of exposure. In the large cohort of Chinese benzene-exposed workers, no increased risks of colorectal cancer were found (RR=0.9, 95% CI=0.5–1.7) (Yin et al., 1996a). Increasing cumulative exposure did not appear to be associated with increased risk (Hayes et al., 1996).
In detailed followup analyses of the population-based case-control study of occupational exposure and cancer in Montreal, the risk of colon cancer was increased with “substantial” exposure to xylene (OR=1.5, 95% CI=0.6–3.7) and toluene (OR=1.5, 95% CI=0.8–2.5) (Goldberg et al., 2001). Risk estimates increased with increasing concentration of xylene and toluene, and risk increased by 20% for every 10 years of exposure. Levels were assessed on the basis of responses to interviews and structured questionnaires that were coded by a team of chemists and industrial hygienists. Low levels were assumed if a person had been exposed peripherally or at normal levels, and high levels were assumed if a person directly handled a product that contained one of the chemicals of concern. Medium concentration fell between those two.
Colon cancer risk was not increased among workers monitored for hydrocarbons, which included styrene, toluene, and xylene (Anttila et al., 1998). In a cohort study of cancer incidence and mortality in toluene-exposed rotogravure workers, Svensson and colleagues (1990) reported an increased risk of combined colon and rectal cancer mortality (SMR=2.18, 95% CI=0.88–4.49) and incidence (SIR=1.49, 95% CI=0.68–2.84). Similar risk estimates were reported among subjects with prolonged exposure.
Two cohort studies of workers exposed to methylene chloride reported no increased colon cancer risk in the roll-coating division at Kodak (Hearne and Pifer, 1999) or in cellulose triacetate film workers in the UK (Tomenson et al., 1997). The committee concluded that these results did not indicate excess risk of colon cancer posed by exposure to methylene chloride.
One study reported no increased colon cancer risk associated with exposure to phenol (Dosemeci et al., 1991). Risk of colon cancer was not associated with exposure to solvents in a cohort of patients with solvent-related disorders (Berlin et al., 1995) or among workers biologically monitored for halogenated hydrocarbons (Anttila et al., 1995). Self-reported occupation as a painter and occupational exposure to solvents were each associated with colon cancer in a study conducted in Sweden (Fredriksson et al., 1989).
Summary and Conclusion
Because the increased risk and exposure-response pattern support an association between colon cancer and exposure to trichloroethylene, several committee members believed that the evidence was limited/suggestive of an association. Other members felt that the positive associations were balanced by the negative findings in other cohort studies and in studies with biologic monitoring of metabolites of exposure. Therefore, the committee decided not to have a consensus conclusion. Additional research will help to clarify the relationship between exposure to trichloroethylene and the risk of colon cancer.
Results of the three studies on tetrachloroethylene and dry-cleaning solvents are insufficient to determine whether an association exists for colon cancer, because of the described
limitations of the cohort study and because the estimates of risk in the case-control studies are imprecise, being based on few exposed cases.
The body of evidence on colon cancer and exposure to benzene and mixtures of toluene and xylene was rather small (five studies), including one high quality case-control study (Goldberg et al., 2001) and two cohort studies that included exposures other than benzene, toluene, or xylene in their analyses (Anttila et al., 1998; Svensson et al., 1990). Anttila and colleagues (1998) assessed the association between colon cancer and hydrocarbons that included styrene in addition to toluene and xylene; and Svensson and colleagues (1990), who examined a cohort of Swedish rotogravure printers, focused primarily on toluene but acknowledged the presence of other solvents and chemical agents. Although one study showed an association with exposure to benzene, toluene, and xylene (Goldberg et al., 2001), the large Chinese factory-worker study (Hayes et al., 1996; Yin et al., 1996b), which combined colon and rectal cancer, did not. The strengths of the Goldberg and colleagues study (2001) included adjustment for most known risk factors and occupational exposures; use of incident, histologically-confirmed cases; and an independent assessment of exposure by experts. The strength of the Chinese cohort study (Hayes et al., 1996) was the relatively accurate estimates of exposure, but its limitations included use of mortality instead of incidence and lack of assessment of confounding factors. As a result, some committee members concluded that the evidence was limited/suggestive of an association, and others concluded that it was insufficient to determine whether an association exists. After much deliberation, the committee decided that it could not reach a consensus on an association of colon cancer and exposure to benzene and mixtures of toluene and xylene. Further studies on these exposure-outcome relationships may provide evidence as to whether an association exists.
For exposure to methylene chloride, phenol, and mixtures of solvents, the studies did not provide any evidence of an association between exposure and risk for colon cancer. All of the studies reviewed by the committee are identified below in Table 6.9, and unless indicated, the study populations include both men and women.
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 solvents under review, other than trichloroethylene, benzene, toluene, and xylene, and colon cancer.
TABLE 6.9 Selected Epidemiologic Studies—Colon Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylenee |
|||
Cohort Studies-Incidence |
|||
Hansen et al., 2001 |
Biologically monitored Danish workers |
|
|
|
Males |
5 |
0.7 (0.2–1.6) |
|
Females |
1 |
0.7 (0.01–4.0) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
|
|
No trichloroethylene exposure |
22 |
4.1 (1.4–11.8) |
|
≤5 unit-years |
15 |
2.9 (1.0–8.9) |
|
5–25 unit-years |
14 |
4.3 (1.4–13.0) |
|
>25 unit-years |
23 |
5.7 (2.0–16.7) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Ris (95% CI) |
Anttila et al., 1995 |
Biologically monitored Finnish workers |
|
|
|
Years since first measurement: |
|
|
|
0–9 years |
3 |
1.23 (0.25–3.59) |
|
10–19 years |
3 |
0.62 (0.13–1.80) |
|
20+ years |
2 |
0.92 (0.11–3.31) |
|
Whole period |
8 |
0.84 (0.36–1.66) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
30 |
1.07 (0.72–1.52) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
54 |
1.4 (0.8–2.4) |
|
Males |
|
|
|
No trichloroethylene exposure |
21 |
1.5 (0.7–3.3) |
|
<5 unit-years |
19 |
1.5 (0.7–3.3) |
|
5–25 unit-years |
12 |
1.5 (0.7–3.6) |
|
>25 unit-years |
15 |
1.5 (0.7–3.3) |
Case-Control Study |
|||
Fredriksson et al., 1989 |
Residents of Sweden |
|
|
Trichloroethylene |
NA |
1.5 (0.4–5.7) |
|
|
Trichloroethylene among dry cleaners |
NA |
7.4 (1.1–47.0) |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Study—Mortality |
|||
Ruder et al., 2001 |
Dry-cleaning labor-union workers (intestine) |
32 |
1.48 (1.01–2.09) |
|
Long-term exposurea |
13 |
1.48 (0.79–2.58) |
|
Tetrachloroethylene only |
8 |
1.18 (0.51–2.33) |
Case-Control Studies |
|||
Paulu et al., 1999 |
Residents of Cape Cod, MA |
|
|
|
Colon-rectum (11-year latency) |
|
|
|
≤Median |
6 |
2.0 (0.6–5.8) |
|
>Median |
5 |
1.5 (0.4–4.4) |
Fredriksson et al., 1989 |
Residents of Sweden |
|
|
Female dry cleaners |
5 |
2.0 (0.5–7.1) |
|
Benzene |
|||
Cohort Studies—Mortality |
|||
Yin et al., 1996a |
Chinese factory workers ever exposed to benzene (colon-rectum) |
|
|
|
Total |
34 |
0.9 (0.5–1.7) |
|
Males |
24 |
1.1 (0.5–2.3) |
|
Females |
10 |
0.7 (0.3–2.0) |
Hayes et al., 1996 |
Chinese factory workers (colorectal; benzene cumulative exposure) |
|
|
|
None |
17 |
1.0 |
|
<10 ppm-years |
7 |
1.5 |
|
10–39 ppm-years |
4 |
0.7 |
|
40–99 ppm-years |
3 |
0.5 |
|
100–400 ppm-years |
8 |
0.8 |
|
400+ ppm-years |
12 |
1.4 |
|
|
|
p-trend=0.91 |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Case-Control Study |
|||
Goldberg et al., 2001 |
Male residents of Montreal, Canada |
|
|
|
Substantial exposure |
21 |
1.6 (0.9–2.8) |
|
Low concentration |
39 |
0.8 (0.5–1.2) |
|
Medium concentration |
26 |
1.5 (0.9–2.4) |
|
High concentration |
6 |
3.4 (1.0–11.2) |
|
Duration (10 years) |
71 |
1.1 (0.9–1.2) |
Xylene and Toluene |
|||
Cohort Studies—Incidence |
|||
Anttila et al., 1998 |
Finnish workers biologically monitored for exposure to aromatic hydrocarbons (styrene, toluene, and xylene) |
2 |
0.34 (0.04–1.21) |
Svensson et al., 1990 |
Male rotogravure workers in Sweden—colon-rectum |
9 |
1.49 (0.68–2.84) |
|
≥5 yrs exposure with >10 yrs latency (primarily toluene) |
8 |
1.74 (0.75–3.43) |
Cohort Study—Mortality |
|||
Svensson et al., 1990 |
Male rotogravure workers in Sweden—colon-rectum |
7 |
2.18 (0.88–4.49) |
|
≥5 yrs exposure with >10 yrs latency (primarily to toluene) |
6 |
2.41 (0.89–5.25) |
Case-Control Study |
|||
Goldberg et al., 2001 |
Male residents of Montreal, Canada |
|
|
|
Xylene |
|
|
|
Substantial exposure |
10 |
1.5 (0.6–3.7) |
|
Low concentration |
44 |
1.4 (0.9–2.0) |
|
Medium concentration |
11 |
1.7 (0.8–3.5) |
|
High concentration |
5 |
4.0 (1.1–15.1) |
|
Duration (10 years) |
60 |
1.2 (1.0–1.4) |
|
Toluene |
|
|
|
Substantial exposure |
27 |
1.5 (0.8–2.5) |
|
Low concentration |
31 |
1.3 (0.8–2.0) |
|
Medium concentration |
31 |
1.3 (0.8–2.1) |
|
High concentration |
9 |
2.4 (1.0–5.7) |
|
Duration (10 years) |
71 |
1.2 (1.0–1.4) |
Methylene Chloride |
|||
Cohort Studies—Mortality |
|||
Hearne and Pifer, 1999 |
Male Kodak workers in New York state (colon-rectum), employed >1 year |
|
|
|
Methylene chloride cohort |
15 |
1.15 (0.64–1.90) |
|
Roll-coating division (external control) |
10 |
0.75 (0.36–1.37) |
|
Roll-coating division (internal control) |
10 |
0.87 (0.42–1.60) |
Tomenson et al., 1997 |
Male cellulose triacetate film workers in Brantham, UK, ever employed |
6 |
0.90 (0.33–1.96) |
Phenol |
|||
Cohort Study—Mortality |
|||
Dosemeci et al., 1991 |
Male workers in five US chemical plants |
|
|
Phenol, any exposure |
33 |
0.9 (0.6–1.3) |
Epidemiologic Studies of Exposure to Organic Solvents and Rectal Cancer
The two studies of workers biologically monitored for a metabolite of trichloroethylene showed imprecise associations (Anttila et al., 1995; Hansen et al., 2001). Risks did not increase with increasing mean urinary trichloroacetic acid, a metabolite of trichloroethylene (SIR=0.85, 95% CI=0.10–3.07) (Anttila et al., 1995).
No associations with rectal cancer mortality were found in the studies of aircraft and aerospace workers. Blair and colleagues (1998) found no increased risk of rectal cancer among aircraft maintenance workers in Utah (SMR=0.4, 95% CI=0.1–1.5). Among a trichloroethylene-exposed subcohort of aerospace workers, the SMR for “high” exposure was 1.38 (95% CI=0.45–3.21) (Morgan et al., 1998). In the cohort of aircraft-manufacturing workers in California, the SMR was 1.29 (95% CI=0.59–2.45) (Boice et al., 1999). Rectal cancer risk was found to be increased in the Montreal case-control study with “any” exposure to trichloroethylene (OR=2.0, 95% CI=1.0–3.9), but it was much lower with “substantial” exposure to trichloroethylene (OR=0.9, 95% CI=0.3–3.2) (Dumas et al., 2000).
The cohort of dry-cleaning union members experienced an excess risk of rectal cancer mortality after exposure to tetrachloroethylene and other dry-cleaning solvents (SMR=2.16, 95% CI=0.86–4.45) (Ruder et al., 2001). Paulu and colleagues (1999) conducted a case-control study of residents of Cape Cod that showed an increased risk of colorectal cancers with exposure to tetrachloroethylene from drinking water (OR11 year latency=2.0, 95% CI=0.6–5.8) when exposure was less than the 50th percentile; the risk was somewhat lower when exposure was equal to or greater than the 50th percentile (OR11 year latency=1.5, 95% CI=0.4–4.4). Because the analysis was based on cases of “intestinal” cancer, the findings are difficult to interpret; different classes of intestinal tract cancers, including cancers of the small and large intestines, are derived from different cells and may have different etiology. Real effects may be masked when diseases with different etiology are studied as one disease. No cases were found in workers exposed only to tetrachloroethylene.
In the large cohort of Chinese benzene-exposed workers, no increased risk of colorectal cancer was found (RR=0.9, 95% CI=0.5–1.7) (Yin et al., 1996a). Increasing cumulative exposure did not appear to be associated with increased risk (Hayes et al., 1996). Only in the population-based case-control study of occupational exposure and cancer in Montreal was
exposure to xylene, toluene, and benzene assessed. Gérin and colleagues (1998) found no association with “high” exposure to benzene (OR=0.8, 95% CI=0.3–2.5). In additional analyses of the data, Dumas and colleagues (2000) found increased rectal cancer risk with “substantial” exposure to xylene (OR=2.9, 95% CI=1.1–7.3) and “substantial” exposure to toluene (OR=1.7, 95% CI=1.0–3.0).
In the cohort study of Finnish workers biologically monitored for exposure to solvents, rectal cancer incidence was associated with exposure to styrene, xylene, and toluene (aromatic hydrocarbons) (SIR=1.88, 95% CI 0.81–3.71) (Anttila et al., 1998).
The cohort study of cellulose triacetate film workers in the UK showed no increased risk of rectal cancer (SMR=0.44, 95% CI=0.05–1.57) (Tomenson et al., 1997). Dumas and colleagues (2000) reported an increased risk of rectal cancer with “any” exposure to methylene chloride (OR=1.2, 95% CI=0.5–2.8); the risk was higher with “substantial” exposure (OR=3.8, 95% CI=1.1–12.9).
The association between rectal cancer and exposure to phenol was assessed in one cohort study (Dosemeci et al., 1991); there was no strong evidence of an association (SMR=1.4, 95% CI=0.8–2.2). Dumas and colleagues (2000) found an increased risk with “any” exposure to acetone (OR=2.3, 95% CI=1.1–4.7), which increased to an OR of 4.8 (95% CI=1.8–13.0) with “substantial” exposure.
There were three cohort studies of rectal cancer and exposure to unspecified mixtures of solvents. An early study of aircraft-manufacturing workers (Garabrant et al., 1988) and a study of Swedish patients with solvent-related disorders (Berlin et al., 1995) showed no associations with rectal cancer (SIR=1.04 and 0.99, respectively). Anttila and colleagues (1995) reported an increased risk of rectal cancer among workers biologically monitored for halogenated hydrocarbon exposure (SIR=1.63, 95% CI=0.87–2.78).
Summary and Conclusion
In summary, there was inconclusive evidence of an association between trichloroethylene and rectal cancer. The main limitation of the studies was the small number of exposed cases; this limits the precision of the estimates and the statistical power to detect associations. For exposure to tetrachloroethylene and dry-cleaning solvents, the committee concluded that the results did not indicate an excess risk of rectal cancer. Despite the suggestive findings on toluene and xylene, only two studies specifically examined rectal cancer risk. To determine whether an association exists, other high-quality studies are required.
Because there were only two studies to draw inferences from, the evidence for methylene chloride was inadequate. Furthermore, the committee could not draw conclusions from single studies of each exposure although there was suggestive evidence from the high-quality study of Dumas and colleagues regarding exposure to acetone. For exposure to solvent mixtures, the findings were mixed with no persuasive evidence of an association.
Table 6.10 identifies the studies and data points considered by the committee in making its conclusion regarding association. Unless indicated, the study populations identified in the table include both men and women.
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 solvents under review and rectal cancer.
TABLE 6.10 Selected Epidemiologic Studies—Rectal Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Studies—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored Danish workers |
7 |
1.3 (0.5–2.7) |
Anttila et al., 1995 |
Biologically monitored Finnish workers |
|
|
|
Entire period since first measurement |
12 |
1.71 (0.88–2.98) |
|
0–9 years |
3 |
1.59 (0.33–4.64) |
|
10–19 years |
8 |
2.22 (0.96–4.36) |
|
20+ years |
1 |
0.67 (0.02–3.72) |
|
Mean personal U-TCA level: |
|
|
|
<100 µmol/L |
9 |
2.34 (1.07–4.44) |
|
100+ µmol/L |
2 |
0.85 (0.10–3.07) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
9 |
1.29 (0.59–2.45) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah, employed >1 year |
5 |
0.4 (0.1–1.5) |
Morgan et al., 1998 |
Aerospace workers in Arizona |
|
|
Trichloroethylene-exposed subcohort |
6 |
1.06 (0.39–2.31) |
|
|
High trichloroethylene-exposure |
5 |
1.38 (0.45–3.21) |
Case-Control Study |
|||
Dumas et al., 2000 |
Male residents of Montreal, Canada |
|
|
|
Any exposure |
12 |
2.0 (1.0–3.9) |
|
Substantial exposure |
3 |
0.9 (0.3–3.2) |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Study—Mortality |
|||
Ruder et al., 2001 |
Dry-cleaning labor-union workers (intestine) |
|
|
|
Tetrachloroethylene plus other solvents |
7 |
2.16 (0.86–4.45) |
Case-Control Study |
|||
Paulu et al., 1999 |
Residents of Cape Cod, MA |
|
|
|
Colon-rectum (11-year latency) |
|
|
|
≤Median |
6 |
2.0 (0.6–5.8) |
|
>Median |
5 |
1.5 (0.4–4.4) |
Benzene |
|||
Cohort Studies—Mortality |
|||
Yin et al., 1996a |
Chinese factory workers ever exposed to benzene (colon-rectum) |
|
|
|
Total |
34 |
0.9 (0.5–1.7) |
|
Males |
24 |
1.1 (0.5–2.3) |
|
Females |
10 |
0.7 (0.3–2.0) |
Hayes et al., 1996 |
Chinese factory workers (colorectal; benzene cumulative exposure) |
|
|
|
None |
17 |
1.0 |
|
<10 ppm-years |
7 |
1.5 |
|
10–39 ppm-years |
4 |
0.7 |
|
40–99 ppm-years |
3 |
0.5 |
|
100–400 ppm-years |
8 |
0.8 |
|
400+ ppm-years |
12 |
1.4 |
|
|
|
p-trend=0.91 |
Case-Control Study |
|||
Gérin et al., 1998 |
Male residents of Montreal, Canada |
|
|
|
High exposure |
4 |
0.8 (0.3–2.5) |
Epidemiologic Studies of Exposure to Organic Solvents and Pancreatic Cancer
Several cohort studies of trichloroethylene-exposed workers showed no increased risk of pancreatic cancer. In the cohort of aircraft-manufacturing workers examined by Boice and
colleagues (1999), risk was shown to decrease (SMR=0.41, 95% CI=0.17–0.85) with potential exposure to trichloroethylene. Blair and co-workers (1998) also found no association between pancreatic cancer incidence and all categories of “unit-years” of exposure. Pancreatic cancer mortality was weakly increased in the same study (SMR=1.2, 95% CI=0.6–2.3). A third cohort study of aerospace workers in Arizona also found no risk of pancreatic cancer posed by exposure to high levels of trichloroethylene (SMR=0.66, 95% CI=0.24–1.43) (Morgan et al., 1998).
Two cohorts of workers biologically monitored for metabolites of trichloroethylene reported mixed findings. Hansen and colleagues (2001) found no association (SIR=1.0, 95% CI =0.2–3.0) between the trichloroethylene metabolite and pancreatic cancer, whereas Anttila and colleagues (1995) found an increased risk (SIR=1.61, 95% CI=0.81–2.88). However, no exposure-response relationship was indicated as the mean concentration of the metabolite increased.
Ruder and colleagues (2001) found an association between pancreatic cancer and exposure to tetrachloroethylene and other solvents (SMR=1.89, 95% CI=1.06–3.11), but no increase in risk was found in the subcohort of workers exposed only to tetrachloroethylene (SMR =0.80, 95% CI=0.17–2.35). An increased risk of pancreatic cancer was found in the cohort of workers monitored for solvents, including tetrachloroethylene (SIR=3.08, 95% CI=0.63–8.99) (Anttila et al., 1995).
The case-control study of multiple cancer sites performed by Gérin and colleagues (1998) indicated no association between pancreatic cancer and medium or high exposure to toluene (OR=0.6, 95% CI=0.2–2.2), xylene (OR=1.1, 95% CI=0.4–3.3), or benzene (OR=0.4, 95% CI=0.1–1.4). In the cohort study of Finnish workers exposed to xylene, toluene, and styrene, Anttila and colleagues (1998) found increased risks of pancreatic cancer (SIR=1.26, 95% CI=0.41–2.93). A case-control study of pancreatic cancer by Ji and colleagues (1999) conducted in Shanghai showed increased risks in various occupational groups, especially among male painters (OR=5.2, 95% CI=1.1–25.0).
The comprehensive cohort study of methylene chloride-exposed workers at Kodak has been followed for a number of years (Hearne et al., 1987, 1990). In the initial publication, an excess of pancreatic cancer was observed (SMR=3.1); however, in the second study, after 4 additional years of followup, there was no increase in pancreatic cancer mortality. In a study examining the same cohort and another cohort of Kodak workers, Hearne and Pifer (1999) showed an increased risk of pancreatic cancer associated with career exposure to methylene chloride of over 800 ppm-years on the basis of three cases (SMR=2.34, compared with internal controls). Among workers who were employed in 1964–1970 in the roll coating division, the highest risk was found in the lowest cumulative-exposure category of less than 400 ppm (SMR=2.58, compared with internal controls). Other cohorts of methylene chloride-exposed workers had very few cases of pancreatic cancer and reported no increased risk (Gibbs et al., 1996; Lanes et al., 1990, 1993; Tomenson et al., 1997).
The study of workers in five chemical plants found no increased risk of pancreatic cancer associated with exposure to phenol (SMR=0.6, 95% CI=0.4–1.1) (Dosemeci et al., 1991).
Several studies reported associations between pancreatic cancer and unspecified mixtures of organic solvents (Table 6.11). The studies showing positive associations included male leather workers in Italy (SMR=1.46, 95% CI=0.39–3.73) (Costantini et al., 1989), aircraft-manufacturing workers (SMR=1.19, 95% CI=0.83–1.67) (Garabrant et al., 1988), and the
case-control study in Finland of high exposure to solvents (OR=2.01, 95% CI=0.98–4.10) (Kauppinen et al., 1995).
Summary and Conclusion
For exposure to trichloroethylene, tetrachloroethylene and dry-cleaning solvents, xylene, toluene, benzene, methylene chloride, phenol, and solvent mixtures and the risk of pancreatic cancer, the evidence was limited by mixed results, the lack of exposure-response relationships, and imprecise estimates of risk. Table 6.11 identifies the studies reviewed by the committee in making its conclusion regarding association. All of the study populations include both men and women unless stated otherwise.
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 solvents under review and pancreatic cancer.
TABLE 6.11 Selected Epidemiologic Studies—Pancreatic Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Studies—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored Danish workers |
3 |
1.0 (0.2–3.0) |
Blair et al., 1998 |
Aircraft maintenance workers in Utah |
|
|
|
No trichloroethylene exposure |
6 |
0.7 (0.2–2.3) |
|
<5 unit-years |
6 |
0.7 (0.2–2.1) |
|
5–25 unit-years |
2 |
0.4 (0.1–1.8) |
|
>25 unit-years |
51 |
0.7 (0.2–2.4) |
Anttila et al., 1995 |
Biologically monitored Finnish workers |
|
|
|
Entire period since first measurement: |
11 |
1.61 (0.81–2.88) |
|
0–9 years |
1 |
0.56 (0.01–3.10) |
|
10–19 years |
8 |
2.30 (0.99–4.52) |
|
20+ years |
2 |
1.31 (0.16–4.74) |
|
Mean personal U-TCA level: |
|
|
|
<100 µmol/L |
6 |
1.61 (0.59–3.50) |
|
100+ µmol/L |
3 |
1.31 (0.27–3.82) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
7 |
0.41 (0.17–0.85) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah, employed >1 year |
33 |
1.2 (0.6–2.3) |
Morgan et al., 1998 |
Aerospace workers in Arizona |
|
|
Trichloroethylene-exposed subcohort |
11 |
0.76 (0.38–1.37) |
|
|
High trichloroethylene-exposure |
6 |
0.66 (0.24–1.43) |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Study—Incidence |
|||
Anttila et al., 1995 |
Biologically monitored Finnish workers |
3 |
3.08 (0.63–8.99) |
Cohort Study—Mortality |
|||
Ruder et al., 2001 |
Dry-cleaning labor-union workers |
18 |
1.53 (0.91–2.42) |
|
Tetrachloroethylene-only |
3 |
0.80 (0.17–2.35) |
|
Tetrachloroethylene-plus other solvents |
15 |
1.89 (1.06–3.11) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Xylene, Toluene, Benzene |
|||
Cohort Study—Incidence |
|||
Anttila et al., 1998 |
Finnish workers biologically monitored for exposure to aromatic hydrocarbons (styrene, toluene, xylene) |
5 |
1.26 (0.41–2.93) |
Case-Control Studies |
|||
Ji et al., 1999 |
Residents of Shanghai, China |
|
|
|
Chemical and rubber workers (female) |
5 |
1.4 (0.4–4.7) |
|
Rubber workers (female) |
5 |
1.7 (0.5–5.8) |
|
Printers (male) |
4 |
5.2 (1.1–25.0) |
Gérin et al., 1998 |
Male residents of Montreal, Canada |
|
|
|
Xylene, medium/high exposure |
4 |
1.1 (0.4–3.3) |
|
Toluene, medium/high exposure |
3 |
0.6 (0.2–2.2) |
|
Benzene, medium/high exposure |
3 |
0.4 (0.1–1.4) |
Methylene Chloride |
|||
Cohort Studies—Mortality |
|||
Hearne and Pifer, 1999 |
Male Kodak workers in New York state, employed >1 year |
|
|
Methylene chloride cohort |
5 |
0.92 (0.30–2.14) |
|
|
Internal comparison, ≥800 ppm-years |
3 |
2.34 |
|
Roll-coating division (New York state control) |
8 |
1.51 (0.65–2.98) |
|
Roll-coating division (Kodak Rochester control) |
8 |
1.55 (0.67–3.06) |
Tomenson et al., 1997 |
Male cellulose triacetate film workers, ever employed |
3 |
0.68 (0.14–1.99) |
Gibbs et al., 1996 |
Cellulose-fiber production workers |
|
|
|
High exposure, males |
1 |
0.35 (0.01–1.92) |
|
High exposure, females |
0 |
0 |
|
Low exposure, males |
2 |
0.89 (0.11–3.22) |
|
Low exposure, females |
1 |
0.58 (0.01–3.23) |
Lanes et al., 1993 |
Cellulose-fiber production plant workers, employed >3 months |
2 |
0.83 (0.10–2.99) |
Phenol |
|||
Cohort Study—Mortality |
|||
Dosemeci et al., 1991 |
Male workers in five US chemical plants |
|
|
Phenol, any exposure |
14 |
0.6 (0.4–1.1) |
|
Unspecified Mixtures of Organic Solvents |
|||
Cohort Study—Incident |
|||
Anttila et al., 1995 |
Finnish workers biologically monitored for exposure to halogenated hydrocarbons (trichloroethylene, tetrachloroethylene, 1,1,1-trichloroethane) |
12 |
1.56 (0.81–2.72) |
Cohort Studies—Mortality |
|||
Fu et al., 1996 |
Shoemakers in England and Florence |
|
|
|
English cohort |
25 |
0.70 (0.45–1.04) |
|
Florence cohort |
2 |
0.54 (0.07–1.95) |
Acquavella et al., 1993 |
Metal-components manufacturing workers, ever exposed |
1 |
2.9 (0.1–16.0) |
Costantini et al., 1989 |
Male leather workers in Tuscany, Italy, employed >6 months |
4 |
1.46 (0.39–3.73) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Garabrant et al., 1988 |
Aircraft-manufacturing workers in California, employed >4 years |
34 |
1.19 (0.83–1.67) |
Pippard and Acheson, 1985 |
Male boot and shoe makers in three English towns |
|
|
Rushden |
21 |
0.96 (0.59–1.46) |
|
|
Street |
2 |
0.40 (0.05–1.46) |
|
Stafford |
6 |
0.96 (0.35–2.11) |
McMichael et al., 1976 |
Male rubber workers in Ohio and Wisconsin |
|
|
Age 40–64 |
17 |
0.95 (0.55–1.52)a |
|
|
Age 65–84 |
40 |
1.08 (0.77–1.47)a |
|
Age 40–84 |
57 |
1.03 (0.78–1.33)a |
Case-Control Study |
|||
Kauppinen et al., 1995 |
Residents of Finland |
|
|
Solvents (all) |
20 |
1.22 (0.73–2.07) |
|
|
Solvents (high) |
14 |
2.01 (0.98–4.10) |
NOTE: U-TCA=urinary metabolite of trichloroethylene. a95% CI calculated by the committee with standard methods from the observed and expected numbers presented in the original study. |
HEPATOBILIARY CANCERS
Description of Case-Control Studies
Two population-based (Hardell et al., 1984; Heinemann et al., 2000) and two hospital-based (Hernberg et al., 1988; Stemhagen et al., 1983) case-control studies examined risk of liver cancer associated with occupational exposure to solvents (Table 6.12). Self-administered questionnaires or interviews were used to obtain occupational history information in each study. The study by Stemhagen and colleagues (1983) used job titles as surrogates of exposure. In two of the other studies, exposures were inferred by industrial hygienists (Heinemann et al., 2000; Hernberg et al., 1988). In the two hospital-based studies, there were no adjustments for potentially confounding variables.
Epidemiologic Studies of Exposure to Organic Solvents and Hepatobiliary Cancers
Anttila and colleagues (1995) found an increased risk (SIR=2.27, 95% CI=0.74–5.29) of liver cancer in the cohort of workers biologically monitored for a metabolite of trichloroethylene. Likewise, Hansen and colleagues (2001) reported an increased risk of cancer of the liver and biliary passages in men in a Danish cohort of biologically monitored workers (SIR=2.6, 95% CI=0.8–6.0).
In a large cohort study of aircraft-manufacturing workers in California, Boice and colleagues (1999) found no association between liver cancer and exposure to trichloroethylene (SMR=0.54, 95% CI=0.15–1.38). Another cohort of aircraft manufacturers (Morgan et al., 1998) showed no increased mortality in trichloroethylene-exposed workers, and there was no evidence of a trend in mortality with cumulative exposure.
In the cohort of workers at Hill Air Force Base in Utah, Blair and colleagues (1998) did not find excess risk of liver cancer mortality or incidence, nor was there any apparent increase with increasing cumulative exposure to trichloroethylene.
TABLE 6.12 Description of Case-Control Studies of Liver Cancer and Exposure to Organic Solvents
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Stemhagen et al., 1983 |
Cases identified through diagnosis in New Jersey hospitals in 1975–1980 or from death certificates in 1975–1979, all with histologic confirmation; controls selected from hospital records and death certificates and matched for age, race, sex, county of residence |
265 |
530 |
Laundering, cleaning, other garment service work |
In-person interview (direct or proxy) to assess occupational history (job titles) |
OR |
None |
Response rates: 89.5% of cases, 77% of controls |
|||||||
Hardell et al., 1984 |
Deceased male cases, age 25–80 years at diagnosis, reported to the Swedish Cancer Registry and diagnosed in 1974–1981, with histologic confirmation; controls selected from the National Population Register, matched on sex, age, year of death, municipality |
98 |
200 |
Organic solvents |
Mailed questionnaires to next of kin, assessing work history (job titles) and occupational or leisure-time exposure to specific chemicals (self-reports) |
Mantel-Haenszel rate ratio, Miettinen 95% CI |
Age |
Hernberg et al., 1988 |
Deceased cases, reported to the Finnish Cancer Register in 1976–1978 and 1981; controls selected from deceased stomach-cancer cases and coronary-infarction patients reported in 1977 |
344 |
476 stomach 385 coronary infarction |
Solvents |
Questionnaire mailed to next of kin to elicit list of occupations and employers; hygienist assigned exposure classification based on occupation |
Likelihood-based ORs |
None |
Response rates: 71.7% of cases, 72.8% of stomach-cancer controls, 69.0% of infarction controls |
|||||||
Heinemann et al., 2000 |
Female cases, under 65 years old, identified at 64 clinics in six European countries in 1990–1994 (prevalent cases) and 1994–1996 (incident cases); hospital controls selected from respective clinics and matched on age; population controls selected from citizen registers |
317 |
1,779 |
Dry-cleaning work Solvents |
In-person interview (direct or proxy) with questionnaire assessing occupational history (industry titles) and specific agent exposures (self-reports) |
Logistic regression |
Age, center, smoking, alcohol, oral contraceptive use, hepatitis infection |
Ritz (1999) found associations between exposure to trichloroethylene and liver cancer among male workers in the uranium-processing industry (SMR=1.66, 95% CI=0.71–3.26). The association is based on a small number of cases and may be confounded by other potential exposures involved in uranium processing. Axelson and colleagues (1994) also found an increased incidence in male Swedish workers exposed to trichloroethylene (SIR=1.41, 95% CI =0.38–3.60). A cohort study of transformer-assembly workers (Greenland et al., 1994) showed no positive associations between occupational exposure to trichloroethylene and cancers of the liver, gallbladder, and biliary tract combined (OR=0.54, 95% CI=0.11–2.63).
In the cohort of aircraft-manufacturing workers (Boice et al., 1999), an association between exposure to tetrachloroethylene and liver cancer was observed (SMR=2.05, 95% CI=0.83–4.23) but no increase was observed with increasing duration of exposure. Bond and colleagues (1990) found an association between mortality and liver cancer in a cohort of chemical workers (OR=1.8, 95% CI=0.8–4.3).
A cohort study of US dry cleaners showed no association to liver cancer (SMR=0.7, 95% CI=0.2–1.7) (Blair et al., 1990). Ruder and colleagues (2001) detected only one case of liver cancer among the subcohort of workers exposed to tetrachloroethylene and other solvents (SMR=0.16, 95% CI=0.00–1.32).
In a case-control study of women in the Multicentre International Liver Tumour Study, three women with hepatocellular cancer reported working as dry cleaners (OR=0.65; 95% CI=0.12–3.44) (Heinemann et al., 2000). Another study of occupational risk factors for liver cancer found an association among men employed in laundering, cleaning, and other garment services (RR=2.5, 95% CI=1.02–6.14) (Stemhagen et al., 1983). Further investigation by the authors showed that the cases were concentrated among people who processed clothes and potentially had exposure to other chemicals.
Friedlander and colleagues (1978) established a cohort of workers in one department at Kodak where methylene chloride was the primary solvent exposure for more than 30 years. In the most recent followup (Hearne and Pifer, 1999), one death from liver cancer was observed (SMR=0.42, 95% CI=0.01–2.36).
A cohort study of workers producing cellulose triacetate fibers at a Hoechst Celanese plant in South Carolina showed an excess risk of biliary and liver cancers (SMR=2.98, 95% CI =0.81–7.63) (Lanes et al., 1993). In another Hoechst Celanese facility manufacturing cellulose triacetate, Gibbs and colleagues (1996) found one death from liver cancer (SMR=0.81, 95% CI =0.02–4.49).
No cases of liver cancer were found in a cohort of male workers producing cellulose triacetate film base at a plant in the UK (Tomenson et al., 1997). A nested case-control study of liver and biliary tract cancer cases identified among male hourly employees of the Dow Chemical Company did not show an excess risk in workers exposed to methylene chloride (RR=0.8, 95% CI=0.2–3.6) (Bond et al., 1990).
Yin and colleagues (1996a,b) followed a cohort of factory workers with known exposure to benzene. Increased relative risks of cancers of the liver and gallbladder combined were reported for men (RR=1.3, 95% CI=0.9–1.9) but not for women (RR=0.4, 95% CI=0.2–1.3). This cohort was further examined by Hayes and colleagues (1996), who evaluated the relative risks according to cumulative exposure to benzene. There was some suggestion that the relative risks for liver and gallbladder cancer increased with increasing cumulative exposure, although chance could not be ruled out confidently (p value for linear trend=0.16).
A nested case-control study by Greenland and colleagues (1994) of transformer-assembly workers exposed to benzene showed a positive association between occupational exposure to benzene and cancers of the liver, gallbladder, and biliary tract combined (OR=2.76, 95% CI=0.68–11.2).
A cohort of toluene-exposed German rotogravure workers studied by Wiebelt and Becker (1999) experienced a higher risk of liver cancer mortality than the population of West Germany (SMR=1.98, 95% CI=0.34–7.16). Dosemeci and colleagues (1991) conducted a study of US industrial workers that showed no increase in liver cancer mortality among those occupationally exposed to phenol (SMR=1.0, 95% CI=0.4–1.9). The association with phenol did not increase markedly from low to medium to high exposure.
Three population-based case-control studies (Hardell et al., 1984; Heinemann et al., 2000; Hernberg et al., 1988) examined the association of liver cancer in relation to the broad category of solvents or mixed solvents. Heinemann and colleagues (2000) found no associations (OR=1.05, 95% CI=0.52–2.09). Hernberg and colleagues (1988) did not find increased risks among males (OR=0.6, 90% CI 0.3–1.3), but increased risks were found among women (OR=3.4, 90% CI 1.3–8.6). Hardell and colleagues (1984) also found an association (OR=1.8, 95% CI=0.99–3.4).
In the cohort studies, no associations were found in aircraft-manufacturing workers (SMR =0.92) (Boice et al., 1999), but the three cohort studies of painters all showed excess risks of liver cancer: Steenland and Palu (1999) found an SMR of 1.25 (95% CI=1.03–1.50), Matanoski and colleagues (1986) an SMR of 1.47 (95% CI=0.98–2.13), and Morgan (1981) an SMR of 1.93.
Summary and Conclusion
Although most studies examined the risk for liver cancer broadly, others combined liver cancer with gallbladder and biliary tract cancers. For exposure to trichloroethylene, tetrachloroethylene and dry-cleaning solvents, toluene, and phenol, most studies did not find an increased risk. Although one study on methylene chloride found a positive association, the small number of cases of liver cancer and the lack of corroborating studies were limitations of the literature. The studies on exposure to benzene were also limited with only three studies of benzene-exposed workers (two of which were on the same cohort), and only weak evidence of excess risks. For exposure to unspecified mixtures of organic solvents, although some of the estimates of risk were positive, others were not, and the role of confounding by other exposures or risk factors was a limitation. Table 6.13 identifies the key studies and the relevant data points reviewed by the committee in drawing its conclusion. Unless indicated in the table, the study populations include both men and women.
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 solvents under review and hepatobiliary cancers.
TABLE 6.13 Selected Epidemiologic Studies—Hepatobiliary Cancers and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Studies—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored Danish workers |
|
|
|
Males |
5 |
2.6 (0.8–6.0) |
|
Females |
0 |
— |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
|
|
Males: |
|
|
|
No exposure |
1 |
0.8 (0.1–12.0) |
|
<5 unit-years |
2 |
1.2 (0.1–13.8) |
|
5–25 unit-years |
1 |
1.0 (0.1–16.0) |
|
>25 unit-years |
3 |
2.6 (0.3–25.0) |
Anttila et al., 1995 |
Biologically monitored workers in Finland |
|
|
|
Entire period since first measurement: |
5 |
2.27 (0.74–5.29) |
|
0–9 years |
0 |
—(0.0–6.59) |
|
10–19 years |
2 |
1.74 (0.21–6.29) |
|
≥20 years |
3 |
6.07 (1.25–17.7) |
|
Mean personal U-TCA level |
|
|
|
<100 µmol/L |
2 |
1.64 (0.20–5.92) |
|
100+ µmol/L |
2 |
2.74 (0.33–9.88) |
Axelson et al., 1994 |
Biologically monitored Swedish workers |
4 |
1.41 (0.38–3.60) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
All exposed factory workers |
4 |
0.54 (0.15–1.38) |
|
Duration of potential exposure (routine or intermittent) |
|
|
|
<1 year |
4 |
0.53 (0.18–1.60) |
|
1–4 years |
3 |
0.52 (0.15–1.79) |
|
≥5 years |
6 |
0.94 (0.36–2.46) |
Ritz, 1999 |
White male US uranium-processing plant workers |
|
|
|
Trichloroethylene, cutting fluids, or kerosene |
8 |
1.66 (0.71–3.26) |
|
Trichloroethylene—light exposure |
|
|
|
>2 years, no latency |
3 |
0.93 (0.19–4.53) |
|
>2 years, 15-year latency |
3 |
1.16 (0.24–5.60) |
|
>5 years, no latency |
3 |
1.90 (0.35–10.3) |
|
>5 years, 15-year latency |
3 |
2.86 (0.48–17.3) |
|
Trichloroethylene—moderate exposure |
|
|
|
>2 years, no latency |
1 |
4.97 (0.48–51.1) |
|
>2 years, 15-year latency |
1 |
5.53 (0.54–56.9) |
|
>5 years, no latency |
1 |
8.82 (0.79–98.6) |
|
>5 years, 15-year latency |
1 |
12.1 (1.03–144) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
|
|
Males |
|
|
|
No exposure |
3 |
0.5 (0.1–2.4) |
|
<5 unit-years |
6 |
1.1 (0.3–4.1) |
|
5–25 unit-years |
3 |
0.9 (0.2–4.3) |
|
>25 unit-years |
3 |
0.7 (0.2–3.2) |
|
Females: |
|
|
|
No exposure |
3 |
4.2 (0.7–25.0) |
|
<5 unit-years |
1 |
1.6 (0.2–18.2) |
|
5–25 unit-years |
0 |
— |
|
>25 unit-years |
2 |
2.3 (0.3–16.7) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Morgan et al., 1998 |
Aerospace workers in Arizona |
|
|
|
Trichloroethylene-exposed subcohort: |
6 |
0.98 (0.36–2.13) |
|
Low cumulative exposure |
3 |
1.32 (0.27–3.85) |
|
High cumulative exposure |
3 |
0.78 (0.16–2.28) |
|
Peak and cumulative exposure:a |
|
|
|
Peak: medium and high vs low and no exposure |
3 |
0.98 (0.29–3.35) |
|
Cumulative (low) |
3 |
2.12 (0.59–7.66) |
|
Cumulative (high) |
3 |
1.19 (0.34–4.16) |
Greenland et al., 1994 |
White male transformer-assembly workers, ever exposed |
NA |
0.54 (0.11–2.63) |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Studies—Mortality |
|||
Ruder et al., 2001 |
US dry-cleaning workers in four labor unions |
1 |
0.16 (0.00–1.32) |
Boice et al., 1999 |
Aircraft- manufacturing workers |
|
|
|
All exposed factory workers |
7 |
2.05 (0.83–4.23) |
|
Duration of potential exposure (routine or intermittent) |
|
|
|
<1 year |
3 |
1.38 (0.40–4.69) |
|
1–4 years |
4 |
0.39 (0.39–3.47) |
|
≥5 years |
5 |
1.29 (0.46–3.65) |
Blair et al., 1990 |
Dry-cleaning union members in Missouri |
5 |
0.7 (0.2–1.7) |
Bond et al., 1990 |
Male chemical-company workers in Michigan, ever exposed |
6 |
1.8 (0.8–4.3) |
Case-Control Studies |
|||
Heinemann et al., 2000 |
Females in the Multicentre International Liver Tumour Study |
|
|
|
Dry-cleaning, ever employed |
3 |
0.65 (0.12–3.44) |
Stemhagen et al., 1983 |
Laundering, cleaning, other garment-services workers in New Jersey, employed >6 months |
10 |
2.50 (1.02–6.14) |
Methylene Chloride |
|||
Cohort Studies—Mortality |
|||
Hearne and Pifer, 1999 |
Male cellulose triacetate photographic-film base workers in Kodak Park, employed >1 year |
1 |
0.42 (0.01–2.36) |
Tomenson et al., 1997 |
Male cellulose triacetate-fiber film base workers in the UK |
|
|
|
Never exposed |
0 |
— |
|
All exposed |
0 |
— |
Gibbs et al., 1996 |
Male cellulose triacetate-fiber production workers in Maryland |
|
|
|
No exposure |
0 |
— |
|
Low exposure |
1 |
0.75 (0.029–4.20) |
|
High exposure |
1 |
0.81 (0.020–4.49) |
Lanes et al., 1993 |
Cellulose triacetate-fiber production workers in South Carolina, employed >3 months |
4 |
2.98 (0.81–7.63) |
Bond et al., 1990 |
Male chemical-company workers in Michigan, ever exposed |
2 |
0.8 (0.2–3.6) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Benzene |
|||
Cohort Studies—Mortality |
|||
Yin et al., 1996a |
Chinese factory workers, ever exposed |
|
|
|
Total cohort |
109 |
1.2 (0.8–1.6) |
|
Men |
101 |
1.3 (0.9–1.9) |
|
Women |
8 |
0.4 (0.2–1.3) |
Hayes et al., 1996 |
Chinese factory workers |
|
|
|
<10 ppm-years |
12 |
1.1 |
|
10–39 ppm-years |
12 |
0.8 |
|
40–99 ppm-years |
9 |
0.6 |
|
100–400 ppm-years |
44 |
1.6 |
|
400+ ppm-years |
28 |
1.2 |
|
|
|
p-trend=0.16 |
Greenland et al., 1994 |
White male transformer-assembly workers, ever exposed |
NA |
2.76 (0.68–11.2) |
Other Specific Organic Solvents |
|||
Cohort Studies—Mortality |
|||
Wiebelt and Becker, 1999 |
Male German rotogravure printing-plant workers, employed >1 year—toluene |
3 |
1.98 (0.34–7.16) |
Dosemeci et al., 1991 |
US white male industrial workers—phenol |
|
|
|
Any exposure |
8 |
1.0 (0.4–1.9) |
|
Level of cumulative exposure: |
|
|
|
None |
4 |
1.2 |
|
Low exposure |
1 |
0.3 |
|
Medium exposure |
6 |
1.6 |
|
High exposure |
1 |
1.4 |
Unspecified Mixtures of Organic Solvents |
|||
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers |
|
|
|
All exposed factory workers |
17 |
0.92 (0.54–1.47) |
|
Duration of potential exposure (routine or intermittent) |
|
|
|
<1 year |
10 |
1.35 (0.63–2.87) |
|
1–4 years |
14 |
0.75 (0.38–1.47) |
|
≥5 years |
31 |
0.97 (0.54–1.72) |
Steenland and Palu, 1999 |
Members of US painters’ unions |
|
|
|
Total cohort |
119 |
1.25 (1.03–1.50) |
|
20 years since first union membership |
90 |
1.17 (0.95–1.44) |
Greenland et al., 1994 |
White male transformer-assembly workers, ever exposed to solvents |
NA |
0.69 (0.18–2.60) |
Matanoski et al., 1986 |
US painters and allied tradesmen |
28 |
1.47 (0.98–2.13) |
Morgan et al., 1981 |
Male US paint or varnish manufacturing workers, employed >1 year |
6 |
1.93 |
Case-Control Studies |
|||
Heinemann et al., 2000 |
Women in Multicentre International Liver Tumor Study, ever exposed to solvents |
18 |
1.05 (0.52–2.09) |
Hernberg et al., 1988 |
Finnish cases and deceased controls |
|
|
|
Solvent exposure, 10-year latency |
|
|
|
Males |
7 |
0.6 (0.3–1.3)b |
|
Females |
7 |
3.4 (1.3–8.6)b |
LUNG CANCER
Description of Case-Control Studies
Three population-based case-control studies (Table 6.14) reported the risk of lung cancer associated with job title and self-reported exposure to specific chemicals (Brownson et al., 1993; Pohlabeln et al., 2000) or to tetrachloroethylene in drinking water (Paulu et al., 1999). Smoking is a known risk factor for lung cancer and was accounted for in each of the studies (see Chapter 2 and Appendix E for more information on smoking).
Epidemiologic Studies of Exposure to Organic Solvents and Lung Cancer
No association was found between incidence of lung cancer and concentrations of the biologic marker of exposure to trichloroethylene (SIR=0.92, 95% CI=0.59–1.35) (Anttila et al., 1995). A cohort of aircraft-manufacturing workers with potential exposure to trichloroethylene was followed for nearly 30 years, but no association between lung cancer and trichloroethylene was reported (SMR=0.76, 95% CI=0.60–0.95) (Boice et al., 1999). The authors noted that most workers were exposed to a variety of substances routinely or intermittently. A mortality study of civilian aircraft-maintenance workers at Hill Air Force Base in Utah that included an extensive assessment of exposure to trichloroethylene did not show an increase in lung cancer mortality or incidence in men (over 25 unit-years: SMR=1.1, 95% CI=0.7–1.8) or women (over 25 unit-years: SMR=0.4, 95% CI=0.1–1.8) (Blair et al., 1998). The cohort study of aircraft manufacturers in Arizona (Morgan et al., 1998) did not show increased mortality from lung cancer in the trichloroethylene-exposed subcohort (SMR=1.10, 95% CI=0.89–1.34).
In addition to those studies, no associations were found for rubber-industry workers exposed to trichloroethylene (OR=0.64) (Wilcosky et al., 1984) or to transformer-assembly workers (OR=1.01, 95% CI=0.69–1.47) (Greenland et al., 1994).
A cohort study of dry-cleaning workers exposed to tetrachloroethylene and other solvents showed increased mortality from lung cancer (SMR=1.46, 95% CI=1.07–1.95) (Ruder et al., 2001). In the subcohort of workers exposed only to tetrachloroethylene, the relative risks were not as great (SMR=1.17, 95% CI=0.71–1.83). Blair and colleagues (1990) reported a comparable relative risk of lung cancer in another cohort of dry cleaners (SMR=1.3, 95% CI=0.9–1.7).
TABLE 6.14 Description of Case-Control Studies of Lung Cancer and Exposure to Organic Solvents
An increased risk of lung cancer was found in workers exposed to tetrachloroethylene (SIR=1.92, 95% CI=0.62–4.48) (Anttila et al., 1995). Among the cohort of aircraft manufacturers, no association was found between exposure to tetrachloroethylene and lung cancer (SMR=1.08, 95% CI=0.79–1.44) (Boice et al., 1999). The authors indicated that concentrations of tetrachloroethylene in the air samples were relatively low and that exposures were well below permissible concentrations. Wilcosky and colleagues (1984), in a study of rubber-industry workers, reported no increased risk of lung cancer with exposure to tetrachloroethylene.
The risk of developing lung cancer in relation to exposure to tetrachloroethylene was evaluated in the two case-control studies, and these were adjusted for smoking. A risk associated with self-reported exposure to tetrachloroethylene was found among lifetime nonsmokers (OR=2.1, 95% CI=1.2–3.7) (Brownson et al., 1993). A case-control study of residents of upper Cape Cod (Paulu et al., 1999) showed excess risks of lung cancer with increasing level of estimated exposure to tetrachloroethylene in drinking water. A third case-control study of female, nonsmoking laundry and dry cleaners also found an increased risk of lung cancer (OR=1.83, 95% CI=0.98–3.40) (Pohlabeln et al., 2000).
Several cohort studies of workers exposed to methylene chloride provided little support for an association between exposure and lung cancer (Gibbs et al., 1996; Hearne and Pifer, 1999; Hearne and Friedlander, 1981; Hearne et al., 1987, 1990; Lanes et al., 1990, 1993; Tomenson et al., 1997). Those large cohort studies followed methylene chloride-exposed workers for many years, some with repeated followup, and examined the association between exposure and cancer mortality, but they reveal no excess of lung cancer associated with exposure.
Yin and colleagues (1996a,b) reported increased relative risks of cancers of the trachea, bronchi, and lung combined in benzene-exposed males (RR=1.5, 95% CI=1.0–2.2) and in the entire cohort of exposed men and women (RR=1.4, 95% CI=1.0–2.0); no association was found in benzene-exposed women (RR=1.0, 95% CI=0.4–2.9). Hayes and colleagues (1996) assessed the cumulative exposure to benzene in the overall cohort and found that the relative risks of tracheal, bronchial, and lung cancers combined increased with increasing exposure (p trend=0.01).
Two nested case-control studies, one of transformer-assembly workers (Greenland et al., 1994) and another of rubber-industry workers (Wilcosky et al., 1984), did not show any associations between occupational exposure to benzene and lung cancer. No data were presented on increasing levels of exposure.
Three studies provided evidence on the association between toluene and lung cancer. A cohort of toluene-exposed German rotogravure workers showed increased lung cancer mortality when compared with the mortality in West Germany (SMR=1.23, 95% CI=0.81–1.92) (Wiebelt and Becker, 1999). Job-specific subcohorts with different levels of exposure to toluene demonstrated a range of lung cancer risk, from no risk in printing-cylinder preparation occupations to an SMR of 1.77 (95% CI=0.77–4.39) in finishing workers who had the lowest level of exposure over the entire observation period.
A Swedish cohort of rotogravure printers showed similar increases in respiratory tract cancer mortality from exposure to toluene (SMR=1.76, 95% CI=1.03–2.91) (Svensson et al., 1990); however, no gradient was found with duration of exposure.
Factory workers who were considered to have high exposure in a plant manufacturing chlorinated toluenes (benzyl chloride, benzal chloride, benzotrichloride, and benzoyl chloride) experienced increased lung cancer mortality (SMR=3.31, 95% CI=1.59–6.09) (Sorahan and
Cathcart, 1989), and there was evidence that risk increased with increasing exposure. In a nested case-control study of 26 cases of lung cancer from the cohort of chlorinated toluene production workers, RR of lung cancer associated with benzotrichloride and “other chlorinated toluenes” was 1.36 (95% CI=0.43–24) and 1.12 (95% CI=0.30–4.22), respectively, per 10 years of exposed employment. In a study of rubber workers, Wilcosky and colleagues (1984) did not find an association (OR=0.55).
There were three studies of the association between exposure to phenol and lung cancer. A cohort study with many exposed cases showed no association (Dosemeci et al., 1991), and no association was reported for workers in the rubber industry (Wilcosky et al., 1984). Kauppinen and colleagues (1993) reported a four-fold excess risk (SMR=4.04, 95% CI=1.83–8.89) after adjusting for smoking among those exposed for at least 1 month.
Several other solvents used in the Gulf War—including naphtha, ethanol, xylenes, isopropanol, ethyl acetate, and acetone (Wilcosky et al., 1984)—were investigated in relation to lung cancer, and no associations with these solvents were found. Anttila and colleagues (1995) found an increase in lung and bronchial cancer risk with exposure to 1,1,1-trichloroethane (SIR=1.31, 95% CI=0.16–4.71).
Several studies, including some described previously, examined the association of lung cancer with unspecified mixtures of solvents. Most studies did not identify “solvents” or “organic solvents” as the exposure being evaluated but instead defined exposure by various occupational titles or groups, such as painters (Engholm and Englund, 1982; Englund 1980; Matanoski et al., 1986; Morgan et al., 1981; Steenland and Palu, 1999; Stockwell and Matanoski, 1985), printers (Malker and Gemne, 1987), workers in transformer assembly (Greenland et al., 1994), ethanol and isopropanol production (Teta et al., 1992), isopropanol and methyl ethyl ketone production (Alderson and Rattan, 1980), shoe manufacturing (Walker et al., 1993), chemical manufacturing (Waxweiler et al., 1981), aircraft manufacturing (Boice et al., 1999), or metal-component manufacturing (Acquavella et al., 1993). As shown in Table 6.15, many of the studies showed positive associations between occupational exposure and lung cancer.
Generally, workers in the studies were exposed to solvents and other chemical agents not reviewed by this committee. More important, although smoking is associated with lung cancer, no adjustments for it were made in most cohort studies. (That is not unusual; obtaining smoking histories, especially in mortality studies, is difficult.) Furthermore, one study that specifically examined lung cancer risk among nonsmokers in the printing industry found no association with occupational exposure (Brownson et al., 1993). Unlike farm workers, who have some of the lowest smoking rates in the United States, painters, truck drivers, construction workers, carpenters, and auto mechanics have some of the highest rates. For example, in a National Center for Health Statistics survey of men 20–64 years old in 1978–1980, 55.1% of painters surveyed reported that they smoked (US Surgeon General, 1985).
To understand the impact of smoking on risk of lung cancer, the committee examined the risk estimates for bladder cancer and cardiovascular disease—diseases for which smoking is also a known risk factor. Almost all the studies reported rates of bladder cancer and cardiovascular disease similar to those of lung cancer. Almost all the studies also stated that asbestos was present in the workplace and probably contributed to the slightly increased observed risks of lung cancer. As a result, the committee determined that exposure to solvents alone was an unlikely explanation for the increased risks of lung cancer and that confounding by smoking was possibly biasing the results.
Summary and Conclusion
Although there are different types of respiratory cancers, most studies assessed exposure in relation to lung cancer. Exposures were typically defined by occupations in which the solvents were known to be present; and confounding factors, especially smoking, were not consistently controlled for in the analyses. In reviewing the literature, the committee found that there was no evidence from any of the studies of a positive association between exposure to trichloroethylene, methylene chloride, benzene, phenol, and other specific solvents and risk of lung cancer.
For exposure to tetrachloroethylene and dry-cleaning solvents, some committee members believed that the overall evidence was limited by the possibility of confounding, and that most findings were based on small numbers of cases exposed by different routes. The cohort studies did not control for other occupational exposures or smoking, an important potential confounder for lung cancer. However, other committee members believed that the consistently positive findings and evidence of a dose-response relationship in the case-control study by Paulu and colleagues were supportive of a conclusion of limited/suggestive evidence. Both case-control studies adjusted for smoking and still found relatively high relative risks of lung cancer. As a result, the committee decided not to state a formal consensus conclusion. Additional studies that control for smoking and address other concerns related to misclassification of exposure are needed before a more definitive conclusion as to exposure to tetrachloroethylene and dry-cleaning solvents and the risk of lung cancer can be reached.
Although several cohort studies reported increased risk of lung cancer associated with exposure to toluene, estimates were weak. Workers were probably exposed to other compounds that were not controlled for in the analyses. In addition, information on smoking was not available. A unique relationship between solvent exposure and lung cancer was not found, and the committee concluded that the evidence was inadequate/insufficient to support an association between exposure to unspecified mixtures of organic solvents and lung cancer.
Several studies on specific organic solvents and solvent mixtures found positive associations between exposure and the risk of lung cancer. However, most studies on specific solvents were too small and inconsistent in their findings to support conclusions. Some studies showed positive associations, but they were limited by lack of information on smoking habits among cohort members.
With respect to exposure to solvent mixtures, many studies reported positive findings; most, however, were based on occupational titles or industries and lacked specific analyses of “solvents” or “organic solvents.” Although their results suggested a possible relationship, the lack of smoking data, the lack of exposure specificity, and the potential for confounding by other occupational exposures (such as to asbestos) limited their utility. Future research with sufficient power would help to clarify whether an association between exposure to solvent mixtures or the interactions of various solvents and lung cancer exists, as is indicated in some of the studies reviewed by the committee. Table 6.15 identifies the key studies and the relevant data points evaluated by the committee in drawing its conclusion. Unless indicated in the tables, the study populations include both men and women.
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 solvents under review, other than tetrachloroethylene and dry-cleaning solvents, and lung cancer.
TABLE 6.15 Selected Epidemiologic Studies—Lung Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
|
Trichloroethylene |
||||
Cohort Studies—Incidence |
||||
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
||
|
Males |
|
||
|
No exposure |
22 |
1.0 (0.5–1.9) |
|
|
<5 unit-years |
24 |
1.0 (0.6–2.0) |
|
|
5–25 unit-years |
11 |
0.8 (0.4–1.6) |
|
|
>25 unit-years |
15 |
0.8 (0.4–1.7) |
|
|
Females |
|
||
|
No exposure |
0 |
— |
|
|
<5 unit-years |
1 |
0.6 (0.1–5.3) |
|
|
5–25 unit-years |
0 |
— |
|
|
>25 unit-years |
0 |
— |
|
Anttila et al., 1995 |
Biologically monitored workers in Finland |
|
||
|
Entire period since first measurement |
25 |
0.92 (0.59–1.35) |
|
|
0–9 years |
11 |
1.19 (0.59–2.13) |
|
|
10–19 years |
9 |
0.67 (0.30–1.26) |
|
|
≥20 years |
5 |
1.11 (0.36–2.58) |
|
|
Mean personal U-TCA level |
|
||
|
<100 µmol/L |
16 |
1.02 (0.58–1.66) |
|
|
100+ µmol/L |
7 |
0.83 (0.33–1.71) |
|
Cohort Studies—Mortality |
||||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
||
|
All exposed factory workers |
78 |
0.76 (0.60–0.95) |
|
|
Duration of potential exposure (routine or intermittent) |
|
||
|
<1 year |
66 |
0.85 (0.65–1.13) |
|
|
1–4 years |
63 |
0.98 (0.74–1.30) |
|
|
≥5 years |
44 |
0.64 (0.46–0.89) |
|
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
||
|
Males |
|
||
|
No exposure |
51 |
1.0 (0.7–1.6) |
|
|
<5 unit-years |
43 |
1.0 (0.6–1.6) |
|
|
5–25 unit-years |
23 |
0.9 (0.5–1.6) |
|
|
>25 unit-years |
38 |
1.1 (0.7–1.8) |
|
|
Females |
|
||
|
No exposure |
2 |
0.4 (0.1–1.6) |
|
|
<5 unit-years |
2 |
0.6 (0.1–2.4) |
|
|
5–25 unit-years |
11 |
0.6 (0.1–4.7) |
|
|
>25 unit-years |
2 |
0.4 (0.1–1.8) |
|
Morgan et al., 1998 |
Aerospace workers in Arizona |
|
||
|
Entire trichloroethylene-exposed cohort |
97 |
1.10 (0.89–1.34) |
|
|
Cumulative |
|
||
|
Low |
45 |
1.49 (1.09–1.99) |
|
|
High |
52 |
0.90 (0.67–1.20) |
|
|
Peak: medium and high vs low and no exposure |
64 |
1.07 (0.82–1.40) |
|
Greenland et al., 1994 |
White male transformer-assembly workers, ever exposed |
NA |
1.01 (0.69–1.47) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Wilcosky et al., 1984 |
Rubber-industry workers in Ohio |
|
|
|
Cumulative exposure of more than 1 year |
|
|
|
White males |
11 |
0.64 |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Studies—Mortality |
|||
Ruder et al., 2001 |
US dry-cleaning workers in four labor unions |
|
|
|
Males, nonwhite |
25 |
1.52 (1.05–2.39) |
|
Females, nonwhite |
16 |
1.88 (1.07–3.05) |
|
Exposed to tetrachloroethylene only |
19 |
1.17 (0.71–1.83) |
|
Exposed to tetrachloroethylene and other dry-cleaning solvents |
46 |
1.46 (1.07–1.95) |
Boice et al., 1999 |
Aircraft manufacturing workers in California |
|
|
|
All exposed factory workers |
46 |
1.08 (0.79–1.44) |
|
Duration of potential exposure (routine or intermittent) |
|
|
|
<1 year |
33 |
1.15 (0.80–1.66) |
|
1–4 years |
51 |
1.09 (0.80–1.48) |
|
≥5 years |
36 |
0.71 (0.49–1.02) |
Anttila et al., 1995 |
Biologically monitored workers in Finland |
5 |
1.92 (0.62–4.48) |
Blair et al., 1990 |
Dry-cleaning union members in Missouri |
47 |
1.3 (0.9–1.7) |
Wilcosky et al., 1984 |
Rubber-industry workers in Ohio |
|
|
|
Cumulative exposure of more than 1 year |
|
|
|
White males |
2 |
0.26 |
Case-Control Studies |
|||
Pohlabeln et al., 2000 |
Occupational exposure among nonsmoking females in Europe |
|
|
|
Laundry and dry cleaners for at least 6 months |
19 |
1.83 (0.98–3.40) |
Paulu et al., 1999 |
Residents in upper Cape Cod |
|
|
|
>75th percentile tetrachloroethylene-water exposure |
|
|
|
0-year latent period |
11 |
1.8 (0.8–3.9) |
|
5-year latent period |
6 |
1.7 (0.6–4.5) |
|
7-year latent period |
5 |
1.6 (0.5–4.4) |
|
9-year latent period |
4 |
1.8 (0.5–6.0) |
|
>90th percentile tetrachloroethylene-water exposure |
|
|
|
0-year latent period |
5 |
3.7 (1.0–11.7) |
|
5-year latent period |
3 |
3.3 (0.6–13.4) |
|
7-year latent period |
3 |
6.2 (1.1–31.6) |
|
9-year latent period |
3 |
19.3 (2.5–141.7) |
Brownson et al., 1993 |
Occupational exposure among females in Missouri—Dry-cleaning |
|
|
|
Lifetime nonsmokers |
23 |
2.1 (1.2–3.7) |
|
Exposure range |
|
|
|
Low: ≤1.125 years |
NA |
0.6 (0.2–1.7) |
|
High: ≥1.125 years |
NA |
2.9 (1.5–5.4) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Methylene Chloride |
|||
Cohort Studies—Mortality |
|||
Hearne et al., 1999 |
Male cellulose triacetate photographic-film base workers in Kodak Park, employed >1 year |
|
|
|
Methylene chloride cohort |
27 |
0.75 (0.49–1.09) |
|
Roll-coating cohort |
|
|
|
New York state external control |
28 |
0.82 (0.55–1.19) |
|
Kodak Rochester external control |
28 |
0.89 (0.59–1.29) |
Tomensen et al., 1997 |
Male cellulose triacetate-fiber production workers in the UK, ever employed |
|
|
|
Never exposed |
1 |
0.16 (0–0.88) |
|
All exposed |
19 |
0.48 (0.29–0.75) |
|
Cumulative exposure (nonsmokers) |
|
|
|
<400 ppm-years |
6 |
0.32 |
|
400–799 ppm-years |
2 |
0.51 |
|
≥800 ppm-years |
1 |
0.37 |
|
Unassigned exposure |
10 |
0.68 |
Gibbs et al., 1996 |
Cellulose triacetate-fiber production workers in Maryland |
|
|
|
Males |
|
|
|
No exposure |
6 |
0.59 (0.22–1.29) |
|
Low exposure |
20 |
0.78 (0.48–1.20) |
|
High exposure |
15 |
0.55 (0.31–0.91) |
|
Females |
|
|
|
No exposure |
0 |
NA (0.0–4.92) |
|
Low exposure |
9 |
1.09 (0.50–2.07) |
|
High exposure |
2 |
2.29 (0.28–8.29) |
Lanes et al., 1993 |
Cellulose triacetate-fiber production workers in South Carolina (cohort), employed >3 months |
13 |
0.80 (0.43–1.37) |
Benzene |
|||
Cohort Studies—Mortality |
|||
Yin et al., 1996a |
Chinese factory workers, ever exposed |
|
|
|
Total cohort |
125 |
1.4 (1.0–2.0) |
|
Males |
109 |
1.5 (1.0–2.2) |
|
Females |
16 |
1.0 (0.4–2.9) |
Hayes et al., 1996 |
Chinese factory workers |
|
|
|
Cumulative exposure |
|
|
|
No exposure |
41 |
1.0 |
|
<10 ppm-years |
10 |
1.2 |
|
10–39 ppm-years |
13 |
1.0 |
|
40–99 ppm-years |
19 |
1.4 |
|
100–400 ppm-years |
38 |
1.4 |
|
400+ ppm-years |
41 |
1.7 |
|
|
|
p-trend=0.01 |
Greenland et al., 1994 |
White male transformer-assembly workers, ever exposed |
NA |
0.58 (0.31–1.07) |
Wilcosky et al., 1984 |
Rubber-industry workers in Ohio |
|
|
|
Cumulative exposure of more than 1 year |
|
|
|
White males |
23 |
0.69 |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Toluene |
|||
Cohort Studies—Mortality |
|||
Wiebelt and Becker, 1999 |
Male German rotogravure printing-plant workers, employed >1 year |
|
|
|
Total cohort |
44 |
1.23 (0.81–1.92) |
|
Printing-cylinder preparation workers |
7 |
0.83 (0.20–2.77) |
|
Printing/proof printing workers |
25 |
1.30 (0.72–2.49) |
|
Finishing workers |
13 |
1.77 (0.77–4.39) |
Svensson et al., 1990 |
Male rotogravure printing-plant workers in Sweden |
|
|
|
Total cohort |
16 |
1.76 (1.03–2.91) |
|
≥5 year exposure, >10 year latency |
9 |
1.26 (0.57–2.38) |
Sorahan and Cathcart, 1989 |
Male chemical-factory workers |
|
|
|
Low exposure to chlorinated toluenes |
16 |
1.39 (0.80–2.27)a |
|
High exposure to chlorinated toluenes |
10 |
3.31 (1.59–6.09)a |
|
Benzotrichloride |
NA |
1.36 (0.43–4.24) |
|
Other chlorinated toluenes |
NA |
1.12 (0.30–4.22) |
Wilcosky et al., 1984 |
White, male rubber-industry workers in Ohio |
|
|
|
Cumulative exposure for more than 1 year |
3 |
0.55 |
Phenol |
|||
Cohort Studies—Mortality |
|||
Kauppinen et al., 1993 |
Finnish woodworkers |
|
|
|
Any exposure (>1 month) |
5 |
4.04 (1.83–8.89) |
|
Duration >5 years |
6 |
3.08 (0.70–13.6) |
Dosemeci et al., 1991 |
US white male industrial workers |
|
|
|
Any exposure |
146 |
1.1 (0.9–1.3) |
|
Level of cumulative exposure |
|
|
|
None |
70 |
1.2 |
|
Low exposure |
68 |
1.2 |
|
Medium exposure |
60 |
1.1 |
|
High exposure |
18 |
1.4 |
Wilcosky et al., 1984 |
White male rubber-industry workers in Ohio |
|
|
|
Cumulative exposure for more than 1 year |
|
|
|
White males |
13 |
0.95 |
|
Black males |
2 |
0.91 |
Other Organic Solvents |
|||
Cohort Studies—Mortality |
|||
Anttila et al., 1995 |
Biologically monitored workers in Finland |
|
|
|
1,1,1-trichloroethane ever measured in urine |
2 |
1.31 (0.16–4.71) |
Wilcosky et al., 1984 |
Rubber-industry workers in Ohio |
|
|
|
Cumulative exposure for more than 1 year |
|
|
|
Specialty naphthas (white males) |
43 |
0.70 |
|
Specialty naphthas (black males) |
2 |
0.39 |
|
Ethanol (white males) |
21 |
1.0 |
|
Xylenes (white males) |
10 |
0.61 |
|
Ethyl acetate (white males) |
6 |
0.84 |
|
Acetone (white males) |
5 |
0.86 |
|
Isopropanol (white males) |
27 |
0.64 |
|
Isopropanol (black males) |
2 |
0.56 |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Unspecified Mixtures of Organic Solvents |
|||
Cohort Studies—Incidence |
|||
Malker and Gemne, 1987 |
Swedish printing-industry workers, employed in 1960 |
|
|
|
Males |
190 |
1.5 (1.2–1.7)b |
|
Females |
9 |
1.3 |
Engholm and England, 1982 |
Male members of the Swedish Painters Union |
|
|
|
Years since entry into the union |
|
|
|
≥0 |
81 |
1.28 (p<0.05) |
|
≥5 |
75 |
1.24 (p<0.05) |
|
≥10 |
74 |
1.31 (p<0.05) |
|
≥15 |
66 |
1.28 (p<0.05) |
|
≥20 |
58 |
1.26 (p<0.05) |
|
≥25 |
51 |
1.32 (p<0.05) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
Potential routine exposure to mixed solvents |
221 |
0.88 (0.77–1.01) |
Steenland and Palu, 1999 |
Members of US painters unions |
|
|
|
Total cohort |
1746 |
1.23 (1.17–1.29) |
|
20 years since first union membership |
1360 |
1.24 (1.18–1.31) |
Greenland et al., 1994 |
White male transformer-assembly workers, ever exposed |
NA |
1.57 (1.08–2.27) |
Acquavella et al., 1993 |
Metal-components manufacturing workers |
|
|
|
Solvents, ever exposed |
4 |
1.9 (0.5–4.9) |
Walker et al., 1993 |
Shoe-manufacturing workers in Ohio, employed >1 month |
|
|
|
Total cohort |
99 |
1.47 (1.20–1.80) |
|
Males |
68 |
1.56 (1.22–1.99) |
|
Females |
31 |
1.30 (0.89–1.86) |
Teta et al., 1992 |
Male ethanol and isopropanol production workers |
|
|
|
South Charleston SC plant |
|
|
|
All workers, ever employed |
14 |
0.87 (0.5–1.5) |
|
Workers in exposed unit ≥10 years |
2 |
0.56 |
|
Texas City, TX plant |
|
|
|
All workers, ever employed |
8 |
1.10 (0.5–2.2) |
|
Workers in exposed unit ≥10 years |
1 |
NA |
Matanoski et al., 1986 |
US painters and allied tradesmen |
|
|
|
Total cohort |
448 |
1.06 (0.96–1.16) |
Stockwell and Matanoski, 1985 |
Male construction and maintenance painters in New York |
|
|
Usual occupation of painter |
51 |
2.75 (1.45–5.21) |
|
Engholm and England, 1982 |
Male members of the Swedish Painters Union |
|
|
|
Years since entry into the union: |
|
|
|
≥0 |
124 |
1.27 (p<0.05) |
|
≥5 |
118 |
1.25 (p<0.05) |
|
≥10 |
114 |
1.28 (p<0.05) |
|
≥15 |
103 |
1.27 (p<0.05) |
|
≥20 |
92 |
1.26 (p<0.05) |
|
≥25 |
80 |
1.27 (p<0.05) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Morgan et al., 1981 |
Male US paint or varnish manufacturing workers |
|
|
|
Solvents excluding lacquer, 1+ years of exposure |
51 |
1.14 |
Waxweiler et al., 1981 |
Male synthetic-chemical plant workers, ever employed |
42 |
1.49 (1.08–2.03)a |
Alderson and Rattan, 1980 |
Male workers at dewaxing plants in the UK, employed >1 year |
|
|
|
Workers in isopropanol alcohol plant |
2 |
0.78 (0.09–2.81)a |
|
Workers in methyl ethyl ketone plant |
1 |
0.17 (0.00–0.93)a |
Englund, 1980 |
Male Swedish painters, ever certified or union member |
124 |
1.27 (1.06–1.52)a |
Case-Control Study |
|||
Brownson et al., 1993 |
Occupational exposure among females in Missouri—Printing industry |
|
|
|
Lifetime nonsmokers |
6 |
0.8 (0.3–2.0) |
|
Exposure range |
|
|
|
Low: ≤8 years |
NA |
0.6 (0.2–2.2) |
|
High: >8 years |
NA |
1.3 (0.5–3.7) |
NOTE: NA=not available; U-TCA=urinary metabolite of trichloroethylene. a95% CI calculated by the committee with standard methods from the observed and expected numbers presented in the original study. b99% confidence limits. |
BONE CANCER
Epidemiologic Studies of Exposure to Organic Solvents and Bone Cancer
Blair and colleagues (1998) extended the followup of a cohort of aircraft-manufacturing workers (Spirtas et al., 1991) that used a detailed exposure-assessment method. An increased bone cancer risk was reported after adjustment for age, calendar time, and sex (RR=2.1, 95% CI =0.2–18.8) in workers exposed to trichloroethylene.
One study assessed whether an association existed between exposure to benzene and bone cancer. To evaluate the specific relationship between exposure to benzene and cancer risk, Wong (1987a) examined mortality among workers employed in seven chemical-manufacturing plants. An increased relative risk of bone cancer was found in the exposed group of workers (SMR=3.17, 95% CI=0.38–11.46). Wong (1987b) also estimated exposure to benzene in terms of 8-hour TWAs and peak levels of exposure and found that the relative risk of bone cancer increased with duration of exposure (SMR=6.63; one exposed case). Those results were inconclusive for an association because of the very small number of exposed cases, which resulted in highly variable risk estimates.
Fu and colleagues (1996) examined two historical cohorts of shoe workers in England and Florence, Italy, and used job titles to assess cancer mortality in relation to exposure to leather dusts and solvents. A slight increase in bone cancer was observed in the English cohort among those with probable solvent exposure (SMR=1.12, 95% CI=0.03–6.26), and no cases of bone cancer were reported in the Florence cohort. The committee reviewed the study by Nielsen and colleagues (1996) in which the risk of bone cancer in a cohort of lithographers was examined. Only one exposed case was observed (SIR=11.4, 95% CI=0.6–56.0).
Summary and Conclusion
The relationship between exposure to organic solvents and bone cancer was reported in only four cohort studies, representing three different solvent exposures. Each study had low power, and exposure assessment relied primarily on job titles as surrogates of exposure. No case-control studies of bone cancer were identified. Studies with larger numbers of exposed cases (increased power) and more precise exposure assessment are needed for the committee to evaluate the relationship between solvent exposures and risk of bone cancer. Table 6.16 identifies the key studies and relevant data points reviewed by the committee in drawing its conclusion. Unless indicated in the table, the study populations include both men and women.
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 solvents under review and bone cancer.
TABLE 6.16 Selected Epidemiologic Studies—Bone Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Study—Mortality |
|||
Blair et al., 1998 |
Aircraft maintenance workers in Utah, employed in exposed area >1 year |
5 |
2.1 (0.2–18.8) |
Benzene |
|||
Cohort Study—Mortality |
|||
Wong, 1987a,b |
Male Chemical Manufacturers Association workers |
|
|
|
Continuous exposure |
2 |
3.17 (0.38–11.46) |
|
Duration of exposure |
|
|
|
<5 years |
1 |
2.63 |
|
5–14 years |
1 |
6.63 |
|
≥15 years |
0 |
— |
Unspecified Mixtures of Organic Solvents |
|||
Cohort Study—Incidence |
|||
Nielsen et al., 1996 |
Danish lithographers, ever employed |
1 |
11.4 (0.6–56.0) |
Cohort Study—Mortality |
|||
Fu et al., 1996 |
Shoe-manufacturing workers |
|
|
|
English cohort, employed in 1939 |
6 |
2.08 (0.76–4.52) |
|
Probable solvent based on work area |
1 |
1.12 (0.03–6.26) |
|
Florence cohort, ever employed |
0 |
0 (0.0–3.45) |
SOFT TISSUE SARCOMA
Because of the lack of available studies on the relationship between exposure to organic solvents and soft tissue sarcomas (STS), a conclusion regarding association could not be drawn. Only one study (Serraino et al., 1992) identified by the committee analyzed the relationship between relevant exposures reviewed in this report (“benzene/solvents” and “dyes/paints”) and STS. Although the population-based case-control study observed an increased risk of STS among men exposed to “benzene/solvents” for more than 10 years (OR=2.2, 95% CI=0.9–5.5), the study was limited by the use of self-reported exposures. Additional studies are needed to support the relationship before a conclusion regarding association can be drawn.
SKIN CANCER
Description of Case-Control Studies
Table 6.17 identifies the study characteristics of two papers from the Montreal multisite cancer case-control study on the association between exposure to specific organic solvents and solvent mixtures and the risk of melanoma. The study was designed so that in-person interviews were used mostly, and telephone interviews or self-administered questionnaires were limited to next of kin or hard-to-interview subjects. The interviews included a job-specific module to obtain detailed information on each job that a subject held in the entire working history, such as dates of employment, the employer’s activities and products, job tasks, and work environment. Using the job-history information, a team of industrial hygienists and chemists estimated exposures to about 300 of the most common occupational agents. The study population was used for exposure-specific and cancer-specific studies. Fritschi and Siemiatycki (1996a) evaluated the relationship between melanoma and exposure to 85 chemical substances, 13 occupations, and 20 industries. The same set of cases was studied by Gérin and colleagues (1998) in relation to occupational exposure to the hydrocarbons benzene, toluene, xylene, and styrene.
Epidemiologic Studies of Exposure to Organic Solvents
No increase in melanoma mortality was found among two cohorts of aircraft-maintenance workers (Blair et al., 1998; Boice et al., 1999), a cohort of workers monitored for a metabolite of trichloroethylene (Hansen et al., 2001), or a cohort of uranium-processing workers (Ritz, 1999). An increased risk of melanoma (for “any exposure,” OR=3.6, 95% CI=1.5–9.1) was found in a case-control study in Montreal (Fritschi and Siemiatycki, 1996a). Two studies of workers monitored for exposure to trichloroethylene found mixed results for nonmelanoma skin cancers (Axelson et al., 1994; Hansen et al., 2001). The studies were based on small numbers of exposed cases and did not control for exposure to sunlight, an important confounding variable.
Two studies of tetrachloroethylene-exposed workers, one in aircraft manufacturing (Boice et al., 1999) and one of dry-cleaning workers (Blair et al., 1990), showed no association between exposure and skin cancer risk. Boice and colleagues examined melanoma specifically, and Blair and colleagues looked at all skin cancers combined.
Several other solvents thought to have been used in the Gulf War—including methylene chloride, benzene, toluene, xylene, and phenol—were investigated in relation to melanoma. The committee identified only one relevant epidemiologic study for each substance. A cohort study of cellulose-fiber production workers showed an increased risk of melanoma mortality (SMR=1.94 95% CI=0.24–7.00) (Lanes et al., 1993). No increased risks were reported for melanoma and exposure to benzene, toluene, or xylene (Gérin et al., 1998) or for any type of skin cancer and exposure to phenol (Dosemeci et al., 1991).
Melanoma was not found to be associated with exposure to unspecified mixtures of solvents, as reported in several occupational studies (Anttila et al., 1995; Berlin et al., 1995; Boice et al., 1999; Bourguet et al., 1987; Fritschi and Siemiatycki, 1996a). The findings on risk of nonmelanoma skin cancer and unspecified mixtures of solvents were inconsistent but tended to be negative. Studies that found positive associations were variable and based on few exposed cases, and sunlight exposure was not controlled for.
TABLE 6.17 Description of Case-Control Studies of Melanoma Skin Cancers and Exposure to Organic Solvents
Summary and Conclusion
Several studies of specific and mixed solvents examined the role of exposure and the risk of skin cancer, specifically melanoma and nonmelanoma. However, small numbers of exposed cases and the lack of validated exposure assessment were limitations of the studies. Almost all studies on specific organic solvents and unspecified mixtures of organic solvents found no association between exposure and incidence or mortality from melanoma, nonmelanoma skin cancer, or skin cancer in general. Several studies used biologic monitoring to assess exposure (e.g., Anttila et al., 1995; Axelson et al., 1994; Hansen et al., 2001), but the inability of most studies to control for well-established risk factors of skin cancer—such as age, ethnicity, geography, presence of nevi, and time spent in the sun—limits the validity of their findings. Tables 6.18–19 identify the key studies and relevant data points reviewed by the committee in drawing its conclusions. Unless indicated in the tables, the study populations include both men and women.
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 solvents under review and melanoma or nonmelanoma skin cancer.
TABLE 6.18 Selected Epidemiologic Studies—Melanoma Skin Cancers and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Study—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored male Danish workers |
2 |
0.9 (0.1–3.4) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers, ever exposed |
2 |
0.46 (0.06–1.67) |
Ritz, 1999 |
White male uranium-processing workers, ever exposed |
|
|
|
Melanoma and nonmelanoma |
4 |
0.64 (0.17–1.63) |
Blair et al., 1998 |
Aircraft-maintenance workers, ever exposed |
9 |
1.0 (0.3–3.1) |
Case-Control Study |
|||
Fritschi and Siemiatycki, 1996a |
Male residents of Montreal, Canada |
|
|
Any exposure |
8 |
3.6 (1.5–9.1) |
|
|
Substantial exposure |
4 |
3.4 (1.0–12.3) |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers, ever exposed |
2 |
0.95 (0.12–3.43) |
Blair et al., 1990 |
Dry-cleaning union members in Missouri, ever employed |
|
|
|
Melanoma and nonmelanoma |
2 |
0.8 (0.1–2.8) |
Other Specific Organic Solvents |
|||
Cohort Studies—Mortality |
|||
Lanes et al., 1993 |
Cellulose-fiber production workers in South Carolina, exposed to methylene chloride |
2 |
1.94 (0.24–7.00) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Dosemeci et al., 1991 |
Male US industrial workers, ever exposed to phenol |
|
|
|
Melanoma and nonmelanoma |
7 |
0.9 (0.4–1.8) |
Case-Control Study |
|||
Gérin et al., 1998 |
Male residents of Montreal, Canada, any exposure |
|
|
|
Benzene |
11 |
0.6 (0.3–1.2) |
|
Toluene |
5 |
0.4 (0.1–0.9) |
|
Xylene |
3 |
0.3 (0.1–0.8) |
Unspecified Mixtures of Organic Solvents |
|||
Cohort Studies—Incidence |
|||
Anttila et al., 1995 |
Workers in Finland biologically monitored for halogenated hydrocarbons |
5 |
0.71 (0.23–1.66) |
Berlin et al., 1995 |
Patients with solvent-related disorders, ever exposed |
3 |
0.7 (0.1–2.0) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers, ever exposed |
|
|
|
Mixed solvents |
10 |
0.87 (0.42–1.60) |
Morgan et al., 1981 |
Male paint and coatings manufacturing workers, ever employed |
|
|
|
Melanoma and nonmelanoma |
4 |
1.48 |
Case-Control Study |
|||
Fritschi and Siemiatycki, 1996a |
Male residents of Montreal, Canada, ever exposed |
|
|
Solvents |
33 |
0.8 (0.5–1.3) |
TABLE 6.19 Selected Epidemiologic Studies—Nonmelanoma Skin Cancers and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Study—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored male Danish workers |
15 |
1.0 (0.6–1.6) |
Cohort Studies—Mortality |
|||
Ritz, 1999 |
White male uranium-processing workers, ever exposed |
|
|
|
Melanoma and nonmelanoma |
4 |
0.64 (0.17–1.63) |
Axelson et al., 1994 |
Biologically monitored male Swedish workers |
|
|
|
Nonmelanoma |
8 |
2.36 (1.02–4.65) |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Study—Mortality |
|||
Blair et al., 1990 |
Dry-cleaning union members in Missouri, ever employed |
|
|
|
Melanoma and nonmelanoma |
2 |
0.8 (0.1–2.8) |
Other Specific Organic Solvents |
|||
Cohort Study—Mortality |
|||
Dosemeci et al., 1991 |
Male US industrial workers, ever exposed to phenol |
|
|
|
Melanoma and nonmelanoma |
7 |
0.9 (0.4–1.8) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Unspecified Mixtures of Organic Solvents |
|||
Cohort Studies—Incidence |
|||
Anttila et al., 1995 |
Workers in Finland biologically monitored for halogenated hydrocarbons |
2 |
0.46 (0.06–1.67) |
Berlin et al., 1995 |
Patients with solvent-related disorders, ever exposed |
4 |
1.5 (0.4–4.0) |
Bourguet et al., 1987 |
Male tire and rubber manufacturing workers, ever exposed |
|
|
|
Low solvent exposure |
15 |
0.6 |
|
Medium solvent exposure |
7 |
1.1 |
|
High solvent exposure |
34 |
1.1 |
Cohort Study—Mortality |
|||
Morgan et al., 1981 |
Male paint and coatings manufacturing workers, ever employed |
|
|
|
Melanoma and nonmelanoma |
4 |
1.48 |
BREAST CANCER
Description of Case-Control Studies
All breast cancer case-control studies were population-based and are identified in Table 6.20 below. Aschengrau and colleagues (1998) evaluated the relationship between the risk of breast cancer and exposure to tetrachloroethylene in drinking water, which was estimated on the basis of an algorithm that accounted for residential history, water flow, and pipe characteristics, as established by Webler and Brown (1993). Three other case-control studies evaluated breast cancer risk and occupational exposure (Band et al., 2000; Hansen, 1999; Petralia et al., 1999). Each of the studies ascertained exposure differently: through use of occupational titles (Band et al., 2000), through linkage of pension-fund occupational-history information with solvent use in industries (Hansen, 1999), and through interviews with subjects to obtain occupational histories, which were linked with job-exposure matrixes to assign cumulative exposure measures (Petralia et al., 1999). Potential confounding variables were handled adequately in three of the four studies (Aschengrau et al., 1998; Band et al., 2000; Petralia et al., 1999).
Epidemiologic Studies of Exposure to Organic Solvents and Breast Cancer
Risk of breast cancer was not increased in two Scandinavian studies of biologically monitored workers exposed to trichloroethylene (Anttila et al., 1995; Hansen et al., 2001). Among women exposed to trichloroethylene as aircraft-maintenance workers, Blair and colleagues (1998) found a risk of breast cancer associated with any exposure to trichloroethylene (SMR=1.8, 95% CI=0.9–3.3) and more than a 3-fold risk associated with continuous low exposure to trichloroethylene (SMR=3.4, 95% CI=1.4–8.0). Other cohort studies of aircraft workers in which trichloroethylene was considered a predominant solvent did not report increased mortality rates from breast cancer (male and female combined) (Boice et al., 1999; Morgan et al., 1998).
TABLE 6.20 Description of Case-Control Studies of Breast Cancer and Exposure to Organic Solvents
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Aschengrau et al., 1998 |
Female cases reported to the Massachusetts Cancer Registry, diagnosed in 1983–1986 among residents of five upper Cape Cod towns; living controls were selected from the records of HCFA and through RDD; deceased controls identified by the state Department of Vital Statistics and Research files |
258 |
686 |
Tetrachloroethylene |
Relative delivered dose estimated in model accounting for location and years of residence, water flow, pipe characteristics |
Multiple logistic regression |
Age at diagnosis, vital status, family and personal history of breast cancer or disease, age at first birth, occupational exposure to solvents |
Response rates: 79% of cases, 76% of HCFA controls, 74% of RDD controls, 79% of next of kin of deceased controls |
|||||||
Petralia et al., 1999 |
Female cases, age 40 years or more, identified through major hospitals in two New York counties in 1986–1991, with histologic confirmation; controls randomly selected from lists of the NY State Department of Motor Vehicles, matched for age and county |
301 |
316 |
Benzene |
In-person interviews to assess lifetime occupational history; occupations and industries coded; assigned potential exposures to polycyclic aromatic hydrocarbons through use of a job-exposure matrix |
Unconditional logistic regression |
Age, years of education, age at first birth, age at menarche, history of benign breast disease, family breast cancer history, Quetelet index, months of lactation |
Participation rates: 66% of cases, 62% of controls |
|||||||
Hansen, 1999 |
Female cases, identified through the Danish Cancer Registry, born in 1934–1969 with diagnosis in 1970–1989; controls randomly selected from the central population register, matched for year of birth and sex |
7,802 |
7,802 |
Industries with extensive solvent use |
Past employment determined through linkage to the national pension fund files; occupations from five industrial groupings (except administrative jobs) classified as exposed to solvents |
Conditional logistic regression |
Age, social class, age at first child, number of children |
Some epidemiologic studies have either specifically addressed exposure to tetrachloroethylene or examined the effect of dry-cleaning work in relation to breast cancer risk. Aschengrau and colleagues (1998) conducted a case-control study in the Cape Cod area where drinking water was contaminated with tetrachloroethylene. Increased risks of breast cancer were found with longer latency. Excluding exposures occurring within the 9 years before diagnosis, the adjusted relative risks of breast cancer increased with increasing exposure (exposure greater than the 90th percentile: OR=7.8, 95% CI=0.9–167.0). A study of aircraft-manufacturing workers showed a slight increase in mortality from breast cancer with potential routine exposure to tetrachloroethylene (SMR=1.16, 95% CI=0.32–2.97) (Boice et al., 1999). A cohort of dry-cleaning union members showed no increase in breast cancer mortality (SMR=0.91, 95% CI=0.55–1.40) or in workers exposed only to tetrachloroethylene (SMR=0.78, 95% CI=0.28–1.69) (Ruder et al., 2001).
Band and colleagues (2000) examined the potential risk of premenopausal and postmenopausal breast cancer in multiple occupations in British Columbia. Increased risk of breast cancer was observed in women reporting any or usual work in laundry and dry-cleaning. Exposure to tetrachloroethylene and other solvents was based on an occupational title of “laundering/dry-cleaning” for premenopausal women and dry-cleaning occupational and industry titles for postmenopausal women. Among numerous positive associations, postmenopausal women experienced an almost 5-fold risk if their usual occupation was laundry and dry-cleaning (OR=4.85, 95% CI=1.26–18.7). The other cohort studies of dry cleaners did not show positive associations between this employment and breast cancer risk in women (Blair et al., 1990).
The association between exposure to benzene and the risk of breast cancer was assessed in two cohort studies and one case-control study. Petralia and colleagues (1999) reported an increased adjusted risk of premenopausal breast cancer with exposure to benzene and that risk increased with probability and duration of exposure (duration at least 4 years: OR=3.38, 95% CI=1.25–9.17). The large cohort study of Chinese benzene-exposed workers did not show an increase in breast cancer mortality (RR=0.9, 95% CI=0.3–3.2) (Yin et al., 1996a). The Danish cohort study, in which exposure was assessed using pension-fund records of job history, showed an increased incidence of breast cancer in men (OR=2.2, 95% CI=1.4–3.6) (Hansen, 2000).
The cohort of aircraft-maintenance workers studied by Blair and colleagues experienced an increased risk of breast cancer with exposure to methylene chloride (RR=3.0, 95% CI=1.0–8.8). The study also produced increased relative risks of breast cancer with exposure to several specific solvents; positive associations with 1,1,1-trichloroethane, acetone, isopropyl alcohol, toluene, and methyl ethyl ketone were found.
Employees of a cellulose-fiber production plant with heavy methylene chloride use did not experience a rate of breast cancer higher than that in the local county population (SMR=0.54, 95% CI=0.11–1.57) (Lanes et al., 1993).
Several studies examined the potential relationship between breast cancer risk and exposure to mixtures of solvents (Anttila et al., 1995, 1998; Berlin et al., 1995; Blair et al., 1998; Cocco et al., 1998; Hansen, 1999, Shannon et al., 1988; Weiderpass et al., 1999). The studies characterized the exposure in general terms, such as “organic solvents” or “mixed solvents.” In two instances (Anttila et al., 1995, 1998), specific constituent solvents were mentioned, but separate analyses were not performed. Hansen (1999) found increased risks of breast cancer (predominantly premenopausal) associated with occupations and industries with heavy solvent use (over 10 years of employment: OR=1.31, 95% CI=1.01–1.75). In a cohort study of lamp manufacturers, Shannon and colleagues (1998) found a 2-fold risk of breast cancer in solvent-
exposed workers in coiling and wire drawing. An association with any exposure to solvents was found among aircraft-maintenance workers (SMR=1.6, 95% CI=0.9–2.8) (Blair et al., 1998). No associations were found in studies of workers exposed to aromatic or halogenated solvents (Anttila et al., 1995, 1998), in patients with solvent-related disorders (Berlin et al., 1995), and in aircraft-manufacturing workers (Garabrant et al., 1988).
Summary and Conclusion
In most occupational settings, multiple solvent exposures occurred, so exposures to specific solvents may be highly correlated. Because many studies used occupational titles as exposure surrogates, the ability to assess an association between specific solvents and breast cancer risk was compromised.
A number of studies assessed breast cancer risk and solvent exposure in general, and others provided exposure estimates for specific individual solvents, such as trichloroethylene, tetrachloroethylene, dry-cleaning solvents, benzene, and methylene chloride. The evidence was limited by nonspecific exposure assessments and a reliance on mortality from breast cancer. Nondifferential misclassification of exposure, poor control for confounding, and low statistical power due to small numbers were additional limitations. Table 6.21 identifies the key studies and relevant data points reviewed by the committee in drawing its conclusion. Unless indicated in the tables, the study populations include both men and women.
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 solvents under review and breast cancer.
TABLE 6.21 Selected Epidemiologic Studies—Breast Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Study—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored workers in Denmark |
|
|
|
Females, ever exposed |
4 |
0.9 (0.2–2.3) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
Potential routine exposure |
7 |
1.31 (0.53–2.69) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah (females) |
|
|
|
Any exposure |
20 |
1.8 (0.9–3.3) |
|
Low, continuous |
8 |
3.4 (1.4–8.0) |
|
Frequent peaks |
10 |
1.4 (0.7–3.2) |
Morgan et al., 1998 |
Aerospace workers in Arizona |
|
|
Ever exposed |
16 |
0.75 (0.43–1.22) |
|
|
Low exposure |
11 |
1.03 (0.51–1.84) |
|
High exposure |
5 |
0.47 (0.15–1.11) |
Anttila et al., 1995 |
Finnish workers biologically monitored for exposure to halogenated hydrocarbons |
34 |
0.85 (0.59–1.18) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Studies—Mortality |
|||
Ruder et al., 2001 |
US dry-cleaning workers |
|
|
|
Dry-cleaning, employed >1 year |
20 |
0.91 (0.55–1.40) |
|
Tetrachloroethylene only |
6 |
0.78 (0.28–1.69) |
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
Potential routine exposure |
4 |
1.16 (0.32–2.97) |
Blair et al., 1990 |
Dry-cleaning union members in Missouri (females) |
36 |
1.0 (0.7–1.4) |
Case-Control Studies |
|||
Band et al., 2000 |
Female cases from the British Columbia Cancer Registry |
|
|
|
Premenopausal |
|
|
|
Laundering or dry-cleaning (occupation) |
|
|
|
Usual exposure |
1 |
— |
|
Ever exposed |
4 |
1.77 (0.41–7.72) |
|
Postmenopausal |
|
|
|
Laundry or dry-cleaning (occupation) |
|
|
|
Usual exposure |
8 |
4.85 (1.26–18.7) |
|
Ever exposed |
8 |
1.33 (0.55–3.19) |
|
Laundering and dry-cleaning (industry) |
|
|
|
Usual exposure |
9 |
5.24 (1.41–19.5) |
|
Ever exposed |
12 |
1.42 (0.68–2.99) |
|
Power laundries or dry cleaners (industry) |
|
|
|
Usual exposure |
9 |
2.00 (0.78–5.13) |
|
Ever exposed |
21 |
1.67 (0.89–3.13) |
Aschengrau et al., 1998 |
Residents of upper Cape Cod, MA |
|
|
Postmenopausal women |
|
||
|
75th percentile (9-year latency) |
NA |
3.4 (0.7–19.1) |
|
90th percentile (9-year latency) |
NA |
7.8 (0.9–167.0) |
Benzene |
|||
Cohort Study—Incidence |
|||
Hansen, 2000 |
Male members of the national pension fund in Denmark |
|
|
|
No lag time |
19 |
2.2 (1.4–3.6) |
|
>10 years lag |
12 |
2.5 (1.3–4.5) |
Cohort Study—Mortality |
|||
Yin et al., 1996a |
Chinese factory workers (females), ever exposed |
8 |
0.9 (0.3–3.2) |
Case-Control Study |
|||
Petralia et al., 1999 |
Female residents of New York state |
|
|
|
Any exposure |
56 |
1.91 (1.18–3.08) |
|
Duration <4 years |
8 |
0.80 (0.30–2.16) |
|
Duration ≥4 years |
16 |
3.38 (1.25–9.17) |
|
Low probability |
8 |
1.22 (0.42–3.56) |
|
Medium or high probability |
16 |
2.14 (0.89–5.12) |
|
Low intensity |
16 |
2.38 (0.97–5.87) |
|
Medium or high intensity |
8 |
1.07 (0.37–3.07) |
|
Low cumulative |
13 |
1.43 (0.59–3.47) |
|
Medium or high cumulative |
11 |
2.21 (0.77–6.36) |
|
10 to 19 year latency |
5 |
1.23 (0.34–4.46) |
|
≥20 year latency |
16 |
2.09 (0.85–5.14) |
FEMALE REPRODUCTIVE CANCERS
Epidemiologic Studies of Exposure to Organic Solvents and Cervical Cancer
Anttila and colleagues (1995) conducted a followup study of cancer incidence among Finnish workers who were biologically monitored for exposure to trichloroethylene and other halogenated hydrocarbons. An increased risk of cervical cancer was observed among women with any exposure to trichloroethylene (SIR=2.42, 95% CI=1.05–4.77), and the relative risks increased with increasing exposure (RRlow=1.86, 95% CI=0.38–5.45; RRhigh=4.35, 95% CI=1.41–10.1). A similar biomonitoring study in Denmark showed a 3.8-fold risk of cervical cancer (SIR=3.8, 95% CI=1.0–9.8) (Hansen et al., 2001), but no exposure-response pattern was reported.
A retrospective cohort study by Blair and colleagues (1998) of US civilians employed in aircraft maintenance showed increased mortality from cervical cancer (SMR=3.0, 95% CI=0.5–6.5); the relative risk was increased among women with high cumulative exposure (SMR=3.0, 95% CI=0.8–11.7). Two studies of aerospace and aircraft-manufacturing workers (Boice et al., 1999; Morgan et al., 1998) found no deaths from cervical cancer.
Only two studies specifically examined the association between exposure to tetrachloroethylene and cervical cancer. However, given that tetrachloroethylene is often used in dry-cleaning work, studies on laundry and dry-cleaning workers were also reviewed.
Boice and colleagues (1999) did not observe any cases of cervical cancer among women exposed to tetrachloroethylene. The biomonitoring study of tetrachloroethylene-exposed workers by Anttila and colleagues (1995) found an increased risk of cervical cancer (SIR=3.20, 95% CI =0.39–11.6).
Ruder and colleagues (2001) found an increased risk of cervical cancer (SMR=1.95, 95% CI=1.00–3.40) among members of a dry-cleaning union representing four areas in the United States, and Blair and colleagues (1990) estimated an SMR of 1.7 (95% CI=1.0–2.0) in a study of dry-cleaning union members in Missouri. Ruder and colleagues (2001) found that the risk of cervical cancer increased further among women who were exposed for more than 5 years (SMR=2.78 for less than 20 years of latency and 2.40 for 20 years or more of latency), but Blair and colleagues (1990) found no increases in risk with increasing exposure.
The available evidence concerning an association between exposure to methylene chloride and risk of cervical cancer was sparse. Gibbs and colleagues (1996) examined the risk of cervical cancer among women employed in cellulose-fiber production. They found an increased risk of cervical cancer among workers with low or high exposure (SMRlow=2.96, 95% CI=0.96–6.92; SMRhigh=5.40, 95% CI=0.14–30.1), but it was also increased in workers with no measured exposure to methylene chloride (SMR=7.02, 95% CI=0.18–39.1). Shannon and colleagues (1988) studied lamp manufacturing workers who were exposed to methylene chloride and other solvents and substances used during the manufacturing process, particularly coiling and wire drawing, and found no increased risk of cervical cancer.
The study of aircraft-manufacturing workers by Boice and colleagues (1999) did not show any cases of cervical cancer in women exposed to mixtures of solvents. In 1995, Berlin and colleagues examined cancer incidence and mortality patterns among patients with suspected solvent-related disorders and found that the incidence of cervical cancer was high (SIR=3.7, 95% CI=2.2–6.2).
Summary and Conclusion
A limited number of papers were found that reported the risk of cervical cancer in connection with exposure to specific solvents. There were no case-control studies, and most of the cohort studies had very few cases. The studies of cervical cancer and specific solvent exposures did not provide evidence of an association between most of the specific solvents or solvent mixtures except for trichloroethylene.
For exposure to trichloroethylene and cervical cancer, three cohort studies showed an increased risk of cervical cancer with exposure to trichloroethylene, and two other studies did not have sufficient numbers or followup to find any deaths. An exposure-response relationship for the highest exposure was reported in two of the biologic monitoring studies (Anttila et al., 1995; Blair et al., 1998). Some committee members believed that the evidence of an association between cervical cancer and exposure to trichloroethylene should be classified as limited/suggestive. However, some committee members were concerned about confounding by socioeconomic status and the increased risk of exposure to the human papilloma virus (HPV), which is associated with the development of cervical cancer (NCI, 2002). The studies compared the risk of cervical cancer among unskilled workers of low socioeconomic status in Scandinavian countries with that of the general population. The positive associations could have been attributed to the lack of control for socioeconomic status or HPV infection. Moreover, no trends were seen with duration of employment or cumulative exposure in the other biologically monitored study of Danish workers (Hansen et al., 2001). There was also a concern that the numbers of studies and exposed cases were too small to support a conclusion that the evidence was limited/suggestive. In addition, three studies (Blair et al., 1998; Boice et al., 1999; Morgan et al., 1998) had no exposed cases, although cases of cervical cancer were expected. Thus, some committee members concluded that the evidence was inadequate/insufficient to determine whether an association exists.
As a result, after extensive discussion, the committee could not reach a consensus as to whether the evidence was limited/suggestive of an association or was inadequate/insufficient to determine whether an association exists between cervical cancer and exposure to trichloroethylene. Future studies that control for socioeconomic status are needed to determine whether there is an association between exposure to trichloroethylene and the risk of cervical cancer.
For exposure to tetrachloroethylene and dry-cleaning solvents, although several studies were positive, exposure-response patterns were absent and limited the strength of the evidence. Only one study on the exposure to unspecified mixtures of organic solvents and risk of cervical cancer was identified. Although the finding was particularly strong, no exposure-relationship pattern was reported. Additional corroborating studies are needed before a determination can be made that an association exists between exposure to solvent mixtures and cervical cancer. Table 6.22 identifies the studies reviewed by the committee in making its conclusion regarding 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 solvents under review, other than trichloroethylene, and cervical cancer.
TABLE 6.22 Selected Epidemiologic Studies—Cervical Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Studies—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored workers in Denmark |
4 |
3.8 (1.0–9.8) |
Anttila et al., 1995 |
Biologically monitored workers in Finland |
|
|
|
Whole period of followup (mean individual urinew level) |
8 |
2.42 (1.05–4.77) |
|
<100 µmol/L |
3 |
1.86 (0.38–5.45) |
|
100+ µmol/L |
5 |
4.35 (1.41–10.1) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
0 |
— |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah, ever exposed |
5 |
1.8 (0.5–6.5) |
|
<5 unit-years |
1 |
0.9 (0.1–8.3) |
|
5–25 unit-years |
0 |
— |
|
>25 unit-years |
4 |
3.0 (0.8–11.7) |
Morgan et al., 1998 |
Aerospace workers in Arizona, employed >6 months |
0 |
— |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Study—Incidence |
|||
Anttila et al., 1995 |
Biologically monitored workers in Finland |
2 |
3.20 (0.39–11.6) |
Cohort Studies—Mortality |
|||
Ruder et al., 2001 |
US dry-cleaning workers |
|
|
|
Employed >1 year |
12 |
1.95 (1.00–3.40) |
|
Employed 5+ years, <20 years of latency |
4 |
2.78 (0.75–7.71) |
|
Employed 5+ years, ≥20 years of latency |
3 |
2.40 (0.48–7.86) |
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
0 |
— |
Blair et al., 1990 |
Dry-cleaning union members in Missouri |
21 |
1.7 (1.0–2.0) |
Methylene Chloride |
|||
Cohort Studies—Mortality |
|||
Gibbs et al., 1996 |
Cellulose triacetate-fiber workers, employed >3 months |
|
|
|
Methylene chloride, no exposure |
1 |
7.02 (0.18–39.1) |
|
Methylene chloride, low probability |
5 |
2.96 (0.96–6.92) |
|
Methylene chloride, high probability |
1 |
5.40 (0.14–30.1) |
Shannon et al., 1988 |
Lamp-manufacturing workers (primary exposure to methylene chloride), employed >6 months |
1 |
1.05 (0.03–5.86) |
Unspecified Mixtures of Organic Solvents |
|||
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
Mixed solvents, potential routine exposure |
0 |
— |
Berlin et al., 1995 |
Swedish patients with solvent-related disorders |
14 |
3.7 (2.2–6.2) |
Epidemiologic Studies of Exposure to Organic Solvents and Ovarian and Uterine Cancer
There was a paucity of studies regarding exposure to specific solvents and ovarian or uterine cancer. No studies showed meaningful increases in the risk of uterine or ovarian cancer in relation to exposure to trichloroethylene. The number of exposed subjects was extremely small in these studies, so the data are not informative in drawing a conclusion regarding association. There were no reports of an association between risk of uterine or ovarian cancer and exposure to methylene chloride or of an association between ovarian cancer and exposure to unspecified mixtures of organic solvents (Boice et al., 1999).
Summary and Conclusion
A limited body of evidence was available for the committee to review concerning specific and unspecified solvent exposure and risk of ovarian or uterine cancer. Very few studies had sufficient power to permit meaningful analyses. Tables 6.23 and 6.24 identify the key studies reviewed by the committee in drawing its conclusions regarding various solvent exposures and ovarian or uterine cancer.
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 solvents under review and ovarian or uterine cancer.
TABLE 6.23 Selected Epidemiologic Studies—Ovarian Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Study—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored workers in Denmark |
2 |
2.1 (0.2–7.6) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
1 |
0.58 (0.01–3.22) |
Morgan et al., 1988 |
Aerospace workers in Arizona, employed >6 months |
|
|
|
Ever exposed |
8 |
1.21 (0.52–2.38) |
|
Low exposure |
2 |
0.61 (0.07–2.21) |
|
High exposure |
6 |
1.79 (0.66–3.88) |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Study—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
0 |
— |
Methylene Chloride |
|||
Cohort Study—Mortality |
|||
Shannon et al., 1988 |
Lamp-manufacturing workers (primary exposure to methylene chloride), employed >6 months |
1 |
1.47 (0.04–8.19) |
Unspecified Mixtures of Organic Solvents |
|||
Cohort Study—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
Mixed solvents, potential routine exposure |
2 |
0.57 (0.07–2.07) |
TABLE 6.24 Selected Epidemiologic Studies—Uterine and Endometrial Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene—Uterine |
|||
Cohort Study—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored workers in Denmark |
1 |
1.0 (0.01–5.4) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
1 |
0.64 (0.02–3.57) |
Morgan et al., 1988 |
Aerospace workers in Arizona, ever exposed |
1 |
0.16 (0.00–0.91) |
Tetrachloroethylene and Dry-cleaning Solvents—Uterine |
|||
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
0 |
— |
Blair et al., 1990 |
Dry-cleaning union members in Missouri |
8 |
1.0 (0.4–2.0) |
Methylene Chloride—Uterine/Endometrial |
|||
Cohort Studies—Mortality |
|||
Shannon et al., 1988 |
Lamp-manufacturing workers (primary exposure to methylene chloride), employed >6 months |
2 |
2.14 (0.26–7.60) |
Unspecified Mixtures of Organic Solvents—Uterine |
|||
Cohort Study—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
Mixed solvents, potential routine exposure |
1 |
0.31 (0.01–1.71) |
UROLOGIC CANCERS
Description of Case-Control Studies
The characteristics of the case-control studies considered by the committee in drawing its conclusions of association are described below for each cancer site. The principal strengths and limitations of the studies are discussed below by cancer site.
Epidemiologic Studies of Exposure to Organic Solvents and Prostate Cancer
Gérin and co-workers (1998) evaluated 15 cancer risks, including the risk of prostate cancer, related to such occupational exposures as the hydrocarbons benzene, toluene, xylene, and styrene. The study had excellent information on exposures, as assessed by in-depth interviews that were coded blindly by a team of chemists and industrial hygienists, and sufficient information on most risk factors (see Table 6.25).
TABLE 6.25 Description of Case-Control Study of Prostate Cancer and Exposure to Organic Solvents
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Gérin et al., 1998 |
Male cases, age 35–75 years, diagnosed in one of 19 large Montreal-area hospitals in 1979–1985 and histologically confirmed; controls identified concurrently at 18 other cancer sites; age-matched, population-based controls were also chosen from electoral lists and random-digit dialing |
449 |
1066, consisting of 533 population controls and 533 randomly selected subjects from other cases of cancer |
Benzene Toluene Xylene |
In-person interviews (direct or proxy) with segments on work histories (job titles and self-reported exposures); analyzed and coded by a team of chemists and industrial hygienists (about 300 exposures on semiquantitative scales) |
Logistic regression |
Age, family income, ethnicity, cigarette smoking, respondent status |
Response rates: 82% of all cases, 71% of population controls |
Prostate cancer mortality and incidence were not associated with exposure to trichloroethylene in the cohort studies conducted in the aircraft industry (Blair et al., 1998: SMR=1.0, 95% CI=0.5–2.1 for 5–25 unit-years of exposure; Boice et al., 1999: SMR=1.03, 95% CI=0.70–1.45). Morgan and colleagues (1998) found an excess risk of 18% (SMR=1.18, 95% CI=0.73–1.80), and the relative risks did not increase with increasing exposure to trichloroethylene. Other studies of occupationally exposed workers also found no association with exposure to trichloroethylene, including studies by Greenland and colleagues (1994) (OR=0.82, 95% CI=0.46–1.46), Hansen and colleagues (2001) (SIR=0.6, 95% CI=0.2–1.3), and Wilcosky and colleagues (1984) (OR=0.62 [CI not provided by the authors, and the committee was unable to calculate it]). A cohort study of US uranium-processing workers found no increase in prostate cancer when the subjects were exposed to “light” amounts of trichloroethylene with increasing years of exposure latency (SMR ranged from 0.78–1.04). After “moderate” exposure, risk increased; the SMR ranged from 1.35 (95% CI=0.17–10.4) after more than 2 years of exposure and no latency to 1.96 (95% CI=0.25–15.6) after more than 5 years of exposure and a 15-year latency (Ritz, 1999).
Axelson and co-workers (1994) reported an increased risk of prostate cancer among Swedish men occupationally exposed to trichloroethylene (RR=1.25, 95% CI=0.84–1.84). Anttila and colleagues (1995) reported an increased risk of prostate cancer after exposure to trichloroethylene (RR=1.38, 95% CI=0.73–2.35).
Two cohort studies of dry-cleaning workers did not show a positive association between tetrachloroethylene and risk of prostate cancer (Blair et al., 1990: SMR=0.7, 95% CI 0.2–1.7; Ruder et al., 1994: SMR=0.82, 95% CI 0.33–1.69).
A German study of rotogravure printers showed no association between prostate cancer and exposure to toluene (SMR=0.67, 95% CI=0.13–2.66) (Wiebelt and Becker, 1999). No increased risk of prostate cancer was found in workers in Montreal who reported exposure to toluene (ORhigh=0.4, 95% CI=0.1–1.4) (Gérin et al., 1998). A study of white, male rubber workers in Ohio found an association between exposure to toluene and prostate cancer (OR=2.6) (Wilcosky et al., 1984).
Both the Montreal study and the rubber-workers study evaluated prostate cancer risk and exposure to xylene: Gérin and co-workers (1998) reported an imprecise estimate of effect of “high” exposure to xylene (OR=1.4, 95% CI=0.5–4.0), and Wilcosky and colleagues (1984) reported an OR of 1.5.
Gérin and colleagues also examined exposure to benzene and risk of prostate cancer. An association was found with “medium” exposure to benzene (OR=1.7, 95% CI=0.9–3.0) but not “high” exposure (OR=0.9, 95% CI=0.4–2.1).
Only one cohort study of US cellulose-fiber production workers reported exposure to methylene chloride. An increased risk of prostate cancer was found (SMRhigh=1.79, 95% CI=0.95–3.06; SMRlow=1.40, 95% CI=0.64–2.66; SMRno exposure=1.04, 95% CI=0.22–3.05) (Gibbs et al., 1996). The magnitude of the risk increased in the high exposure group, with 20 years or more of latency (SMR=2.08; p<0.05) and with 20 years or more of exposure with 20 years of latency (SMR=2.91; p<0.05).
No increased risk of prostate cancer with exposure to unspecified mixtures of solvents was apparent in the studies the committee reviewed except one (Anttila et al., 1995). Studies that showed no increase include cohort studies by Boice and colleagues (1999) (SMR=1.0, 95% CI 0.78–1.26), Garabrant and colleagues (1988) (SMR=0.93,
95% CI=0.60–1.37), Matanoski and colleagues (1986) (SMR=0.99, 95% CI=0.82–1.18), Morgan and colleagues (1981) (SMR=0.84 [CI not provided by the study authors, and the committee was unable to calculate it]), and Greenland and colleagues (1994) (OR=0.84, 95% CI=0.49–1.42). The cohort study by Anttila and colleagues (1995) of Finnish workers monitored for exposure to halogenated hydrocarbons showed an SIR of 1.38 (95% CI=0.76–2.32).
Summary and Conclusion
Results of several large cohort studies of trichloroethylene exposed workers did not support an association between exposure and risk of prostate cancer, nor did the cohort studies of dry-cleaning workers. Although one positive study was identified for exposure to toluene, xylene, and benzene individually, other studies did not find an association, or the studies lacked any evidence of an exposure-response relationship. For exposure to methylene chloride, one study provided evidence for increased risk of prostate cancer with increasing years of exposure and latency, but other corroborating studies were not found. All but one of the studies on solvent mixtures found a positive association, therefore the committee was not able to determine whether an association exists between exposure and prostate cancer. Table 6.26 provides the key data points for each exposure reviewed by the committee in drawing its conclusion.
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 solvents under review and prostate cancer.
TABLE 6.26 Selected Epidemiologic Studies—Prostate Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Studies—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored Danish workers, ever exposed |
6 |
0.6 (0.2–1.3) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
|
|
No exposure |
61 |
1.0 (0.7–1.4) |
|
<5 unit-years |
64 |
1.1 (0.7–1.6) |
|
5–25 unit-years |
38 |
1.0 (0.6–1.6) |
Anttila et al., 1995 |
Finnish workers monitored for exposure |
|
|
|
Entire period since first measurement |
13 |
1.38 (0.73–2.35) |
|
0–9 years |
2 |
1.09 (0.13–3.91) |
|
10–19 years |
3 |
0.56 (0.12–1.64) |
|
20+ years |
8 |
3.57 (1.54–7.02) |
Axelson et al., 1994 |
Swedish men occupationally exposed, trichloroethylene |
26 |
1.25 (0.84–1.84) |
Cohort Studies—Mortality |
|||
Ritz, 1999 |
White male US uranium-processing workers |
|
|
|
Duration of exposure, exposure lag |
|
|
|
Trichloroethylene, light exposure |
|
|
|
>2 years, no lag |
10 |
0.78 (0.33–1.85) |
|
>2 years, 15-year lag |
10 |
0.91 (0.38–2.18) |
|
>5 years, no lag |
8 |
0.83 (0.33–2.09) |
|
>5 years, 15-year lag |
8 |
1.04 (0.40–2.70) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
|
Trichloroethylene, moderate exposure |
|
|
|
>2 years, no lag |
1 |
1.35 (0.17–10.4) |
|
>2 years, 15-year lag |
1 |
1.44 (0.19–11.4) |
|
>5 years, no lag |
1 |
1.58 (0.20–12.5) |
|
>5 years, 15-year lag |
1 |
1.96 (0.25–15.6) |
Boice et al., 1999 |
Aircraft-manufacturing workers in California, routine exposure |
32 |
1.03 (0.70–1.45) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
|
|
No trichloroethylene exposure |
33 |
1.2 (0.7–2.1) |
|
<5 unit-years |
19 |
0.9 (0.5–1.8) |
|
5–25 unit-years |
13 |
1.0 (0.5–2.1) |
Morgan et al., 1998 |
Aerospace workers in Arizona |
|
|
|
Any exposure |
21 |
1.18 (0.73–1.80) |
|
Low exposure |
7 |
1.29 (0.52–2.66) |
|
High exposure |
14 |
1.13 (0.62–1.89) |
Greenland et al., 1994 |
White male US transformer manufacturers, ever exposed |
NA |
0.82 (0.46–1.46) |
Wilcosky et al., 1984 |
White male rubber workers in Ohio, exposed >1 year |
3 |
0.62 |
Tetrachloroethylene and Dry-Cleaning Solvents |
|||
Cohort Studies—Mortality |
|||
Ruder et al., 1994 |
Dry-cleaning labor-union workers |
7 |
0.82 (0.33–1.69) |
Blair et al., 1990 |
Members of a dry-cleaning union in St. Louis, MO |
5 |
0.7 (0.2–1.7) |
Toluene |
|||
Cohort Studies—Mortality |
|||
Wiebelt and Becker, 1999 |
Male German rotogravure printers, Employed >1 year |
2 |
0.67 (0.13–2.66) |
Wilcosky et al., 1984 |
White male rubber workers in Ohio, exposed >1 year |
3 |
2.6 |
Case-Control Study |
|||
Gérin et al., 1998 |
Male residents of Montreal, Canada |
|
|
|
Low exposure |
51 |
1.0 (0.7–1.5) |
|
Medium exposure |
17 |
1.3 (0.7–2.5) |
|
High exposure |
3 |
0.4 (0.1–1.4) |
Xylene |
|||
Cohort Study—Mortality |
|||
Wilcosky et al., 1984 |
White male rubber workers in Ohio, exposed >1 year |
8 |
1.5 |
Case-Control Study |
|||
Gérin et al., 1998 |
Male residents of Montreal, Canada |
|
|
|
Low exposure |
46 |
1.2 (0.8–1.8) |
|
Medium exposure |
11 |
0.8 (0.4–1.7) |
|
High exposure |
6 |
1.4 (0.5–4.0) |
Benzene |
|||
Cohort Study—Mortality |
|||
Wilcosky et al., 1984 |
White male rubber workers in Ohio, exposed >1 year |
11 |
0.73 |
Epidemiologic Studies of Exposure to Organic Solvents and Bladder Cancer
All but one (Aschengrau et al., 1993) of the case-control studies of bladder cancer reviewed by the committee used occupational history to assess exposure, and in some studies information on specific chemical exposures was also obtained (Gérin et al., 1998; Pesch et al., 2000a). The study by Aschengrau and colleagues assessed exposure on the basis of estimated doses of tetrachloroethylene found in public drinking water in five towns of Cape Cod, Massachusetts. Two studies included interviews with proxies if subjects were too ill to be interviewed (Morrison et al., 1985; Teschke et al., 1997). Most studies simply grouped exposure defined broadly on the basis of occupation, including work in the painting industry (Cordier et al., 1993; Jensen et al., 1987; La Vecchia et al., 1990; Morrison et al., 1985; Vineis and Magnani, 1985), in laundry and dry-cleaning services (Silverman et al., 1989a,b; Smith et al., 1985), and in both fields (Schoenberg et al., 1984; Teschke et al.,
1997). Very low response rates were found in the study by Risch and colleagues (1988) of exposure to paints. A number of case-control studies used self-reported information on exposures that were not otherwise validated (Jensen et al., 1987; La Vecchia et al., 1990; Risch et al., 1988; Schoenberg et al., 1984; Smith et al., 1985; Vineis and Magnani, 1985) and thus may be subject to recall bias if the controls were not ill.
The main accepted risk factor for bladder cancer is cigarette smoking, and all but one (Smith et al., 1985) of the case-control studies of bladder cancer and exposure to specific and unspecified organic solvents reviewed by the committee accounted for smoking in some way. In most studies, subjects were asked whether they currently smoked; others inquired about the number of cigarettes smoked per day (Aschengrau et al., 1993), lifetime cigarette consumption (Risch et al., 1988), or duration of cigarette smoking (Schoenberg et al., 1984).
Case-control studies of bladder cancer and exposure to organic solvents that had reasonably good assessments of exposure, adequate control for confounding, and histologic confirmation of outcome include those by: Aschengrau et al., 1993; Cordier et al., 1993; Gérin et al., 1998; Pesch et al., 2000a; and Silverman et al., 1989a,b (see Table 6.27).
In addition to the case-control study by Pesch and colleagues (2000a) described above, there were several cohort studies of biologically monitored workers, transformer manufacturers, and aircraft and aerospace workers. One study of US aircraft-maintenance workers showed an RRany exposure of 1.2 (95% CI=0.5–2.9) for bladder cancer (Blair et al., 1998); another showed no association (RR=0.55, 95% CI=0.18–1.28) (Boice et al., 1999). An increased risk of bladder cancer also was observed in a cohort of US aerospace-manufacturing workers (SMR=1.36, 95% CI=0.59–2.68) (Morgan et al., 1998). Three other cohort studies of workers biologically monitored for exposure to trichloroethylene, as shown by the presence of a urinary metabolite, showed no association (relative risks ranged from 0.61 to 1.1) between this marker and bladder cancer (Anttila et al., 1995; Axelson et al., 1994; Hansen et al., 2001). A nested case-control study within a cohort of transformer-assembly facility workers did not find an association between risk of bladder cancer and exposure to trichloroethylene (OR=0.85, 95% CI=0.32–3.32) (Greenland et al., 1994).
The case-control study by Pesch and colleagues (2000a) suggested a positive association with urothelial carcinoma (a cancer of the urinary tract that affects mostly the bladder). Using a job-exposure matrix, the authors found a 10% excess risk (OR=1.1; 95% CI=0.9–1.4) among men with “high” exposure and a 60% excess risk among women with “high” exposure (OR=1.6, 95% CI=1.0–2.5). On the basis of the job task-exposure matrix, the magnitude of the OR for men with “high” exposure was increased to 1.3 (95% CI=0.9–1.7). The job task-exposure matrix was not used to evaluate exposure of women.
The committee used two cohort studies and several case-control studies of dry-cleaning workers and other workers exposed to tetrachloroethylene in determining whether there is an association between exposure and bladder cancer. The two dry-cleaner cohort studies showed increased mortality from bladder cancer: Blair and colleagues (1990) reported an increased SMR of 1.7 (95% CI=0.7–3.3), and Ruder and colleagues (2001) found a 122% increase in mortality from bladder cancer (SMR=2.22, 95% CI=1.06–4.08). The magnitude of the association was higher (SMR=4.31, 95% CI=1.85–8.76) among workers employed more than 5 years and in whom 20 years had passed since the first exposure.
TABLE 6.27 Description of Case-Control Studies of Bladder Cancer and Exposure to Organic Solvents
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Schoenberg et al., 1984 |
Male cases, age 21–84 years, with histologically confirmed diagnosis in New Jersey in February 1978–1979; controls identified through RDD (age 21–64 years) and HCFA records (age 65–85 years), stratified for age |
658 |
1258 |
Painting or artistic work Dry-cleaning work |
In-person interviews with questionnaires assessing lifetime occupational history (job titles) |
Logistic regression |
Age, duration of cigarette smoking, other occupations |
Response rates: 89.7% of cases, 86.6% of controls |
|||||||
Morrison et al., 1985 |
Cases, age 21–89 years, identified at hospitals in Boston; Greater Manchester County, UK; and Nagoya, Japan, in 1976–1978; controls selected from respective areas’ electoral registers, matched for age and sex |
430 Boston 399 UK 226 Japan |
397 Boston 493 UK 443 Japan |
Painting work |
In-person interview (direct or proxy) assessing occupational history (job titles); job titles were coded |
Logistic regression |
Age, cigarette smoking |
No response rates provided |
|||||||
Smith et al., 1985 |
Cases and controls, age 21–84 years, residing in the nine SEER population-based areas and New Jersey, who participated in the NCI National Bladder Cancer Study; cases with histologically confirmed cancer; controls frequency matched for age and sex |
7748 total participants with and without bladder cancer, classified as: worked in dry-cleaning operations (N=103), experienced related exposures (N=5776), or neither (unexposed; N=1869) |
Laundry and dry-cleaning work |
In-person interview with structured questionnaire regarding occupational history (job or industry titles) |
Logistic regression |
Age, sex |
|
No response rates provided |
|||||||
Vineis and Magnani, 1985 |
Cases, age less than 70 years, identified from the Main Hospital in Torino, Italy, in 1978–1983; controls from same hospital diagnosed with benign urologic conditions, matched for age |
512 |
596 |
Painting work |
In-person interviews regarding lifetime occupational history (job or industry titles) obtained in hospital and blindly coded |
Mantel-Haenszel |
Age, smoking |
No response rates provided |
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Jensen et al., 1987 |
Cases reported to the Danish Cancer Registry from Copenhagen area in 1979–1981, with 99% histologic verification; controls selected from the residents of the municipalities from which cases arose, matched for sex and age |
371 |
771 |
Painting work |
In-person interviews with questionnaire assessing occupational history (job titles and self-reported exposures) |
Logistic regression |
Age, sex, smoking |
Response rates: 94.4% of cases, 75.1% of controls |
|||||||
Risch et al., 1988 |
Cases, age 35–79 years, identified through a combination of cancer registry reporting and hospital record review in four cities in Canada in 1979–1982 with histologic confirmation; controls selected randomly from population listings and matched on birth year, sex, and residence area |
826 |
792 |
Organic solvents Paints |
In-person interview with questionnaire assessing specific occupational exposures (self-reports) |
Conditional logistic regression |
Matching variables, lifetime cigarette consumption |
Response rates: 67% of cases, 53% of controls |
|||||||
Silverman et al., 1989a |
White cases, age 21–84 years, in 10 US areas in 1977–1978 with histologic confirmation; controls identified through RDD (age 21–64 years) and HCFA records (age 65–84 years), matched for age and geographic area |
2100 |
3874 |
Dry-cleaning, ironing, and pressing work |
Questionnaire administered by in-person interview (job or industry titles); industries and job titles coded by study authors and grouped by potential exposures |
Logistic regression |
Smoking, age |
No response rates provided |
|||||||
Silverman et al., 1989b |
Nonwhite cases, same study as above (Silverman et al., 1989a) |
126 |
383 |
See above |
See above |
See above |
See above |
La Vecchia et al., 1990 |
Cases, age less than 75 years, admitted to NCI or clinics and hospitals in Milan, Italy, in 1985–1988 with histologic confirmation; controls admitted to the same network of hospitals for acute nonneoplastic conditions |
263 |
287 |
Painting work Chemical-industry work |
Structured questionnaire to assess lifetime employment in 19 industries or occupations and 14 specific agents (job or industry titles and self-reported exposures) |
Mantel-Haenszel |
Age, sex, smoking |
Response rate: >97% of cases and controls |
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Aschengrau et al., 1993 |
Cases reported to the Massachusetts Cancer Registry, diagnosed in 1983–1986 among residents of five upper Cape Cod towns; living controls were selected from HCFA records and through RDD; deceased controls identified by the state Department of Vital Statistics and Research files |
61 |
852 |
Tetrachlorid e-ethylene |
Exposure dose estimated in areas of contaminated drinking water, accounting for location and years of residence, water flow, pipe characteristics |
Logistic regression |
Sex, age at diagnosis, vital status, educational level, usual number of cigarettes smoked, occupational exposure to solvents, specific cancer risk factors controlled for in respective analyses |
Response rates: 80.6% of cases, 75.9% of HCFA controls, 73.9% of RDD controls, 78.8% of next of kin of deceased controls |
|||||||
Cordier et al., 1993 |
Cases, under age 80 years, from seven French hospitals in 1984–1987, with histologic confirmation; controls selected from the same hospitals from patients admitted for causes other than cancer, respiratory disease, or symptoms related to bladder cancer, matched for sex, age, ethnicity, and residence |
765 |
765 |
Solvents Painting work |
In-person interviews with segments on work histories (job titles); analyzed and coded by a team of experts in industrial hygiene |
Logistic regression |
Smoking status, hospital, age, place of residence |
No response rates provided |
|||||||
Teschke et al., 1997 |
Cases, age 19 years and over, registered with the British Columbia Cancer Agency in 1990–1991 with histologic confirmation; controls selected from the provincial voters list and matched on age and sex |
105 |
139 |
Laundry personnel Painters |
Occupational histories (job titles) and self-reported exposures obtained (direct or proxy) through standardized questionnaire (in-person or telephone interview) |
Adjusted ORs |
Sex, age, cigarette smoking |
Response rates: 88.2% of cases, 80.3% of controls |
Several case-control studies reported increased relative risks of bladder cancer with exposure in the dry-cleaning industry. Schoenberg and colleagues (1984) showed an OR of 1.33 (95% CI=0.50–3.58), and Teschke and colleagues (1997) found an OR of 2.3 (95% CI=0.4–13.9) in people ever employed as laundry personnel. Smith and co-workers (1985) showed an increased risk of bladder cancer among laundry and dry-cleaning workers, and this risk was higher among exposed smokers (OR=3.94, 95% CI=2.39–6.51) than among exposed nonsmokers (OR=1.31, 95% CI=0.85–2.03).
On the basis of exposure to tetrachloroethylene in public drinking water, Aschengrau and colleagues (1993) showed an OR of 1.16 (95% CI=0.48–2.48) for low levels of exposure and an OR of 6.04 (95% CI=1.32–21.84) for high levels of exposure. Using a job-exposure matrix, Pesch and colleagues (2000a) demonstrated an increased risk in men exposed to high levels of tetrachloroethylene (OR=1.2, 95% CI=1.0–1.5) and no increased risk in women (OR=1.0, 95%CI=0.6–1.9).
Two studies provided data on exposure to benzene and bladder cancer. Exposure to benzene, as assigned by industrial hygienists after reviewing detailed job histories, was not associated with bladder cancer in the Montreal case-control study (Gérin et al., 1998). In the study by Pesch and colleagues (2000a), there was an indication among men of risks increasing with increasing exposure on the basis of three methods of assessing exposure. For example, for “substantial” exposure to benzene, according to a British job-exposure matrix (Pannett et al., 1985), the RR of bladder cancer in men was 1.5 (95% CI=1.0–2.1) and in women 1.4 (95% CI =0.6–3.3) (Pesch et al., 2000a). However, the risks did not increase with increasing exposure among women according to the other two exposure-determination methods.
Three small occupational cohort studies (Svensson et al., 1990; Walker et al., 1993; Wiebelt and Becker, 1999) and a population-based case-control study (Gérin et al., 1998) found no evidence of an association between bladder cancer and exposure to toluene or xylene. Most of the estimates of RR were below unity, and the highest was 1.20 (95% CI=0.25–3.51) in women working as shoe manufacturers (Walker et al., 1993).
The study that had the largest number of exposed cases was the cohort study of US painters and other union members that showed an increased risk of bladder cancer among painters (SMR=1.23, 95% CI=1.05–1.43) but not in nonpainters (SMR=0.74, 95% CI=0.46–1.11) (Steenland and Palu, 1999). A formal Poisson regression analysis comparing painters and nonpainters showed an RR of 1.77 (95% CI=1.13–2.77) in painters. A smaller study of US painters (Matanoski et al., 1986) and a small study of paint-manufacturing workers (Morgan et al., 1981) showed no increased risk of bladder cancer (RR=1.06, 95% CI=0.78–1.41 and RR=0.98 [no CI was available, and the committee was not able to calculate it], respectively). Boice and colleagues (1999) did not find an association in aircraft-manufacturing workers (SMR=0.85, 95% CI=0.49–1.35). Anttila and colleagues (1995) also found no increased risk of bladder cancer (SIR=0.73, 95% CI=0.24–1.71) among Finnish workers occupationally exposed to halogenated hydrocarbons. A cohort study of US aircraft-manufacturing workers in California showed a 26% excess risk of bladder cancer (SMR=1.26, 95% CI=0.74–2.03) (Garabrant et al., 1988). The study of US transformer-assembly workers showed a 21% increase in mortality (OR=1.21, 95% CI=0.49–2.98) (Greenland et al., 1994).
Pesch and colleagues (2000a) found an increased risk in painters in Germany who had a “very long” duration of exposure (OR=1.6, 95% CI=0.5–4.7) and in men who had “substantial” exposure to paints (OR=1.6, 95% CI=1.1–2.3). The authors did not show that the risk in painters increased with increasing duration of exposure (medium: OR=1.3, 95% CI=
0.6–2.6; long: OR=0.7, 95% CI=0.3–1.61; very long: OR=1.6, 95% CI=0.5–4.7). Those analyses were adjusted for smoking. In British Columbia (Teschke et al., 1997), the risk was increased in people who had ever been employed as painters (OR=2.8, 95% CI=0.4–21.3) and after 20 years since first employment (OR=2.0, 95% CI 0.1–33.0). The risk of bladder cancer increased in the Copenhagen study (OR=2.54, 95% CI=1.12–5.73) and increased with increasing duration of employment (1–19 years: OR=1.6, 95% CI=0.5–5.5; 20 years or more: OR=4.1, 95% CI=1.2–13.9) (Jensen et al., 1987). Positive associations were also found in studies in Milan (OR=1.8, 95% CI=0.8–3.7) (La Vecchia et al., 1990), Canada (OR=1.18, 95% CI=0.87–1.62) (Risch et al., 1988), Boston (OR=1.5, 95% CI 0.9–2.4) (Morrison et al., 1985), and New Jersey (OR=1.53, 95% CI=0.96–2.44) (Schoenberg et al., 1984).
Summary and Conclusions
Several studies of trichloroethylene and bladder cancer showed weak and imprecise associations. Most suffered from low statistical power and probable exposure misclassification, so the committee concluded that there was insufficient evidence to determine whether an association exists.
For exposure to tetrachloroethylene and dry-cleaning solvents, a number of cohort and case-control studies showed a positive association between exposure and risk of bladder cancer. Therefore, the committee judged that the data, though limited, was suggestive of an association.
The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between chronic exposure to tetrachloroethylene and dry-cleaning solvents and bladder cancer.
Based on the consistency of association in the case-control studies (Jensen et al., 1987; Morrison et al., 1985; Pesch et al., 2000b; Schoenberg et al., 1984) and the positive findings in the US cohorts of painters (Steenland and Palu, 1999) and aircraft workers (Garabrant et al., 1988), the committee decided that the evidence between exposure to unspecified mixtures of organic solvents and bladder cancer was both limited and suggestive of an association.
The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between chronic exposure to unspecified mixtures of organic solvents and bladder cancer.
In contrast, the committee considered the findings for exposure to benzene and risk of bladder cancer to be inconsistent. The studies on toluene and xylene did not find an association. Table 6.28 identifies the studies used by the committee in making its conclusions, and unless indicated in the table, the study populations include both men and women.
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 other solvents under review and bladder cancer.
TABLE 6.28 Selected Epidemiologic Studies—Bladder Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Studies—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored Danish workers |
|
|
|
Males, ever exposed |
10 |
1.1 (0.5–2.0) |
|
Females, ever exposed |
0 |
— |
Blair et al., 1998 |
Aircraft maintenance in Utah |
|
|
|
No trichloroethylene exposure |
10 |
1.3 (0.5–3.5) |
|
<5 unit-years |
13 |
1.7 (0.6–4.4) |
|
5–25 unit-years |
9 |
1.7 (0.6–4.9) |
Anttila et al., 1995 |
Finnish workers occupationally exposed |
|
|
|
Entire period since first measurement |
5 |
0.82 (0.27–1.90) |
|
0–9 |
1 |
0.65 (0.02–3.59) |
|
10–19 |
2 |
0.61 (0.07–2.22) |
|
20+ |
2 |
1.51 (0.18–5.44) |
Axelson et al., 1994 |
Swedish men, occupationally exposed |
8 |
1.02 (0.44–2.00) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, routine exposure |
5 |
0.55 (0.18–1.28) |
Blair et al., 1998 |
Aircraft maintenance workers in Utah |
|
|
|
Any exposure |
17 |
1.2 (0.5–2.9) |
|
No trichloroethylene exposure |
4 |
0.7 (0.2–2.8) |
|
<5 unit-years |
7 |
1.8 (0.5–6.2) |
|
5–25 unit-years |
5 |
2.1 (0.6–8.0) |
|
Low-level intermittent |
10 |
1.5 (0.4–4.8) |
|
Low-level continuous |
9 |
2.0 (0.6–6.4) |
Morgan et al., 1998 |
Aerospace workers in Arizona |
|
|
Any exposure |
8 |
1.36 (0.59–2.68) |
|
|
Low exposure |
1 |
0.51 (0.01–2.83) |
|
High exposure |
7 |
1.79 (0.72–3.69) |
Greenland et al., 1994 |
White male US transformer manufacturers, ever exposed |
NA |
0.85 (0.32–3.32) |
Case-Control Study |
|||
Pesch et al., 2000a |
Participants in multiple centers in Germany |
|
|
|
German job-exposure matrix |
|
|
|
Trichloroethylene (males) |
|
|
|
Medium |
154 |
1.1 (0.8–1.3) |
|
High |
182 |
1.1 (0.9–1.4) |
|
Substantial |
68 |
1.3 (0.9–1.7) |
|
Trichloroethylene (females) |
|
|
|
Medium |
21 |
1.0 (0.6–1.7) |
|
High |
32 |
1.6 (1.0–2.5) |
|
Substantial |
3 |
0.6 (0.2–2.3) |
|
Job task-exposure matrix approach |
|
|
|
Trichloroethylene (males) |
|
|
|
Medium |
47 |
0.8 (0.6–1.2) |
|
High |
74 |
1.3 (0.9–1.7) |
|
Substantial |
36 |
1.8 (1.2–2.7) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Studies—Mortality |
|||
Ruder et al., 2001 |
Dry-cleaning labor-union workers |
10 |
2.22 (1.06–4.08) |
|
≥5 years exposure with >20 years latency |
8 |
4.31 (1.85–8.76) |
|
Tetrachloroethylene plus other solvents (likely Stoddard) |
10 |
3.15 (1.51–5.79) |
Blair et al., 1990 |
Members of a dry-cleaning union in St. Louis, MO |
8 |
1.7 (0.7–3.3) |
Case-Control Studies |
|||
Pesch et al., 2000a |
Participants in multiple centers in Germany |
|
|
|
German job-exposure matrix |
|
|
|
Tetrachloroethylene (males) |
|
|
|
Medium |
162 |
1.1 (0.9–1.3) |
|
High |
172 |
1.2 (1.0–1.5) |
|
Substantial |
71 |
1.4 (1.0–1.9) |
|
Tetrachloroethylene (females) |
|
|
|
Medium |
21 |
1.8 (1.0–3.0) |
|
High |
16 |
1.0 (0.6–1.9) |
|
Substantial |
3 |
0.7 (0.2–2.5) |
|
Job task-exposure matrix approach |
|
|
|
Tetrachloroethylene (males) |
|
|
|
Medium |
37 |
1.0 (0.7–1.5) |
|
High |
47 |
1.2 (0.8–1.7) |
|
Substantial |
22 |
1.8 (1.1–3.1) |
Teschke et al., 1997 |
Residents of British Columbia, Canada |
|
|
Laundry personnel, ever employed |
5 |
2.3 (0.4–13.9) |
|
|
Laundry personnel, most recent 20 years removed |
4 |
1.8 (0.3–11.3) |
Aschengrau et al., 1993 |
Residents of upper Cape Cod, MA |
|
|
Any exposure (no latency) |
13 |
1.55 (0.74–3.01) |
|
|
Low exposure |
9 |
1.16 (0.48–2.48) |
|
High exposure |
4 |
6.04 (1.32–21.84) |
Silverman et al., 1989b |
Nonwhite males in 10 US areas |
|
|
Dry cleaner, ironer, or presser, ever employed |
11 |
2.8 (1.1–7.4) |
|
|
<5 years duration |
7 |
5.3 |
|
5+ years duration |
4 |
1.8 |
Smith et al., 1985 |
Incident cases in 10 US areas |
|
|
|
Laundry and dry cleaners, ever employed |
|
|
|
Nonsmoker |
NA |
1.31 (0.85–2.03) |
|
Former smoker |
NA |
2.99 (1.80–4.97) |
|
Current smoker |
NA |
3.94 (2.39–6.51) |
|
Chemically related exposure group |
|
|
|
Nonsmoker |
NA |
1.11 (0.99–1.25) |
|
Former smoker |
NA |
2.01 (1.69–2.40) |
|
Current smoker |
NA |
3.12 (2.62–3.71) |
Schoenberg et al., 1984 |
Male residents of New Jersey |
|
|
Dry-cleaning, ever employed |
7 |
1.33 (0.50–3.58) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Benzene |
|||
Case-Control Studies |
|||
Pesch et al., 2000a |
Participants in multiple centers in Germany |
|
|
|
British job-exposure matrix |
|
|
|
Benzene (males) |
|
|
|
Medium |
95 |
1.1 (0.8–1.4) |
|
High |
70 |
0.9 (0.7–1.2) |
|
Substantial |
47 |
1.5 (1.0–2.1) |
|
Benzene (females) |
|
|
|
Medium |
21 |
1.2 (0.7–2.0) |
|
High |
18 |
1.5 (0.9–2.8) |
|
Substantial |
8 |
1.4 (0.6–3.3) |
|
German job-exposure matrix |
|
|
|
Benzene (males) |
|
|
|
Medium |
177 |
1.1 (0.9–1.3) |
|
High |
169 |
1.2 (1.0–1.6) |
|
Substantial |
68 |
1.2 (0.8–1.6) |
|
Benzene (females) |
|
|
|
Medium |
27 |
1.0 (0.7–1.7) |
|
High |
23 |
0.8 (0.5–1.4) |
|
Substantial |
5 |
0.6 (0.2–1.6) |
|
Job task-exposure matrix approach |
|
|
|
Benzene (males) |
|
|
|
Medium |
51 |
0.7 (0.5–1.0) |
|
High |
71 |
1.0 (0.7–1.3) |
|
Substantial |
37 |
1.4 (0.9–2.1) |
|
Benzene (females) |
|
|
|
Medium |
2 |
0.4 (0.1–1.8) |
|
High |
3 |
0.4 (0.1–1.2) |
|
Substantial |
2 |
0.8 (0.2–3.7) |
Gérin et al., 1998 |
Male residents of Montreal, Canada |
|
|
|
Low exposure |
65 |
1.0 (0.7–1.3) |
|
Medium exposure |
22 |
1.2 (0.7–2.0) |
|
High exposure |
2 |
0.2 (0.0–0.6) |
Toluene |
|||
Cohort Study—Incidence |
|||
Svensson et al., 1990 |
Male rotogravure printers in Sweden, employed >3 months |
|
|
|
Bladder and kidney cancer |
4 |
0.64 (0.18–1.65) |
|
≥5 yrs exoposed with >10 yrs latency |
4 |
0.85 (0.23–2.16) |
Cohort Study—Mortality |
|||
Wiebelt and Becker, 1999 |
Male German rotogravure printers, employed >1 year |
2 |
0.66 (0.08–3.27) |
Walker et al., 1993 |
Shoe manufacturers in two plants in Ohio, potentially exposed to toluene and other solvents |
|
|
|
Total |
7 |
0.99 (0.40–2.05) |
|
Males |
4 |
0.87 (0.24–2.25) |
|
Females |
3 |
1.20 (0.25–3.51) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Svensson et al., 1990 |
Male rotogravure printers in Sweden, employed >3 months |
|
|
|
Bladder and kidney cancer |
1 |
0.45 (0.01–2.53) |
|
≥5 yrs exoposed with >10 yrs latency |
1 |
0.57 (0.01–3.20) |
Case-Control Study |
|||
Gérin et al., 1998 |
Male residents of Montreal, Canada |
|
|
|
Low exposure |
52 |
0.9 (0.6–1.3) |
|
Medium exposure |
6 |
0.3 (0.1–0.7) |
|
High exposure |
7 |
1.0 (0.4–2.5) |
Xylene |
|||
Case-Control Study |
|||
Gérin et al., 1998 |
Male residents of Montreal, Canada |
|
|
|
Low exposure |
35 |
0.8 (0.5–1.1) |
|
Medium exposure |
16 |
1.0 (0.5–1.8) |
|
High exposure |
3 |
0.8 (0.2–3.2) |
Unspecified Mixtures of Organic Solvents |
|||
Cohort Study—Incidence |
|||
Anttila et al., 1995 |
Finnish workers monitored for exposure |
|
|
|
Halogenated hydrocarbons |
5 |
0.73 (0.24–1.71) |
Cohort Studies—Mortality |
|||
Steenland and Palu, 1999 |
US painters and other union members |
|
|
Painters |
166 |
1.23 (1.05–1.43) |
|
|
20 years since membership |
146 |
1.25 (1.06–1.47) |
|
Nonpainters |
22 |
0.74 (0.46–1.11) |
|
20 years since membership |
19 |
0.84 (0.51–1.31) |
|
Poisson regression comparing painters with nonpainters: |
|
|
|
Rate ratio |
166 |
1.77 (1.13–2.77) |
|
Rate ratio, ≥20 years since membership |
146 |
1.55 (0.96–2.51) |
Greenland et al., 1994 |
White male US transformer-assembly workers |
NA |
1.21 (0.49–2.98) |
|
Solvents, ever exposed |
|
|
Garabrant et al., 1988 |
Aircraft-manufacturing workers in California |
|
|
|
Entire cohort |
17 |
1.26 (0.74–2.03) |
|
25–29 years of employment |
2 |
2.66 (0.32–9.50)a |
|
30+ years of employment |
1 |
2.45 (0.06–13.59)a |
Matanoski et al., 1986 |
US painters and allied tradesmen union members |
48 |
1.06 (0.78–1.41) |
Morgan et al., 1981 |
Male US paint and coatings manufacturers, employed >1 year |
16 |
0.98 |
Walker et al., 1993 |
Shoe-manufacturing workers in Ohio, potentially exposed |
7 |
0.99 (0.40–2.05) |
|
Males |
4 |
0.87 (0.24–2.25) |
|
Females |
3 |
1.20 (0.25–3.51) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Case-Control Studies |
|||
Pesch et al., 2000a |
Residents of multiple centers in Germany |
|
|
|
Duration of exposure—painters: |
|
|
|
Medium |
12 |
1.3 (0.6–2.6) |
|
Long |
6 |
0.7 (0.3–1.6) |
|
Very long |
5 |
1.6 (0.5–4.7) |
|
Job-exposure approach, organic solvents: |
|
|
|
Males, substantial exposure |
43 |
1.4 (0.9–2.0) |
|
Females, substantial exposure |
8 |
1.5 (0.6–3.5) |
|
Job-exposure approach, paints: |
|
|
|
Males, substantial exposure |
38 |
1.6 (1.1–2.3) |
|
Females, substantial exposure |
2 |
0.3 (0.1–1.13) |
|
Job task-exposure matrix, paints: |
|
|
|
Males, substantial exposure |
33 |
1.5 (1.0–2.3) |
|
Females, substantial exposure |
10 |
2.1 (1.0–4.4) |
Teschke et al., 1997 |
Painters in British Columbia, Canada |
|
|
Ever employed |
4 |
2.8 (0.4–21.3) |
|
|
20 years since employment |
2 |
2.0 (0.1–33.0) |
Cordier et al., 1993 |
Residents of France |
|
|
|
Painter, ever employed |
19 |
0.97 (0.50–1.88) |
|
Solvents, ever exposed |
171 |
1.28 (0.98–1.68) |
La Vecchia et al., 1990 |
Residents of Milan, Italy |
|
|
Painting, ever employed |
NA |
1.8 (0.8–3.7) |
|
|
Chemical industry, ever exposed |
NA |
1.7 (0.9–3.3) |
Silverman et al., 1989a |
White males employed as painters |
|
|
<5 years |
50 |
1.7 |
|
|
5–9 years |
14 |
0.9 |
|
10–24 years |
26 |
1.6 |
|
25+ years |
22 |
1.9 |
Risch et al., 1988 |
Residents of Canada |
|
|
|
Organic solvents, ever exposed |
208 |
1.14 (0.82–1.57) |
|
Organic solvents, exposed 8–28 years |
NA |
1.03 (0.70–1.52) |
|
Paints, ever exposed |
204 |
1.18 (0.87–1.62) |
|
Paints, exposed 8–28 years |
NA |
1.11 (0.77–1.60) |
Jensen et al., 1987 |
Residents of Copenhagen, Denmark |
|
|
|
Painting, ever employed |
13 |
2.54 (1.12–5.73) |
|
1–19 years |
5 |
1.6 (0.5–5.5) |
|
≥20 years |
8 |
4.1 (1.2–13.9) |
Vineis and Magnani, 1985 |
Painters in Turin, Italy |
|
|
Painter in building industry |
12 |
1.0 (0.4–2.2) |
|
|
Painter in carpentry |
1 |
0.6 (0.04–8.4) |
|
Car painter |
7 |
2.0 (0.6–7.0) |
|
Spray-painter |
2 |
1.2 (0.2–5.8) |
Morrison et al., 1985 |
Residents occupationally exposed to paints |
|
|
Boston, MA |
35 |
1.5 (0.9–2.4)b |
|
|
Manchester, UK |
23 |
0.7 (0.5–1.2)b |
|
Nagoya, Japan |
5 |
0.7 (0.3–1.7)b |
Epidemiologic Studies of Exposure to Organic Solvents and Kidney Cancer
Exposure to organic solvents was determined by using responses from in-person interviews or structured questionnaires about job titles and occupational and industrial exposures. Many of the studies reviewed on kidney cancer included small numbers of cases, which limited their statistical power. Several of the studies with large numbers of cases used self-reports to determine exposure, including those by: Asal et al., 1988; Dosemeci et al., 1999; Jensen et al., 1988; Mandel et al., 1995; McCredie and Stewart, 1993; Mellemgaard et al., 1994; Schlehofer et al., 1995; Sharpe et al., 1989; and Vamvakas et al., 1998. Such exposure determinations may be subject to misclassification errors that would affect risk estimates.
Although several studies included assessment of risk associated with specific solvent exposure, exposure was based on job titles that were then linked to potential exposure information determined by a job-exposure matrix or by industrial hygienists (Harrington et al., 1989; Partanen et al., 1991; Pesch et al., 2000b). Risk factors for kidney cancer that would require consideration in analyses are not well established.
Like the studies of bladder cancer, the case-control studies considered by the committee to be of relatively high quality had good information on exposure, controlled adequately for confounding, and used histologic confirmation of outcomes (Aschengrau et al., 1993; Asal et al., 1988; Gérin et al., 1998; Partanen et al., 1991; and Pesch et al., 2000b) (see Table 6.29).
Kidney cancer was not associated with exposure to trichloroethylene in three studies of biologically monitored workers in Scandinavian countries (Anttila et al., 1995; Axelson et al., 1994; Hansen et al., 2001) or in a study of US transformer manufacturers (Greenland et al., 1994). In the study by Anttila and colleagues, the SIR was 0.87 (95% CI=0.32–1.89) in all workers exposed, 1.16 (95% CI=0.42–2.52) in Swedish men in Axelson and colleagues’ study, and 0.9 (95% CI=0.2–2.6) in Danish workers in Hansen and colleagues’ study. Greenland and colleagues showed an OR of 0.99 (95% CI=0.30–3.32) in the transformer cohort. Three cohort studies of workers in aircraft and aerospace industries were inconsistent; no association (SMR=0.99, 95% CI=0.40–2.04) was found in a California aircraft-manufacturing study (Boice et al., 1999). Studies of aircraft-maintenance workers in Utah (Blair et al., 1998) and aerospace workers in Arizona (Morgan et al., 1998) showed increased relative risks but no exposure-response relationships.
TABLE 6.29 Description of Case-Control Studies of Kidney Cancer and Exposure to Organic Solvents
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Asal et al., 1988 |
Cases from 29 hospitals in Oklahoma diagnosed and confirmed in 1981–1984; hospital controls selected from the same hospitals and matched on age, sex, race, hospital, and date of admission; population-based controls selected through RDD |
315 renal cell carcinoma |
313 hospital 336 population |
Dry-cleaning work Painter or paint-manufacturing work |
In-person interview assessing occupations (job titles) and industrial exposures |
Logistic regression |
Weight, age, alcohol consumption, occupations, smoking, snuff use, coffee consumption, kidney stones, hypertension, other medical factors |
|
No response rates provided |
|
|||||
Jensen et al., 1988 |
Cases, under age 80 years, reported to the Danish Cancer Registry from Copenhagen and the surrounding island of Sjaelland in 1979–1982, with 90% histologic verification; controls selected from the hospitals from which cases arose, excluding those with urinary tract and smoking-related diseases; controls matched for hospital, sex, and age |
96 renal pelvis and ureter |
288 |
Painter or paint-manufacturing work |
In-person interviews with questionnaire assessing personal habits and occupational history (job or industry titles and self-reported exposures) |
Logistic regression |
Sex, lifetime tobacco smoking |
|
Response rates: 99.0% of cases, 100.0% of controls |
|
|||||
Harrington et al., 1989 |
Cases diagnosed and histologically confirmed in 1984–1985 and reported to the West Midlands Regional Cancer Registry (UK); controls randomly selected from practitioner records and matched for age, sex, ethnicity, location, and socioeconomic group |
54 renal |
54 |
Solvents |
In-person interviews with questionnaire assessing lifetime occupational history (job titles); exposure indexes determined by occupational hygienist or chemist |
Matched analyses |
None |
|
No response rates provided |
|
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Sharpe et al., 1989 |
Cases diagnosed at one of four Montreal-area hospitals in 1982–1986 and one of five other hospitals in 1982–1987; cases were histologically confirmed and alive at time of chart review; controls selected from suspected renal-cell carcinoma cases, but final diagnoses were not cancer; matched 1:1 for sex, age, and urologist |
164 renal |
161 |
Organic solvents |
History of exposure to hydrocarbons obtained through mailed questionnaire and supplemented by telephone interview (self-reports) |
Univariat e analysis |
None |
|
Response rate: 97% overall |
|
|||||
Partanen et al., 1991 |
Cases, age over 20 years, identified through the Finnish Cancer Registry in 1977–1978; controls randomly selected from the Population Register Centre matched for year of birth, sex, and survival status |
408 renal cell |
819 |
Nonchlorinat ed solvents |
Mailed questionnaire or phone interview (direct or proxy) assessing lifetime occupational history (job or industry titles); industrial hygienist coded and assigned summary indicators of specific exposures |
Condition al logistic regression |
Matching variables, smoking, coffee consumption, obesity |
|
Response rates: 69% of cases, 68% of controls |
|
|||||
Aschengrau et al., 1993 |
Cases reported to the Massachusetts Cancer Registry, diagnosed in 1983–1986 among residents of five upper Cape Cod towns; living controls were selected from HCFA records and RDD; deceased controls identified by the state Department of Vital Statistics and Research files |
35 kidney |
777 |
Ethylene-ethylene |
Exposure dose estimated in areas of contaminated drinking water, accounting for location and years of residence, water flow, pipe characteristics |
Logistic regression |
Sex, age at diagnosis, vital status, educational level, usual number of cigarettes smoked, occupational exposure to solvents, specific cancer risk factors controlled for in respective analyses |
|
Response rates: 80.6% of cases, 75.9% of HCFA controls, 73.9% of RDD controls, 78.8% of next of kin of deceased controls |
|
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
McCredie and Stewart, 1993 |
Cases, age 20–79 years, among residents of New South Wales in 1989–1990 identified from the New South Wales Central Cancer Registry and from physicians; controls selected from electoral rolls and matched on age distribution |
489 renal cell 147 renal pelvic |
523 |
Dry-cleaning industry work |
Questionnaire (in-person interview or mailed with telephone followup) to assess employment in specific occupations and industries (job or industry titles) |
Logistic regression |
Age, sex, interview method, cigarette smoking, body mass index, education, analgesics use |
|
No response rates provided |
|
|||||
Mellemgaar d et al., 1994 |
Cases, age 20–79 years, identified from the Danish Cancer Registry and pathology departments in 1989–1992 with histologic confirmation; controls selected from the Central Population Register and matched for age and sex |
368 renal cell |
396 |
Dry-cleaning work Solvents |
In-person interviews with questionnaire assessing most recent and longest-held occupation (job titles) and exposure to specific agents (self-reports) |
Logistic regression |
Age, body mass index, smoking |
|
Response rates: 93.2% of cases, 85.6% of controls |
|
|||||
Mandel et al., 1995 |
Cases, age 20–79 years, from six international sites, diagnosed and confirmed in 1989–1991 using cancer registries or surveillance of clinical and pathology departments; controls selected from population registers, electoral rolls, residential lists, HCFA records, or RDD, depending on the site; controls matched on age and sex |
1732 renal |
2309 |
Dry-cleaning solvents Dry-cleaning work |
In-person interviews to assess lifetime occupational history (job titles) and exposure to specific agents (self-reports) |
Logistic regression |
Age, center, body-mass index, cigarette smoking |
|
No response rates provided |
|
|||||
|
(Related to McCredie and Stewart, 1993) |
|
|||||
Schlehofer et al., 1995 |
Cases, age 20–75 years, identified through 10 urology departments in the Rhein-Neckar-Odenwald area of Germany in 1989–1991 with histologic confirmation; controls randomly selected from population register and matched on age and sex |
277 renal cell |
286 |
Chlorinated solvents |
In-person interview with questionnaire assessing exposure (in excess of 5 years) from list of specific substances (self-reports) |
Logistic regression |
|
|
Response rates: 97.3% of cases, 75% of controls |
|
A small cohort study of German cardboard manufacturers exposed to trichloroethylene showed an increased risk of kidney cancer (SIR=7.97, 95% CI 2.59–8.59 and SMR=3.28, 95% CI=0.40–11.84) (Henschler et al., 1995). A case-control study using different cases from the same area as that investigated by Henschler and colleagues also showed an increased risk of kidney cancer (OR=10.8, 95% CI=3.36–34.75) (Vamvakas et al., 1998). A case-control study of kidney cancer in Minnesota showed an association only in women (OR=1.96, 95% CI=1.0–4.0) (Dosemeci et al., 1999). Pesch and colleagues (2000b) showed an increased risk of kidney cancer in men but not women with substantial exposure to trichloroethylene (OR=1.3, 95% CI =0.9–1.8; OR=0.8, 95% CI=0.3–1.9, respectively).
Some of the studies described above that investigated the risk of bladder cancer and exposure to tetrachloroethylene or dry-cleaning solvents also provided results on kidney cancer. The cohort studies of dry-cleaning workers had few exposed cases, and the associations had wide confidence intervals. Ruder and colleagues (2001) reported an increased risk of kidney cancer in dry-cleaning union workers (SMR=1.41, 95% CI=0.46–3.30) and in workers exposed to tetrachloroethylene only (SMR=1.73, 95% CI=0.21–6.25). The study by Blair and colleagues (1990) of dry-cleaning union members found no increased risk of kidney cancer (SMR=0.5, 95% CI=0.1–1.8), and Anttila and colleagues (1995) reported an increased risk of kidney cancer among workers occupationally exposed to tetrachloroethylene (SIR=1.82, 95% CI=0.22–6.56).
Pesch and colleagues (2000b) found an OR of 1.4 (95% CI=1.0–2.0) in men who had “substantial” exposure to tetrachloroethylene according to the German job-exposure matrix; the OR in women was 0.7 (95% CI=0.3–2.2). Mandel and colleagues (1995) also observed an increased risk of kidney cancer among those ever exposed to dry-cleaning solvents (OR=1.4, 95% CI=1.1–1.7). Both studies included large numbers of exposed cases, and the analyses were adjusted for smoking. Although a study of dry cleaners in Germany also reported an association with kidney cancer (OR=2.52, 95% CI=1.23–5.16), the authors indicated that subjects were exposed to a combination of tetrachloroethylene and tetrachlorocarbonate. The latter is a solvent not on the committee’s list to review, so this study (Schlehofer et al., 1995) was not considered critical to the committee’s review of tetrachloroethylene.
Other case-control studies reported associations with kidney cancer. Dosemeci and colleagues showed an OR of 1.12 (95% CI=0.7–1.7) in men exposed to tetrachloroethylene in Minnesota but an OR of 0.82 (95% CI=0.3–2.1) in women. A case-control study of dry cleaners in Denmark (Mellemgaard et al., 1994) showed an OR of 2.3 (95% CI=0.2–2.7) in men and an OR of 2.9 (95% CI=0.3–33) in women. A study in New South Wales (McCredie and Stewart, 1993) showed ORs of 2.49 (95% CI=0.97–6.35) for renal cancer and 4.68 (95% CI=1.32–16.56) for renal pelvic cancer. Another study of dry cleaners in Oklahoma (Asal et al., 1988) found an OR of 8.7 (95% CI=0.9–81.3) for kidney cancer. A study of residents in Cape Cod, Massachusetts (Aschengrau et al., 1993), reported an OR of 1.23 (95% CI=0.45–3.45) for kidney cancer after any exposure to tetrachloroethylene.
Gérin and colleagues (1998) investigated the risk of kidney cancer and exposure to benzene, toluene, and xylene; a weak association with no apparent exposure-response relationship was found for exposure to benzene (low exposure: OR=1.2, 95% CI=0.7–1.9; medium or high exposure: OR=1.3, 95% CI=0.7–2.4). No association was found for either toluene (medium or high exposure: OR=1.0, 95% CI=0.5–2.1) or xylene (medium or high exposure: OR=1.0, 95% CI=0.4–2.4).
The committee reviewed two other studies that investigated the association between kidney cancer and exposure to toluene. Wiebelt and Becker (1999) found no association (OR=0.49, 95% CI=0.06–2.34), and Walker and colleagues (1993) reported an increased risk in men who were potentially exposed to toluene in the shoe-manufacturing industry (SMR=1.71, 95% CI=0.62–3.73).
A cohort study of US isopropyl manufacturers found an association (SMR=6.45, 95% CI=0.78–23.29) between exposure to isopropyl alcohol and kidney cancer (Alderson and Rattan, 1980).
The committee reviewed several cohort studies of painters and workers in aircraft manufacturing (Boice et al., 1999; Garabrant et al., 1988), shoe manufacturing (Fu et al., 1996; Walker et al., 1993), transformer assembly (Greenland et al., 1994), and petroleum refining (Poole et al., 1993) and several case-control studies conducted in Minnesota (Dosemeci et al., 1999), Denmark (Mellemgaard et al., 1994), New South Wales (McCredie and Stewart, 1993), Finland (Partanen et al., 1991), and the United Kingdom (Harrington et al., 1989).
The largest cohort study of painters showed no association between being a painter and kidney cancer (SMR=1.06, 95% CI=0.86–1.29) (Steenland and Palu, 1999), but a positive association was found in other cohorts of painters, including a study by Matanoski and colleagues (1986) (SMR=1.28, 95% CI=0.91–1.76). A study of paint-manufacturing workers showed no association with kidney cancer (SMR=0.39) (Morgan et al., 1981). Several case-control studies that considered occupation as a painter or in paint manufacturing reported positive associations with kidney cancer (Asal et al., 1988: OR=1.3, 95% CI=0.7–2.6; Jensen et al., 1988: OR=1.8, 95% CI=0.7–4.6). Pesch and colleagues (2000b) found that relative risks increased with increasing duration of exposure (medium: OR=1.6, 95% CI=0.8–3.0; very long: OR=2.3, 95% CI 0.8–6.8).
No evidence of an association between exposure to unspecified mixtures of solvents and kidney cancer was found in two cohorts of aircraft manufacturers in California (Boice et al., 1999: SMR=0.81, 95% CI=0.44–1.36; Garabrant et al., 1988: SMR=0.93, 95% CI=0.48–1.64), and the association decreased with increasing years of exposure (Boice et al., 1999). No association was found in an incidence study of Finnish workers monitored for halogenated hydrocarbon exposure (SIR=0.89, 95% CI=0.36–1.82) (Anttila et al., 1995) or among US petroleum-refinery workers exposed to aromatic hydrocarbons (OR=0.95, 95% CI=0.50–1.80). However, a study of dry cleaners in Germany exposed to a mixture of solvents, including tetrachloroethylene and tetrachlorocarbonate, reported an association with kidney cancer (OR=2.52, 95% CI=1.23–5.16) (Schlehofer et al., 1995), as did a study of US transformer-assembly workers exposed to solvents (OR=1.64, 95% CI=0.49–5.50) (Greenland et al., 1994). Two cohort studies of shoe-manufacturing workers also showed an increased association, including Fu and colleagues’ (1996) study of Florence workers (SMR=4.00, 95% CI=0.83–11.69 for high solvent exposure) and Walker and colleagues’ (1993) study (SMR=1.71, 95% CI=0.62–3.73 among men; the SMR was 0.97 among women).
Case-control studies that analyzed self-reported exposure to organic solvents include studies conducted in Minnesota (Dosemeci et al., 1999) and Denmark (Mellemgaard et al., 1994). The study in Minnesota showed ORs close to 1.0: in men, it was 1.12 (95% CI=0.7–1.7), and in women it was 0.82 (95% CI=0.3–2.1). The study in Denmark showed increased risks in both men (OR=2.3, 95% CI=0.2–27) and women (OR=2.9, 95% CI=0.3–33). Other case-control studies reported an association between kidney cancer and nonchlorinated solvents (Partanen et al., 1991: OR=3.46, 95% CI=0.91–13.2) and organic solvents (Sharpe et al.,
1989: OR=1.68, 95% CI=0.89–3.18). Pesch and colleagues (2000b) found positive associations between exposure to organic solvents specifically, using a job-exposure matrix, and to solvents broadly, using a job task-exposure matrix. The relative risks in men were increased on the basis of the job-exposure matrix (OR=1.6, 95% CI=1.1–2.3) and the job task-exposure matrix (OR=1.5, 95% CI=1.0–2.3). The risks were increased in women on the basis of the job task-exposure matrix (OR=2.1, 95% CI=1.0–4.4), but not the job-exposure matrix (OR=0.3, 95% CI=0.1–1.3). No association was found in the study by Harrington and colleagues (1989) that examined exposure to solvents in the UK (OR=1.0, 95% CI=0.2–4.9).
Summary and Conclusions
Because of their small numbers of cases, most studies on exposure to trichloroethylene and kidney cancer lacked the power to detect excess risks. Although positive associations were suggested by three studies (Henschler et al., 1995; Pesch et al., 2000b; Vamvakas et al., 1998), one was based on self-reported exposures (Vamvakas et al., 1998), and the committee was concerned about bias. The committee did not find the results of the other case-control study to be persuasive (Pesch et al., 2000b). The findings of the cohort study (Henschler et al., 1995) were based on a cluster of cases. For exposure to benzene, toluene, xylene, and isopropyl alcohol, there was only a small number of studies available, and they lacked consistently positive findings. Therefore, the committee determined that the evidence for these exposes was insufficient to determine whether an association exists for kidney cancer.
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 solvents under review, other than tetrachloroethylene and dry-cleaning solvents, and kidney cancer.
For exposure to tetrachloroethylene and dry-cleaning solvents, positive associations were observed in several well-conducted studies (Mandel et al., 1995; McCredie and Stewart, 1993; Pesch et al., 2000b), and the committee determined that the evidence between exposure to tetrachloroethylene and dry-cleaning solvents and risk of kidney cancer was limited/suggestive of an association.
The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between chronic exposure to tetrachloroethylene and dry-cleaning solvents and kidney cancer.
Although several case-control studies showed an increased risk of kidney cancer with exposure to unspecified mixtures of organic solvents (including Dosemeci et al., 1999; Jensen et al., 1988; Mellemgaard et al., 1994; Partanen et al., 1991; Pesch et al., 2000b; and Sharpe et al., 1989), several cohort studies did not, including the largest study of painters (Steenland and Palu, 1999), the painter study by Morgan and colleagues (1981), two studies of aircraft manufacturers (Boice et al., 1999; Garabrant et al., 1988), a biologically monitored study (Anttila et al., 1995), and a study on petroleum-refinery workers (Poole et al., 1993). As a result, the committee was unable to reach a consensus on an association between kidney cancer and exposure to organic solvents. Some committee members believed that the evidence was limited/suggestive, and others believed that it was inadequate/insufficient to determine whether an association exists. In evaluating each study and the overall body of evidence, committee members differed in their judgment about the extent to which bias and confounding affected the results.
The large number of positive findings from the case-control studies, especially among women, and the use of a job-exposure matrix by Pesch and colleagues (2000b) were supportive of a conclusion that the evidence was limited/suggestive of an association between exposure to unspecified mixtures of solvents and kidney cancer. In contrast, the lack of positive findings in large cohorts of occupationally exposed populations—such as painters, aircraft manufacturers, and petroleum refinery workers—and in a biologically monitored cohort of Finnish workers (Anttila et al., 1995), the lack of increased risks as exposure and duration of exposure increased (Boice et al., 1999), and the large number of case-control studies that relied on self-reported exposures (Asal et al., 1988; Dosemeci et al., 1999; Jensen et al., 1988; McCredie and Stewart, 1993; Mellemgaard et al., 1994; Schlehofer et al., 1995; Sharpe et al., 1989) supported a conclusion that the evidence was inadequate/insufficient to determine whether an association exists.
Thus, the committee could not reach a consensus conclusion for kidney cancer and exposure to unspecified mixtures of organic solvents. As more studies are conducted on organic solvents and the risk of kidney cancer, future committees may revisit this literature in evaluating the evidence of association.
The studies reviewed by the committee in making its conclusions are identified below in Table 6.30. Unless indicated in the table, the study populations include both men and women.
TABLE 6.30 Selected Epidemiologic Studies—Kidney Cancer and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Studies—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored Danish workers |
|
|
Males, ever exposed |
3 |
0.9 (0.2–2.6) |
|
|
Females, ever exposed |
1 |
2.4 (0.03–14) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
|
|
No exposure |
9 |
1.6 (0.5–5.4) |
|
<5 unit-years |
9 |
1.4 (0.4–4.7) |
|
5–25 unit-years |
5 |
1.3 (0.3–4.7) |
Henschler et al., 1995 |
Male German cardboard manufacturers, employed >1 year |
5 |
7.97 (2.59–8.59) |
Anttila et al., 1995 |
Finnish workers occupationally exposed |
|
|
Entire period since first measurement |
6 |
0.87 (0.32–1.89) |
|
|
0–9 |
1 |
0.53 (0.01–2.95) |
|
10–19 |
5 |
1.39 (0.45–3.24) |
|
20+ |
0 |
—(0.00–2.48) |
Axelson et al., 1994 |
Swedish men occupationally exposed |
6 |
1.16 (0.42–2.52) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, routine exposure |
7 |
0.99 (0.40–2.04) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
|
|
No trichloroethylene exposure |
10 |
2.5 (0.7–8.9) |
|
<5 unit-years |
8 |
2.0 (0.5–7.6) |
|
5–25 unit-years |
1 |
0.4 (0.1–4.0) |
|
Low-level intermittent |
12 |
2.1 (0.6–7.5) |
|
Low-level continuous |
9 |
2.2 (0.6–8.1) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Morgan et al., 1998 |
Aerospace workers in Arizona |
|
|
Any exposure |
8 |
1.32 (0.57–2.60) |
|
|
Low exposure |
1 |
0.47 (0.01–2.62) |
|
High exposure |
7 |
1.78 (0.72–3.66) |
Henschler et al., 1995 |
Male German cardboard manufacturers, employed >1 year |
2 |
3.28 (0.40–11.84) |
Greenland et al., 1994 |
White male US transformer manufacturers, ever exposed |
NA |
0.99 (0.30–3.32) |
Case-Control Studies |
|||
Pesch et al., 2000b |
Participants in multiple centers in Germany |
|
|
German job-exposure matrix |
|
||
|
Trichloroethylene (males) |
|
|
|
Medium |
135 |
1.1 (0.9–1.4) |
|
High |
138 |
1.1 (0.9–1.4) |
|
Substantial |
55 |
1.3 (0.9–1.8) |
|
Trichloroethylene (females) |
|
|
|
Medium |
28 |
1.2 (0.8–1.8) |
|
High |
29 |
1.3 (0.8–2.0) |
|
Substantial |
6 |
0.8 (0.3–1.9) |
|
Job task-exposure matrix approach |
|
|
|
Trichloroethylene (males) |
|
|
|
Medium |
68 |
1.3 (1.0–1.8) |
|
High |
59 |
1.1 (0.8–1.5) |
|
Substantial |
22 |
1.3 (0.8–2.1) |
|
Trichloroethylene (females) |
|
|
|
Medium |
11 |
1.3 (0.7–2.6) |
|
High |
7 |
0.8 (0.4–1.9) |
|
Substantial |
5 |
1.8 (0.6–5.0) |
Dosemeci et al., 1999 |
Residents of Minnesota |
55 |
1.30 (0.9–1.9) |
Males |
33 |
1.04 (0.6–1.7) |
|
|
Females |
22 |
1.96 (1.0–4.0) |
Vamvakas et al., 1998 |
Residents of Germany with long-term exposure |
19 |
10.8 (3.36–34.75) |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Study—Incidence |
|||
Anttila et al., 1995 |
Finnish workers monitored for exposure |
2 |
1.82 (0.22–6.56) |
Cohort Studies—Mortality |
|||
Ruder et al., 2001 |
Dry-cleaning labor-union workers |
5 |
1.41 (0.46–3.30) |
Tetrachloroethylene only |
2 |
1.73 (0.21–6.25) |
|
|
Tetrachloroethylene plus other solvents (likely Stoddard) |
3 |
1.27 (0.26–3.72) |
Blair et al., 1990 |
Members of a dry-cleaning union in St. Louis, MO |
2 |
0.5 (0.1–1.8) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Case-Control Studies |
|||
Pesch et al., 2000b |
Participants in multiple centers in Germany |
|
|
German job-exposure matrix |
|
||
|
Tetrachloroethylene (males) |
|
|
|
Medium |
154 |
1.4 (1.1–1.7) |
|
High |
119 |
1.1 (0.9–1.4) |
|
Substantial |
50 |
1.4 (1.0–2.0) |
|
Tetrachloroethylene (females) |
|
|
|
Medium |
12 |
0.7 (0.4–1.3) |
|
High |
19 |
1.1 (0.7–1.9) |
|
Substantial |
4 |
0.7 (0.3–2.2) |
|
Job task-exposure matrix approach |
|
|
|
Tetrachloroethylene (males) |
|
|
|
Medium |
44 |
1.2 (0.9–1.7) |
|
High |
39 |
1.1 (0.7–1.5) |
|
Substantial |
15 |
1.3 (0.7–2.3) |
|
Tetrachloroethylene (females) |
|
|
|
Medium |
8 |
2.2 (0.9–5.2) |
|
High |
6 |
1.5 (0.6–3.8) |
|
Substantial |
3 |
2.0 (0.5–7.8) |
Dosemeci et al., 1999 |
Residents of Minnesota |
50 |
1.07 (0.7–1.6) |
Males, ever exposed |
42 |
1.12 (0.7–1.7) |
|
|
Females, ever exposed |
8 |
0.82 (0.3–2.1) |
Schlehofer et al., 1995 |
Residents of Germany |
|
|
Tetrachloroethylene and tetrachlorocarbonate, exposed >5 years |
27 |
2.52 (1.23–5.16) |
|
Mandel et al., 1995 |
International renal cell carcinoma cases |
|
|
Dry-cleaning industry, ever employed |
8 |
0.9 (0.3–2.4) |
|
|
Dry-cleaning solvents, ever exposed |
245 |
1.4 (1.1–1.7) |
|
1–7 years |
70 |
1.2 (0.9–1.8) |
|
8–25 years |
98 |
1.7 (1.2–2.4) |
|
26–60 years |
75 |
1.2 (0.9–1.8) |
Mellemgaard et al., 1994 |
Residents of Denmark, employed >10 years before as dry cleaners |
|
|
|
Males |
2 |
2.3 (0.2–27) |
|
Females |
2 |
2.9 (0.3–33) |
McCredie and Stewart, 1993 |
Residents of New South Wales, ever employed in dry-cleaning industry |
|
|
|
Renal |
16 |
2.49 (0.97–6.35) |
|
Renal pelvis |
8 |
4.68 (1.32–16.56) |
Aschengrau et al., 1993 |
Residents of upper Cape Cod, MA |
|
|
Any exposure |
6 |
1.23 (0.40–3.11) |
|
|
Low exposure |
6 |
1.36 (0.45–3.45) |
Asal et al., 1988 |
Female residents of Oklahoma, usual dry-cleaning occupation |
NA |
8.7 (0.9–81.3) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Benzene |
|||
Case-Control Study |
|||
Gérm et al., 1998 |
Male residents of Montreal, Canada |
|
|
Low exposure |
27 |
1.2 (0.7–1.9) |
|
|
Medium or high exposure |
12 |
1.3 (0.7–2.4) |
Toluene |
|||
Cohort Studies—Mortality |
|||
Wiebelt and Becker, 1999 |
Male German rotogravure printers, employed >1 year |
2 |
0.49 (0.06–2.34) |
Walker et al., 1993 |
Shoe manufacturers in two plants in Ohio, potentially exposed to toluene and other solvents |
|
|
|
Total |
9 |
1.36 (0.62–2.59) |
|
Males |
6 |
1.71 (0.62–3.73) |
|
Females |
3 |
0.97 (0.20–2.84) |
Case-Control Study |
|||
Gérin et al., 1998 |
Male residents of Montreal, Canada |
|
|
Low exposure |
17 |
0.9 (0.5–1.5) |
|
|
Medium or high exposure |
8 |
1.0 (0.5–2.1) |
Xylene |
|||
Case-Control Study |
|||
Gérin et al., 1998 |
Male residents of Montreal, Canada |
|
|
Low exposure |
17 |
1.0 (0.6–1.7) |
|
|
Medium or high exposure |
6 |
1.0 (0.4–2.4) |
Isopropyl Alcohol |
|||
Cohort Study—Mortality |
|||
Alderson and Rattan, 1980 |
Male UK isopropyl manufacturers, employed >1 year |
2 |
6.45 (0.78–23.29)a |
Unspecified Mixtures of Organic Solvents |
|||
Cohort Study—Incidence |
|||
Anttila et al., 1995 |
Finnish workers monitored for exposure |
|
|
Halogenated hydrocarbons |
7 |
0.89 (0.36–1.82) |
|
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
Mixed solvents, routine exposure |
14 |
0.81 (0.44–1.36) |
|
|
Years exposed |
|
|
|
<1 |
11 |
1.54 (0.74–3.20) |
|
1–4 |
19 |
1.08 (0.58–2.01) |
|
≥5 |
14 |
0.41 (0.20–0.82) |
Steenland and Palu, 1999 |
US painters and other union members |
|
|
Painters |
100 |
1.06 (0.86–1.29) |
|
|
20 years since membership |
71 |
0.97 (0.76–1.22) |
|
Nonpainters |
21 |
0.77 (0.48–1.18) |
|
20 years since membership |
12 |
0.67 (0.34–1.17) |
Fu et al., 1996 |
Shoe-manufacturing workers |
|
|
|
English workers: |
|
|
|
Probable solvent exposure |
1 |
0.25 (0.01–1.37) |
|
High solvent exposure |
0 |
— |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
|
Florence workers: |
|
|
|
Probable solvent exposure |
3 |
3.53 (0.73–10.31) |
|
High solvent exposure |
3 |
4.00 (0.83–11.69) |
Greenland et al., 1994 |
White male US transformer-assembly workers |
|
|
Solvents, ever exposed |
NA |
1.64 (0.49–5.50) |
|
Poole et al., 1993 |
Male US petroleum-refinery workers |
|
|
Aromatic hydrocarbons, ever exposed |
80 |
0.95 (0.50–1.80) |
|
|
Chlorinated solvents, ever exposed |
12 |
0.69 (0.32–1.50) |
Walker et al., 1993 |
Shoe-manufacturing workers in Ohio, potentially exposed |
9 |
1.36 (0.62–2.59) |
|
Males |
6 |
1.71 (0.62–3.73) |
|
Females |
3 |
0.97 (0.20–2.84) |
Garabrant et al., 1988 |
Aircraft-manufacturing workers in California |
12 |
0.93 (0.48–1.64) |
Matanoski et al., 1986 |
US painters and allied tradesmen, union members |
38 |
1.28 (0.91–1.76) |
Morgan et al., 1981 |
Male US paint and coatings manufacturers, employed >1 year |
5 |
0.39 |
Case-Control Studies |
|||
Pesch et al., 2000b |
Residents of multiple centers in Germany |
|
|
Painters or dyers, males, duration of exposure: |
|
||
|
Medium |
12 |
1.6 (0.8–3.0) |
|
Long |
10 |
1.4 (0.7–2.8) |
|
Very long |
5 |
2.3 (0.8–6.8) |
|
Job-exposure matrix, organic solvents: |
|
|
|
Males, substantial exposure |
38 |
1.6 (1.1–2.3) |
|
Females, substantial exposure |
2 |
0.3 (0.1–1.3) |
|
Job task-exposure matrix, solvents: |
|
|
|
Males, substantial exposure |
33 |
1.5 (1.0–2.3) |
|
Females, substantial exposure |
10 |
2.1 (1.0–4.4) |
Dosemeci et al., 1999 |
Residents of Minnesota |
|
|
Solvents, ever exposed |
126 |
1.16 (0.9–1.5) |
|
|
Males |
91 |
0.93 (0.7–1.3) |
|
Females |
35 |
2.29 (1.3–4.2) |
Schlehofer et al., 1995 |
Residents of Germany |
|
|
Tetrachloroethylene and tetrachlorocarbonate, exposed >5 years |
27 |
2.52 (1.23–5.16) |
|
Mellemgaard et al., 1994 |
Residents of Denmark |
|
|
Solvents, exposed >10 years before |
|
||
|
Males |
50 |
1.5 (0.9–2.4) |
|
Females |
16 |
6.4 (1.8–23.0) |
McCredie and Stewart, 1993 |
Residents of New South Wales, ever exposed to solvents |
|
|
|
Renal |
109 |
1.54 (1.11–2.14) |
|
Renal pelvis |
24 |
1.40 (0.82–2.40) |
BRAIN AND OTHER CENTRAL NERVOUS SYSTEM CANCERS
Description of Case-Control Studies
Three case-control studies of brain cancer were identified. They included different histologic types of brain cancer: astrocytic (Heineman et al., 1994; Thomas et al., 1987), gliomas (Rodvall et al., 1996), and unspecified brain cancers (Paulu et al., 1999). Occupational exposure information was obtained from next of kin (Heineman et al., 1994; Thomas et al., 1987) or from subjects (Rodvall et al., 1996), and in a study of tetrachloroethylene in drinking water the exposure information was based on water quality data (Paulu et al., 1999). In two studies, industrial hygienists attributed exposure to specific solvents on the basis of their own expertise and information provided by subjects (Rodvall et al., 1996; Thomas et al., 1987), and a job-exposure matrix was used in an updated analysis of the Thomas and colleagues’ study (1987) (Heineman et al., 1994) (see Table 6.31).
Epidemiologic Studies of Exposure to Organic Solvents and Brain and Central Nervous System Cancers
Most studies found null associations when investigating the relationship between trichloroethylene and risk of brain and other CNS cancers, including studies of workers biologically monitored for exposure (SIR=1.09, 95% CI=0.50–2.07) (Anttila et al., 1995), of workers in the aircraft and aerospace industries (Blair et al., 1998: SMR=0.8, 95% CI=0.2–2.2; Boice et al., 1999: SMR=0.54, 95% CI=0.15–1.37; Morgan et al., 1998: SMR=0.55, 95% CI=0.15–1.40), and of workers in transformer assembly (OR=0.93, 95% CI=0.32–2.69) (Greenland et al., 1994).
TABLE 6.31 Description of Case-Control Studies of Brain and Central Nervous System Cancers and Exposure to Organic Solvents
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Thomas et al., 1987 |
White, male cases, age 30 years or more, identified from death certificates in southern Louisiana, northern New Jersey, and Philadelphia in 1978–1981; deceased controls from other causes collected in the same fashion, matched for age, year of death, and study area (see also Heineman et al., 1994) |
300 astrocytic brain tumors |
386 |
Organic solvents |
In-person interview of next of kin with structured questionnaire to assess lifetime occupational history (job titles); probability of exposure determined by industrial hygienist assessment |
Maximum likelihood estimate |
Age at death, cigarette smoking, alcoholism, ethnicity, education |
|
Response rates (next-of-kin): 74% of cases, 63% of controls |
|
|||||
Heineman et al., 1994 |
See above, Thomas et al., 1987 |
Same cases as above |
320 |
Trichloroethylene Tetrachloroethylene Methylene chloride Chloroform Organic solvents |
In-person interview of next of kin with structured questionnaire to assess lifetime occupational history (job titles); probability of exposure to six chlorinated hydrocarbons determined with job-exposure matrixes |
Logistic regression |
Age, study area |
|
Response rates (next-of-kin): 74% of cases, 63% of controls |
|
|||||
Rodvall et al., 1996 |
Cases, age 25–74 years, reported to the Regional Cancer Registry among residents of the catchment area of the Uppsala University Hospital in Sweden, with histologic confirmation; controls selected from parish records and matched for sex and age |
151 brain gliomas |
343 |
Trichloroethylene Benzene Toluene Xylene Solvents |
Self-reported occupational history (job titles) and exposure to specific agents (self-reports) reviewed by occupational hygienist and to assess probability of exposure to specific agents |
Multiple logistic regression |
Sex, age, population density |
|
Response rates: 79% of cases, 82% of controls |
|
Three studies reported positive associations. Ritz (1999) found a 27% increase in mortality in US uranium processing plant workers (SMR=1.27, 95% CI=0.66–2.22) and found that relative risks increased with duration as well as with level of exposure to trichloroethylene. Heineman and colleagues (1994), in a case-control study of astrocytic brain cancer, found no increases in relative risk of brain cancer (OR=1.1, 95% CI=0.8–1.6), although relative risks increased with duration of exposure among subjects whose exposures were classified as highly probable (2–20 years: OR=1.1, 95% CI=0.3–3.7; more than 20 years: OR=6.1, 95% CI=0.7–143.5). Rodvall and colleagues (1996) found an increased risk of glioma among men who reported exposure to trichloroethylene (OR=2.4, 95% CI=0.9–6.4).
No associations between exposure to tetrachloroethylene or to dry-cleaning solvents and brain or other CNS cancers were found in the three cohort studies reviewed by the committee (Anttila et al., 1995; Blair et al., 1990; Boice et al., 1999). No association was found in the case-control study of contaminated drinking water (Paulu et al., 1999). A 20% increased risk (OR=1.2, 95% CI=0.8–1.6) was found in the case-control study by Heineman and colleagues (1994), but the relative risks did not increase with increasing probability of exposure.
Two studies of photographic film-base manufacturing workers showed an increased risk of brain and other CNS cancer deaths (Hearne and Pifer, 1999: SMR=2.16, 95% CI=0.79–4.69; Tomensen et al., 1997: SMR=1.45, 95% CI=0.40–3.72). In a study of two nuclear facilities, Carpenter and colleagues (1988) found that the risk of CNS cancer increased with increasing years of exposure to methylene chloride (10–20 years of exposure, 10-year latency: OR=1.8; over 20 years of exposure, 10-year latency: OR=4.01), but the numbers of cases were too small to form any meaningful inferences. In contrast, Heineman and colleagues (1994) found that the risk of astrocytic brain cancer increased with the probability of exposure (medium probability: OR=1.6, 95% CI=0.8–3.0; high probability: OR=2.4, 95% CI=1.0–5.9) and that risk increased with duration of exposure among subjects with high probability of exposure to methylene chloride (2–20 years: OR=1.8, 95% CI=0.6–6.0; over 20 years: OR=6.1, 95% CI 1.1–43.8).
Yin and colleagues (1996a) studied benzene-exposed workers in China and reported a 30% increase in the risk of malignant brain tumors and benign tumors of the brain and unspecified CNS (RR=1.3, 95% CI=0.5–4.1). When levels of exposure to benzene were incorporated into a second analysis (Hayes et al., 1996), risk did not increase with increasing cumulative exposure. In a cohort study of women in Shanghai, China, with high probability of exposure to benzene, Heineman and colleagues (1995) found an 80% excess incidence of brain cancer (SIR=1.8, 95% CI=1.1–2.8); they also found a dose-response relationship between low exposure to benzene and high exposure (SIR=1.5, 95% CI=0.6–3.4 for low, and SIR=1.8, 95% CI=1.1–2.9 for high). In a cohort of benzene-exposed workers at Monsanto chemical plants, risk among production workers increased with increasing cumulative exposure, and maintenance workers showed a 20% excess risk (SMR=1.2, 95% CI=0.4–2.5) (Ireland et al., 1997).
A nested case-control study of transformer-assembly workers showed an increased risk of malignant and unspecified brain tumors (OR=2.1, 95% CI=1.0–4.4) (Greenland et al., 1994). The nested case-control study of workers at two nuclear facilities showed no increase in CNS tumors among those exposed to benzene (ever exposed, 10-year latency: OR=0.57) (Carpenter et al., 1988). In a population-based case-control study of brain gliomas in Sweden (Rodvall et al., 1996), a 450% increase in relative risk was found (OR=5.5, 95% CI=1.4–21.3).
Only a few investigations have examined the relationship between brain and other CNS cancers and other solvents, including xylene, toluene (Anttila et al., 1998; Rodvall et al., 1996), phenol (Dosemeci et al., 1991), diethylene glycol, ethanol, isopropanol (Leffingwell et al., 1983), and chloroform (Heineman et al., 1994). They yielded no strong support of associations with any of these solvents.
Many of the previously described studies also examined the risk of brain and other CNS cancers in relation to unspecified mixtures of organic solvents. Of the cohort studies, only Boice and colleagues (1999) did not show an increased relative risk among aircraft-manufacturing workers in California who were routinely exposed to mixed solvents (SMR=0.68, 95% CI=0.36–1.16). The study of women in Shanghai, China, showed an SIR of 2.0 (95% CI=1.3–3.0) with high probability of exposure to solvent mixtures (Heineman et al., 1995), which was supported by a study of US transformer-assembly workers who were ever exposed to solvents (OR=2.65, 95% CI=0.84–8.36) (Greenland et al., 1994). On the basis of probability of exposure to solvents, Heineman and colleagues (1995) observed a dose-response relationship with an SIR of 1.2 (95% CI=1.0–1.5) for low probability of exposure and 2.0 (95% CI=1.3–3.0) for high probability. Carpenter and colleagues (1988) also showed an increased relative risk among workers at two nuclear facilities exposed to various solvents (exposed to trichloroethylene, tetrachloroethylene, and methyl chloroform, no latency: OR=1.76; with 10-year latency: OR=1.26). Those exposed to toluene, xylene, and methyl ethyl ketone showed an OR of 1.96 with no latency and 1.37 with 10-year latency.
Two case-control studies also showed positive associations between exposure to unspecified mixtures of organic solvents and brain and other CNS cancer. The study by Rodvall and colleagues (1996) showed an OR of 2.6 (95% CI=1.3–5.2) for brain gliomas among men with self-reported exposure to solvents; the OR for women was 0.4 (95% CI=0.1–2.0). Among people with astrocytic brain tumors in Louisiana, New Jersey, and Philadelphia, the odds ratios increased with increasing probability of exposure (low probability: OR=1.1, 95% CI=0.6–1.7; medium probability: OR=1.5, 95% CI=0.8–2.7; high probability: OR=1.4, 95% CI=0.9–2.1) and with duration of employment (2–20 years: OR=1.1, 95% CI=0.7–1.7; over 20 years: OR=1.7, 95% CI=1.1–2.6).
Summary and Conclusion
Although several studies on trichloroethylene exposure and brain and CNS cancers were positive, a number of limitations weakened their support for an association. Of particular concern was the study by Ritz (1999) of uranium processing plant workers who were also exposed to radioactive dust that could have been associated with brain cancer. In addition, most studies had wide CIs associated with the relative risk estimates, and there was a lack of a body of evidence related to specific types of brain cancer. For exposure to tetrachloroethylene and dry-cleaning solvents, most of the studies did not find an association. In contrast, one study on methylene chloride showed a strong association with astrocytic brain cancer (Heineman et al., 1994) but it was not supported by findings from the cohort studies of all types of brain and other CNS cancers.
Two cohort studies (Greenland et al., 1994; Heineman et al., 1995) and one population-based study in Sweden (Rodvall et al., 1996) of brain cancer showed increased risks with exposure to benzene. In the cohort studies, all brain cancers were grouped together; in the case-control study, histologically confirmed cases of glioma were included (Rodvall et al., 1996). There is no likelihood of recall bias in the case-control study by Rodvall and colleagues,
inasmuch as exposures were attributed by industrial hygienists unaware of the status of subjects. The committee did not believe that any of these studies were subject to strong confounding biases, in that risk factors for brain and other CNS cancer are not well known. A dose-response relationship between brain and other CNS cancers and increasing levels of exposure was supported by two studies: Heineman et al., 1995; Ireland et al., 1997. However, the study by Hayes and colleagues (1996) did not yield a dose-response relationship based on years of exposure to benzene, nor did the nested case-control study by Carpenter and colleagues (1988) support an association with brain or other CNS cancers. Moreover, several studies were based on small numbers of exposed cases. As a result, the committee did not reach a consensus. Some committee members believed that the evidence was limited/suggestive of an association; others believed it was inadequate/insufficient to determine whether an association exists. Additional research will help to clarify whether an association exists between exposure to benzene and the risk of brain and other CNS cancers.
All but one of the studies reviewed by the committee reported positive associations between exposure to solvent mixtures and brain and other CNS cancers, including two that showed a slight dose-response pattern (Heineman et al., 1994, 1995). However, the studies did not examine the same cancer outcomes; some evaluated only brain cancer, others looked at brain and other CNS cancers together, and still others evaluated specific subtypes of brain cancer. Furthermore, the mixtures of solvents were known in some studies and unspecified in others. Given those concerns and the consistently positive findings, the committee could not reach a consensus; the evidence was neither wholly inadequate/insufficient to determine whether an association exists nor wholly limited/suggestive.
Table 6.32 identifies the key studies and relevant data points reviewed by the committee in drawing its conclusions. Unless indicated in the tables, the study populations include both men and women.
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 the solvents under review, other than benzene, and brain or other central nervous system cancers.
TABLE 6.32 Selected Epidemiologic Studies—Brain and Central Nervous System Tumors and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Study—Incidence |
|||
Anttila et al., 1995 |
Biologically monitored workers in Finland |
|
|
|
Entire period since first measurement |
9 |
1.09 (0.50–2.07) |
|
0–9 years |
0 |
—(0–1.26) |
|
10–19 years |
8 |
2.00 (0.86–3.93) |
|
20+ years |
1 |
0.76 (0.02–4.26) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
4 |
0.54 (0.15–1.37) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Ritz, 1999 |
White male US uranium-processing plant workers |
|
|
|
Trichloroethylene, cutting fluids, or kerosene |
12 |
1.27 (0.66–2.22) |
|
Trichloroethylene—light exposure |
|
|
|
>2 years, no latency |
6 |
1.81 (0.49–6.71) |
|
>2 years, 15-year latency |
4 |
2.29 (0.42–12.5) |
|
>5 years, no latency |
3 |
1.32 (0.28–6.17) |
|
>5 years, 15-year latency |
3 |
5.41 (0.87–33.9) |
|
Trichloroethylene—moderate exposure |
|
|
|
>2 years, no latency |
1 |
3.26 (0.37–28.9) |
|
>2 years, 15-year latency |
1 |
6.94 (0.66–73.1) |
|
>5 years, no latency |
1 |
4.52 (0.49–41.5) |
|
>5 years, 15-year latency |
1 |
14.4 (1.24–167.0) |
Blair et al., 1998 |
Male aircraft-maintenance workers in Utah |
11a |
0.8 (0.2–2.2) |
|
<5 unit-years |
3 |
2.0 (0.2–19.7) |
|
5–25 unit-years |
4 |
3.9 (0.4–34.9) |
|
>25 unit-years |
1 |
0.8 (0.1–13.2) |
Morgan et al., 1998 |
Aerospace workers in Arizona, employed >6 months |
4 |
0.55 (0.15–1.40) |
Greenland et al., 1994 |
White male US transformer-assembly workers, ever exposed |
NA |
0.93 (0.32–2.69) |
Case-Control Studies |
|||
Rodvall et al., 1996 |
Hospital catchment-area residents of Sweden, ever exposed (gliomas) |
NA |
2.4 (0.9–6.4) |
Heineman et al., 1994 |
Male residents of Louisiana, New Jersey, and Philadelphia (astrocytic brain tumors) |
|
|
|
Ever exposed |
128 |
1.1 (0.8–1.6) |
|
Low probability |
67 |
1.1 (0.7–1.7) |
|
Medium probability |
42 |
1.1 (0.6–1.8) |
|
High probability |
12 |
1.1 (0.5–2.8) |
|
Duration of employment |
|
|
|
2–20 years |
7 |
1.1 (0.3–3.7) |
|
21+ years |
5 |
6.1 (0.7–143.5) |
Tetrachloroethylene and Dry-cleaning Solvents |
|||
Cohort Study—Incidence |
|||
Anttila et al., 1995 |
Biologically monitored workers in Finland, ever exposed |
2 |
1.15 (0.14–4.15) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
2 |
0.59 (0.07–2.14) |
Blair et al., 1990 |
Dry-cleaning union members in Missouri |
1 |
0.2 (0.0–1.2) |
Case-Control Studies |
|||
Paulu et al., 1999 |
Massachusetts residents exposed through public drinking water |
3 |
0.6 (0.1–1.7) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Heineman et al., 1994 |
Male residents of Louisiana, New Jersey, and Philadelphia (astrocytic brain tumors) |
|
|
|
Ever exposed |
111 |
1.2 (0.8–1.6) |
|
Low probability |
72 |
1.3 (0.8–1.9) |
|
Medium probability |
30 |
0.9 (0.5–1.6) |
|
High probability |
9 |
1.2 (0.4–3.5) |
|
Duration of employment |
|
|
|
2–20 years |
71 |
1.1 (0.7–1.6) |
|
21+ years |
28 |
1.4 (0.7–2.7) |
Methylene Chloride |
|||
Cohort Studies—Mortality |
|||
Hearne and Pifer, 1999 |
Male US photographic-film base manufacturing workers, employed >1 year |
6 |
2.16 (0.79–4.69) |
Tomenson et al., 1997 |
Male UK photographic-film base manufacturing workers, ever employed |
4 |
1.45 (0.40–3.72) |
Carpenter et al., 1988 |
Workers at two nuclear facilities |
|
|
|
All workers |
|
|
|
No latency |
29 |
1.38 |
|
10-year latency |
21 |
1.00 |
|
Workers with moderate or high exposure: |
|
|
|
>1 and ≤3 years of exposure |
|
|
|
No latency |
2 |
1.19 |
|
10-year latency |
0 |
— |
|
>3 and ≤10 years of exposure |
|
|
|
No latency |
3 |
1.33 |
|
10-year latency |
2 |
0.83 |
|
>10 and ≤20 years of exposure |
|
|
|
No latency |
1 |
0.50 |
|
10-year latency |
1 |
1.80 |
|
>20 years of exposure |
|
|
|
No latency |
1 |
4.00 |
|
10-year latency |
1 |
4.01 |
Case-Control Study |
|||
Heineman et al., 1994 |
Male residents of Louisiana, New Jersey, and Philadelphia (astrocytic brain tumors) |
|
|
|
Ever exposed |
119 |
1.3 (0.9–1.8) |
|
Low probability |
71 |
1.0 (0.7–1.6) |
|
Medium probability |
29 |
1.6 (0.8–3.0) |
|
High probability |
19 |
2.4 (1.0–5.9) |
|
Duration of employment |
|
|
|
2–20 years |
9 |
1.8 (0.6–6.0) |
|
21+ years |
8 |
6.1 (1.1–43.8) |
Benzene |
|||
Cohort Study—Incidence |
|||
Heineman et al., 1995 |
Women in Shanghai, China |
|
|
|
Low exposure probability |
5 |
1.6 (0.5–3.7) |
|
High exposure probability |
19 |
1.8 (1.1–2.8) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
|
Low-level exposure |
6 |
1.5 (0.6–3.4) |
|
High-level exposure |
18 |
1.8 (1.1–2.9) |
|
High probability and high-level exposure |
16 |
1.7 (1.0–2.8) |
Cohort Studies—Mortality |
|||
Ireland et al., 1997 |
Benzene-exposed male Monsanto workers |
|
|
|
Production workers |
|
|
|
<12 ppm-month |
1 |
1.6 (0.0–8.7) |
|
12–72 ppm-month |
1 |
1.9 (0.0–10.5) |
|
≥72 ppm-month |
2 |
4.4 (0.5–15.8) |
|
Maintenance workers |
6 |
1.2 (0.4–2.5) |
Yin et al., 1996a |
Chinese factory workers, ever exposed |
13 |
1.3 (0.5–4.1) |
Hayes et al., 1996 |
Benzene-exposed workers in China |
|
|
|
Cumulative exposure |
|
|
|
<10 ppm-years |
1 |
0.8 |
|
10–39 ppm-years |
3 |
1.9 |
|
40–99 ppm-years |
2 |
1.3 |
|
100–400 ppm-years |
1 |
0.4 |
|
400+ ppm-years |
5 |
2.3 |
|
p trend=0.48 |
||
Greenland et al., 1994 |
White male US transformer-assembly workers, ever exposed, high probability |
NA |
2.1 (1.0–4.4) |
Carpenter et al., 1988 |
Workers at two nuclear facilities, ever exposed |
|
|
|
No latency |
28 |
0.76 |
|
10-year-latency |
20 |
0.57 |
Case-Control Study |
|||
Rodvall et al., 1996 |
Hospital catchment-area residents of Sweden, ever exposed (gliomas) |
NA |
5.5 (1.4–21.3) |
Other Specific Organic Solvents |
|||
Cohort Study—Incidence |
|||
Anttila et al., 1998 |
Finnish workers biologically monitored for exposure to aromatic hydrocarbons |
|
|
|
Toluene |
3 |
1.09 (0.22–3.18) |
|
Xylene |
3 |
1.62 (0.33–4.72) |
Cohort Studies—Mortality |
|||
Dosemeci et al., 1991 |
Male US industrial workers exposed to phenol |
10 |
0.7 (0.4–1.4) |
Leffingwell et al., 1983 |
Male workers at a Texas chemical plant, ever exposed (gliomas) |
|
|
|
Diethylene glycol |
11 |
1.25 (0.48–3.25)b |
|
Ethanol |
11 |
1.19 (0.47–3.01)b |
|
Isopropanol |
13 |
1.73 (0.59–5.07)b |
Case-Control Studies |
|||
Rodvall et al., 1996 |
Hospital catchment-area residents of Sweden, ever exposed (gliomas) |
|
|
|
Toluene |
NA |
3.4 (0.6–19.3) |
|
Xylene |
NA |
3.3 (0.6–18.6) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Heineman et al., 1994 |
Male residents of Louisiana, New Jersey, and Philadelphia, ever exposed to chloroform (astrocytic brain tumors) |
|
|
|
All |
46 |
1.0 (0.6–1.6) |
|
Low probability |
30 |
0.8 (0.5–1.4) |
|
Medium probability |
12 |
3.2 (0.9–12.0) |
|
High probability |
1 |
0.2 (0.0–1.8) |
Unspecified Mixtures of Organic Solvents |
|||
Cohort Study—Incidence |
|||
Heineman et al., 1995 |
Women in Shanghai, China |
|
|
|
Low probability of exposure |
89 |
1.2 (1.0–1.5) |
|
High probability of exposure |
27 |
2.0 (1.3–3.0) |
|
Low-level exposure |
68 |
1.7 (1.0–1.6) |
|
High-level exposure |
48 |
1.5 (1.1–2.0) |
|
High probability and high-level exposure |
24 |
1.9 (1.2–2.8) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
Mixed solvents, potential routine exposure |
13 |
0.68 (0.36–1.16) |
Greenland et al., 1994 |
White male US transformer-assembly workers, ever exposed |
NA |
2.65 (0.84–8.36) |
Carpenter et al., 1988 |
Workers at two nuclear facilities, ever exposed |
|
|
|
Trichloroethylene, tetrachloroethylene, or methyl chloroform |
|
|
|
No latency |
29 |
1.76 |
|
10-year latency |
21 |
1.26 |
|
Toluene, xylene, or methyl ethyl ketone |
|
|
|
No latency |
28 |
1.96 |
|
10-year latency |
19 |
1.37 |
Case-Control Studies |
|||
Rodvall et al., 1996 |
Hospital catchment-area residents of Sweden, ever exposed (gliomas) |
|
|
|
Males |
23 |
2.6 (1.3–5.2) |
|
Females |
2 |
0.4 (0.1–2.0) |
Heineman et al., 1994 |
Male residents of Louisiana, New Jersey, and Philadelphia (astrocytic brain tumors) |
|
|
|
Ever exposed |
186 |
1.4 (0.9–1.8) |
|
Low probability |
48 |
1.1 (0.6–1.7) |
|
Medium probability |
32 |
1.5 (0.8–2.7) |
|
High probability |
106 |
1.4 (0.9–2.1) |
|
Duration of employment |
|
|
|
2–20 years |
80 |
1.1 (0.7–1.7) |
|
21+ years |
87 |
1.7 (1.1–2.6) |
LYMPHATIC AND HEMATOPOIETIC CANCERS
Issue of Classification
Until recently, the International Classification of Diseases (especially ICD-7 and earlier versions) had rubrics for general types of lymphatic and hematopoietic cancers, including lymphosarcoma and reticulosarcoma (ICD-200), Hodgkin’s disease (ICD-201), and lymphatic leukemia (ICD-204). There were no categories for distinguishing specific types of cancers, such as acute leukemia. Thus, in the older epidemiologic studies, all lymphatic and hematopoietic neoplasms were grouped together instead of handled as individual types of cancer (such as Hodgkin’s disease) or specific cell types (such as acute lymphocytic leukemia). The amalgamation of these relatively rare cancers would increase the apparent sample size but could result in diluted estimates of effect if the different sites of cancer were not associated in similar ways with the exposures of interest. In addition, before the use of immunophenotyping to distinguish ambiguous diseases, diagnoses of these cancers may have been misclassified; for example, non-Hodgkin’s lymphoma (NHL) may have been misclassified as Hodgkin’s disease (HD) (Irons, 1992). Misclassification of specific types of cancer, if unrelated to exposure, would have attenuated estimates of relative risk and reduced statistical power to detect associations. When the outcome was mortality, rather than incidence, misclassification would be greater because of the errors in the coding of underlying causes of death on death certificates.
For exposures to organic solvents, the committee reviewed studies that combined all lymphatic and hematopoietic cancers because past exposures were considered substantially higher than the lower permissible exposure limits of today. Given the high exposures of the past, the committee believed that observations of increased risks in some groups of the lymphatic and hematopoietic cancers might be indicative of risk of more specific cancer types. Therefore, the results provided by studies that grouped all the lymphatic and hematopoietic cancers together were used as background information during the committee’s deliberations, and the findings from studies with greater specificity of cancer type were used as the primary evidence in drawing conclusions of associations between exposure to organic solvents and NHL, Hodgkin’s disease (HD), multiple myeloma (MM), acute and adult leukemia, and myelodysplastic syndromes.
NON-HODGKIN’S LYMPHOMA
In reviewing the literature on NHL, the committee faced an issue of misclassification or selection bias with respect to the accuracy of diagnosis. As explained at the beginning of this section, past ICD codes did not allow for identification of specific cancer types. As a result, epidemiologists may have grouped NHL cases with other lymphatic and hematopoietic cancers to establish sufficient statistical power. The issue was particularly evident when the literature on exposure to nonspecific solvents was reviewed. When a study did not specifically identify NHL as the cancer type being studied, the committee indicated the diagnosis used by the study authors. All these results are presented at the end of this section.
Description of Case-Control Studies
The characteristics of the case-control studies considered by the committee in drawing its conclusions of association are described below in Table 6.33. Most case-control studies reviewed evaluated NHL specifically (Bernard et al., 1984; Blair et al., 1992; Fabbro-Peray et al., 2001; Fritschi and Siemiatycki, 1996b; Hardell et al., 1994; Holly et al., 1997; Olsson and Brandt, 1988; Scherr et al., 1992; Tatham et al., 1997); others studied lymphohematopoietic cancer (Costantini et al. 2001) or malignant lymphoma (Hardell et al., 1981; Persson and Fredriksson, 1999). All case-control studies included interviews with study subjects concerning occupational history, and some interviews included questions about specific chemical exposures.
Some studies relied on the use of a job-exposure matrix (Blair et al., 1992) or industrial hygienist review of questionnaire responses (Costantini et al., 2001; Fritschi and Siemiatycki, 1996b) to determine exposures, but exposure assessment in most of the studies was based on self-reports (Bernard et al., 1984; Fabbro-Peray et al., 2001; Hardell et al., 1981, 1994; Holly et al., 1997; Olsson and Brandt, 1988; Persson and Frederikson, 1999; Persson et al., 1989, 1993; Scherr et al., 1992). Case-control studies on lymphohematopoietic cancer and exposure to organic solvents that had reasonably good assessments of exposure and a sufficient number of exposed cases include those conducted by Blair and colleagues (1992) and Fritschi and Siemiatycki (1996b).
Epidemiologic Studies of Exposure to Organic Solvents and Non-Hodgkin’s Lymphoma
The principal cohort studies that provided information concerning risk of NHL and benzene were the study of Chinese factory workers (Hayes et al., 1997; Yin et al., 1996a,b) and the study of American chemical workers (Wong, 1987a,b). A nested case-control study identified from a cohort of petroleum-distribution workers exposed to benzene at relatively low levels also provided information regarding the association (Schnatter et al., 1996a). Increased relative risks of NHL were found in two analyses in the Chinese study (Hayes et al., 1997: RR=3.0, 95% CI=0.9–10.5; Yin et al., 1996a,b: RR=3.0, 95% CI=1.0–13.0). Risks increased as the duration of occupational exposure to benzene increased, but not as much as with increasing cumulative exposure (Hayes et al., 1997).
TABLE 6.33 Description of Case-Control Studies of Non-Hodgkin’s Lymphoma and Exposure to Organic Solvents
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Hardell et al., 1981 |
Male cases, age 25–80 years at diagnosis, admitted to the Department of Oncology in Umea, Sweden and diagnosed in 1974–1978 with histologic confirmation; living controls selected from the National Population Register, matched on sex, age, and place of residence; deceased controls selected from the National Registry for Causes of Death, matched for the above and year of death |
105 |
335 |
Organic solvents |
Self-administered questionnaire with possible telephone followup to assess solvent exposure (self-reports) |
Unadjusted OR |
None |
Bernard et al., 1984 |
Cases identified through registries and clinician reporting among residents of the Yorkshire Health Region, UK, with diagnosis in 1979–1981 and histologic confirmation; controls selected from hospital inpatients, matched for age, sex, and geographic area |
158 |
158 |
Benzene Solvents |
In-person interview to assess occupational history (job titles) and details of solvent and chemical contacts (self-reports) |
Maximum likelihood estimate |
Sex, age |
Olsson and Brandt, 1988 |
Male cases, age 20–81 years, admitted to the Department of Oncology in Lund, Sweden in 1978–1981, with histologic confirmation; controls selected from previous control groups in studies on Hodgkin’s disease and soft-tissue sarcoma |
167 |
130 |
Solvents |
In-person interview with structured questionnaire to assess lifetime occupational exposure history (self-reports) |
Logistic regression |
Age, herbicides, chlorophenols |
Persson et al., 1989 |
Cases, age 20–80 years, identified in 1964–1986 at the Orebro Medical Centre Hospital, Sweden; controls randomly selected from population registers (see also Persson and Fredriksson, 1999; Persson et al., 1993) |
106 |
275 |
Trichloroethylene White spirit Solvents |
Mailed questionnaire to assess occupational exposures (self-reports) |
Unadjusted OR |
None |
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Blair et al., 1992 |
White, male cases identified in Iowa through the Iowa State Health Registry in 1981–1983 and in Minnesota through a surveillance network of hospitals in 1980–1982 with histologic confirmation; controls identified through RDD (alive, age 21–64 years), the records of HCFA (alive, age over 65 years), and vital records (deceased), stratified for state, age, and year of death |
622 |
1,245 |
Benzene Solvents Paints |
In-person interview (direct or proxy) with structured questionnaire to assess lifetime occupational history (job titles); probability of exposure determined by industrial hygienist assessment and job-exposure matrixes |
Unconditional logistic regression |
Age, state, smoking, family cancer history, respondent status, exposure to pesticides and hair dyes |
|
Response rates: 87% of cases, 77% of RDD controls, 79% of HCFA controls, 77% of next-of-kin of deceased controls |
|
|||||
Scherr et al., 1992 |
Cases identified from nine hospitals in the Boston metropolitan area in 1980–1982 with histologic confirmation; controls selected from town residency lists, matched for sex, age, town, and precinct of residence |
303 |
303 |
Benzene Chlorinated solvents |
In-person interview or mailed questionnaire to assess lifetime occupational and exposure history (self-reports) |
Unadjusted OR |
None |
Persson et al., 1993 |
Cases, age 20–80 years, identified in 1975–1984 at the University Hospital in Linkoping, Sweden, with histologic confirmation; controls randomly selected from population registers (see also Persson and Fredriksson, 1999; Persson et al., 1989) |
31 |
204 |
Trichloroethylene White spirit Solvents |
Mailed questionnaire to assess occupational exposures (self-reports) |
Logistic regression |
Age, other exposures |
Hardell et al., 1994 |
Male cases, age 25–80 years at diagnosis, admitted to the Department of Oncology in Umea, Sweden and diagnosed in 1974–1978 with histologic confirmation; living controls selected from the National Population Register, matched on sex, age, and place of residence; deceased controls selected from the National Registry for Causes of Death, matched for the above and year of death |
105 |
335 |
Benzene Trichloroethylene White spirit Organic solvents |
Self-administered questionnaire with possible telephone followup to assess solvent exposure (self-reports) |
Mantel-Haenszel |
None |
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Fritschi and Siemiatycki, 1996b |
Male cases and controls, age 35–70 years, diagnosed in 19 large Montreal-area hospitals in 1979–1985 and histologically confirmed for one of 19 anatomic cancer sites; age-matched, population-based controls were also chosen from electoral lists and RDD |
215 |
1,066 (533 population controls and 533 randomly selected subjects from the eligible cancer control group) |
Benzene Solvents |
In-person interviews with segments on work histories (job titles); analyzed and coded by a team of chemists and industrial hygienists (about 300 exposures on semiquantitative scales) |
Unconditional logistic regression |
Age, proxy status, income, ethnicity |
|
Response rates: 83% of cases, 71% of population controls |
|
|||||
Holly et al., 1997 |
Male cases identified through the Northern California Cancer Center from hospitals in six counties; controls selected through RDD, and matched for sex, county, and age |
312 |
420 |
Benzene Chlorinated solvents |
In-person interview with structured questionnaire to assess chemical and occupational exposures (self-reports) |
Unconditional logistic regression |
Age |
Tatham et al., 1997 |
Male cases from the Selected Cancers Study, born in 1929–1953, identified from eight population-based cancer registries in 1984–1988 with histologic confirmation; controls selected through RDD and matched for registry and date of birth |
1,048 |
1,659 |
Chlorinated hydrocarbons Chemical solvents |
Telephone interviews (direct or proxy) with questionnaire to assess work (job titles) and exposure history (self-reports) |
Conditional logistic regression |
Age at diagnosis, year entering study, ethnicity, education, Jewish religion, marital status, smoking status, service in Vietnam, other medical factors |
|
Response rates: 88% of cases, 83% of controls |
|
|||||
Persson and Fredriksson, 1999 |
Cases, age 20–80 years, identified in 1964–1986 at the Orebro Medical Centre Hospital and in 1975–1984 at the University Hospital in Linkoping, Sweden, with histologic confirmation; controls randomly selected from population registers (see also Persson et al., 1989, 1993) |
199 |
479 |
Benzene Trichloroethylene White spirit Solvents |
Mailed questionnaire to assess occupational exposures (self-reports) |
Mantel-Haenszel |
Age, sex |
The US chemical-worker study (Wong, 1987a,b) had only five exposed cases. It showed a weak association with continuous exposure (SMR=1.13, 95% CI=0.23–3.30) and no increase in risk with increasing cumulative exposure. The authors examined duration of exposure categorized, but there was only one exposed case per category. In the study of petroleum distributors, with eight exposed cases (Schnatter et al., 1996a), relative risks did not increase with increasing levels of exposure. Wilcosky and colleagues (1984) found a 3-fold risk among rubber-plant workers (OR=3.0; the authors did not provide CIs, and the committee was not able to calculate them), and Bond and colleagues (1986) in a study of chemical workers found about a 100% increase in mortality (MSR=1.99, 95% CI=0.24–7.22). Another cohort study of benzene-exposed oil-refinery workers (Tsai et al., 1983) reported no exposed cases.
Among the case-control studies in which the association between exposure to benzene and NHL was assessed, increased risks were found in the studies by Fabbro-Peray and colleagues (2001) (OR=2.0, 95% CI=1.1–3.9); odds ratios increased with duration of exposure. Blair and colleagues (1992) found increased odds ratios for “higher” exposures (OR=1.5, 95% CI=0.7–3.1), and Hardell and colleagues (1994) found very large excess risks associated with self-reported exposure to benzene (OR=28, 95% CI=1.8–730). No associations were found in several other small case-control studies (Bernard et al., 1984; Fritschi and Siemiatycki, 1996b; Holly et al., 1997; Persson and Fredriksson, 1999; Scherr et al., 1992; Schumacher and Delzell, 1988).
The cohort studies of trichloroethylene-exposed workers and NHL risk include studies of Finnish and Danish biologically monitored workers (Anttila et al., 1995; Hansen et al., 2001), US aircraft and aerospace maintenance and manufacturing workers (Blair et al., 1998, Boice et al., 1999; Morgan et al., 1998), and workers in Sweden (Axelson et al., 1994).
In the Finnish biologic-monitoring study (Anttila et al., 1995), relative risks were increased (SIR=2.01, 95% CI=0.65–4.69). In the Danish cohort study (Hansen et al., 2001) of workers biologically monitored for trichloroethylene, a 3.5-fold increased risk of NHL was observed (95% CI=1.5–6.9). The risk did not increase with increasing levels of exposure, but the statistical power was too low to detect trends.
Increased NHL mortality was found in the US aircraft-maintenance worker study in Utah (Blair et al., 1998) (SMR=2.0, 95% CI=0.9–4.6), but it did not increase with cumulative exposure among male and female workers. A 140% increase in risk (OR=2.4; CI was not provided in the study, and the committee was not able to calculate it) was also found in rubber workers exposed to trichloroethylene (Wilcosky et al., 1984). In the study of aircraft-manufacturing workers in California (Boice et al., 1999), no overall increase in risk was found (SMR=1.19, 95% CI=0.65–1.99), but relative risks increased as duration of exposure increased. Axelson and colleagues (1994) found an 85% increase in incidence (SIR=1.85, 95% CI=0.38–5.41) among Swedish workers, but no association was found (SMR=0.96, 95% CI=0.20–2.81) in the study of aerospace workers in Arizona (Morgan et al., 1998). Two case-control studies in Sweden found increases in NHL risk of 7.2 (95% CI=1.3–42) (Hardell et al., 1994) and 1.2 (95% CI=0.5–2.4) (Persson and Fredriksson, 1999) for NHL, but both were based on self-reported exposures.
In several cohort and case-control studies, relative risks of NHL were calculated according to exposure to tetrachloroethylene and dry-cleaning solvents (Anttila et al., 1995; Blair et al., 1990; Boice et al., 1999; Costantini et al., 2001; Fabbro-Peray et al., 2001), toluene or xylene (Anttila et al., 1998; Blair et al., 1998; Svensson et al., 1990; Wilcosky et al., 1984), phenol (Dosemeci et al., 1991), white spirits (Persson and Fredrickson, 1999; Hardell et al.,
1994), and other specific solvents (Blair et al, 1998; Wilcosky et al., 1984). No consistent positive associations were found between NHL and any of those solvents except white spirits, with which positive associations were found by Persson and Fredrickson (1999) in a Swedish study (OR=2.6, 95% CI=1.3–4.7) and by Hardell and colleagues (1994) (OR=3.2, 95% CI=1.3–8.3).
The association between exposure to mixtures of organic solvents and NHL has been examined in several studies, many of which are occupational studies, including aircraft manufacturing and maintenance workers (Blair et al., 1998; Boice et al., 1999), uranium-processing plant workers (Ritz, 1999), painters (Blair et al., 1992; Costantini et al., 2001; Lundberg and Milatou-Smith, 1998; Steenland and Palu, 1999), printers (e.g., Costantini et al., 2001; Leon, 1994; Nielsen et al., 1996), and people in several other occupations (such as shoe manufacturing and rubber work). Some studies showed positive associations, and others showed associations close to unity.
Summary and Conclusion
Although there is a substantial body of literature on the association between exposure to specific organic solvents and solvent mixtures and risk of NHL, most studies are based on small numbers of exposed cases. An association between comparatively high relative risks of NHL and exposure to benzene was seen consistently in a number of cohort studies. The studies on exposure to benzene and NHL provide consistently positive findings because the populations or groups had known exposure and there was evidence of exposure-response relationships.
The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between chronic exposure to benzene and non-Hodgkin’s lymphoma.
Two cohort studies suggested that there was an increased risk of dying from NHL with exposure to trichloroethylene (Blair et al., 1998; Wilcosky et al., 1984). However, in the rubber worker study, (Wilcosky et al., 1984) they were exposed to numerous other chemicals in addition to trichloroethylene. The Blair study did not demonstrate an exposure-response relationship in examining mortality risk and found no association in relation to incidence risk. One case-control study showed a very strong association (Hardell et al., 1994), but the committee did not feel that it constituted compelling evidence inasmuch there was a high probability that the relative risks were overstated. The evidence between exposure to white spirit and other specific organic solvents was also limited by Hardell and colleagues’ study (1994) that used self-reported exposures and lacked credibility owing to possible recall bias. For exposure to unspecified mixtures of solvents, as is the case with many of the other exposures discussed above, statistical fluctuations made it difficult to form any conclusion. Table 6.34 identifies the studies reviewed by the committee in drawing its conclusion regarding association. Unless indicated in the table, the study populations include both men and women.
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 the solvents under review, other than benzene, and non-Hodgkin’s lymphoma.
TABLE 6.34 Selected Epidemiologic Studies—Non-Hodgkin’s Lymphoma and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Studies—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored Danish workers |
|
|
|
Male workers, ever exposed |
8 |
3.5 (1.5–6.9) |
|
Cumulative exposure: |
|
|
|
Unknown |
2 |
3.6 (0.4–13.0) |
|
<1080 months, mg/m3 |
3 |
3.9 (0.8–11.0) |
|
≥1080 months, mg/m3 |
3 |
3.1 (0.6–9.1) |
Blair et al, 1998 |
Aircraft-maintenance workers in Utah |
|
|
|
Cumulative exposure, males (incidence) |
|
|
|
No exposure |
5 |
0.5 (0.2–1.7) |
|
<5 unit-years |
8 |
0.9 (0.3–2.6) |
|
5–25 unit-years |
4 |
0.7 (0.2–2.6) |
|
>25 unit-years |
7 |
1.0 (0.4–2.9) |
|
Cumulative exposure, females (incidence) |
|
|
|
No exposure |
0 |
— |
|
<5 unit-years |
1 |
0.6 (0.1–5.0) |
|
5–25 unit-years |
0 |
— |
|
>25 unit-years |
2 |
0.9 (0.2–4.5) |
Anttila et al., 1995 |
Finnish workers exposed to halogenated hydrocarbons |
8 |
1.81 (0.78–3.56) |
|
Exposure level |
|
|
|
<100 µmol/L |
5 |
2.01 (0.65–4.69) |
|
100 + µmol/L |
2 |
1.40 (0.17–5.04) |
Axelson et al., 1994 |
Swedish workers |
5 |
1.56 (0.51–3.64) |
|
≥2 years of exposure and 10-year latency |
3 |
1.85 (0.38–5.41) |
|
49 mg/L |
2 |
1.64 (0.20–5.92) |
|
50–99 mg/L |
0 |
— |
|
100 + mg/L |
1 |
8.33 (0.22–46.43) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
Trichloroethylene, ever exposed (routine) |
14 |
1.19 (0.65–1.99) |
|
Years of exposure (routine or intermittent) |
|
|
|
<1 |
7 |
0.74 (0.32–1.72) |
|
1–4 |
10 |
1.33 (0.64–2.78) |
|
≥5 |
14 |
1.62 (0.82–3.22) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah, ever exposed |
28 |
2.0 (0.9–4.6) |
|
Cumulative exposure, males (mortality) |
|
|
|
No exposure |
11 |
1.6 (0.5–4.5) |
|
<5 unit-years |
10 |
1.8 (0.6–5.4) |
|
5–25 unit-years |
6 |
1.9 (0.6–6.3) |
|
>25 unit-years |
5 |
1.1 (0.3–3.8) |
|
Cumulative exposure, females (mortality) |
|
|
|
No exposure |
2 |
2.0 (0.3–12.2) |
|
<5 unit-years |
3 |
3.8 (0.8–18.9) |
|
5–25 unit-years |
0 |
— |
|
>25 unit-years |
4 |
3.6 (0.8–16.2) |
|
Exposure levels (males) |
|
|
|
Low-level intermittent |
15 |
1.5 (0.5–4.3) |
|
Low-level continuous |
12 |
1.8 (0.6–5.2) |
|
Frequent peaks |
9 |
1.5 (0.5–4.4) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
|
Exposure levels (females) |
|
|
|
Low-level intermittent |
4 |
3.9 (0.8–17.7) |
|
Low-level continuous |
2 |
3.4 (0.5–21.7) |
|
Frequent peaks |
5 |
3.8 (0.9–16.2) |
Morgan et al., 1998 |
Aerospace workers in Arizona |
|
|
|
Trichloroethylene-exposed subcohort |
|
|
|
Lymphosarcoma and reticulosarcoma |
3 |
0.96 (0.20–2.81) |
|
All other lymphopoietic tissue |
11 |
1.01 (0.51–1.81) |
Wilcosky et al., 1984 |
Male US rubber-industry workers, exposed >1 year |
3 |
2.4 |
Case-Control Studies |
|||
Persson and Fredriksson, 1999 |
Residents of Sweden |
|
|
1+ years exposed, latency 5–45 years |
16 |
1.2 (0.5–2.4) |
|
Hardell et al., 1994 |
Male residents of Sweden |
|
|
|
Ever exposed |
4 |
7.2 (1.3–42) |
Benzene |
|||
Cohort Studies—Incidence |
|||
Hayes et al., 1997 |
Chinese factory workers |
16 |
3.0 (0.9–10.5) |
|
Exposed workers, year of hire |
|
|
|
<1972 |
15 |
4.1 |
|
≥1972 |
1 |
0.5 |
|
Exposed workers, average ppm |
|
|
|
<10 |
7 |
2.7 (0.7–10.6) |
|
10–24 |
2 |
1.7 (0.3–10.2) |
|
≥25 |
7 |
4.7 (1.2–18.1) |
|
Exposed workers, duration |
|
|
|
<5 years |
1 |
0.7 (0.1–7.2) |
|
5–9 years |
4 |
3.3 (0.7–14.7) |
|
≥10 years |
11 |
4.2 (1.1–15.9) |
|
Exposed workers, cumulative exposure |
|
|
|
<40 ppm-years |
6 |
3.3 (0.8–13.1) |
|
40–99 ppm-years |
1 |
1.1 (0.1–11.1) |
|
≥100 ppm-years |
9 |
3.5 (0.9–13.2) |
Yin et al., 1996a,b |
Chinese factory workers, ever exposed |
17 |
3.0 (1.0–13.0) |
Cohort Studies—Mortality |
|||
Schnatter et al., 1996a |
Male Canadian petroleum-distribution workers |
|
|
|
0.00–0.49 ppm-years |
4 |
1.00 |
|
0.50–7.99 ppm-years |
3 |
1.21 (0.16–8.07) |
|
8.00–19.99 ppm-years |
1 |
1.14 (0.02–22.1) |
|
20–219.8 ppm-years |
0 |
0.0 (0.0–27.6) |
Wong, 1987a,b |
Male US chemical workers |
5 |
0.91 (0.29–2.11) |
|
Continuously exposed |
3 |
1.13 (0.23–3.30) |
|
Continuous exposure by duration |
|
|
|
<5 years |
1 |
0.65 |
|
5–14 years |
1 |
1.56 |
|
≥15 years |
1 |
2.18 |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
|
Cumulative exposure |
|
|
|
<180 ppm-months |
3 |
2.57 (0.24–3.41) |
|
180–719 ppm-months |
3 |
1.61 (0.38–5.45) |
|
≥720 ppm-months |
1 |
1.34 (0.19–4.14) |
|
p-trend=0.71 |
||
Bond et al., 1986 |
Male US chemical workers |
|
|
|
Lymphosarcoma and reticulosarcoma |
|
|
|
Entire cohort |
2 |
1.80 (0.22–6.57) |
|
Cohort less those exposed to arsenic, asbestos, or high levels of vinyl chloride |
2 |
1.99 (0.24–7.22) |
|
Other lymphatic tissue |
|
|
|
Entire cohort |
1 |
0.76 (0.02–4.29) |
|
Cohort less those exposed to arsenic, asbestos, or high levels of vinyl chloride |
1 |
0.84 (0.02–4.64) |
Wilcosky et al., 1984 |
Male US rubber-industry workers, exposed >1 year |
6 |
3.0 |
Tsai et al., 1983 |
Texas refinery workers |
|
|
|
1+ years employment in benzene areas |
|
|
|
All lymphopoietic cancer |
0 |
— |
Case-Control Studies |
|||
Fabbro-Peray et al., 2001 |
Residents of France, ever exposed |
22 |
2.0 (1.1–3.9) |
≤15 years exposed |
9 |
1.7 (0.7–4.3) |
|
|
>15 years exposed |
13 |
2.4 (0.9–5.9) |
Persson and Fredriksson, 1999 |
Residents of Sweden |
|
|
1+ years exposed, latency 5–45 years |
3 |
0.8 (0.1–3.8) |
|
Holly et al., 1997 |
Male residents of San Francisco Bay Area |
|
|
|
<10 hours of exposure |
294 |
1.0 |
|
10+ hours of exposure |
17 |
1.2 (0.62–2.4) |
Fritschi and Siemiatycki, 1996b |
Male residents of Montreal |
|
|
Nonsubstantial |
20 |
0.7 (0.4–1.1) |
|
|
Substantial |
6 |
0.8 (0.3–2.1) |
Hardell et al., 1994 |
Male residents of Sweden, ever exposed |
3 |
28 (1.8–730) |
Blair et al., 1992 |
Male residents of Iowa and Minnesota |
|
|
|
Potential exposure |
153 |
1.1 (0.9–1.4) |
|
Lower intensity |
141 |
1.1 (0.8–1.4) |
|
Higher intensity |
12 |
1.5 (0.7–3.1) |
Scherr et al., 1992 |
Residents of Boston, MA, ever exposed |
4 |
1.2 (0.5–2.6) |
Schumacher and Delzell, 1988 |
Residents of North Carolina |
|
|
Occupational exposure (ever): |
|
||
|
White males |
56 |
0.77 (0.56–1.07) |
|
Black males |
10 |
0.94 (0.47–1.87) |
Bernard et al., 1984 |
Residents of Yorkshire, England, benzene use |
|
|
|
Males |
NA |
0.49 (0.21–2.00) |
Other Specific Organic Solvents |
|||
Cohort Studies—Incidence |
|||
Anttila et al., 1998 |
Finnish workers monitored for exposure to solvents |
|
|
|
Toluene or xylene, all years |
3 |
1.18 (0.24–3.45) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Anttila et al., 1995 |
Finnish workers biologically monitored for halogenated hydrocarbons |
|
|
|
Tetrachloroethylene |
3 |
3.76 (0.77–11.0) |
|
1,1,1-Trichloroethane |
1 |
3.87 (0.10–21.5) |
Svensson et al., 1990 |
Male rotogravure-plant workers in Sweden |
|
|
|
Toluene |
|
|
|
All exposed |
1 |
0.33 (0.01–1.86) |
|
≥5 years of exposure, >10-year latency |
1 |
0.52 (0.01–2.91) |
Cohort Studies-Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
Tetrachloroethylene, ever exposed (routine) |
8 |
1.70 (0.73–3.34) |
|
Years of exposure (routine or intermittent) |
|
|
|
<1 |
4 |
1.25 (0.43–3.57) |
|
1–4 |
6 |
1.11 (0.46–2.70) |
|
≥5 |
10 |
1.41 (0.67–3.00) |
Blair et al., 1998 |
Aircraft maintenance workers in Utah |
|
|
|
Males, ever exposed |
|
|
|
Stoddard solvent |
16 |
1.3 (0.5–3.5) |
|
Isopropyl alcohol |
7 |
1.8 (0.6–5.8) |
|
Other alcohols |
3 |
2.1 (0.5–9.0) |
|
Acetone |
6 |
1.7 (0.5–5.5) |
|
Toluene |
3 |
1.0 (0.2–4.2) |
|
Methyl ethyl ketone |
4 |
1.4 (0.4–5.1) |
|
Methylene chloride |
6 |
3.0 (0.9–10.0) |
|
Females, ever exposed |
|
|
|
Stoddard solvent |
5 |
2.4 (0.6–9.9) |
|
Isopropyl alcohol |
2 |
5.8 (1.0–34.6) |
|
Other alcohols |
0 |
— |
|
Acetone |
1 |
1.3 (0.1–12.8) |
|
Toluene |
2 |
2.2 (0.4–13.1) |
|
Methyl ethyl ketone |
1 |
1.6 (0.2–15.7) |
|
Methylene chloride |
0 |
— |
Dosemeci et al., 1991 |
White, male chemical-manufacturing workers |
|
|
|
Phenol, ever exposed |
4 |
0.4 (0.1–1.1) |
Blair et al., 1990 |
Members of a dry-cleaning union in St. Louis, MO |
|
|
|
Lymphosarcoma or reticulosarcoma |
7 |
1.7 (0.7–3.4) |
|
Other lymphatic cancers |
4 |
0.7 (0.2–1.8) |
Wilcosky et al., 1984 |
US rubber-industry workers, exposed >1 year |
|
|
|
Specialty naphthas |
6 |
1.4 |
|
Xylenes |
4 |
3.7 |
|
Isopropanol |
6 |
2.9 |
Case-Control Studies |
|||
Costantini et al., 2001 |
Residents of 12 areas of Italy |
|
|
|
Launderers, dry cleaners, and pressers |
3 |
1.6 (0.3–9.1) |
Fabbro-Peray et al., 2001 |
Residents of France |
|
|
Dry-cleaning solvents, ever exposed |
35 |
1.0 (0.6–1.6) |
|
Persson and Fredriksson, 1999 |
Residents of Sweden |
|
|
White spirit, 1+ years exposed, latency 5–45 years |
27 |
2.6 (1.3–4.7) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Hardell et al., 1994 |
Male residents of Sweden |
|
|
|
White spirit (ever exposed) |
12 |
3.2 (1.3–8.3) |
Unspecified Mixtures of Organic Solvents |
|||
Cohort Studies—Incidence |
|||
Anttila et al., 1998 |
Biologically monitored Finnish workers |
|
|
|
Aromatic hydrocarbons, all years |
2 |
0.52 (0.06–1.88) |
Lundberg and Milatou-Smith, 1998 |
Swedish paint-industry workers |
|
|
Male workers, ≤5 years of employment |
2 |
1.0 (0.1–3.4) |
|
Nielsen et al., 1996 |
Danish lithographer-union members, malignant lymphoma |
2 |
1.5 (0.3–5.0) |
Berlin et al., 1995 |
Swedish workers occupationally exposed to solvents |
7 |
1.9 (0.8–4.0) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
All factory workers |
137 |
0.94 (0.79–1.11)a |
|
Mixed solvents, ever exposed (routine) |
29 |
1.02 (0.68–1.47) |
|
Years of exposure (routine or intermittent) |
|
|
|
<1 |
9 |
0.77 (0.37–1.62) |
|
1–4 |
20 |
0.79 (0.45–1.39) |
|
≥5 |
52 |
1.01 (0.64–1.61) |
Ritz, 1999 |
White male US uranium-processing plant workers, employed >3 months |
8 |
1.71 (0.73–3.36) |
Steenland and Palu, 1999 |
US painter union members |
|
|
Painters (all members) |
137 |
1.06 (0.89–1.25) |
|
|
Painters (20 years since first union membership) |
110 |
1.10 (0.91–1.32) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
|
|
Any solvent, ever exposed |
|
|
|
Males |
31 |
1.6 (0.6–4.1) |
|
Females |
9 |
2.8 (0.8–4.5) |
|
Solvents, unspecified, ever exposed |
|
|
|
Males |
31 |
1.6 (0.6–4.1) |
|
Females |
9 |
2.9 (0.8–10.6) |
Fu et al., 1996 |
Shoe-manufacturing workers |
|
|
|
English cohort |
6 |
0.55 (0.20–1.20) |
|
Probable solvent exposure |
2 |
0.54 (0.07–1.96) |
|
High solvent exposure |
0 |
— |
|
Florence cohort |
2 |
1.06 (0.13–3.82) |
|
Probable solvent exposure |
2 |
2.44 (0.30–8.81) |
|
High solvent exposure |
2 |
2.74 (0.33–9.90) |
Hunting et al., 1995 |
Male vehicle mechanics in Washington, DC |
|
|
|
Solvents or fuels, high exposure (lymphatic and hematopoietic) |
3 |
4.22 (0.87–12.34) |
|
Solvents or fuels, high exposure (other neoplasms of lymphatic and hematopoietic) |
1 |
2.57 (0.06–14.27) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Leon, 1994 |
Male trade-union members in the British printing industry |
|
|
|
Machine managers |
2 |
1.21 (0.15–4.37) |
|
Compositors |
4 |
1.17 (0.32–2.99) |
|
Machine assistants |
4 |
2.16 (0.59–5.54) |
|
Publishing-room men |
2 |
2.68 (0.32–9.68) |
Wong et al., 1993 |
US gasoline-distribution workers |
|
|
|
Land-based terminal cohort (cancer of other lymphatic tissue) |
18 |
0.92 (0.54–1.45) |
|
Marine-based cohort (cancer of other lymphatic tissue) |
11 |
0.73 (0.39–1.25) |
Walker et al., 1993 |
Shoe-manufacturing workers in Ohio, employed >1 month |
5 |
0.75 (0.24–1.77) |
Teta et al., 1992 |
Male workers at ethanol and isopropanol production plants in Texas |
|
|
|
All workers (South Charlestown plant) |
5 |
5.60 (1.8–13.0) |
Paci et al., 1989 |
Shoe-manufacturing plant in Florence, Italy, ever employed |
|
|
|
Other lymphatic and hematopoietic neoplasms |
|
|
|
Males |
1 |
0.55 (0.0–3.1)a |
|
Females |
1 |
1.11 (0.0–6.2)a |
Sorahan et al., 1989 |
British rubber-industry workers (lymphoid cancers) |
50 |
0.91 (0.68–1.21)a |
Garabrant et al., 1988 |
Aircraft-manufacturing workers in California, employed >4 years |
|
|
|
Lymphosarcoma and reticulosarcoma |
13 |
0.82 (0.44–1.41) |
|
Other neoplasms of lymphatic and hematopoetic tissue |
5 |
0.65 (0.21–1.52) |
Wilcosky et al., 1984 |
Male US rubber-industry workers, exposed >1 year |
|
|
|
Solvent “A” (mixture of toluene and other solvents) |
6 |
2.6 |
Paganini-Hill et al., 1980 |
Newspaper web pressmen union members in Los Angeles, CA (other lymphatic and hematopoietic neoplasms) |
5 |
1.29 (0.42–2.99)a |
Case-Control Studies |
|||
Costantini et al., 2001 |
Residents of 12 areas of Italy |
|
|
|
Painters, ever employed |
20 |
1.2 (0.6–2.4) |
|
Printers, ever employed |
11 |
1.2 (0.6–2.9) |
Fabbro-Peray et al., 2001 |
Residents of France |
|
|
Rubber industry, ever employed |
16 |
1.6 (0.8–3.4) |
|
|
Paints, ever exposed |
26 |
0.8 (0.5–1.3) |
Persson and Fredriksson, 1999 |
Residents of Sweden |
|
|
1+ years exposed, latency 5–45 years |
|
||
|
Solvents |
61 |
1.6 (1.0–2.5) |
|
Solvents, high intensity |
51 |
1.8 (1.1–2.9) |
Holly et al., 1997 |
Male residents of the San Francisco Bay area |
|
|
|
Chlorinated solvents |
|
|
|
<10 hours of exposure |
291 |
1.0 |
|
10+ hours of exposure |
20 |
0.73 (0.41–1.3) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Tatham et al., 1997 |
Males in US cancer registries |
|
|
|
Chemical solvents, ever exposed |
451 |
1.10 (0.90–1.30) |
|
Chlorinated hydrocarbons, ever exposed |
49 |
0.91 (0.62–1.30) |
Fritschi and Siemiatycki, 1996b |
Male residents of Sweden |
|
|
Nonsubstantial |
26 |
0.6 (0.4–1.0) |
|
|
Substantial |
48 |
0.9 (0.6–1.3) |
Hardell et al., 1994 |
Male residents of Sweden |
|
|
|
Organic solvents |
|
|
|
All |
45 |
2.4 (1.4–3.9) |
|
High grade |
31 |
2.9 (1.6–5.6) |
|
Low grade |
14 |
1.8 (0.8–3.8) |
Partanen et al., 1993 |
Finnish production workers in the wood industry (leukemias and lymphomas pooled) |
|
|
|
Solvents, ever exposed |
4 |
5.62 (0.99–32.0) |
|
Solvents, adjusted for formaldehyde |
4 |
5.07 (0.40–63.5) |
Blair et al., 1992 |
Male residents of Iowa and Minnesota |
|
|
|
Solvents (excluding benzene) |
|
|
|
Potentially exposed |
359 |
1.1 (0.9–1.4) |
|
Lower intensity |
334 |
1.1 (0.8–1.4) |
|
Higher intensity |
25 |
1.4 (0.8–2.5) |
|
Paints: |
|
|
|
Potentially exposed |
116 |
1.1 (0.9–1.5) |
|
Lower intensity |
107 |
1.1 (0.9–1.5) |
|
Higher intensity |
9 |
1.1 (0.5–2.6) |
Scherr et al., 1992 |
Residents of Boston, MA |
|
|
|
Chlorinated solvents, ever exposed |
24 |
1.2 (0.8–1.8) |
Persson et al., 1989 |
Residents of Sweden |
|
|
|
Solvents |
33 |
2.0 (1.2–3.5)a |
|
Solvents, high intensity |
27 |
2.1 (1.2–3.7)a |
Olsson and Brandt, 1988 |
Male residents of Sweden |
|
|
Solvent exposure, ever (based on observed cases) |
NA |
2.0 (1.5–2.6) |
|
|
120 months |
NA |
1.8 (1.2–2.7) |
|
240 months |
NA |
3.3 (1.5–7.1) |
|
360 months |
NA |
6.0 (1.9–19.0) |
Bernard et al., 1984 |
Residents of Yorkshire, England |
|
|
|
Occupational solvents (excluding benzene) |
|
|
|
Males |
NA |
1.52 (0.70–3.26) |
|
Females |
NA |
7.71 (1.24–47.93) |
|
Solvent use as a hobby, males |
NA |
1.39 (0.30–6.46) |
Hardell et al., 1981 |
Male residents of Sweden (malignant lymphoma) |
|
|
|
Organic solvents, low grade |
10 |
1.2 (0.5–2.6) |
|
Organic solvents, low and high grade |
50 |
2.4 (1.5–3.8) |
|
Solvents, phenoxy acids, or chlorophenols |
23 |
8.5 (4.2–17.2) |
NOTE: NA=not available. a95% CI was calculated by the committee with standard methods from the observed and expected numbers presented in the original papers. |
HODGKIN’S DISEASE
Description of Case-Control Studies
The characteristics of the case-control studies considered by the committee in drawing its conclusion regarding association are described in Table 6.35. All case-control studies of HD reviewed by the committee included interviews with study subjects about occupational history; some also inquired about specific chemical exposures. Although some studies relied on industrial hygienist review of questionnaire responses (Costantini et al., 2001) to determine exposure, exposure assessment in other studies was based on self-reports (Bernard et al., 1984; Hardell and Bengtsson, 1983; Persson et al., 1989, 1993).
Epidemiologic Studies Regarding Exposure to Organic Solvents and Hodgkin’s Disease
Each of the studies of exposure to trichloroethylene reviewed showed an increased risk of HD. However, most studies had small numbers of exposed cases (Anttila et al., 1995; Axelson et al., 1994; Blair et al., 1998; Boice et al., 1999; Morgan et al., 1998; Persson et al., 1993); therefore, the confidence intervals were broad and included unity. The only study showing markedly increased risk was by Persson and colleagues (1989) (OR=2.8, 95% CI 0.96–7.86).
Two studies provided results on the relationship between exposure to benzene and risk of HD. A cohort study of male chemical-plant workers (Wong, 1987a) who were continuously exposed to benzene did not show any increased risk (SMR=1.12, 95% CI=0.14–4.05), and a case-control study among residents in Yorkshire, England (Bernard et al., 1984) also showed no relationship between exposure to benzene and HD (OR=1.00, 95% CI=0.50–1.50).
Studies of other specific solvents—including tetrachloroethylene (Blair et al., 1990; Boice et al., 1999), toluene and xylene (Anttila et al., 1998), phenol (Dosemeci et al., 1991), and white spirit (Persson et al., 1989, 1993)—did not show any evidence of increased risk of HD.
The risk of HD associated with exposure to unspecified mixtures of solvents or employment in solvent-related occupations—including aircraft-manufacturing workers, painters, printers, and dry cleaners—was investigated in several cohort and case-control studies. Although several studies yielded positive relative risks, most had considerable statistical variability in their estimates. Only one study (Hardell and Bengston, 1983) showed a risk that was well above the null value; its subjects had concomitant exposure to phenoxy acids and chlorophenols, and exposure to all substances conferred an almost 7-fold excess risk (OR=6.6, 95% CI 2.4–18.5).
TABLE 6.35 Description of Case-Control Studies of Hodgkin’s Disease and Exposure to Organic Solvents
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Hardell and Bengtsson, 1983 |
Male cases, age 25–80 years at diagnosis, admitted to the Department of Oncology in Umea, Sweden, and diagnosed in 1974–1978 with histologic confirmation; living controls selected from the National Population Register, matched on sex, age, and place of residence; deceased controls selected from the National Registry for Causes of Death, matched for the above and year of death |
60 |
335 |
Organic solvents |
Self-administered questionnaire with possible telephone followup to assess solvent exposure (self-reports) |
Mantel-Haenszel |
None |
Bernard et al., 1984 |
Cases identified through registries and clinician reporting among residents of the Yorkshire Health Region, UK, with diagnosis in 1979–1981 and histologic confirmation; controls selected from hospital inpatients, matched for age, sex, and geographic area |
48 |
48 |
Benzene Solvents |
In-person interview to assess occupational history (job titles) and details of solvent and chemical contacts (self-reports) |
Logistic regression |
Sex, age |
Persson et al., 1989 |
Cases, age 20–80 years, identified in 1964–1986 at the Orebro Medical Centre Hospital, Sweden; controls randomly selected from population registers |
54 |
275 |
Trichloroethylene White spirit Solvents |
Mailed questionnaire to assess occupational exposures (self-reports) |
Unadjusted OR, Logistic regression |
Age, sex, other exposures |
Persson et al., 1993 |
Cases, age 20–80 years, identified in 1975–1984 at the University Hospital in Linkoping, Sweden, with histologic confirmation; controls randomly selected from population registers |
31 |
204 |
Trichloroethylene White spirit Solvents |
Mailed questionnaire to assess occupational exposures (self-reports) |
Unadjusted OR, Logistic regression |
Age, other exposures |
Costantini et al., 2001 |
Cases, age 20–74 years, identified through periodic hospital survey and diagnosed in 12 regions in Italy in 1991–1993 with histologic confirmation; controls randomly selected from municipal demographic files and the National Health Services files, matched for age and sex |
365 |
1,779 |
Launderers, dry cleaners, pressers |
In-person interview (direct or proxy) with standardized and job-specific questionnaires to assess lifetime occupational history (job titles) and exposure to solvents (self reports); probability of exposure further determined by industrial hygienist |
Mantel-Haenszel |
Age, sex |
|
Response rates: 88% of cases, 81% of controls |
|
Summary and Conclusion
Overall, the studies reviewed by the committee did not show any persuasive evidence of associations between HD and exposure to specific solvents or solvent mixtures. Although many of the studies of exposure to mixtures of solvents yielded increased risk estimates, there was considerable statistical variability in them. The incidence of HD is low, and most studies had small numbers of exposed cases to evaluate. Having such small numbers may lead to spuriously increased relative risks when the null hypothesis of no association is true. That limitation is reflected in the wide CIs observed in most of the studies. The lack of specific or validated exposure-assessment information and the impact of bias are other limitations that the committee considered in drawing its conclusion. Table 6.36 identifies the key studies reviewed for each exposure and the data points evaluated by the committee. Unless indicated in the tables, the study populations include both men and women.
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 solvents under review and Hodgkin’s disease.
TABLE 6.36 Selected Epidemiologic Studies—Hodgkin’s Disease and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Study—Incidence |
|||
Anttila et al., 1995 |
Biologically monitored workers in Finland |
3 |
1.70 (0.35–4.96) |
|
<100 µmol/L |
2 |
2.00 (0.24–7.22) |
|
≥100 µmol/L |
1 |
1.83 (0.05–10.2) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California, potential routine exposure |
4 |
2.77 (0.76–7.10) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah, employed >1 year |
5 |
1.4 (0.2–12.0) |
Morgan et al., 1998 |
Aerospace workers in Arizona |
|
|
|
All exposed |
1 |
0.60 (0.02–3.35) |
|
Low exposure |
1 |
1.55 (0.04–8.64) |
|
High exposure |
0 |
— |
Axelson et al., 1994 |
Biologically monitored male workers in Sweden |
1 |
1.07 (0.03–5.95) |
Case-Control Study |
|||
Persson et al., 1989 |
Residents of Sweden, exposed >1 year |
7 |
2.8 (0.96–7.86)a |
Benzene |
|||
Cohort Study—Mortality |
|||
Wong, 1987a,b |
US male chemical-plant workers |
3 |
0.81 (0.16–2.36) |
|
Benzene, continuously exposed |
2 |
1.12 (0.14–4.05) |
|
Not exposed to benzene |
1 |
0.75 (0.19–4.15) |
|
Duration of exposure, continuously exposed to benzene: |
|
|
|
<5 years |
1 |
0.88 |
|
5–14 years |
1 |
2.37 |
|
≥15 years |
0 |
— |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
||
Case-Control Study |
|||||
Bernard et al., 1984 |
Residents of Yorkshire, England |
NA |
1.00 (0.50–1.50) |
||
Other Specific Organic Solvents |
|||||
Cohort Study—Incidence |
|||||
Anttila et al., 1998 |
Biologically monitored workers in Finland (includes HD, NHL, and other lymphohematopoietic cancers) |
3 |
0.78 (0.16–2.28) |
||
|
Toluene |
3 |
1.18 (0.24–3.45) |
||
|
Xylene |
|
|||
Cohort Studies—Mortality |
|||||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|||
|
Tetrachloroethylene, potential routine exposure |
0 |
— |
||
Dosemeci et al., 1991 |
US male plant workers |
|
|||
|
Phenol |
|
|||
|
Any exposure |
10 |
1.7 (0.8–3.1) |
||
|
No exposure |
2 |
0.5 |
||
|
Low cumulative exposure |
8 |
2.3 |
||
|
Medium cumulative exposure |
2 |
0.9 |
||
|
High cumulative exposure |
0 |
— |
||
Blair et al., 1990 |
Members of a dry-cleaning union in Missouri |
|
|||
|
Dry-cleaning solvents |
4 |
2.1 (0.6–5.3) |
||
Case-Control Studies |
|||||
Persson et al., 1993 |
Residents of Sweden |
|
|||
|
White spirits, exposed >1 year |
4 |
1.4 (0.36–4.67)a |
||
Unspecified Mixtures of Organic Solvents |
|||||
Cohort Studies—Incidence |
|||||
Anttila et al., 1998 |
Biologically monitored workers in Finland |
|
|||
|
Aromatic hydrocarbons |
3 |
1.49 (0.31–4.36) |
||
Anttila et al., 1995 |
Biologically monitored workers in Finland |
|
|||
|
Halogenated hydrocarbons |
3 |
1.45 (0.30–4.23) |
||
Berlin et al., 1995 |
Swedish workers occupationally exposed to solvents |
2 |
6.3 (0.8–22.7) |
||
Cohort Studies—Mortality |
|||||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|||
|
Mixed solvents, potential routine exposure |
6 |
1.61 (0.59–3.51) |
||
Ritz, 1999 |
White male uranium-processing workers in Ohio |
|
|||
|
Ever exposed to solvents |
6 |
2.09 (0.76–4.54) |
||
Steenland and Palu, 1999 |
Members of the US Painters Union |
|
|||
|
Ever employed as a painter |
16 |
1.30 (0.74–2.11) |
||
|
Nonpainter |
4 |
0.54 (0.06–1.93) |
||
|
20 years since first union membership |
10 |
1.17 (0.56–2.15) |
||
Walker et al., 1993 |
Ohio shoe-manufacturing plants, employed >1 month |
4 |
1.12 (0.31–2.88) |
||
Garabrant et al., 1988 |
Aircraft-manufacturing workers in California, employed >4 years |
4 |
0.73 (0.20–1.88) |
||
Wen et al., 1985 |
Cohort of male oil refinery workers |
|
|||
|
Total lubricating cohort |
1 |
1.61 (0.04–8.98) |
||
|
Other lubricating cohort |
1 |
2.17 (0.28–12.10) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Alderson and Rattan, 1980 |
Male British workers in dewaxing plants |
|
|
Isopropyl alcohol production-plant workers |
0 |
0.09 (0.0–33.55)b |
|
|
Methyl ethyl ketone production-plant workers |
0 |
0.10 (0.0–20.50)b |
Case-Control Studies |
|||
Costantini et al., 2001 |
Residents in 12 areas of Italy |
|
|
|
Launderers, dry cleaners, and pressers |
1 |
2.5 (0.3–24.6) |
Persson et al., 1993 |
Residents of Sweden |
|
|
|
Solvents, high intensity |
7 |
1.8 (0.7–4.6)c |
Bernard et al., 1984 |
Residents of Yorkshire, England |
|
|
|
Solvents (excluding benzene) |
NA |
0.45 (0.15–1.42) |
|
Petrol products |
NA |
1.15 (0.37–3.56) |
Hardell and Bengtsson, 1983 |
|||
Male residents of three counties of Sweden |
|
||
|
Low-grade exposure (age 25–85 years) |
4 |
1.2 (0.4–3.8) |
|
High-grade exposure (age 25–85 years) |
14 |
3.0 (1.4–6.1) |
|
Ever exposed to solvents or phenoxy acids or chlorophenols |
7 |
6.6 (2.4–18.5) |
NOTE: NA=not available. a95% CIs were calculated by the committee with standard methods from the observed numbers presented in the original study. bEstimated risk and 95% CIs were calculated by the committee with standard methods from the observed and expected numbers presented in the original study. c90% CI is reported. |
MULTIPLE MYELOMA
Description of Case-Control Studies
Table 6.37 describes the two case-control studies that the committee reviewed to assess the association between MM and exposure to organic solvents. Morris and colleagues (1986) evaluated the association between risk of MM and self-reported exposure to 20 chemicals that were included in a standard questionnaire administered to subjects or to family members if a subject was deceased or too ill to be interviewed. Using the same study population, Demers and co-workers (1993) evaluated the association between MM and employment in a variety of occupations and industries. Eriksson and Karlsson (1992) conducted a population-based case-control study in Sweden in which subjects or the next of kin of deceased subjects were interviewed with self-administered questionnaires and by telephone. Occupational and leisure-time exposure to organic solvents was reported by the subjects.
TABLE 6.37 Description of Case-Control Studies of Multiple Myeloma and Exposure to Organic Solvents
Epidemiologic Studies of Exposure to Organic Solvents and Multiple Myeloma
The association between MM and exposure to trichloroethylene was evaluated in cohort studies of workers who were monitored biologically for a metabolite of trichloroethylene (SIR=0.9, 95% CI=0.01–4.7) (Hansen et al., 2001), in trichloroethylene-production workers (SIR=0.57, 95% CI=0.01–3.17) (Axelson et al., 1994), in aircraft-manufacturing workers (SMR=0.91, 95% CI=0.34–1.99) (Boice et al., 1999), and in aircraft-maintenance workers (SMR=1.3, 95% CI=0.5–3.4) (Blair et al., 1998). In the Blair and colleagues’ study (1998), no increases in relative risk with increasing cumulative exposure were found, but women exposed intermittently to trichloroethylene at low levels had an RR of 4.4 (95% CI=1.0–20.4).
The authors of four cohort studies examined the relationship between exposure to benzene and the risk of MM. Rinsky and colleagues (1987) reported an SMR of 4.09 (95% CI=1.10–10.47) in the cohort of Pliofilm workers in Ohio. Additional years of followup did not add any cases of MM; with the increased number of person-years of observation, the strength of the association was reduced by about 70% (SMR=2.91, 95% CI=0.79–7.45) (Wong, 1995).
Among Monsanto chemical-plant workers who used benzene in various production operations, an RR of 3.23 (95% CI=0.7–9.4) was observed (Ireland et al., 1997), but no exposure-response pattern was found. A nested case-control study based on a cohort of Canadian petroleum-distribution workers showed an increased risk of MM only when benzene exposures were more than 20 ppm per year (OR=1.22, 95% CI=0.07–20.0; two cases) (Schnatter et al., 1996a), but there was no evidence of an exposure trend. In the Chinese study of benzene-exposed workers, no increased risk of MM was found (one exposed case; Yin et al., 1996a,b).
Cohort studies of aircraft workers and aircraft-maintenance workers assessed the association between risk of MM and exposure to solvents, other than trichloroethylene. Boice and colleagues (1999) found no evidence of an association with tetrachloroethylene. Blair and colleagues (1998) reported an increased risk of MM in those ever exposed to toluene (RRwomen=5.0, 95% CI=1.1–23.1), methyl ethyl ketone (RRwomen=4.6, 95% CI=0.9–23.2), or methylene chloride (RRmen=3.4, 95% CI=0.9–13.2).
A number of cohort and case-control studies were used to examine the association between exposures to unspecified mixtures of organic solvents and risk of MM, including several studies of painters (Boice et al., 1999; Demers et al., 1993; Lundberg and Milatou-Smith, 1998; Steenland and Palu, 1999), aircraft maintenance and manufacturing workers (Blair et al., 1998; Boice et al., 1999), and shoe manufacturers (Fu et al., 1996), all of whom used various solvent mixtures in their occupations. In one study (of shoe-manufacturing workers), benzene was a likely component of the mixtures, but relative risks were not specifically reported (Fu et al., 1996).
In a cohort study of paint manufacturers (Lundberg and Milatou-Smith, 1998), increased mortality from and incidence of MM were observed (SMR=3.8, 95% CI=1.0–9.7; SIR=3.2, 95% CI=0.9–8.3). Painters were at increased risk (SMR=1.70, 95% CI=0.46–4.35) in one study (Boice et al., 1999), but not in a study of painter-union members (SMR=0.97, 95% CI=0.75–1.24); it was similar to the risk found for nonpainters (SMR=0.90, 95% CI=0.52–1.46) (Steenland and Palu, 1999).
Other studies of MM and exposure to unspecified mixtures of organic solvents were conducted. Blair and colleagues (1998) found a 30% excess MM mortality among men (RR=1.3, 95% CI=0.4–3.8) and women (RR=1.9, 95% CI=0.4–8.2) exposed to any solvent. An
increased incidence of MM was found among a cohort of Swedish workers occupationally exposed to solvents (SIR=2.0, 95% CI=0.4–5.7) (Berlin et al., 1995). The study by Boice and colleagues (1999) did not show an association (other than in painters) between exposure to mixtures of solvents and risk of MM (SMR=1.17, 95% CI=0.95–1.45).
One case-control study (Demers et al., 1993; Morris et al., 1986) showed an increased relative risk of MM among painters. Morris and colleagues (1986) found an 80% increase in incidence of MM among subjects exposed to paints or mixtures of solvents (OR=1.8, 95% CI=1.2–2.7). Using the same population, Demers and colleagues (1993) observed a positive exposure-response pattern among painters according to length of employment (less than 10 years: OR=1.4, 95% CI=0.6–2.8; 10 years or more duration: OR=4.1, 95% CI=1.8–10.4).
Summary and Conclusion
None of the studies yielded persuasive evidence that exposure to trichloroethylene increased the risk of MM. The lack of increased relative risks was observed in the studies on exposure to benzene. Most studies on other specific solvents, such as tetrachloroethylene, toluene, methyl ethyl ketone, or methylene chloride, did not find a positive association, or if they did, they were not supported by other corroborating studies.
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 solvents under review and multiple myeloma.
For exposure to solvent mixtures, a number of studies on painters found increased risk of MM, including one study that found an increasing risk with increasing years of employment (Demers et al., 1993). Table 6.38 identifies the key studies reviewed for each exposure and the data points evaluated by the committee. Unless indicated in the tables, the study populations include both men and women.
The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between chronic exposure to solvents (as observed in studies of painters) and multiple myeloma.
TABLE 6.38 Selected Epidemiologic Studies—Multiple Myeloma and Exposures to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Trichloroethylene |
|||
Cohort Study—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored Danish workers |
|
|
|
Males, ever exposed |
1 |
0.9 (0.01–4.7) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
Routine exposure |
6 |
0.91 (0.34–1.99) |
|
Routine or intermittent |
|
|
|
<1 year of exposure |
3 |
0.45 (0.13–1.54) |
|
1–4 years of exposure |
8 |
1.48 (0.64–3.41) |
|
≥5 years of exposure |
3 |
0.51 (0.15–1.76) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
||
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
|||
|
Any exposure (males and females) |
14 |
1.3 (0.5–3.4) |
||
|
Males |
|
|||
|
Low level intermittent |
4 |
0.5 (0.1–1.9) |
||
|
Low level continuous |
4 |
0.8 (0.2–3.2) |
||
|
Frequent peaks |
4 |
0.8 (0.2–3.3) |
||
|
Females |
|
|||
|
Low level intermittent |
4 |
4.4 (1.0–20.4) |
||
|
Low level continuous |
1 |
2.4 (0.2–24.3) |
||
|
Frequent peaks |
1 |
0.9 (0.1–8.9) |
||
|
Cumulative exposure, males (mortality) |
|
|||
|
No exposure |
10 |
1.7 (0.5–5.5) |
||
|
<5 unit-years |
4 |
1.0 (0.2–4.2) |
||
|
5–25 unit-years |
2 |
0.8 (0.1–4.4) |
||
|
>25 unit-years |
4 |
1.2 (0.3–4.7) |
||
|
Cumulative exposure, females (mortality) |
|
|||
|
No exposure |
11 |
1.0 (0.1–9.9) |
||
|
<5 unit-years |
2 |
3.2 (0.5–19.8) |
||
|
5–25 unit-years |
1 |
4.3 (0.4–43.4) |
||
|
≥25 unit-years |
1 |
1.3 (0.1–13.2) |
||
Axelson et al., 1994 |
Male workers in Sweden, ever exposed |
1 |
0.57 (0.01–3.17) |
||
Benzene |
|||||
Cohort Studies—Mortality |
|||||
Ireland et al., 1997 |
Male US chemical-plant workers |
|
|||
|
Production workers |
|
|||
|
Nonexposed |
1 |
0.5 (0.0–2.8) |
||
|
Any exposure |
3 |
3.2 (0.7–9.4) |
||
|
<12ppm-month |
0 |
0.0 (0.0–10.1) |
||
|
12–72 ppm-month |
2 |
6.8 (0.8–2.5) |
||
|
>72 ppm-month |
1 |
3.7 (0.1–20.1) |
||
Schnatter et al., 1996a |
Male Canadian petroleum-distribution workers |
|
|||
|
0.00–0.49 ppm-years |
3 |
1.00 |
||
|
0.50–7.99 ppm-years |
1 |
0.39 (0.01–5.16) |
||
|
8.00–1 9.99 ppm-years |
1 |
0.60 (0.01–7.83) |
||
|
20–219.8 ppm-years |
2 |
1.22 (0.07–20.0) |
||
Yin et al., 1996a,b |
Chinese factory workers, ever exposed |
1 |
0.4 (0.0–10.7) |
||
Wong, 1995 |
Male US Pliofilm workers in Ohio (through 1987) |
4 |
2.91 (0.79–7.45) |
||
|
<40 ppm-years |
3 |
3.21 (0.66–9.39) |
||
|
40–200 ppm-years |
0 |
0 (0–12.29) |
||
|
200–400 ppm-years |
0 |
0 (0–36.89) |
||
|
>400 ppm-years |
1 |
25.17 (0.63–139.83) |
||
Rinsky et al., 1987 |
Male US Pliofilm workers in Ohio (through 1981) |
4 |
4.09 (1.10–10.47) |
||
|
<40 ppm-years |
3 |
4.58 (0.92–13.39) |
||
|
40–200 ppm-years |
0 |
0 |
||
|
200–400 ppm-years |
0 |
0 |
||
|
>400 ppm-years |
1 |
53.47 (0.70–297.53) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
||
Other Organic Solvents |
|||||
Cohort Studies—Mortality |
|||||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|||
|
Tetrachloroethylene, routine exposure |
1 |
0.40 (0.01–2.25) |
||
|
Routine or intermittent exposure |
|
|||
|
<1 year of exposure |
1 |
0.46 (0.06–3.48) |
||
|
1–4 years of exposure |
4 |
1.13 (0.38–3.35) |
||
|
≥5 years of exposure |
1 |
0.24 (0.03–1.84) |
||
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
|||
|
Stoddard solvent |
|
|||
|
Males |
96 |
1.0 (0.3–3.2) |
||
|
Females |
3 |
1.6 (0.3–8.2) |
||
|
Isopropyl alcohol (males) |
4 |
1.5 (0.4–6.4) |
||
|
Trichloroethane (females) |
2 |
13.2 (2.2–80.4) |
||
|
Acetone |
|
|||
|
Males |
4 |
1.6 (0.4–6.7) |
||
|
Females |
2 |
3.8 (0.6–23.8) |
||
|
Toluene |
|
|||
|
Males |
2 |
0.9 (0.2–4.8) |
||
|
Females |
4 |
5.0 (1.1–23.1) |
||
|
Methyl ethyl ketone |
|
|||
|
Males |
1 |
0.4 (0.1–4.0) |
||
|
Females |
3 |
4.6 (0.9–23.2) |
||
|
Methylene chloride (males) |
5 |
3.4 (0.9–13.2) |
||
Unspecified Mixtures of Organic Solvents |
|||||
Cohort Studies—Incidence |
|||||
Lundberg and Milatou-Smith, 1998 |
Male Swedish paint-industry workers, ever employed |
|
|||
|
Incidence |
4 |
3.2 (0.9–8.3) |
||
Berlin et al., 1995 |
Swedish workers occupationally exposed to solvents |
3 |
2.0 (0.4–5.7) |
||
Lynge et al., 1995 |
Printing-industry workers in Denmark |
|
|||
|
Bookbinders, ever employed |
1 |
1.27 (0.02–7.04) |
||
|
Typographer (printing establishment), ever employed |
4 |
1.14 (0.31–2.93) |
||
Cohort Studies—Mortality |
|||||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|||
|
Factory workers, ever exposed |
90 |
1.17 (0.95–1.45)a |
||
|
Mixed solvents, routine exposure |
15 |
0.98 (0.55–1.61) |
||
|
Routine or intermittent exposure |
|
|||
|
<1 year of exposure |
3 |
0.34 (0.10–1.14) |
||
|
1–4 years of exposure |
13 |
0.63 (0.32–1.25) |
||
|
≥5 years of exposure |
34 |
0.80 (0.46–1.38) |
||
|
Painter, employed >1 year |
4 |
1.70 (0.46–4.35) |
||
Steenland and Palu, 1999 |
US painters-union members |
|
|||
|
Painters |
64 |
0.97 (0.75–1.24) |
||
|
20-year membership |
54 |
1.01 (0.76–1.32) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Lundberg and Milatou-Smith, 1998 |
Male Swedish paint-industry workers, ever employed |
|
|
Mortality |
4 |
3.8 (1.0–9.7) |
|
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
|
|
Any solvent |
|
|
|
Males |
19 |
1.3 (0.4–3.8) |
|
Females |
5 |
1.9 (0.4–8.2) |
Fu et al., 1996 |
Shoe-manufacturing workers |
|
|
|
English cohort |
7 |
0.99 (0.40–2.05) |
|
Probable solvent exposure |
3 |
1.15 (0.24–3.36) |
|
High solvent exposure |
1 |
5.26 (0.13–29.30) |
|
Florence cohort |
3 |
3.70 (0.76–10.80) |
|
Probable solvent exposure |
1 |
2.17 (0.05–12.10) |
|
High solvent exposure |
1 |
2.44 (0.06–13.60) |
Case-Control Studies |
|||
Demers et al., 1993 |
Residents of four US states |
|
|
|
Painters |
31 |
2.1 (1.2–3.6) |
|
Employed <10 years |
15 |
1.4 (0.6–2.8) |
|
Employed ≥10 years |
16 |
4.1 (1.8–10.4) |
|
Printing machine operators |
4 |
0.6 (0.1–2.0) |
Eriksson and Karlsson, 1992 |
Residents of northern Sweden |
|
|
Organic solvents (occupational), ever used |
21 |
0.50 (0.30–0.80)b |
|
|
Duration of exposure (occupational) |
|
|
|
≤5 years |
NA |
0.37 (0.09–1.48)b |
|
6–20 years |
NA |
0.59 (0.28–1.25)b |
|
≥21 years |
NA |
0.37 (0.26–0.74)b |
|
Organic solvents (leisure use), ever used |
43 |
1.22 (0.80–1.89)b |
Morris et al., 1986 |
Residents of four US states |
|
|
|
Ever exposed to: |
|
|
|
Aldehydes or ketones |
7 |
1.1 (0.4–3.6) |
|
Aromatic hydrocarbons |
16 |
0.8 (0.5–1.4) |
|
Chlorinated hydrocarbons |
70 |
1.0 (0.7–1.4) |
|
Paints or solvents |
39 |
1.8 (1.2–2.7) |
NOTE: NA=not available. a95% CI calculated by the committee with standard methods from the observed and expected numbers presented in the original study. b90% CI reported. |
ADULT LEUKEMIA
With the introduction of the eighth and ninth revisions of the ICD codes and an increased ability to identify subtypes of leukemia, epidemiologists could more easily identify specific hematopoietic cancers in their studies. However, in most of the studies reviewed, especially those conducted early, it was not possible to identify specific subtypes of adult leukemia. Furthermore, in the small cohort studies, there were often insufficient cases of any particular type of leukemia, so all subtypes were combined in the analyses to improve statistical power. In contrast with the literature on insecticide exposure, there were enough studies on the specific subtypes of leukemia to present findings according to the following five groups: adult leukemia
broadly, acute leukemia, chronic leukemia, lymphatic leukemia, and hairy cell leukemia. The committee acknowledges that the literature on adult leukemia could be divided by specific cell type but believes that there were too few studies to support valid conclusions on each specific type of leukemia. The committee therefore determined that there were enough high quality studies to support conclusions regarding the broad category of adult leukemia and acute leukemia only, which includes acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL). The decision to group leukemia types by onset (acute vs chronic) rather than by cell type was based on the available literature. The studies on acute leukemia, including AML and ALL, appeared to share more risk factors and findings than the more limited literature on chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Thus, the literature directed the committee to draw conclusions of association that encompassed both subtypes of acute leukemia.
Description of Case-Control Studies
The characteristics of the case-control studies considered by the committee in drawing its conclusions of association are described below in Table 6.39. All but one case-control study (Aschengrau et al., 1993) included interviews with study subjects concerning occupational history. Several questionnaires also included queries about specific chemical exposures, including benzene, trichloroethylene, and tetrachloroethylene (Albin et al., 2000; Bernard et al., 1984; Clavel et al., 1996; Nordström et al., 1998; Richardson et al., 1992; Staines and Cartwright, 1993). In many studies, experts reviewed questionnaire responses and attributed exposures unaware of case or control status (Albin et al., 2000; Ciccone et al., 1993; Clavel et al., 1996, 1998; Costantini et al., 2001; Lazarov et al., 2000; Malone et al., 1989; Richardson et al., 1992). Another study used a job—exposure matrix (Clavel et al., 1998) to determine exposures. However, in some studies, self-reported exposures were used as the metric (Bernard et al., 1984; Clavel et al., 1995; Flodin et al., 1981; Mele et al., 1994; Nordström et al., 1998; Staines and Cartwright, 1993). Unlike most occupational studies of leukemia, the study by Aschengrau and colleagues (1993) assessed exposure to tetrachloroethylene on the basis of estimated concentrations in public drinking water in five towns of Cape Cod, Massachusetts. Case-control studies of leukemia and exposure to organic solvents that had reasonably good assessments of exposure and enough exposed cases include those by Albin and colleagues (2000), Clavel and colleagues (1996), Lazarov and colleagues (2000), Malone and colleagues (1989), and Richardson and colleagues (1992).
Epidemiologic Studies of Exposure to Organic Solvents and Adult Leukemia
Several large cohort studies provided evidence for evaluating the association between exposure to benzene and adult leukemia. The principal cohort studies included several occupational populations with estimated levels of exposure, including the Pliofilm workers (Crump, 1994; Rinsky et al., 1981, 1987), Chinese factory workers (Hayes et al., 1997; Yin et al., 1996a,b), US chemical workers (Bond et al., 1986; Ireland et al., 1997; Wong, 1987a,b), US and British petroleum-distribution and oil-refinery workers (Rushton and Alderson, 1981; Wong et al., 1993), and, in nested case-control studies, petroleum-distribution workers in Canada (Schnatter et al., 1996a,b) and the UK (Rushton and Romaniuk, 1997).
TABLE 6.39 Description of Case-Control Studies of Leukemia and Exposure to Organic Solvents
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Viadana and Bross, 1972 |
White cases from the Tri-State Leukemia Survey, covering New York (New York City excluded), Baltimore, and Minnesota in 1959–1962; controls randomly selected from the same geographic areas |
1345 leukemia |
1,237 |
Painting work Printing work |
In-person interviews (direct or proxy) to assess occupational history (job titles) |
OR |
Age |
Flodin et al., 1981 |
Deceased cases, identified through the records of the Linkoping University Hospital (Sweden) and parish registers, in 1972–1978; controls selected from parish registers, matched for age and sex |
42 AML |
244 |
Solvents |
Mailed questionnaire to next of kin to assess occupational exposures (self-reports) |
Unadjusted OR |
None |
Bernard et al., 1984 |
Cases identified through registries and clinician reporting among residents of the Yorkshire Health Region, UK, with diagnosis in 1979–1981 and hematologic confirmation; controls selected from hospital inpatients, matched for age, sex, and geographic area |
79 lymphoid leukemia |
79 |
Benzene Solvents |
In-person interview to assess occupational history (job titles) and details of solvent and chemical contacts (self-reports) |
Logistic regression |
Sex, age |
Malone et al., 1989 |
Cases, age less than 80 years, diagnosed in four US SEER study areas in 1977–1981; controls selected through RDD or area sampling, depending on the study area, and matched for sex, race, and age |
427 CLL |
1683 |
Dry-cleaning industry work Aromatic hydrocarbons Paints |
Interview (in-person or telephone) with standardized questionnaire to assess lifetime occupational and leisure exposure history (self-reports) |
Logistic regression |
Age, sex, race, education level, area of residence |
|
Participation rates: 82.5% of cases, 83% of controls |
|
|||||
Richardson et al., 1992 |
Cases, age 30 years or over, identified through hospital hematology departments in Paris and Creteil, France, in 1984–1988; hospital controls selected from other departments, matched for sex, age, ethnicity, and usual residence |
185 acute leukemia |
513 |
Benzene Solvents Other hydrocarbon solvents Halogenated solvents Oxygenated solvents |
Interview with standardized questionnaire to assess lifetime occupational and leisure exposure history (self-reports) with solvent- exposure probability and level determined by industrial hygienist review |
Conditional logistic regression |
Matching variables, prior history of radiotherapy or chemotherapy |
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Aschengrau et al., 1993 |
Cases reported to the Massachusetts Cancer Registry, diagnosed in 1983–1986 among residents of five upper Cape Cod towns; living controls were selected from the records of the HCFA and through RDD; deceased controls identified by the state Department of Vital Statistics and Research files |
34 leukemia |
737 |
Tetrachloroethylene |
Relative delivered dose estimated in model accounting for location and years of residence, water flow, pipe characteristics |
Logistic regression |
Sex, age at diagnosis, vital status, educational level, occupational exposure to solvents, specific cancer risk factors |
|
Response rates: 79.5% of cases, 75.9% of HCFA controls, 73.9% of RDD controls, 78.8% of next of kin of deceased controls |
|
|||||
Ciccone et al., 1993 |
Cases, age 15–74 years, treated in the Main Hospital of Torino, Italy, newly diagnosed in 1989–1990; hospital controls selected in the same interval, matched for sex, age, and area of residence; population controls randomly selected from residents of Torino, matched on above |
50 AML 17 CML |
246 |
Benzene |
Interview with standardized questionnaire to assess lifetime occupational history (job titles) with exposure to solvents determined by industrial hygienist |
Logistic regression |
Age, area of residence and of birth, smoking |
|
Response rates: 91% of cases, 99% of hospital controls, 82% of population controls |
|
|||||
Staines and Cartwright, 1993 |
Cases from the Yorkshire and Trent (UK) Regional Health Authority areas, identified through Leukemia Research Fund data collection or hematologist participation in 1985–1990 with histologic confirmation; hospital controls matched for sex, age, and hospital |
50 HCL |
95 |
Benzene Solvents Organic chemicals |
In-person interview with structured questionnaire to assess occupational history and exposure to chemicals (self-reports) |
Conditional logistic regression |
Matching variables |
Mele et al., 1994 |
Cases, age 15 years or over, identified by hematology departments in three Italian cities in 1986–1990; outpatients without hematologic disorders selected as controls |
252 AML 100 ALL 156 CML |
1,161 |
Painting work Shoemakers |
In-hospital interview to assess lifetime behavioral and occupational exposure histories (job titles; self-reports) |
Logistic regression |
Age, sex, education, residence outside study town, other occupations |
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Clavel et al., 1995 |
Cases diagnosed in 18 French hospitals in 1980–1990; hospital controls selected from admission records during same interval, matched on sex, date of birth, date of admission, and residence (see also Clavel et al., 1996, 1998) |
291 HCL 229 men 62 women |
541 425 men 116 women |
Solvents |
Mailed questionnaire to assess lifetime occupational history (job titles) with supplementary telephone interview on exposure to solvents (self-reports) |
Conditional logistic regression |
Matching variables |
Clavel et al., 1996 |
Male cases diagnosed in 18 French hospitals in 1980–1990; hospital controls selected from admission records during same interval, matched on sex, date of birth, date of admission, and residence (see also Clavel et al., 1995, 1998) |
226 HCL |
425 |
Benzene Painters |
Mailed questionnaire to assess lifetime occupational history (job titles) with supplementary telephone interview on exposure to solvents (self-reports) and use of job-exposure matrix |
Conditional logistic regression |
Matching variables, smoking, farm work |
Clavel et al., 1998 |
Male cases diagnosed in 18 French hospitals in 1980–1990; hospital controls selected from admission records during same interval, matched on sex, date of birth, date of admission, and residence (see also Clavel et al., 1995, 1996) |
226 HCL |
425 |
Organic solvents Launderers and dry cleaners Painters Printers Spray painters |
Mailed questionnaire to assess lifetime occupational history (job titles) with supplementary telephone interview on exposure to solvents (self-reports) and use of job-exposure matrix |
Conditional logistic regression |
Matching variables, smoking, farm work |
Nordström et al., 1998 |
Male cases reported to the Swedish Cancer Registry in 1987–1992; controls selected from the National Population Registry, matched for age and county |
111 HCL |
400 |
Trichloroethylene Acetone White spirit Solvents Paint |
Mailed questionnaire (with supplemental telephone followup) to assess lifetime occupational history (job titles) and exposure to solvents (self-reports) |
Logistic regression |
Age |
In the Pliofilm workers study (Crump, 1994; Rinsky et al., 1981, 1987), subjects included workers exposed to benzene for at least 1 day from 1940 to 1950. In the last followup study, there were 14 deaths from leukemia, resulting in an SMR of 2.9 (95% CI=1.61–4.95). The relative risk of leukemia was found to increase with cumulative exposure, regardless of the methods used to estimate levels of exposure. In the study by Crump (1994), the RR was 1.2 (95% CI=0.26–3.64) for exposure at 0–45 ppm per year and 3.1 for exposure at 400–1,000 ppm per year (95% CI=0.37–11.11); in the Rinsky and colleagues’ study (1987), the RR was 1.09 (95% CI=0.12–3.94) for 0.001–40 ppm per year and 3.22 (95% CI=0.36–11.65) for 40–200 ppm per year.
Yin and colleagues (1996a) investigated the relationship between leukemia and exposure to benzene among Chinese workers and reported increased leukemia mortality (RR=2.3, 95% CI=1.1–5.0) and incidence (RR=2.6, 95% CI=1.3–5.7). Hayes and colleagues (1997) evaluated the exposure-response relationships and did not find clear dose-response relationships, but they did find that the relative risks generally increased by year of hire, average exposure (ppm), duration of employment (years), and cumulative exposure (ppm-years).
Evidence of an association between exposure to benzene and leukemia was also provided by several other cohort studies, including studies of US chemical workers and petroleum-distribution workers. The studies tended to be small and lacked the statistical power to detect a small to moderate association. Specifically, findings from the US chemical-worker studies (Bond et al., 1986; Ireland et al., 1997; Wong, 1987a,b) showed increased risks but no clear dose-response relationships. Associations were found in the UK study of oil-refinery workers (SMR=2.33, 95% CI=0.98–5.56) (Rushton and Alderson, 1981) and the study of petroleum-marketing and -distribution workers (SMR=1.35, 95% CI=0.14–12.8 for at least 45 ppm per year), but no clear dose-response pattern emerged (Rushton and Romaniuk, 1997). In the study of Canadian petroleum-distribution workers (Schnatter et al., 1996a), no associations were found.
Associations between exposure to trichloroethylene and leukemia were not found in several cohort studies that had relatively accurate information on occupational exposures. They included studies of biologically monitored workers (Hansen et al., 2001), workers at a uranium-processing plant (Ritz, 1999), and aircraft and aerospace maintenance and manufacturing workers (Blair et al., 1998; Boice et al., 1999; Morgan et al., 1998). The studies were generally of high quality with sufficient statistical power to detect relative risks of leukemia.
Investigations of most other specific organic solvents were restricted to single studies, and estimates of relative risk were usually based on small numbers of exposed cases. As a result, in most studies, no associations with leukemia were reported (Boice et al., 1999; Dosemeci et al., 1991). However, in one study of Swedish rotogravure-plant workers (Svensson et al., 1990) exposed to toluene, an increased risk of leukemia was observed (SMR=1.67, 95% CI=0.34–4.88). The risk was higher in those exposed for 5 years or more and with at least a 10-year latency (SMR=2.54, 95% CI=0.52–7.42).
Occupations in which large quantities of organic solvents were used have been studied to identify health risks and instigate interventions to reduce exposure. In several studies reviewed by the committee, increased risks of leukemia were observed among painters (Costantini et al., 2001: OR=1.7, 95% CI=0.8–3.8; Lundberg and Milatou-Smith, 1998: SIR=1.5, 95% CI=0.3–4.3; Viadana and Bross, 1972: RR=2.82), car mechanics (Hunting et al., 1995: SMR=9.26, 95% CI=1.12–33.43), shoe-manufacturing workers (Fu et al., 1996: SMR=2.80, 95% CI =0.76–7.16; Paci et al., 1989: SMR=4.95, 95% CI=1.82–10.79), employees at a naval nuclear shipyard (Stern et al., 1986: OR=2.32, 95% CI=0.85–6.29), workers exposed to solvents
occupationally (Berlin et al., 1995: SIR=2.1, 95% CI=0.8–4.6), and leather or tannery workers (Costantini et al., 1989: SMR=1.64, 95% CI=0.53–3.82). Studies in which associations were not found (Anttila et al., 1998; Boice et al., 1999; Garabrant et al., 1988; Matanoski et al., 1986; Steenland and Palu, 1999; Walker et al., 1993; Wolf et al., 1981; Wong et al., 1993) generally had small numbers of exposed cases. Two studies (Anttila et al., 1995; Fu et al., 1996) provided evidence of a dose-response relationship with increasing relative risks as exposure increased.
Summary and Conclusion
IARC and the US Environmental Protection Agency (EPA) have determined that benzene is carcinogenic in humans on the basis of both animal and human studies (ATSDR, 1997a; IARC, 1987; NTP, 2001). That determination was based primarily on the findings on leukemia defined broadly. In addition, epidemiologic studies of occupations exposed to mixtures of solvents, including benzene have shown increased risks of developing cancer. Among those at risk are rubber workers, mechanics, and some groups of chemical workers, printers and paper-industry workers, and shoe and leather workers (IARC, 1987, 1989).
Based on its review of the literature on exposure to benzene, the committee found that the combination of consistently positive findings in the cohort of workers with known exposures to benzene and evidence of a dose-response relationship fulfilled the criteria for a conclusion of sufficient evidence of an association between exposure to benzene and adult leukemia. However, the committee decided that the evidence of an association between exposure to benzene and adult leukemia was not as strong as that for acute leukemia. Thus, it did not warrant a conclusion of causality. The findings, although mostly positive, are not as consistent and statistically precise as the findings on acute leukemia. Most likely, the positive studies on adult leukemia and exposure to benzene include cases of acute leukemia. However, they may also include cases of chronic leukemia, lymphatic leukemia, and hairy cell leukemia, for which the existence of associations is not as clear. On the basis of the studies reviewed, the committee believes that the evidence on exposure to benzene and adult leukemia, defined broadly, met the definition of sufficient evidence of an association but not sufficient evidence of a causal relationship.
The committee concludes, from its assessment of the epidemiologic literature, that there is sufficient evidence of an association between chronic exposure to benzene and adult leukemia.
For exposure to other solvents, such as trichloroethylene and toluene, the overall paucity of studies and the lack of consistently positive findings limits the evidence that the committee had to review.
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, other than benzene, and adult leukemia.
In contrast, the findings for unspecified mixtures of organic solvents and adult leukemia showed increased relative risks, including two studies that provided evidence for a dose-response relationship with increasing levels of exposure. Table 6.40 identifies the key studies reviewed by the committee on adult leukemia. Unless indicated in the table, the study populations include both men and women.
The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of association between chronic exposure to unspecified mixtures of organic solvents and adult leukemia.
TABLE 6.40 Selected Epidemiologic Studies—Adult Leukemia and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Benzene |
|||
Cohort Studies—Mortality |
|||
Crump, 1994 |
Male US Pliofilm workers |
14 |
2.9 (1.61–4.95)a |
|
Cumulative exposure |
|
|
|
0–45 ppm-years |
3 |
1.2 (0.26–3.64)a |
|
45–400 ppm-years |
4 |
2.7 (0.73–6.83)a |
|
400–1,000 ppm-years |
2 |
3.1 (0.37–11.11)a |
|
>1000 ppm-years |
5 |
28.1 (9.00–64.83)a |
Yin et al., 1996a |
Chinese factory workers |
|
|
|
Mortality, total |
38 |
2.3 (1.1–5.0) |
|
Males |
25 |
2.1 (1.0–5.3) |
|
Females |
13 |
2.8 (0.8–17.6) |
|
|
42 |
|
|
Incidence, total |
|
2.6 (1.3–5.7) |
Hayes et al., 1997 |
Chinese factory workers |
|
|
|
All exposed workers |
38 |
2.5 (1.2–5.1) |
|
Exposed workers, year of hire |
|
|
|
<1972 |
25 |
2.4 |
|
≥1972 |
13 |
3.4 |
|
Exposed workers, average ppm |
|
|
|
<10 |
15 |
2.0 (0.9–4.5) |
|
10–24 |
13 |
3.7 (1.6–8.7) |
|
≥25 |
10 |
2.3 (0.9–5.7) |
|
p trend=0.02 |
||
|
Exposed workers, duration |
|
|
|
<5 years |
14 |
4.0 (1.7–9.6) |
|
5–9 years |
11 |
3.1 (1.3–7.5) |
|
≥10 years |
13 |
1.5 (0.6–3.6) |
|
p trend=0.98 |
||
|
Exposed workers, cumulative exposure |
|
|
|
<40 ppm-years |
11 |
1.9 (0.8–4.7) |
|
40–99 ppm-years |
8 |
3.1 (1.2–8.0) |
|
≥100 ppm-years |
19 |
2.7 (1.2–6.0) |
|
p trend=0.04 |
||
Ireland et al., 1997 |
Male US chemical-plant workers |
|
|
|
<12 ppm-months |
2 |
2.5 (0.3–8.9) |
|
12–72 ppm-months |
0 |
0.0 (0.0–5.4) |
|
≥72 ppm-months |
3 |
4.6 (0.9–13.4) |
Rushton and Romaniuk, 1997 |
Male UK petroleum marketing and distribution workers |
|
|
Cumulative exposure |
|
||
|
<0.45 ppm-years |
22 |
1.00 |
|
0.45–4.49 ppm-years |
47 |
1.42 (0.77–2.61) |
|
4.5–44.9 ppm-years |
20 |
2.48 (0.73–3.00) |
|
≥45 ppm-years |
1 |
1.35 (0.14–12.8) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Schnatter et al., 1996a |
Male Canadian petroleum distribution workers |
|
|
|
By median, 75th, and 90th percentiles |
|
|
|
0.0–0.49 ppm-years |
10 |
1.00 |
|
0.50–7.99 ppm-years |
1 |
0.22 (0.0–1.82) |
|
8.0–19.99 ppm-years |
1 |
0.42 (0.01–3.95) |
|
20.0–219.8 ppm-years |
2 |
0.96 (0.09–6.81) |
|
Exposure by regulatory standards |
|
|
|
0.00–0.45 ppm-years |
10 |
1.00b |
|
>0.45–4.5 ppm-years |
1 |
0.43 (0.0–4.05) |
|
4.5–45 ppm-years |
1 |
0.16 (0.0–4.55) |
|
≥45 ppm-years |
2 |
1.47 (0.16–13.1) |
Rinsky et al., 1987 |
Male US Pliofilm workers |
|
|
|
Ever exposed |
9 |
3.37 (1.54–6.41) |
|
0.001–40 ppm-years |
2 |
1.09 (0.12–3.94) |
|
40–200 ppm-years |
2 |
3.22 (0.36–11.65) |
|
200–400 ppm-years |
2 |
11.86 (1.33–42.85) |
|
>400 ppm-years |
3 |
66.37 (13.34–193.9) |
Wong, 1987a,b |
Male chemical manufacturing workers |
|
|
|
Entire cohort |
7 |
0.75 (0.30–1.54) |
|
Continuously exposed |
6 |
1.35 (0.49–2.95) |
|
Cumulative exposure |
|
|
|
<180 ppm-months |
2 |
0.97 (0.12–3.49) |
|
180–719 ppm-months |
1 |
0.78 (0.20–4.34) |
|
≥720 ppm-months |
3 |
2.76 (0.57–8.06) |
Bond et al., 1986 |
Male chemical workers, ever exposed |
|
|
|
Cohort less those exposed to arsenic, asbestos, or high levels of vinyl chloride |
3 |
1.62 (0.33–4.61) |
Rushton and Alderson, 1981 |
Male employees in eight UK oil refineries, ever exposed |
NA |
2.33 (0.98–5.56) |
Trichloroethylene |
|||
Cohort Study—Incidence |
|||
Hansen et al., 2001 |
Biologically monitored Danish workers |
|
|
|
Males |
5 |
1.9 (0.6–4.4) |
|
Females |
1 |
3.1 (0.04–18.0) |
Cohort Studies—Mortality |
|||
Ritz, 1999 |
White male employees at a uranium-processing plant in Ohio |
12 |
1.09 (0.56–1.91) |
Boice et al., 1999 |
Aircraft-manufacturing workers in California, ever exposed |
2 |
1.05 (0.54–1.84) |
Blair et al., 1998 |
Aircraft-maintenance workers in Utah |
|
|
|
Combined early and recent followup cohort |
16 |
0.6 (0.3–1.2) |
|
Men (cumulative exposure) |
|
|
|
No exposure |
9 |
1.0 (0.4–2.9) |
|
<5 unit-years |
7 |
1.0 (0.3–3.2) |
|
5–25 unit-years |
0 |
— |
|
>25 unit-years |
7 |
1.2 (0.4–3.6) |
Morgan et al., 1998 |
Aerospace workers in Arizona, ever exposed |
10 |
1.05 (0.50–1.93) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Other Specific Organic Solvents |
|||
Cohort Study—Incidence |
|||
Svensson et al., 1990 |
Male rotogravure workers in Sweden—toluene |
|
|
|
All exposed |
3 |
1.67 (0.34–4.88) |
|
≥5 years of exposure and >10-year latency |
3 |
2.54 (0.52–7.42) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
Ever exposed—tetrachloroethylene |
5 |
1.09 (0.35–2.55) |
Dosemeci et al., 1991 |
Male workers exposed to phenol |
|
|
|
No exposure |
7 |
0.9 |
|
All exposed |
14 |
0.9 (0.5–1.4) |
|
High exposure |
1 |
0.8 |
|
Medium exposure |
5 |
0.7 |
|
Low exposure |
8 |
1.0 |
Case-Control Studies |
|||
Costantini et al., 2001 |
Residents of 12 areas of Italy |
|
|
|
Launderers, dry cleaners, pressers, ever employed |
2 |
3.3 (0.3–32.4) |
Aschengrau et al., 1993 |
Residents of Cape Code, MA—tetrachloroethylene |
|
|
|
Exposure history |
|
|
|
Any |
7 |
1.77 (0.63–4.33) |
|
Low |
5 |
1.38 (0.40–3.78) |
|
High |
2 |
5.95 (0.58–31.72) |
Unspecified Mixtures of Organic Solvents |
|||
Cohort Studies—Incidence |
|||
Anttila et al., 1998 |
Finnish workers monitored for exposure to solvents |
|
|
|
Aromatic hydrocarbons, all years |
1 |
0.30 (0.01–1.67) |
Lundberg and Milatou-Smith, 1998 |
Swedish paint-industry workers |
|
|
Incidence, male workers, ≥5 years |
3 |
1.5 (0.3–4.3) |
|
Berlin et al., 1995 |
Swedish workers occupationally exposed to solvents |
|
|
|
Incidence |
6 |
2.1 (0.8–4.6) |
Anttila et al., 1995 |
Finnish workers exposed to halogenated hydrocarbons |
|
|
|
Ever exposed, male and female for the entire measurement period |
5 |
1.08 (0.35–2.53) |
|
Mean personal level |
|
|
|
<100 µmol/L |
1 |
0.39 (0.01–2.19) |
|
100+ µmol/L |
4 |
2.65 (0.72–6.78) |
Cohort Studies—Mortality |
|||
Boice et al., 1999 |
Aircraft-manufacturing workers in California |
|
|
|
Mixed solvents, ever exposed |
28 |
1.02 (0.68–1.48) |
Steenland and Palu, 1999 |
Painter-union members |
|
|
|
Painters (all members) |
138 |
0.92 (0.78–1.11) |
|
Painters (20 years since first union membership) |
111 |
1.11 (0.74–1.08) |
Lundberg and Milatou-Smith, 1998 |
Swedish paint-industry workers |
|
|
Mortality, male workers, ≥5 years |
2 |
1.2 (0.2–4.3) |
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Fu et al., 1996 |
Shoe-manufacturing workers |
|
|
|
English cohort |
16 |
0.89 (0.51–1.45) |
|
Probable solvent |
4 |
0.68 (0.19–1.75) |
|
High solvent |
0 |
— |
|
Florence cohort |
8 |
2.14 (0.92–4.21) |
|
Probable solvent |
4 |
2.52 (0.69–6.44) |
|
High solvent |
4 |
2.80 (0.76–7.16) |
Hunting et al., 1995 |
Male vehicle mechanics in the District of Columbia |
|
|
|
Solvents or fuels, high exposure |
2 |
9.26 (1.12–33.43) |
Berlin et al., 1995 |
Swedish workers occupationally exposed to solvents |
|
|
|
Mortality |
4 |
2.3 (0.6–5.8) |
Walker et al., 1993 |
Shoe-manufacturing workers, employed >1 month |
15 |
1.11 (0.63–1.85) |
Wong et al., 1993 |
Gasoline distribution workers in the United States |
|
|
|
Land-based terminal cohort |
27 |
0.89 (0.59–1.29) |
|
Marine-based terminal cohort |
16 |
0.70 (0.42–1.09) |
Costantini et al., 1989 |
Male tannery workers in Tuscany, employed >6 months |
5 |
1.64 (0.53–3.82) |
Paci et al., 1989 |
Shoe factory workers in Italy |
|
|
|
Total years of exposure (males) |
6 |
4.95 (1.82–10.79)a |
Garabrant et al., 1988 |
Aircraft manufacturing workers in California |
|
|
|
Employed >4 years |
16 |
0.82 (0.47–1.34) |
Matanoski et al., 1986 |
Painters and allied tradesmen union members |
44 |
0.93 (0.68–1.25)b |
Stern et al., 1986 |
Male employees at a naval nuclear shipyard |
|
|
|
Ever worked in job with solvent exposure |
NA |
2.32 (0.85–6.29) |
|
8.59 years in a solvent job |
NA |
1.82 (0.93–3.58) |
Wolf et al., 1981 |
Workers in the US rubber industry |
|
|
|
High solvent |
8 |
0.8 (p=0.64) |
|
Medium solvent |
38 |
1.1 (p=0.79) |
|
Low solvent |
23 |
0.6 (p=0.05) |
Alderson and Rattan, 1980 |
Male chemical-plant workers |
|
|
Methyl ethyl ketone plant production workers |
1 |
2.86 (0.07–15.91)a |
|
Chiazze et al., 1980 |
Male spray painters at automobile-assembly plants |
2 |
1.13 (0.14–4.08)b |
Case-Control Studies |
|||
Costantini et al., 2001 |
Residents of 12 areas of Italy |
|
|
|
Painters, ever employed |
10 |
1.7 (0.8–3.8) |
Viadana and Bross, 1972 |
Residents of New York, Baltimore, and Minnesota |
|
|
|
(Tri-State Leukemia Survey) |
|
|
|
Painters, white males |
|
|
|
15–44 years |
4 |
2.20 |
|
45–64 years |
12 |
3.29 |
|
65–48 years |
15 |
2.90 |
Epidemiologic Studies of Exposure to Organic Solvents and Acute Leukemia
Virtually all studies of exposure to benzene and acute leukemia (specifically AML or acute nonlymphocytic leukemia [ANLL], and ALL) showed positive associations (Albin et al., 2000; Ciccone et al., 1993; Crump, 1994; Ireland et al., 1997; Richardson et al., 1992; Rushton and Romaniuk, 1996; Wong, 1995; Yin et al., 1996a,b). In several cohort and case-control studies, the risks of acute leukemia were found to increase as the level or duration of exposure to benzene increased (Ireland et al., 1997; Richardson et al., 1992; Rushton and Romaniuk, 1996; Wong, 1995).
Increases in incidence of and mortality from AML were reported in the cohort studies of Chinese factory workers (SMR=3.1, 95% CI=1.2–10.7) (Yin et al., 1996a,b) and Pliofilm workers in Ohio (SMR=5.03, 95% CI=1.84–10.97) (Wong, 1995) respectively. Increased risks of AML were also reported in the cohort of petroleum-distribution workers in the UK (Rushton and Romaniuk (1996) and in a case-control study in Sweden by Albin and colleagues (2000) (OR=1.5, 95% CI=0.89–2.6 for all exposure levels). In a case-control study in France, Richardson and colleagues (1992) found an increased odds ratio among those with “medium/high” exposure to benzene (OR=2.8, 95% CI=1.3–5.9) when other occupational exposures were adjusted for. Increased risk of ANLL (RR=1.4, 95% CI=0.4–3.42) was reported from the cohort study of Monsanto chemical workers (Ireland et al., 1997). Yin and colleagues (1996a,b) found increased ALL risk among benzene-exposed workers, although the CIs were quite broad (SIR=2.8, 95% CI=0.5–54.5). Weak positive associations were observed in a low-powered case-control study in which exposure to solvents was assessed by industrial hygienists (Ciccone et al., 1993).
A number of case-control studies showed mostly positive associations between acute leukemia and exposure to unspecified mixtures of organic solvents (Albin et al., 2000; Flodin et al., 1981; Lazarov et al., 2000; Mele et al., 1994; Richardson et al., 1992). To increase the accuracy of exposure and to reduce recall bias, industrial hygienists, unaware of the case status of subjects, attributed exposure on the basis of job descriptions (Albin et al., 2000; Lazarov et al., 2000; and Richardson et al., 1992). In a case-control study by Albin and colleagues (2000), the OR for AML for all levels of exposure to organic solvents was 1.6 (95% CI=1.1–2.4) and 2.3 (95% CI=1.0–5.0) for moderate to high levels of exposure. For exposure to solvents in general, Lazarov and colleagues (2000) also showed an increased risk of AML (OR=2.52, 95% CI=1.45–4.39); the risk increased to 3.86 (95% CI=1.83–8.14) for “probable exposure” to solvents. In the case-control study by Flodin and colleagues (1981), the risk of AML increased to 6.3 (95% CI=2.6–15.3). A study of people ever employed as painters or shoemakers showed increased relative risks of both AML and ALL: for painters, the OR was 3.2 (95% CI=0.5–20.8)
for AML and 4.7 (95% CI=0.6–34.2) for ALL; for shoemakers, the OR was 2.4 (95% CI=0.9–6.9) for AML and 1.3 (95% CI=0.2–10.2) for ALL.
Summary and Conclusion
On the basis of the consistently high relative risks in studies in which the exposure to benzene is well known, the committee decided that the evidence meets the requirement for a conclusion of causality between chronic exposure to benzene and acute leukemia. Furthermore, given the strong positive associations in the cohort studies of highly exposed subjects, it is likely that confounding and selection bias do not account for the findings. Experimental evidence supports a biologic mechanism that strengthens the conclusion. The details of that experimental evidence are provided in Chapter 4 and discussed below.
The metabolism of benzene, which occurs in the liver and to a smaller 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. Benzene oxide can 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 on laboratory animals show that benzene affects the bone marrow in a dose-dependent manner, causing anemia, leukopenia, and thrombocytopenia; continued exposure causes aplasia and pancytopenia (Bruckner and Warren, 2001). Benzene also has carcinogenic properties. In experimental animals, increases in incidence of malignant lymphoma and some solid tumors have been seen after exposure to high doses of benzene.
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 acute leukemia.
For exposure to unspecified mixtures of organic solvents, the studies were virtually all positive, including several that were statistical strong. One study provided evidence of an exposure-response relationship in terms of both increasing levels and increasing duration of exposure. Table 6.41 identifies all the studies reviewed by the committee. Unless indicated in the table, the study populations include both men and women.
The committee concludes, from its assessment of the epidemiologic literature, that there is sufficient evidence of an association between chronic exposure to unspecified mixtures of organic solvents and acute leukemia.
TABLE 6.41 Selected Epidemiologic Studies—Acute Leukemia and Exposure to Organic Solvents
Reference |
Study Population and Cancer Type |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Benzene |
|||
Cohort Studies—Mortality |
|||
Ireland et al., 1997 |
Male Monsanto Company production workers in Sauget, Illinois-ANLL |
|
|
|
<12ppm-months |
1 |
3.7 (0.1–20.6) |
|
12–72 ppm-months |
0 |
0.0 (0.0–44.1) |
|
>72 ppm-months |
1 |
4.5 (0.1–25.3) |
|
Ever exposed |
4 |
1.4 (0.4–3.42)a |
Reference |
Study Population and Cancer Type |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Rushton and Romaniuk, 1996 |
Male petroleum-distribution workers in the UK—AML (myeloid and monocytic) |
|
|
|
<0.45 ppm-years |
7 |
1 |
|
0.45–4.49 ppm-years |
15 |
2.17 (0.77–6.09) |
|
4.5–44.9 ppm-years |
9 |
2.82 (0.82–9.38) |
|
>45 ppm-years |
— |
— |
Yin et al., 1996a,b |
Chinese factory workers, ever exposed |
|
|
|
Incidence of AML |
23 |
3.1 (1.2–10.7) |
|
Incidence of ALL |
5 |
2.8 (0.5–54.5) |
Wong, 1995 |
Male Pliofilm workers in Ohio—AML (myeloid and monocytic) |
|
|
|
<40 ppm-years |
1 |
1.19 (0.03–6.63) |
|
40–200 ppm-years |
0 |
0 (0–14.75) |
|
200–400 ppm-years |
2 |
27.21 (3.29–98.24) |
|
>400 ppm-years |
3 |
98.37 (20.28–287.65) |
|
Total |
6 |
5.03 (1.84–10.97) |
Crump, 1994 |
Male Pliofilm workers in Ohio—AML (myeloid and monocytic) |
|
|
|
Total (two cases could not be identified as to type) |
8–10 |
5.0–6.2 |
|
0–45 ppm-years) |
0–2 |
0.0–2.4 |
|
45–400 ppm-years |
1 |
2.0 (0.05–10.92)b |
|
400–1000 ppm-years |
2 |
9.1 (1.10–32.82)b |
|
>1000 ppm-years |
5 |
82.8 (27.00–194.50)b |
Case-Control Studies |
|||
Albin et al., 2000 |
Residents of Lund, Sweden—AML |
|
|
|
All exposure levels |
39 |
1.5 (0.89–2.6) |
|
Hobby—low levels |
28 |
1.6 (0.89–3.1) |
|
Moderate-high levels |
11 |
1.3 (0.52–3.1) |
Ciccone et al., 1993 |
Residents in the Main Hospital of Torino, Italy—AML, CML, MDS; ever exposed |
10 |
1.7 (0.6–5.5) |
Richardson et al., 1992 |
Residents of Paris and Créteil, France—acute leukemia; occupationally exposed |
|
|
|
All exposure levels |
22 |
1.3 (0.8–2.3) |
|
High or medium exposure |
15 |
2.8 (1.3–5.9) |
Unspecified Mixtures of Organic Solvents |
|||
Case-Control Studies |
|||
Albin et al., 2000 |
Residents of Lund, Sweden—AML |
|
|
|
Organic solvents, all exposure levels |
88 |
1.6 (1.1–2.4) |
|
Low levels (hobby use) |
70 |
1.5 (1.0–2.3) |
|
1–7 years-duration |
10 |
0.72 (0.32–1.6) |
|
8–14 years-duration |
18 |
1.5 (0.73–3.1) |
|
15–20 years-duration |
42 |
2.1 (1.2–3.7) |
|
Moderate-high levels |
18 |
2.3 (1.0–5.0) |
|
Moderate for 1–20 years |
9 |
1.6 (0.57–4.3) |
|
High for 1–20 years |
9 |
3.9 (1.0–15) |
|
Chlorinated solvents |
12 |
0.78 (0.36–1.7) |
Reference |
Study Population and Cancer Type |
Exposed Cases |
Estimated Relative Risk (95% CI) |
||
Lazarov et al., 2000 |
Residents of Novi Sad, Yugoslavia, and London, England—AML |
|
|||
|
Solvents (multivariate analysis) |
53 |
2.52 (1.45–4.39) |
||
|
Possible exposure |
24 |
2.28 (1.12–4.62) |
||
|
Probable exposures |
29 |
3.86 (1.83–8.14) |
||
|
Painters and related workers |
7 |
4.57 (1.29–16.14) |
||
|
Paints |
23 |
1.28 (0.68–2.43) |
||
|
Oils |
32 |
1.56 (0.87–2.81) |
||
|
Machinery mechanics and fitters |
12 |
4.03 (1.44–11.23) |
||
Mele et al., 1994 |
Residents of Italy |
|
|||
|
Painters, ever employed |
|
|||
|
AML |
4 |
3.2 (0.5–20.8) |
||
|
ALL |
4 |
4.7 (0.6–34.2) |
||
|
Shoemakers, ever employed |
4 |
2.4 (0.9–6.9) |
||
|
AML |
1 |
1.3 (0.2–10.2) |
||
|
ALL |
|
|||
Richardson et al., 1992 |
Residents of Paris and Créteil, France—acute leukemia; ever exposed |
|
|||
|
Solvents, all exposure levels |
71 |
1.1 (0.7–1.5) |
||
|
Other hydrocarbon solvents, all exposure levels |
28 |
1.0 (0.6–1.6) |
||
|
High or medium exposure |
11 |
0.9 (0.4–1.8) |
||
|
Halogenated solvents, all exposure levels |
44 |
1.1 (0.7–1.6) |
||
|
High or medium exposure |
23 |
1.0 (0.6–1.7) |
||
|
Oxygenated solvents, all exposure levels |
42 |
1.5 (1.0–2.4) |
||
|
High or medium exposure |
15 |
1.5 (0.7–2.7) |
||
Flodin et al., 1981 |
Residents of Linköping, Sweden—AML |
|
|||
|
Solvents, ever exposed |
11 |
6.3 (2.6–15.3)b |
||
aRR and 95% CI calculated by the committee with standard methods from the observed and expected numbers presented in the original study. b95% CI calculated by the committee with standard methods from the observed and expected numbers presented in the original study. |
Epidemiologic Studies of Exposure to Organic Solvents and Chronic Leukemia
An association between exposure to benzene and risk of chronic leukemia was reported in several studies (Ireland et al., 1997: SMR=2.3, 95% CI=0.7–5.3; Rushton and Romaniuk, 1997: SMR=1.22, 95% CI=0.38–3.89 for 4.5–44.9 ppm-years; Yin et al., 1996a,b: SMR=2.6, 95% CI=0.7–16.9). No excess risks (OR=1.1, 95% CI=0.6–2.0) were observed for self-reported exposure to aromatic hydrocarbons (the class of solvents that includes benzene, toluene, and xylene) in a population-based case-control study of CLL (Malone et al., 1989). Except for one exposure level, the case-control study by Rushton and Romaniuk (1997) showed relative risks close to unity.
A case-control study of leukemia and preleukemia conducted in Italy found that shoemakers and painters were at high risk for CML (OR=4.5, 95% CI=1.6–13.0 for shoemakers; OR=7.6, 95% CI=1.5–39.8 for painters) (Mele et al., 1994). Positive associations between exposure to mixed solvents and CLL were found in a US study reporting previous exposures to paints (OR=1.4, 95% CI=0.8–2.2) and hobby painting (OR=1.4, 95% CI=0.9-
2.0), but no increased risks were found (OR=0.9) among those employed in the dry-cleaning industry (Malone et al., 1989).
The committee drew no conclusion on an association between exposure to benzene or unspecified mixtures of organic solvents and chronic leukemia. Table 6.42 identifies the studies reviewed by the committee on chronic leukemia. Unless indicated in the table, the study populations include both men and women.
TABLE 6.42 Selected Epidemiologic Studies—Chronic Leukemia and Exposure to Organic Solvents
Reference |
Study Population and Cancer Type |
Exposed Cases |
Estimated Relative Risk (95 % CI) |
Benzene |
|||
Cohort Studies—Mortality |
|||
Ireland et al., 1997 |
Male Monsanto plant workers in Sauget, IL |
|
|
|
Production workers exposed to benzene (all leukemias) |
5 |
2.3 (0.7–5.3) |
|
CLL (exposure to benzene category) |
|
|
|
<12 ppm-months |
1 |
5.9 (0.1–32.6) |
|
12–72 ppm-months |
0 |
0.0 (0.0–24.7) |
|
>72 ppm-months |
1 |
6.7 (0.2–37.7) |
Rushton and Romaniuk, 1997 |
Male UK petroleum marketing and distribution workers CLL (exposure to benzene) |
|
|
<0.45 ppm-years |
8 |
1 |
|
|
0.45–4.49 ppm-years |
16 |
1.07 (0.40–2.86) |
|
4.5–44.9 ppm-years |
7 |
1.22 (0.38–3.89) |
|
≥45 ppm-years |
0 |
0 |
|
CML (exposure to benzene) |
|
|
|
<0.45–4.49 ppm-years |
9 |
1 |
|
4.5–44.9 ppm-years |
2 |
0.76 (0.14–4.06) |
|
≥45 ppm-years |
0 |
— |
Yin et al., 1996a,b |
Chinese factory workers—CML |
|
|
|
Any exposure |
9 |
2.6 (0.7–16.9) |
Case-Control Study |
|||
Malone et al., 1989 |
US residents of four areas—CLL |
|
|
|
Aromatic hydrocarbons, any exposure |
26 |
1.1 (0.6–2.0) |
Unspecified Mixtures of Organic Solvents |
|||
Case-Control Studies |
|||
Mele et al., 1994 |
Residents of Italy |
|
|
|
Painters, ever employed—CML |
5 |
7.6 (1.5–39.8) |
|
Shoemakers, ever employed—CML |
6 |
4.5 (1.6–13.0) |
Malone et al., 1989 |
US residents of four areas—CLL |
|
|
|
Paints, ever exposed |
26 |
1.4 (0.8–2.2) |
|
Dry-cleaning industry, ever employed |
14 |
0.9 (0.4–1.8) |
|
Hobby painting, ever exposed |
48 |
1.4 (0.9–2.0) |
Epidemiologic Studies on Exposure to Organic Solvents and Lymphatic Leukemia
Several studies of lymphatic leukemia examined associations with exposure to benzene. Positive associations between lymphatic leukemia and exposure to benzene were observed in several studies (Bernard et al., 1984; Wilcosky et al., 1984), but there was considerable variability in the estimates.
Wilcosky found increased risk estimates associated with almost all exposures, including ethyl acetate (OR=5.3, p<0.05) and acetone (OR=6.8, p<0.01); this study was a large-scale investigation of rubber workers in which individual estimates for a variety of solvents were made on the basis of company records. Bernard and colleagues (1984) found a positive association between lymphatic leukemia and occupational solvents, excluding benzene (OR=1.56, 95% CI =0.47–5.17). Among rubber workers, relative risks increased with increasing estimated levels of exposure to mixed solvents (McMichael et al., 1975; Wolf et al., 1981). A cohort study of lymphatic leukemia in nuclear-plant workers found increased risk associated with jobs entailing exposure to unspecified mixtures of organic solvents (RR=1.99, 95% CI=0.46–8.67) (Stern et al., 1986).
No conclusions were drawn on an association between exposure to benzene, other specific organic solvents, or unspecified mixtures of solvents and lymphatic leukemia. Table 6.43 identifies the key studies on lymphatic leukemia reviewed by the committee. Unless indicated in the table, the study populations include both men and women.
TABLE 6.43 Selected Epidemiologic Studies—Lymphatic Leukemia and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Benzene |
|||
Cohort Studies—Mortality |
|||
Wilcosky et al., 1984 |
White, male US rubber workers, exposed >1 year |
4 |
2.5 |
Arp et al., 1983 |
US rubber workers |
|
|
|
Primary exposure to benzene |
3 |
4.50 |
|
Secondary exposure to benzene |
2 |
1.50 |
Case-Control Study |
|||
Bernard et al., 1984 |
Male residents of Yorkshire, England, ever exposed |
NA |
3.06 (0.98–11.97) |
Other Specific Solvents |
|||
Cohort Study—Mortality |
|||
Wilcosky et al., 1984 |
White, male US rubber workers, exposed >1 year |
|
|
|
Acetone |
3 |
6.8 |
|
Ethanol |
4 |
2.0 |
|
Ethyl acetate |
3 |
5.3 |
|
Isopropanol |
6 |
1.8 |
|
Solvent “A” (mixture of toluene and other solvents) |
7 |
2.8 |
|
Specialty naphthas |
8 |
2.8 |
|
Perchloroethylene (tetrachloroethylene) |
1 |
— |
|
Phenol |
1 |
— |
|
Toluene |
2 |
3.0 |
|
Trichloroethylene |
2 |
0.81 |
|
VM and P naphthas |
3 |
2.9 |
|
Xylenes |
4 |
3.3 |
Unspecified Mixtures of Solvents |
|||
Cohort Studies—Mortality |
|||
Stern et al., 1986 |
Male Portsmouth Naval Shipyard workers |
|
|
|
Solvent job |
NA |
1.99 (0.46–8.67) |
Arp et al., 1983 |
US rubber workers |
|
|
|
Primary exposure to other solvents |
11 |
4.50 |
|
Secondary exposure to other solvent |
8 |
1.60 |
Epidemiologic Studies of Exposure to Organic Solvents and Hairy Cell Leukemia
In a study by Clavel and colleagues (1995, 1996, 1998), no excess risks were observed between exposure to benzene and hairy cell leukemia. In another case-control study, exposure to benzene was associated with risk of hairy cell leukemia (Staines and Cartwright, 1993), although CIs included unity (OR=2.00, 95% CI=0.50–8.00).
Nordström and colleagues (1998) found an association between hairy cell leukemia and self-reported exposures to white spirit (or naphtha) (OR=2.0, 95% CI=1.2–3.4), acetone (OR=1.2, 95% CI=0.3–4.3), and trichloroethylene (OR=1.5, 95% CI=0.7–3.3).
Clavel and colleagues (1995, 1998) inquired about exposure to organic solvents and found little evidence of an association between hairy cell leukemia and exposure to solvent mixtures or occupations involving exposure to organic solvents, such as painting, spray painting, printing, and laundry and dry cleaning. Staines and Cartwright (1993) also did not find strong evidence of an association with organic solvents (OR=1.45, 95% CI=0.58–3.66), while Nordström and colleagues (1998) found positive associations between hairy cell leukemia and exposure to all solvents (OR=1.5, 95% CI=0.99–2.3) and working with paints (OR=4.3, 95% CI=1.8–10.3).
No conclusions were drawn on an association between exposure to specific solvents or unspecified mixtures of organic solvents and hairy cell leukemia. Table 6.44 identifies the studies related to hairy cell leukemia and solvent exposure. Unless indicated in the table, the study populations include both men and women.
TABLE 6.44 Selected Epidemiologic Studies—Hairy Cell Leukemia and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Benzene |
|||
Case-Control Studies |
|||
Clavel et al., 1996 |
Male residents of France |
|
|
|
All exposures to benzene |
34 |
0.8 (0.5–1.2)a |
|
Pure exposure to benzene |
2 |
0.7 (0.1–4.1)a |
|
Painters (exposed to benzene) |
4 |
0.8 (0.2–3.3)a |
Staines and Cartwright, 1993 |
Residents of Yorkshire and Trent, UK |
|
|
Benzene, any exposure for any duration |
4 |
2.00 (0.50–8.00) |
MYELODYSPLASTIC SYNDROMES
Myelodysplastic syndromes (MDS) are a group of conditions characterized by abnormalities of the bone marrow cells. Because most of the blood cells produced by these abnormal marrow cells are defective, they are usually destroyed before leaving the bone marrow or shortly after entering the bloodstream, and this results in low blood-cell counts. In about 30% of cases, the bone marrow cells develop further abnormalities and eventually develop into acute leukemia. Therefore, the term preleukemia, used in the past to refer to MDS, is not accurate, in that not all patients with MDS develop leukemia.
Description of Case-Control Studies
All case-control studies of MDS reviewed included interviews with study subjects concerning occupational history, some of which yielded information on specific chemical exposures (Table 6.45). Some studies relied on expert review of questionnaire responses (Ciccone et al., 1993; Nisse et al., 2001; West et al., 1995, 2000) to determine exposures; assessments of exposure in other studies were based on self-reports (Goldberg et al., 1990; Ido et al., 1996; Mele et al., 1994; Nagata et al., 1999; Rigolin et al., 1998). Case-control studies of MDS and exposure to organic solvents that had reasonably good assessments of exposure and enough exposed cases include those by Nisse and colleagues (2001) and West and co-workers (1995).
Epidemiologic Studies of Exposure to Organic Solvents
Although several epidemiologic studies were used to examine the association between mixtures of organic solvents and MDS, in only one cohort study of Chinese workers occupationally exposed to benzene (Hayes et al., 1997), was MDS evaluated; however, cases of MDS were combined with cases of ANLL. An RR of 4.1 (95% CI=1.4–11.6) was observed, and the relative risk increased as average exposure to benzene increased (RR=3.2 for constant low-level exposure at under 10 ppm, 7.1 for constant high-level exposure at 25 ppm or higher). This was the first epidemiologic study to demonstrate an association between exposure to benzene and MDS and ANLL.
Earlier case series of benzene-exposed workers noted abnormalities in bone marrow and peripheral blood consistent with MDS specifically (Aksoy and Erdem, 1978; Goguel et al., 1967; Van den Berghe et al., 1979), but the recognition of this disease is relatively recent and has not always been considered in evaluating risks related to exposure to benzene.
Several studies examined the association between exposure to organic solvent mixtures and the risk of MDS. On the basis of qualitative and quantitative assessments of exposure by occupational experts, a study of 204 newly diagnosed cases of MDS and 204 sex- and age-matched controls (Nisse et al., 2001) assessed the association between exposure to solvents and the risk of MDS. Based on 43 exposed cases, the study observed a statistically precise OR of 2.6 (95% CI=1.6–5.4). That increased risk was supported by the other studies reviewed, including a study of 29 cases exposed to organic solvents (Rigolin et al., 1998) that found an OR of 7.11 (95% CI=2.42–20.88). Although those exposed to solvents had an increased risk (OR=7.11. 95% CI=2.42–20.88), those identified as painters, printers, shoemakers, and chemical-industry workers combined did not (OR=0.81, 95% CI=0.33–2.00). The study by Mele and colleagues (1994) found high odds ratios for shoemakers and painters individually (OR=4.3, 95% CI=0.9–21.1 and OR=5.4, 95% CI=0.5–61.0, respectively). The numbers of exposed cases were extremely small, as evidenced by the wide CIs, and the case definition of MDS included those with refractory anemia who had an excess of blasts; this made the health-outcome assessment less precise.
Studies by West and colleagues (2000) and Nagata and colleagues (1999) found increased risks of MDS among residents of the UK (OR=1.8, 95% CI=0.6–6.0) and Japan (OR =1.99, 95% CI=0.97–4.10), respectively. An earlier study in Japan (Ido et al., 1996) also showed increased risks of MDS in men and women exposed to organic solvents occupationally (OR=1.50, 95% CI=0.85–2.64).
TABLE 6.45 Description of Case-Control Studies of Myelodysplastic Syndromes and Exposure to Organic Solvents
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Goldberg et al., 1990 |
Cases, age 28–88 years, referred to the hematology-oncology division of the Medical College of Pennsylvania in 1976–1989 with hematologic confirmation; controls selected from the primary-care and cardiology clinics of the same hospital, matched for age, sex, and socioeconomic group |
52 |
52 |
Solvents |
Questionnaire developed by the American Lung Association to assess occupational history and lifetime exposure to solvents (self-reports) |
Fisher exact test |
None |
Ciccone et al., 1993 |
Cases, age 15–74 years, treated in the Main Hospital of Torino, Italy, newly diagnosed in 1989–1990; hospital controls selected in the same interval, matched for sex, age, and area of residence; population controls randomly selected from residents of Torino, matched on above |
19 |
246 |
Benzene Solvents |
Interview with standardized questionnaire to assess lifetime occupational history with exposure to solvents determined by industrial hygienist |
Logistic regression |
Age, area of residence and of birth, smoking |
|
Response rates: 91% of cases; 99% of hospital controls; 82% of population controls |
|
|||||
Mele et al., 1994 |
Cases, age 15 years or over, identified by hematology departments in three Italian cities in 1986–1990; outpatients without hematological disorders selected as controls |
111 (refractory anemia with excess of blasts) |
1161 |
Painting work Shoemakers |
In-hospital interview to assess lifetime behavioral and occupational exposure histories (self-reports) |
Logistic regression |
Age, sex, education, residence outside study town, other occupations |
West et al., 1995 |
Cases, age 15 years or more, from areas of the UK; controls selected from outpatient clinics and inpatient wards, matched for age, sex, area of residence and hospital, and year of diagnosis (see also West et al., 2000) |
400 |
400 |
Solvents |
In-person interview with questionnaire to assess lifetime occupational and exposure history, duration and intensity of exposure (self-reports) |
Matched pairs analysis |
Matching variables |
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Ido et al., 1996 |
Cases, age 20–74 years, selected from 32 hospitals in Japan in 1992–1993 with hematologic confirmation; controls selected from outpatient departments of each hospital, matched for age, sex, and hospital |
116 |
116 |
Organic solvents |
Self-administered questionnaire to assess lifetime employment in specific occupations; exposure to solvents was determined from a list of occupations with probable or possible exposure |
Conditional logistic regression |
Matching variables |
Rigolin et al., 1998 |
Consecutive cases referred to the Institute of Haematology of Ferrara, Italy, in 1990–1996 with hematologic confirmation; controls randomly selected from institute outpatients, matched for sex, date of birth, and geographic area |
178 |
178 |
Solvents Occupational exposure: painters, printers, shoemakers, chemical industry |
In-person or telephone interview with questionnaire to assess types and duration of exposure (self-reports) |
Unadjusted OR |
None |
Nagata et al., 1999 |
Cases, age 20–74 years, selected from 28 institutes in Japan in 1995–1996 with hematologic confirmation; controls selected through use of telephone directories, matched for sex and prefecture |
111 |
830 |
Organic solvents |
Self-administered questionnaire to assess occupational exposure to solvents (self-reports) |
Conditional logistic regression |
Matching variables, age |
West et al., 2000 |
Cases, age 15 years or over, from three specialist regional centers in the UK; controls selected from outpatients, matched for age, sex, and area of residence (see also West et al., 1995) |
400 |
400 |
Organic chemicals |
In-person interview with questionnaire to assess lifetime occupational and exposure history, duration and intensity of exposure |
Matched pairs analysis |
Matching variables |
Nisse et al., 2001 |
Cases diagnosed in the hematology department of the University Hospital of Lille, France, in 1991–1996 with hematologic confirmation; controls randomly selected from electoral registers, matched for sex and age |
204 |
204 |
Solvents |
In-person interview with questionnaire to assess lifetime occupational history; exposure to solvents was determined by a team of experts |
Mantel-Haenszel |
Matching variables |
Summary and Conclusion
All but one (Goldberg et al., 1990) of the studies reviewed by the committee and identified below in Table 6.46 found consistently positive odds ratios for the association between MDS and exposure to unspecified mixtures of organic solvents. Given that all the studies reviewed are case-control studies, almost all relied exclusively on self-reported exposures, which may be subject to recall bias. The difficulty in classifying MDS accurately and consistently is another limitation that the committee considered in evaluating the literature.
The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between chronic exposure to unspecified mixtures of organic solvents and myelodysplastic syndromes.
For exposure to specific solvents, such as benzene, the rarity of the disease and the difficulty in classifying MDS as a separate entity have limited the evaluation of associations in most studies. Additional studies are needed to elucidate and support the association between exposure to benzene and MDS. They should also attempt to separate MDS from other cancers, such as ANLL, so that the relationship between exposure to benzene and MDS can be further understood. Table 6.46 identifies the studies related to MDS and solvent exposure. Unless indicated in the table, the study populations include both men and women.
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 benzene and myelodysplastic syndromes.
TABLE 6.46 Selected Epidemiologic Studies—Myelodysplastic Syndromes and Exposure to Organic Solvents
Reference |
Study description |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Benzene |
|||
Cohort Study—Incidence |
|||
Hayes et al., 1997 |
Chinese factory workers |
|
|
|
ANLL or MDS |
|
|
|
All unexposed |
4 |
1.0 |
|
All exposed |
28 |
4.1 (1.4–11.6) |
|
Rubber workers |
2 |
6.1 |
|
Chemical workers |
4 |
4.5 |
|
Constant exposure, ANLL or MDS |
|
|
|
<10 ppm |
10 |
3.2 (1.0–10.3) |
|
10–24 ppm |
4 |
5.1 (1.3–20.6) |
|
≥25 ppm |
8 |
7.1 (2.1–23.7) |
|
p-trend=0.0003 |
||
Unspecified Mixtures of Organic Solvents |
|||
Case-Control Studies |
|||
Nisse et al., 2001 |
Residents of northern France |
|
|
|
Solvents, ever exposed |
43 |
2.6 (1.6–5.4) |
|
Glue adhesives, ever exposed |
11 |
2.8 (0.8–11.8) |
West et al., 2000 |
Residents of the UK |
|
|
|
Organic chemicals, >50 hours of exposure at moderate intensity |
75 |
1.8 (0.6–6.0) |
Reference |
Study description |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Nagata et al., 1999 |
Residents of Japan |
|
|
|
Organic solvents, occupational exposure |
|
|
|
Males and females |
12 |
1.99 (0.97–4.10) |
|
Males |
9 |
1.66 (0.74–3.73) |
Rigolin et al., 1998 |
Residents in Ferrara, Italy |
|
|
|
Solvent, ever exposed |
25 |
7.11 (2.42–20.88) |
|
Occupational exposure (painters, printers, shoemakers, chemical industry) |
9 |
0.81 (0.33–2.00) |
Ido et al., 1996 |
Residents of Japan |
|
|
|
Organic solvents, occupational exposure |
|
|
|
Males and females |
42 |
1.50 (0.85–2.64) |
|
Males |
34 |
1.28 (0.69–2.36) |
|
Females |
8 |
3.50 (0.73–16.8) |
West et al., 1995 |
Residents of the UK |
|
|
|
Solvents, low threshold |
38 |
1.03 |
|
Solvents, medium threshold |
17 |
0.89 |
|
Solvents, high threshold |
11 |
1.22 |
Mele et al., 1994 |
Residents of Italy |
|
|
|
Shoemakers |
3 |
4.3 (0.9–21.1)a |
|
Painters |
2 |
5.4 (0.5–61.0)a |
Goldberg et al., 1990 |
Residents of Pennsylvania |
|
|
|
Solvents, ever exposed |
5 |
0.35 (0.08–1.54)b |
aIncludes refractory anemia with excess of blasts. bRisk estimate and 95% CI calculated by the committee using standard methods from the observed and expected numbers presented in the original study. |
CHILDHOOD CANCER
Early studies of parental occupation and childhood cancers followed from work by Fabia and Thuy (1974), who found an association between paternal hydrocarbon-related occupations and childhood cancer. A number of studies have since examined potential exposures to hydrocarbons (e.g., DeRoos et al., 2001; Johnson et al., 1987; Van Steensel-Moll, 1985; Zack et al., 1980), and others have focused on parental exposure to solvent mixtures (e.g., Cordier et al., 1997; Smulevich et al., 1999; Shu et al., 1999) as a potential risk factor. Given that the committee was charged with evaluating exposures that occurred during the Gulf War and that soldiers, if they were determined to be pregnant, were removed from the area immediately, the committee did not review studies that considered exposure during pregnancy or after the birth of a child; those studies were not considered directly relevant to the exposure period of interest for this review. Instead, the committee focused its evaluation and conclusions on studies that analyzed preconception exposures. Discussion of the rationale for that exclusion criterion is in Chapter 5 in the childhood cancer section.
Description of Case-Control Studies
Studies of parental occupational exposure and childhood cancer have relied on four approaches to determine exposure: use of occupation or industry as surrogates of exposure, self-reporting of specific exposure, the use of a job-exposure matrix, and review of occupational-
history information by an industrial hygienist. Most case-control studies relied on the use of occupational or industrial titles as indexes of exposure. The childhood cancers that were examined include brain tumors (Cordier et al., 1997), leukemia (Lowengart et al., 1987), neuroblastoma (Olshan et al., 1999), and multiple cancers simultaneously (Smulevich et al., 1999). Other case-control studies of childhood cancer used self-reported exposure, including studies of leukemia (Lowengart et al., 1987) or specific subtypes of leukemia—ANLL (Buckley et al., 1989) and ALL (Shu et al., 1999)—and of neuroblastoma (De Roos et al., 2001). A smaller number of studies either used a job-exposure matrix (Cordier et al., 1997; Feingold et al., 1992; Smulevich et al., 1999) or relied on expert review by industrial hygienists (De Roos et al., 2001; Olshan et al., 1999). Table 6.47 describes the study design characteristics of each of the case-control studies reviewed by the committee.
Epidemiologic Studies of Exposure to Organic Solvents and Childhood Leukemia
The literature consisted of studies that analyzed all types of childhood leukemia together and studies that focused on specific leukemia cell types. The committee reported the findings as presented in the literature.
In one cohort study, paternal exposure (Feychting et al., 2001) to solvents and benzene was determined by linking the fathers’ occupational information with a job-exposure matrix; increased RRs of 1.25 for exposure to solvents (95% CI=0.80–1.95) and 1.23 for exposure to benzene (95% CI=0.39–3.85) were found. The exposure period was defined as the period 2–26 months before the child’s birth, which includes both preconception and pregnancy-related exposure. As a result, the study is not completely relevant to this review, given the committee’s focus on preconception exposures.
Two case-control studies examined both maternal and paternal exposures (Lowengart et al., 1987; Smulevich et al., 1999). In a Russian case-control study (Smulevich et al., 1999), maternal occupational exposure to solvents was found to have an OR of 3.1 (95% CI=1.5–6.3). An increased risk of childhood leukemia was also found to be associated with paternal occupational exposure to solvents prior to conception (OR=1.4, 95% CI=0.95–2.1). In a case-control study in Los Angeles County, Lowengart and colleagues (1987) found associations with preconception paternal exposure to chlorinated solvents (OR=2.2, p=0.09), trichloroethylene (OR=2.0, p=0.16), and methyl ethyl ketone (OR=1.7, p=0.24). Mothers of too few cases were occupationally exposed for analysis in this study.
Shu and colleagues (1999) conducted an extensive study of children with ALL and found an association with mothers’ self-reports of exposure to any solvents (OR=1.8, 95% CI=1.3–2.5), to chlorinated solvents (OR=1.8, 95% CI=0.2–20.8), to nonchlorinated organic solvents (OR=2.0, 95% CI=1.0–4.2), to trichloroethylene (OR=1.8, 95% CI=0.6–5.2), to tetrachloroethylene (OR=1.4, 95% CI=0.2–8.6), to toluene (OR=1.5, 95% CI=0.6–3.8), and to paint remover (OR=2.5, 95% CI=1.0–5.9), but not with exposure to benzene (OR=0.7, 95% CI=0.3–1.8) or to methyl ethyl ketone (OR=0.8, 95% CI=0.3–1.9). For preconception paternal exposure, associations were found with exposure to nonchlorinated, organic solvents (OR=1.3, 95% CI=0.8–1.9) and to benzene (OR=1.2, 95% CI=0.8–1.2), but no associations were found with other exposures. Feingold and colleagues (1992) found increased risks of ALL associated with paternal exposure to solvents (OR=1.7, 95% CI=0.4–8.2), to benzene (OR=1.6, 95% CI=0.5–5.8), and to diethylene glycol (OR=1.4, 95% CI=0.4–4.5) in the year before birth.
TABLE 6.47 Description of Case-Control Studies of Childhood Cancer and Exposure to Organic Solvents
Reference |
Description of Study Population |
Number of Cases |
Number of Controls |
Relevant Exposure(s) |
Determination of Exposure |
Analysis |
Adjustment for Confounding |
Lowengart et al., 1987 |
Cases, age 10 years and under, identified from the Los Angeles County Cancer Surveillance Program in 1980–1984; controls selected from friends of case children or through RDD, matched on age, sex, and race (including native Spanish-speaking Caucasians) |
123 leukemia |
123 |
Trichloroethylene MEK Chlorinated solvents |
Telephone interview with questionnaire to assess parental occupational and exposure history (self-reports) |
Matched pairs |
Matching variables |
|
Participation rate: 79% of cases |
|
|||||
Buckley et al., 1989 |
Cases, age under 18 years, selected from the Childrens Cancer Study Group with diagnosis in 1980–1984; controls selected through RDD, matched for date of birth and race |
204 ANLL |
204 |
Solvents |
Telephone interviews used to assess lifetime occupational history (job titles) and exposure contacts of parents |
Conditional logistic regression |
Matching variables |
Feingold et al., 1992 |
Cases, age 14 years or under, identified through the Colorado Central Cancer Registry of Denver residents diagnosed in 1976–1983 with almost complete histologic confirmation; controls selected through RDD, matched for age, sex, and telephone exchange area |
59 ALL 48 brain |
222 |
Benzene Diethylene glycol Solvents |
In-person or telephone interview with questionnaire to assess parental occupational history (job-industry titles); job-exposure matrix used to assess exposures |
Mantel-Haenszel |
Father’s education |
|
Participation rates: 70.8% of cases, 79.9% of controls |
|
|||||
Cordier et al., 1997 |
Cases, age 15 years or under, identified in centers in Paris, Milan, and Valencia with partial histologic verification (72–87% complete); population controls selected from census information or local health-service records, depending on location, selectively matched for year of birth, sex, and area of residence |
251 brain |
601 |
Solvents |
In-person interviews to assess parental occupations (job titles) held from 5 years before the child’s birth; job-exposure matrix used to assess exposures |
Unconditional logistic regression |
Child’s age, sex, exposure to tobacco and ionizing radiation, mother’s age, years of schooling |
Olshan et al., 1999 |
Cases, age under 19 years, selected from the Childrens Cancer Group and Pediatric Oncology Group with diagnosis in 1992–1996; controls selected through RDD, matched for date of birth |
504 neuroblastoma |
504 |
Painter (paternal occupation) |
Telephone interview to assess parental occupational and exposure history (job-industry titles) |
Conditional logistic regression |
Maternal race, maternal age, maternal education, household income |
|
Participation rates: 73% of cases, 74% of controls |
|
Only one study investigated ANLL in conjunction with preconception solvent exposure (Buckley et al., 1989). On the basis of self-reported exposure, a positive association between ANLL and paternal solvent exposure before pregnancy (OR=2.2, p<0.05) was found. No estimates of relative risk for maternal exposure to solvents were presented.
Summary and Conclusion
The studies on childhood leukemia and exposure to organic solvents generally followed similar procedures for ascertaining cases, matching controls, and interviewing parents to obtain relevant information. Studies generally controlled for known confounders, but in most cases risk factors are not well understood. Studies that examined parental occupational exposure often did not differentiate whether the exposure occurred before, during, or after pregnancy. Little information was available on preconception exposure for each cancer type. Exposure measures were based largely on interviews and, thus, were subject to recall bias or random misclassification of exposures; the former tends to artificially increase the odds ratio, and the latter attenuates toward the null value. Many of the studies presented the additional concern that mothers who reported on their husbands’ work exposure further increased the likelihood of misclassification of the fathers’ exposure.
For childhood leukemias combined, several studies showed positive associations with exposure to solvents. Several studies were limited by misclassification bias related to self-reporting of exposure and by the fact that some looked at all childhood leukemias and others focused on specific cell types, such as ALL and ANLL. Given the combination of the limitations of this body of evidence and the consistently positive findings, the committee was unable to reach a consensus conclusion. Some committee members believed that the evidence fulfilled the category of inadequate/insufficient, while others believed it was limited/suggestive of an association. Future studies that address some of the limitations identified above are needed to understand the association between childhood leukemia and exposure to solvents. Table 6.48 identifies all the studies evaluated by the committee.
TABLE 6.48 Selected Epidemiologic Studies—Childhood Leukemia and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Leukemia (all types) |
|||
Cohort Study—Incidence |
|||
Feychting et al., 2001 |
Children in Sweden |
|
|
|
Paternal preconception exposure |
|
|
|
Solvents |
23 |
1.25 (0.80–1.95) |
|
Benzene |
3 |
1.23 (0.39–3.85) |
Case-Control Studies |
|||
Smulevich et al., 1999 |
Children in Moscow |
|
|
|
Occupational exposure before conception |
|
|
|
Maternal exposure to solvents |
20 |
3.1 (1.5–6.3) |
|
Paternal exposure to solvents |
70 |
1.4 (0.95–2.1) |
Lowengart et al., 1987 |
Children in Los Angeles County |
|
|
|
Paternal preconception exposure |
|
|
|
Chlorinated solvents |
9 |
2.2 (p=0.09) |
|
Trichloroethylene |
6 |
2.0 (p=0.16) |
|
Methyl ethyl ketone |
5 |
1.7 (p=0.24) |
Epidemiologic Studies of Exposure to Organic Solvents and Neuroblastoma
Olshan and colleagues (1999) reported an increased risk of neuroblastoma in children whose fathers were painters (OR=2.1, 95% CI=0.9–4.8); this was the most relevant of the 73 paternal occupations listed for solvent exposure. In a followup study, the investigators used a job-exposure matrix to evaluate maternal and paternal occupational exposure to 65 chemical compounds or broad categories of substances (De Roos et al., 2001). As reviewed by an industrial hygienist, neuroblastoma risk was not markedly increased based on maternal exposures to halogenated hydrocarbons (OR=0.7, 95% CI=0.2–2.1), to volatile hydrocarbons (OR=1.2, 95% CI=0.7–2.1), to acetone (OR=1.1, 95% CI=0.4–2.8), or to alcohols (OR=1.0, 95% CI=0.5–2.1). However, for paternal exposures, risk estimates were higher: volatile hydrocarbons (OR=1.5, 95% CI=1.0–2.1), alcohols (OR=1.8, 95% CI=0.9–3.3), benzene (OR=2.0, 95% CI=0.4–10.3), methyl ethyl ketone (OR=1.4, 95% CI=0.5–3.8), naphtha (OR=1.4, 95% CI=0.4–5.9), and xylene (OR=1.4, 95% CI=0.5–4.3). Paternal exposure to acetone,
trichloroethylene, tetrachloroethylene, methylene chloride, and chloroform did not show increased risks.
Summary and Conclusion
The two studies identified were well-conducted. They evaluated a large number of neuroblastoma cases and possible exposures, while considering the possibility of recall bias. However, other corroborating studies are needed to clarify whether an association exists. Table 6.49 identifies the study reviewed by the committee for neuroblastoma.
The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between either maternal or paternal preconception exposure to solvents under review and neuroblastoma.
TABLE 6.49 Selected Epidemiologic Studies—Childhood Neuroblastoma and Exposure to Organic Solvents
Reference |
Study Population |
Exposed Cases |
Estimated Relative Risk (95% CI) |
Neuroblastoma |
|||
Case-Control Studies |
|||
De Roos et al., 2001 |
Children registered at Children’s Cancer Group or Pediatric Oncology Group hospitals |
|
|
|
Occupational exposure in the 2 years before child’s birtha |
|
|
|
Maternal exposure |
|
|
|
Halogenated hydrocarbons |
6 |
0.7 (0.2–2.1) |
|
Volatile hydrocarbons |
27 |
1.2 (0.7–2.1) |
|
Acetone |
9 |
1.1 (0.4–2.8) |
|
Alcohols |
14 |
1.0 (0.5–2.1) |
|
Paternal exposure |
|
|
|
Halogenated hydrocarbons |
34 |
0.9 (0.5–1.5) |
|
Trichloroethylene |
9 |
0.9 (0.3–2.5) |
|
Volatile hydrocarbons |
122 |
1.5 (1.0–2.1) |
|
Acetone |
23 |
0.9 (0.5–1.7) |
|
Benzene |
5 |
2.0 (0.4–10.3) |
|
Methyl ethyl ketone |
12 |
1.4 (0.5–3.8) |
|
Xylene |
10 |
1.4 (0.5–4.3) |
|
Tetrachloroethylene |
4 |
0.5 (0.1–1.7) |
|
Methylene chloride |
4 |
0.7 (0.2–2.8) |
|
Chloroform |
3 |
1.2 (0.2–7.5) |
|
Alcohols |
49 |
1.8 (0.9–3.3) |
|
Naphtha |
11 |
1.4 (0.4–5.9) |
Olshan et al., 1999 |
Children registered at Children’s Cancer Group or Pediatric Oncology Group hospitals |
|
|
|
Paternal occupation—painter |
18 |
2.1 (0.9–4.8) |
aIndustrial hygienist-reviewed exposure information. |
Epidemiologic Studies of Exposure to Organic Solvents and Brain Cancer
A European case-control study of brain cancer and parental occupation found that “high” maternal occupational exposure to solvents was strongly associated with an increased risk of brain cancer (OR=2.4, 95% CI=1.2–4.9) and primitive neuroectodermal tumor (PNET) (OR=
3.2, 95% CI=1.0–10.3); estimates of risk of astroglial tumors were also increased for “high” levels of exposure to solvents (OR=2.3, 95% CI=0.9–5.8) and other glial tumors were not (OR =0.8, 95% CI=0.1–6.6) (Cordier et al., 1997). Like maternal exposure, high paternal exposure to solvents was associated with increased risk of brain cancer (OR=1.2, 95% CI=0.7–1.9) and astroglial tumors (OR=1.3, 95% CI=0.7–2.3), but not other glial tumors (OR=0.4, 95% CI 0.1–1.4). A second case-control study of childhood brain cancer and paternal occupational exposure showed no association with exposure to benzene (OR=0.7, 95% CI=0.1–3.1) (Feingold et al., 1992). However, an association was found with exposure to solvents (OR=1.2, 95% CI=0.2–8.5) and diethylene glycol (OR=1.3, 95% CI=0.3–5.2).
Summary and Conclusion
On the basis of those two case-control studies, the committee decided that the body of evidence was too small and inconsistent in outcome (brain cancer broadly vs PNET vs astroglial tumors). Table 6.50 identifies the studies reviewed by the committee in drawing its conclusion.
The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between either maternal or paternal preconception exposure to solvents under review and childhood brain cancers.
TABLE 6.50 Selected Epidemiologic Studies—Childhood Brain Cancers and Exposure to Organic Solvents
REFERENCES
Acquavella J, Leet T, Johnson G. 1993. Occupational experience and mortality among a cohort of metal components manufacturing workers. Epidemiology 4(5):428–434.
Aksoy M, Erdem S. 1978. Followup study on the mortality and the development of leukemia in 44 pancytopenic patients with chronic exposure to benzene. Blood 52(2):285–292.
Albin M, Bjork J, Welinder H, Tinnerberg H, Mauritzson N, Johansson B, Billstrom R, Stromberg U, Mikoczy Z, Ahlgren T, Nilsson PG, Mitelman F, Hagmar L. 2000. Acute myeloid leukemia and clonal chromosome aberrations in relation to past exposure to organic solvents. Scandinavian Journal of Work, Environment and Health 26(6):482–491.
Alderson MR, Rattan NS. 1980. Mortality of workers on an isopropyl alcohol plant and two MEK dewaxing plants. British Journal of Industrial Medicine 37(1):85–89.
Anttila A, Pukkala E, Sallmen M, Hernberg S, Hemminki K. 1995. Cancer incidence among Finnish workers exposed to halogenated hydrocarbons. Journal of Occupational and Environmental Medicine 37(7):797–806.
Anttila A, Pukkala E, Riala R, Sallmen M, Hemminki K. 1998. Cancer incidence among Finnish workers exposed to aromatic hydrocarbons. International Archives of Occupational and Environmental Health 71(3):187–193.
Arp EW, Wolf PH, Checkoway H. 1983. Lymphocytic leukemia and exposures to benzene and other solvents in the rubber industry. Journal of Occupational Medicine 25(8):598–602.
Asal NR, Geyer JR, Risser DR, Lee ET, Kadamani S, Cherng N. 1988. Risk factors in renal cell carcinoma. II. Medical history, occupation, multivariate analysis, and conclusions. Cancer Detection and Prevention 13(3–4):263–279.
Aschengrau A, Ozonoff D, Paulu C, Coogan P, Vezina R, Heeren T, Zhang Y. 1993. Cancer risk and tetrachloroethylene-contaminated drinking water in Massachusetts. Archives of Environmental Health 48(5):284–292.
Aschengrau A, Paulu C, Ozonoff D. 1998. Tetrachloroethylene-contaminated drinking water and the risk of breast cancer. Environmental Health Perspectives 106(Suppl 4):947–953.
ATSDR (Agency for Toxic Substances and Disease Registry). 1997a. Toxicological Profile for Benzene. Atlanta, GA: ATSDR.
ATSDR. 1997b. Toxicological Profile for Trichloroethylene. Atlanta, GA: ATSDR.
ATSDR. 1997c. Toxicological Profile for Tetrachloroethylene. Atlanta, GA: ATSDR.
ATSDR. 1997d. Toxicological Profile for Chloroform. Atlanta, GA: ATSDR.
ATSDR. 1998. Toxicological Profile for Phenol. Atlanta, GA: ATSDR.
ATSDR. 2000. Toxicological Profile for Methylene Chloride. Atlanta, GA: ATSDR.
Axelson O, Andersson K, Hogstedt C, Holmberg B, Molina G, de Verdier A. 1978. A cohort study on trichloroethylene exposure and cancer mortality. Journal of Occupational Medicine 20(3):194–196.
Axelson O, Selden A, Andersson K, Hogstedt C. 1994. Updated and expanded Swedish cohort study on trichloroethylene and cancer risk. Journal of Occupational Medicine 36(5):556–562.
Band PR, Le ND, Fang R, Deschamps M, Gallagher RP, Yang P. 2000. Identification of occupational cancer risks in British Columbia. A population-based case-control study of 995 incident breast cancer cases by menopausal status, controlling for confounding factors. Journal of Occupational and Environmental Medicine 42(3):284–310.
Berlin K, Edling C, Persson B, Ahlborg G, Hillert L, Hogstedt B, Lundberg I, Svensson BG, Thiringer G, Orbaek P. 1995. Cancer incidence and mortality of patients with suspected solvent-related disorders. Scandinavian Journal of Work, Environment and Health 21(5):362–367.
Bernard SM, Cartwright RA, Bird CC, Richards ID, Lauder I, Roberts BE. 1984. Aetiologic factors in lymphoid malignancies: A case-control epidemiological study. Leukemia Research 8(4):681–689.
Blair A, Stewart PA, Tolbert PE, Grauman D, Moran FX, Vaught J, Rayner J. 1990. Cancer and other causes of death among a cohort of dry cleaners. British Journal of Industrial Medicine 47(3):162–168.
Blair A, Linos A, Stewart PA, Bermeister LF, Gibson R, Everett G, Schuman L, Cantor KP. 1992. Comments on occupational and environmental factors in the origin of non-Hodgkin’s lymphoma. Cancer Research 52(Suppl 19):5501s–5502s.
Blair A, Hartge P, Stewart PA, McAdams M, Lubin J. 1998. Mortality and cancer incidence of aircraft maintenance workers exposed to trichloroethylene and other organic solvents and chemicals: Extended follow up. Occupational and Environmental Medicine 55(3):161–171.
Boice JD Jr, Marano DE, Fryzek JP, Sadler CJ, McLaughlin JK. 1999. Mortality among aircraft manufacturing workers. Occupational and Environmental Medicine 56(9):581–597.
Bond GG, McLaren EA, Baldwin CL, Cook RR. 1986. An update of mortality among chemical workers exposed to benzene. British Journal of Industrial Medicine 43(10):685–691.
Bond GG, McLaren EA, Sabel FL, Bodner KM, Lipps TE, Cook RR. 1990. Liver and biliary tract cancer among chemical workers. American Journal of Industrial Medicine 18(1):19–24.
Bourguet CC, Checkoway H, Hulka BS. 1987. A case-control study of skin cancer in the tire and rubber manufacturing industry. American Journal of Industrial Medicine 11(4):461–473.
Brown DP, Kaplan SD. 1987. Retrospective cohort mortality study of dry cleaner workers using perchloroethylene. Journal of Occupational Medicine 29(6):535–541.
Brownson RC, Alavanja MC, Chang JC. 1993. Occupational risk factors for lung cancer among nonsmoking women: A case-control study in Missouri (United States). Cancer Causes and Control 4(5):449–454.
Bruckner JV, Warren DA. 2001. Toxic effects of solvents and vapors. In: Klaassen CD, ed. Casarett and Doull’s Toxicology: The Basic Science of Poisons. 6th ed. New York: McGraw-Hill. Pp. 869–916.
Buckley JD, Robison LL, Swotinsky R, Garabrant DH, LeBeau M, Manchester P, Nesbit ME, Odom L, Peters JM, Woods WG, Hammond GD. 1989. Occupational exposures of parents of children with acute nonlymphocytic leukemia: A report from the Childrens Cancer Study Group. Cancer Research 49(14):4030–4037.
Carpenter AV, Flanders WD, Frome EL, Tankersley WG, Fry SA. 1988. Chemical exposures and central nervous system cancers: A case-control study among workers at two nuclear facilities. American Journal of Industrial Medicine 13(3):351–362.
Chiazze L, Ference LD, Wolf PH. 1980. Mortality among automobile assembly workers. I. Spray painters. Journal of Occupational Medicine 22(8):520–526.
Ciccone G, Mirabelli D, Levis A, Gavarotti P, Rege-Cambrin G, Davico L, Vineis P. 1993. Myeloid leukemias and myelodysplastic syndromes: Chemical exposure, histologic subtype and cytogenetics in a case-control study. Cancer Genetics and Cytogenetics 68(2):135–139.
Clavel J, Mandereau L, Cordier S, Le Goaster C, Hemon D, Conso F, Flandrin G. 1995. Hairy cell leukaemia, occupation, and smoking. British Journal of Haematology 91(1):154–161.
Clavel J, Conso F, Limasset JC, Mandereau L, Roche P, Flandrin G, Hemon D. 1996. Hairy cell leukaemia and occupational exposure to benzene. Occupational and Environmental Medicine 53(8):533–539.
Clavel J, Mandereau L, Conso F, Limasset JC, Pourmir I, Flandrin G, Hemon D. 1998. Occupational exposure to solvents and hairy cell leukaemia. Occupational and Environmental Medicine 55(1):59–64.
Cocco P, Figgs L, Dosemeci M, Hayes R, Linet MS, Hsing AW. 1998. Case-control study of occupational exposures and male breast cancer. Occupational and Environmental Medicine 55(9):599–604.
Cordier S, Clavel J, Limasset JC, Boccon-Gibod L, Le MN, Mandereau L, Hemon D. 1993. Occupational resks of bladder cancer in France: A multicentre case-control study. International Journal of Epidemiology 22(3):403–411.
Cordier S, Lefeuvre B, Filippini G, Peris-Bonet R, Farinotti M, Lovicu G, Mandereau L. 1997. Parental occupation, occupational exposure to solvents and polycyclic aromatic hydrocarbons and risk of childhood brain tumors (Italy, France, Spain). Cancer Causes and Control 8(5):688–697.
Costantini AS, Paci E, Miligi L, Buiatti E, Martelli C, Lenzi S. 1989. Cancer mortality among workers in the Tuscan tanning industry. British Journal of Industrial Medicine 46(6):384–388.
Costantini AS, Miligi L, Kriebel D, Ramazzotti V, Rodella S, Scarpi E, Stagnaro E, Tumino R, Fontana A, Masala G, Vigano C, Vindigni C, Crosignani P, Benvenuti A, Vineis P. 2001. A multicenter case-control study in Italy on hematolymphopoietic neoplasms and occupation. Epidemiology 12(1):78–87.
Crump KS. 1994. Risk of benzene-induced leukemia: A sensitivity analysis of the Pliofilm cohort with additional followup and new exposure estimates. Journal of Toxicology and Environmental Health 42(2):219–242.
Crump KS. 1996. Risk of benzene-induced leukemia predicted from the Pliofilm cohort. Environmental Health Perspectives 104(Suppl 6):1437–1441.
Crump K, Allen B. 1984. Quantitative Estimates of Risk of Leukemia From Occupational Exposure to Benzene. Washington, DC: OSHA Docket H 059b Exhibit 152 (Appendix B).
Demers PA, Vaughan TL, Koepsell TD, Lyon JL, Swanson GM, Greenberg RS, Weiss NS. 1993. A case-control study of multiple myeloma and occupation. American Journal of Industrial Medicine 23(4):629–639.
De Roos AJ, Olshan AF, Teschke K, Poole C, Savitz DA, Blatt J, Bondy ML, Pollock BH. 2001. Parental occupational exposures to chemicals and incidence of neuroblastoma in offspring. American Journal of Epidemiology 154(2):106–114.
Dosemeci M, Blair A, Stewart PA, Chandler J, Trush MA. 1991. Mortality among industrial workers exposed to phenol. Epidemiology 2(3):188–193.
Dosemeci M, Cocco P, Chow WH. 1999. Sex differences in risk of renal cell carcinoma and occupational exposures to chlorinated aliphatic hydrocarbons. American Journal of Industrial Medicine 36(1):54–59.
Dumas S, Parent ME, Siemiatycki J, Brisson J. 2000. Rectal cancer and occupational risk factors: A hypothesis-generating, exposure-based case-control study. International Journal of Cancer 87(6):874–879.
Ekstrom AM, Eriksson M, Hansson LE, Lindgren A, Signorello LB, Nyren O, Hardell L. 1999. Occupational exposures and risk of gastric cancer in a population-based case-control study. Cancer Research 59(23):5932–5937.
Engholm G, Englund A. 1982. Cancer incidence and mortality among Swedish painters. In: Mehlman, MA, ed. Advances in Modern Environmental Toxicology. Vol. 2. Princeton Junction, NJ: Senate Press. Pp. 173–185.
Englund A. 1980. Cancer incidence among painters and some allied trades. Journal of Toxicological and Environmental Health 6(5–6):1267–1273.
Eriksson M, Karlsson M. 1992. Occupational and other environmental factors and multiple myeloma: A population based case-control study. British Journal of Industrial Medicine 49(2):95–103.
Fabbro-Peray P, Daures JP, Rossi JF. 2001. Environmental risk factors for non-Hodgkin’s lymphoma: A population-based case-control study in Languedoc-Roussillon, France. Cancer Causes and Control 12(3):201–212.
Fabia J, Thuy TD. 1974. Occupation of father at time of birth of children dying of malignant diseases. British Journal of Preventive and Social Medicine 28(2):98–100.
Feingold L, Savitz DA, John EM. 1992. Use of a job-exposure matrix to evaluate parental occupation and childhood cancer. Cancer Causes and Control 3(2):161–169.
Feychting M, Plato N, Nise G, Ahlbom A. 2001. Paternal occupational exposures and childhood cancer. Environmental Health Perspectives 109(2):193–196.
Flodin U, Andersson L, Anjou C-G, Palm U-B, Vikrot O, Axelson O. 1981. A case-referent study on acute myeloid leukemia, background radiation and exposure to solvents and other agents. Scandinavian Journal of Work, Environment and Health 7(3):169–178.
Fredriksson M, Bengtsson NO, Hardell L, Axelson O. 1989. Colon cancer, physical activity, and occupational exposures. A case-control study. Cancer 63(9):1838–1842.
Friedlander BR, Hearne T, Hall S. 1978. Epidemiologic investigation of employees chronically exposed to methylene chloride. Mortality analysis. Journal of Occupational Medicine 20(10):657–666.
Fritschi L, Siemiatycki J. 1996a. Melanoma and occupation: Results of a case-control study. Occupational and Environmental Medicine 53(3):168–173.
Fritschi L, Siemiatycki J. 1996b. Lymphoma, myeloma and occupation: Results of a case-control study. International Journal of Cancer 67(4):498–503.
Fu H, Demers PA, Costantini AS, Winter P, Colin D, Kogevinas M, Boffetta P. 1996. Cancer mortality among shoe manufacturing workers: An analysis of two cohorts. Occupational and Environmental Medicine 53(6):394–398.
Garabrant DH, Held J, Langholz B, Bernstein L. 1988. Mortality of aircraft manufacturing workers in southern California. American Journal of Industrial Medicine 13(6):683–693.
Gérin M, Siemiatycki J, Desy M, Krewski D. 1998. Associations between several sites of cancer and occupational exposure to benzene, toluene, xylene, and styrene: Results of a case-control study in Montreal. American Journal of Industrial Medicine 34(2):144–156.
Gibbs GW, Amsel J, Soden K. 1996. A cohort mortality study of cellulose triacetate-fiber workers exposed to methylene chloride. Journal of Occupational and Environmental Medicine 38(7):693–697.
Goguel A, Cavigneaux A, Bernard J. 1967. Benzene leukemias in the Paris region between 1950 and 1965 (study of 50 cases). Nouvelle Revue Francaise d’Hematologie 7(4):465–480.
Goldberg H, Lusk E, Moore J, Nowell PC, Besa EC. 1990. Survey of exposure to genotoxic agents in primary myelodysplastic syndrome: Correlation with chromosome patterns and data on patients without hematological disease. Cancer Research 50(21):6876–6881.
Goldberg MS, Parent ME, Siemiatycki J, Desy M, Nadon L, Richardson L, Lakhani R, Latreille B, Valois MF. 2001. A case-control study of the relationship between the risk of colon cancer in men and exposures to occupational agents. American Journal of Industrial Medicine 39(6):531–546.
Greenland S, Salvan A, Wegman DH, Hallock MF, Smith TJ. 1994. A case-control study of cancer mortality at a transformer-assembly facility. International Archives of Occupational and Environmental Health 66(1):49–54.
Guberan E, Usel M, Raymond L, Tissot R, Sweetnam PM. 1989. Disability, mortality, and incidence of cancer among Geneva painters and electricians: A historical prospective study. British Journal of Industrial Medicine 46(1):16–23.
Hansen J. 1999. Breast cancer risk among relatively young women employed in solvent-using industries. American Journal of Industrial Medicine 36(1):43–47.
Hansen J. 2000. Elevated risk for male breast cancer after occupational exposure to gasoline and vehicular combustion products. American Journal of Industrial Medicine 37(4):349–352.
Hansen J, Raaschou-Nielsen O, Christensen JM, Johansen I, McLaughlin JK, Lipworth L, Blot WJ, Olsen JH. 2001. Cancer incidence among Danish workers exposed to trichloroethylene. Journal of Occupational and Environmental Medicine 43(2):133–139.
Hardell L, Bengtsson NO. 1983. Epidemiological study of socioeconomic factors and clinical findings in Hodgkin’s disease, and reanalysis of previous data regarding chemical exposure. British Journal of Cancer 48(2):217–225.
Hardell L, Eriksson M, Lenner P, Lundgren E. 1981. Malignant lymphoma and exposure to chemicals, especially organic solvents, chlorophenols and phenoxy acids: A case-control study. British Journal of Cancer 43(2):169–176.
Hardell L, Johansson B, Axelson O. 1982. Epidemiological study of nasal and nasopharyngeal cancer and their relation to phenoxy acid or chlorophenol exposure. American Journal of Industrial Medicine 3(3):247–257.
Hardell L, Bengtsson NO, Jonsson U, Eriksson S, Larsson LG. 1984. Aetiological aspects on primary liver cancer with special regard to alcohol, organic solvents and acute intermittent porphyria—An epidemiological investigation. British Journal of Cancer 50(3):389–397.
Hardell L, Eriksson M, Degerman A. 1994. Exposure to phenoxyacetic acids, chlorophenols, or organic solvents in relation to histopathology, stage, and anatomical localization of non- Hodgkin’s lymphoma. Cancer Research 54(9):2386–2389.
Harrington JM, Whitby H, Gray CN, Reid FJ, Aw TC, Waterhouse JA. 1989. Renal disease and occupational exposure to organic solvents: A case-referent approach. British Journal of Industrial Medicine 46(9):643–650.
Hayes RB, Yin SN, Dosemeci M, Li GL, Wacholder S, Chow WH, Rothman N, Wang YZ, Dai TR, Chao XJ, Jiang ZL, Ye PZ, Zhao HB, Kou QR, Zhang WY, Meng JF, Zho JS, Lin XF, Ding CY, Li CY, Zhang ZN, Li DG, Travis LB, Blot WJ, Linet MS. 1996. Mortality among benzene-exposed workers in China. Environmental Health Perspectives 104(Suppl 6):1349–1352.
Hayes RB, Yin SN, Dosemeci M, Li GL, Wacholder S, Travis LB, Li CY, Rothman N, Hoover RN, Linet MS. 1997. Benzene and the dose-related incidence of hematologic neoplasms in China. Chinese Academy of Preventive Medicine—National Cancer Institute Benzene Study Group. Journal of the National Cancer Institute 89(14):1065–1071.
Hearne FT, Friedlander BR. 1981. Followup of methylene chloride study. Journal of Occupational Medicine 23(10):660.
Hearne FT, Pifer JW. 1999. Mortality study of two overlapping cohorts of photographic film base manufacturing employees exposed to methylene chloride. Journal of Occupational and Environmental Medicine 41(12):1154–1169.
Hearne FT, Grose F, Pifer JW, Friedlander BR, Raleigh RL. 1987. Methylene chloride mortality study: Dose-response characterization and animal model comparison. Journal of Occupational Medicine 29(3):217–228.
Hearne FT, Pifer JW, Grose F. 1990. Absence of adverse mortality effects in workers exposed to methylene chloride: An update. Journal of Occupational Medicine 32(3):234–240.
Heineman EF, Cocco P, Gomez MR, Dosemeci M, Stewart PA, Hayes RB, Zahm SH, Thomas TL, Blair A. 1994. Occupational exposure to chlorinated aliphatic hydrocarbons and risk of astrocytic brain cancer. American Journal of Industrial Medicine 26(2):155–169.
Heineman EF, Gao Y-T, Dosemeci M, McLaughlin JK. 1995. Occupational risk factors for brain tumors among women in Shanghai, China. Journal of Occupational and Environmental Medicine 37(3):288–293.
Heinemann K, Willich SN, Heinemann LAJ, DoMinh T, Mohner M, Heuchert GE. 2000. Occupational exposure and liver cancer in women: Results of the Multicentre International Liver Tumour Study (MILTS). Occupational Medicine 50(6):422–429.
Henschler D, Vamvakas S, Lammert M, Dekant W, Kraus B, Thomas B, Ulm K. 1995. Increased incidence of renal cell tumors in a cohort of cardboard workers exposed to trichloroethene. Archives of Toxicology 69(5):291–299.
Hernberg S, Kauppinen T, Riala R, Korkala ML, Asikainen U. 1988. Increased risk for primary liver cancer among women exposed to solvents. Scandinavian Journal of Work, Environment and Health 14(6):356–365.
Holly EA, Lele C, Bracci P. 1997. Non-hodgkin’s lymphoma in homosexual men in the San Francisco bay area: Occupational, chemical, and environmental exposures. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 15(3):223–231.
Hunting KL, Longbottom H, Kalavar SS, Stern F, Schwartz E, Welch LS. 1995. Haematopoietic cancer mortality among vehicle mechanics. Occupational and Environmental Medicine 52(10):673–678.
IARC (International Agency for Research on Cancer). 1987. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs, Volumes 1 to 42. Suppl. 7. Lyon, France: IARC.
IARC. 1989. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Some Organic Solvents, Resin Monomers and Related Compounds, Pigments and Occupational Exposures in Paint Manufacture and Painting. Vol. 47. Lyon, France: IARC.
IARC. 1995. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Dry-cleaning, Some Chlorinated Solvents and Other Industrial Chemicals. Vol. 63. Lyon, France: IARC.
IARC. 1999. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Some Chemicals that Cause Tumours of the Kidney or Urinary Bladder in Rodents, and Some Other Substances. Vol. 73. Lyon, France: IARC.
Ido M, Nagata C, Kawakami N, Shimizu H, Yoshida Y, Nomura T, Mizoguchi H. 1996. A case-control study of myelodysplastic syndromes among Japanese men and women. Leukemia Research 20(9):727–731.
Infante PF, Rinsky RA, Wagoner JK, Young RJ. 1977. Leukaemia in benzene workers. Lancet 2(8028):76–78.
Ireland B, Collins JJ, Buckley CF, Riordan SG. 1997. Cancer mortality among workers with benzene exposure. Epidemiology 8(3):318–320.
Irons RD. 1992. Benzene and other hemotoxins. In: Sullivan JB, Krieger GR, Eds. Hazardous Materials Toxicology: Clinical Principles of Environmental Health. Baltimore: Williams & Wilkins. Pp. 718–731.
Jensen OM, Wahrendorf J, Knudsen JB, Sorensen BL. 1987. The Copenhagen case-referent study on bladder cancer. Risks among drivers, painters and certain other occupations. Scandinavian Journal of Work, Environment and Health 13(2):129–134.
Jensen OM, Knudsen JB, McLaughlin JK, Sorensen BL. 1988. The Copenhagen case-control study of renal pelvis and ureter cancer: Role of smoking and occupational exposures. International Journal of Cancer 41(4):557–561.
Ji BT, Silverman DT, Dosemeci M, Dai Q, Gao YT, Blair A. 1999. Occupation and pancreatic cancer risk in Shanghai, China. American Journal of Industrial Medicine 35(1):76–81.
Johnson CC, Annegers JF, Frankowski RF, Spitz MR, Buffler PA. 1987. Childhood nervous system tumors—an evaluation of the association with paternal occupational exposure to hydrocarbons. American Journal of Epidemiology 126(4):605–613.
Kaerlev L, Teglbjaerg PS, Sabroe S, Kolstad HA, Ahrens W, Eriksson M, Gonzalez AL, Guenel P, Hardell L, Launoy G, Merler E, Merletti F, Suarez-Varela MM, Stang A. 2000. Occupation and small bowel adenocarcinoma: A European case-control study. Occupational and Environmental Medicine 57(11):760–766.
Kauppinen TP, Partanen TJ, Hernberg SG, Nickels JI, Luukkonen RA, Hakulinen TR, Pukkala EI. 1993. Chemical exposures and respiratory cancer among Finnish woodworkers. British Journal of Industrial Medicine 50(2):143–148.
Kauppinen T, Partanen T, Degerth R, Ojajarvi A. 1995. Pancreatic cancer and occupational exposures. Epidemiology 6(5):498–502.
Lagorio S, Forastiere F, Iavarone I, Rapiti E, Vanacore N, Perucci CA, Carere A. 1994. Mortality of filling station attendants. Scandinavian Journal of Work, Environment and Health 20(5):331–338.
Lanes SF, Cohen A, Rothman KJ, Dreyer NA, Soden KJ. 1990. Mortality of cellulose fiber production workers. Scandinavian Journal of Work, Environment and Health 16(4):247–251.
Lanes SF, Rothman KJ, Dreyer NA, Soden KJ. 1993. Mortality update of cellulose fiber production workers. Scandinavian Journal of Work, Environment and Health 19(6):426–428.
La Vecchia C, Negri E, D’Avanzo B, Franceschi S. 1990. Occupation and the risk of bladder cancer. International Journal of Epidemiology 19(2):264–268.
Lazarov D, Waldron HA, Pejin D. 2000. Acute myeloid leukaemia and exposure to organic solvents—A case-control study. European Journal of Epidemiology 16(3):295–301.
Leffingwell SS, Waxweiler R, Alexander V, Ludwig HR, Halperin W. 1983. Case-control study of gliomas of the brain among workers employed by a Texas City, Texas chemical plant, USA. Neuroepidemiology 2(3–4):179–195.
Leon DA. 1994. Mortality in the British printing industry: A historical cohort study of trade union members in Manchester. Occupational and Environmental Medicine 51(2):79–86.
Li GL, Linet MS, Hayes RB, Yin SN, Dosemeci M, Wang YZ, Chow WH, Jiang ZL, Wacholder S, Zhang WU, et al. 1994. Gender differences in hematopoietic and lymphoproliferative disorders and other cancer risks by major occupational group among workers exposed to benzene in China. Journal of Occupational Medicine 36(8):875–881.
Logsdon JE, Loke RA. 1996. Isopropyl alcohol. In: Kirk RE, Kroschwitz JI, Howe-Grant M, eds. Encyclopedia of Chemical Technology. Vol. 20. 4th ed. New York: John Wiley & Sons.
Lowengart RA, Peters JM, Cicioni C, Buckley J, Bernstein L, Preston-Martin S, Rappaport E. 1987. Childhood leukemia and parents’ occupational and home exposures. Journal of the National Cancer Institute 79(1):39–46.
Lundberg I. 1986. Mortality and cancer incidence among Swedish paint industry workers with long-term exposure to organic solvents. Scandinavian Journal of Work, Environment and Health 12(2):108–13.
Lundberg I, Milatou-Smith R. 1998. Mortality and cancer incidence among Swedish paint industry workers with long-term exposure to organic solvents. Scandinavian Journal of Work, Environment and Health 24(4):270–275.
Lynge E, Thygesen L. 1990. Primary liver cancer among women in laundry and dry-cleaning work in Denmark. Scandinavian Journal of Work, Environment and Health 16(2):108–112.
Lynge E, Rix BA, Villadsen E, Andersen I, Hink M, Olsen E, Moller UL, Silfverberg E. 1995. Cancer in printing workers in Denmark. Occupational and Environmental Medicine 52(11):738–744.
Lynge E, Andersen A, Nilsson R, Barlow L, Pukkala E, Nordlinder R, Boffetta P, Grandjean P, Heikkila P, Horte LG, Jakobsson R, Lundberg I, Moen B, Partanen T, Riise T. 1997. Risk of cancer and exposure to gasoline vapors. American Journal of Epidemiology 145(5):449–458.
Malker HS, Gemne G. 1987. A register-epidemiology study on cancer among Swedish printing industry workers. Archives of Environmental Health 42(2):73–82.
Malone KE, Koepsell TD, Daling JR, Weiss NS, Morris PD, Taylor JW, Swanson GM, Lyon JL. 1989. Chronic lymphocytic leukemia in relation to chemical exposures. American Journal of Epidemiology 130(6):1152–1158.
Mandel JS, McLaughlin JK, Schlehofer B, Mellemgaard A, Helmert U, Lindblad P, McCredie M, Adami HO. 1995. International renal-cell cancer study. IV. Occupation. International Journal of Cancer 61(5):601–605.
Matanoski GM, Stockwell HG, Diamond EL, Haring-Sweeney M, Joffe RD, Mele LM, Johnson ML. 1986. A cohort mortality study of painters and allied tradesmen. Scandinavian Journal of Work, Environment and Health 12(1):16–21.
McCredie M, Stewart JH. 1993. Risk factors for kidney cancer in New South Wales. IV. Occupation. British Journal of Industrial Medicine 50(4):349–354.
McMichael AJ, Spirtas R, Kupper LL, Gamble JF. 1975. Solvent exposure and leukemia among rubber workers: An epidemiologic study. Journal of Occupational Medicine 17(4):234–239.
McMichael AJ, Andjelkovic DA, Tyroler HA. 1976. Cancer mortality among rubber workers: An epidemiologic study. Annals of the New York Academy of Sciences 271:125–137.
Mele A, Szklo M, Visani G, Stazi MA, Castelli G, Pasquini P, Mandelli F. 1994. Hair dye use and other risk factors for leukemia and pre-leukemia: A case-control study. Italian Leukemia Study Group. American Journal of Epidemiology 139(6):609–619.
Mellemgaard A, Engholm G, McLaughlin JK, Olsen JH. 1994. Occupational risk factors for renal-cell carcinoma in Denmark. Scandinavian Journal of Work, Environment and Health 20(3):160–165.
Morgan RW, Kaplan SD, Gaffey WR. 1981. A general mortality study of production workers in the paint and coatings manufacturing industry. A preliminary report. Journal of Occupational Medicine 23(1):13–21.
Morgan RW, Kelsh MA, Zhao K, Heringer S. 1998. Mortality of aerospace workers exposed to trichloroethylene. Epidemiology 9(4):424–431.
Morris PD, Koepsell TD, Daling JR, Taylor JW, Lyon JL, Swanson GM, Child M, Weiss NS. 1986. Toxic substance exposure and multiple myeloma: A case-control study. Journal of the National Cancer Institute 76(6):987–994.
Morrison AS, Ahlbom A, Verhoek WG, Aoki K, Leck I, Ohno Y, Obata K. 1985. Occupation and bladder cancer in Boston, USA, Manchester, UK, and Nagoya, Japan. Journal of Epidemiology and Community Health 39(4):294–300.
Nagata C, Shimizu H, Hirashima K, Kakishita E, Fujimura K, Niho Y, Karasawa M, Oguma S, Yoshida Y, Mizoguchi H. 1999. Hair dye use and occupational exposure to organic solvents as risk factors for myelodysplastic syndrome. Leukemia Research 23(1):57–62.
NCI (National Cancer Institute). 2002. What You Need to Know About Cancer of the Cervix: Information About Detection, Symptoms, Diagnosis, and Treatment of Cervical Cancer. Available: http://www.nci.nih.gov/cancer_information/cancer_type/cervical [accessed May 2002].
Nielsen H, Henriksen L, Olsen JH. 1996. Malignant melanoma among lithographers. Scandinavian Journal of Work, Environment and Health 22(2):108–111.
NIOSH (National Institute for Occupational Safety and Health). 1997. NIOSH Pocket Guide to Chemical Hazards. Cincinnati, OH: NIOSH
Nisse C, Haguenoer JM, Grandbastien B, Preudhomme C, Fontaine B, Brillet JM, Lejeune R, Fenaux P. 2001. Occupational and environmental risk factors of the myelodysplastic syndromes in the North of France. British Journal of Haematology 112(4):927–935.
Nordström M, Hardell L, Magnuson A, Hagberg H, Rask-Andersen A. 1998. Occupational exposures, animal exposure and smoking as risk factors for hairy cell leukaemia evaluated in a case-control study. British Journal of Cancer 77(11):2048–2052.
NTP (National Toxicology Program). 2001. 9th Report of Carcinogens. Research Triangle Park, NC: NTP.
Olshan AF, De Roos AJ, Teschke K, Neglia JP, Strain DO, Pollock BH, Castleberry RP. 1999. Neuroblastoma and parental occupation. Cancer Causes and Control 10(6):539–549.
Olsson H, Brandt L. 1988. Risk of non-Hodgkin’s lymphoma among men occupationally exposed to organic solvents. Scandinavian Journal of Work, Environment and Health 14(4):246–251.
Ott MG, Skory LK, Holder BB, Bronson JM, Williams PR. 1983. Health evaluation of employees occupationally exposed to methylene chloride. Mortality. Scandinavian Journal of Work, Environment and Health 9(Suppl 1):8–16.
Paci E, Buiatti E, Seniori CA, Miligi L, Pucci N, Scarpelli A, Petrioli G, Simonato L, Winkelmann R, Kaldor JM. 1989. Aplastic anemia, leukemia and other cancer mortality in a cohort of shoe workers exposed to benzene. Scandinavian Journal of Work, Environment and Health 15(5):313–318.
Paganini-Hill A, Glazer E, Henderson BE, Ross RK. 1980. Cause-specific mortality among newspaper web pressmen. Journal of Occupational Medicine 22(8):542–544.
Pannett B, Coggon D, Acheson ED. 1985. A job-exposure matrix for use in population based studies in England and Wales. British Journal of Industrial Medicine 42(11):777–783.
Parent ME, Siemiatycki J, Fritschi L. 2000. Workplace exposures and oesophageal cancer. Occupational and Environmental Medicine 57(5):325–334.
Parkes HG, Veys CA, Waterhouse JA, Peters A. 1982. Cancer mortality in the British rubber industry. British Journal of Industrial Medicine 39(3):209–220.
Partanen T, Heikkila P, Hernberg S, Kauppinen T, Moneta G, Ojajarvi A. 1991. Renal cell cancer and occupational exposure to chemical agents. Scandinavian Journal of Work, Environment and Health 17(4):231–239.
Partanen T, Kauppinen T, Luukkonen R, Hakulinen T, Pukkala E. 1993. Malignant lymphomas and leukemias, and exposures in the wood industry: An industry-based case-referent study. International Archives of Occupational and Environmental Health 64(8):593–596.
Paulu C, Aschengrau A, Ozonoff D. 1999. Tetrachloroethylene-contaminated drinking water in Massachusetts and the risk of colon-rectum, lung, and other cancers. Environmental Health Perspectives 107(4):265–271.
Paustenbach DJ, Price PS, Ollison W, Blank C, Jernigan JD, Bass RD, Peterson HD. 1992. Reevaluation of benzene exposure for the Pliofilm (rubberworker) cohort (1936–1976). Journal of Toxicology and Environmental Health 36(3):177–231.
Paxton MB, Chinchilli VM, Brett SM, Rodricks JV. 1994a. Leukemia risk associated with benzene exposure in the Pliofilm cohort: I. Mortality update and exposure distribution. Risk Analysis 14(2):147–154.
Paxton MB, Chinchilli VM, Brett SM, Rodricks JV. 1994b. Leukemia risk associated with benzene exposure in the Pliofilm cohort. II. Risk estimates. Risk Analysis 14(2):155–161.
Paxton MB. 1996. Leukemia risk associated with benzene exposure in the Pliofilm cohort. Environmental Health Perspectives 104(Suppl 6):1431–1436.
Persson B, Fredriksson M. 1999. Some risk factors for non-Hodgkin’s lymphoma. International Journal of Occupational Medicine and Environmental Health 12(2):135–142.
Persson B, Dahlander A-M, Fredriksson M, Noorlind BH, Ohlson C-G, Axelson O. 1989. Malignant lymphomas and occupational exposures. British Journal of Industrial Medicine 46(8):516–520.
Persson B, Fredriksson M, Olsen K, Boeryd B, Axelson O. 1993. Some occupational exposures as risk factors for malignant lymphomas. Cancer 72(5):1773–1778.
Pesch B, Haerting J, Ranft U, Klimpel A, Oelschlagel B, Schill W. 2000a. Occupational risk factors for urothelial carcinoma: Agent-specific results from a case-control study in Germany. MURC Study Group. Multicenter Urothelial and Renal Cancer. International Journal of Epidemiology 29(2):238–247.
Pesch B, Haerting J, Ranft U, Klimpel A, Oelschlagel B, Schill W. 2000b. Occupational risk factors for renal cell carcinoma: Agent-specific results from a case-control study in Germany. MURC Study Group. Multicenter Urothelial and Renal Cancer study. International Journal of Epidemiology 29(6):1014–1024.
Petralia SA, Vena JE, Freudenheim JL, Dosemeci M, Michalek A, Goldberg MS, Brasure J, Graham S. 1999. Risk of premenopausal breast cancer in association with occupational exposure to polycyclic aromatic hydrocarbons and benzene. Scandinavian Journal of Work, Environment and Health 25(3):215–221.
Pippard EC, Acheson ED. 1985. The mortality of boot and shoe makers, with special reference to cancer. Scandinavian Journal of Work, Environment and Health 11(4):249–255.
Pohlabeln H, Boffetta P, Ahrens W, Merletti F, Agudo A, Benhamou E, Benhamou S, Bruske-Hohlfeld K, Ferro G, Fortes C, Kreuzer M, Mendes A, Nyberg F, Pershagen G, Saracci R, Schmid G, Siemiatycki J, Simonato L, Whitley E, Wichmann HE, Winck C, Zambon P, Jockel KH. 2000. Occuptional risks for lung cancer among nonsmokers. Epidemiology 11(5):532–538.
Poole C, Dreyer NA, Satterfleld MH, Levin L, Rothman KJ. 1993. Kidney cancer and hydrocarbon exposures among petroleum refinery workers. Environmental Health Perspectives 101(Suppl 6):53–62.
Richardson S, Zittoun R, Bastuji-Garin S, Lasserre V, Guihenneuc C, Cadiou M, Viguie F, Laffont-Faust I. 1992. Occupational risk factors for acute leukaemia: A case-control study. International Journal of Epidemiology 21(6):1063–1073.
Rigolin GM, Cuneo A, Roberti MG, Bardi A, Bigoni R, Piva N, Minotto C, Agostini P, De Angeli C, Del Senno L, Spanedda R, Castoldi G. 1998. Exposure to myelotoxic agents and myelodysplasia: Case-control study and correlation with clinicobiological findings. British Journal of Haematology 103(1):189–197.
Rinsky RA, Young RJ, Smith AB. 1981. Leukemia in benzene workers. American Journal of Industrial Medicine 2(3):217–245.
Rinsky RA, Smith AB, Hornung R, Filloon TG, Young RJ, Okun AH, Landrigan PJ. 1987. Benzene and leukemia. An epidemiologic risk assessment. New England Journal of Medicine 316(17):1044–1050.
Risch HA, Burch JD, Miller AB, Hill GB, Steele R, Howe GR. 1988. Occupational factors and the incidence of cancer of the bladder in Canada. British Journal of Industrial Medicine 45(6):361–367.
Ritz B. 1999. Cancer mortality among workers exposed to chemicals during uranium processing. Journal of Occupational and Environmental Medicine 41(7):556–566.
Rodvall Y, Ahlbom A, Spannare B, Nise G. 1996. Glioma and occupational exposure in Sweden, a case-control study. Occupational and Environmental Medicine 53(8):526–537.
Ruder AM, Ward EM, Brown DP. 1994. Cancer mortality in female and male dry-cleaning workers. Journal of Occupational Medicine 36(8):867–874.
Ruder AM, Ward EM, Brown DP. 2001. Mortality in dry-cleaning workers: An update. American Journal of Industrial Medicine 39(2):121–132.
Rushton L, Alderson MR. 1981. A case-control study to investigate the association between exposure to benzene and deaths from leukaemia in oil refinery workers. British Journal of Cancer 43(1):77–84.
Rushton L, Romaniuk H. 1997. A case-control study to investigate the risk of leukaemia associated with exposure to benzene in petroleum marketing and distribution workers in the United Kingdom. Occupational and Environmental Medicine 54(3):152–166.
Scherr PA, Hutchison GB, Neiman RS. 1992. Non-Hodgkin’s lymphoma and occupational exposure. Cancer Research 52(Suppl 19):5503–5509.
Schlehofer B, Heuer C, Blettner M, Niehoff D, Wahrendorf J. 1995. Occupation, smoking and demographic factors, and renal cell carcinoma in Germany. International Journal of Epidemiology 24(1):51–57.
Schnatter AR, Armstrong TW, Nicolich MJ, Thompson FS, Katz AM, Huebner WW, Pearlman ED. 1996a. Lymphohaematopoietic malignancies and quantitative estimates of exposure to benzene in Canadian petroleum distribution workers. Occupational and Environmental Medicine 53(11):773–781.
Schnatter AR, Armstrong TW, Thompson LS, Nicolich MJ, Katz AM, Huebner WW, Pearlman ED. 1996b. The relationship between low-level benzene exposure and leukemia in Canadian petroleum distribution workers. Environmental Health Perspectives 104(Suppl 6):1375–1379.
Schoenberg JB, Stemhagen A, Mogielnicki AP, Altman R, Abe T, Mason TJ. 1984. Case-control study of bladder cancer in New Jersey. I. Occupational exposures in white males. Journal of the National Cancer Institute 72(5):973–981.
Schumacher MC, Delzell E. 1988. A death-certificate case-control study of non-Hodgkin’s lymphoma and occupation in men in North Carolina. American Journal of Industrial Medicine 13(3):317–330.
Serraino D, Franceschi S, La Vecchia C, Carbone A. 1992. Occupation and soft-tissue sarcoma in northeastern Italy. Cancer Causes and Control 3(1):25–30.
Shannon HS, Haines T, Bernholz C, Julian JA, Verma DK, Jamieson E, Walsh C. 1988. Cancer morbidity in lamp manufacturing workers. American Journal of Industrial Medicine 14(3):281–290.
Sharpe CR, Rochon JE, Adam JM, Suissa S. 1989. Case-control study of hydrocarbon exposures in patients with renal cell carcinoma. Canadian Medical Association Journal 140(11):1309–1318.
Shu XO, Stewart P, Wen WQ, Han D, Potter JD, Buckley JD, Heineman E, Robison LL. 1999. Parental occupational exposure to hydrocarbons and risk of acute lymphocytic leukemia in offspring. Cancer Epidemiology, Biomarkers and Prevention 8(9):783–791.
Silverman DT, Levin LI, Hoover RN, Hartge P. 1989a. Occupational risks of bladder cancer in the United States: I. White men. Journal of the National Cancer Institute 81(19):1472–1480.
Silverman DT, Levin LI, Hoover RN. 1989b. Occupational risks of bladder cancer in the United States: II. Nonwhite men. Journal of the National Cancer Institute 81(19):1480–1483.
Smith EM, Miller ER, Woolson RF, Brown CK. 1985. Bladder cancer risk among laundry workers, dry cleaners, and others in chemically-related occupations. Journal of Occupational Medicine 27(4):295–297.
Smulevich VB, Solionova LG, Belyakova SV. 1999. Parental occupation and other factors and cancer risk in children: II. Occupational factors. International Journal of Cancer 83(6):718–722.
Sorahan T, Cathcart M. 1989. Lung cancer mortality among workers in a factory manufacturing chlorinated toluenes: 1961–84. British Journal of Industrial Medicine 46(6):425–427.
Sorahan T, Parkes HG, Veys CA, Waterhouse JA. 1986. Cancer mortality in the British rubber industry: 1946–1980. British Journal of Industrial Medicine 43(6):363–373.
Sorahan T, Parkes HG, Veys CA, Waterhouse JA, Straughan JK, Nutt A. 1989. Mortality in the British rubber industry 1946–85. British Journal of Industrial Medicine 46(1):1–10.
Spirtas R, Stewart PA, Lee JS, Marano DE, Forbes CD, Grauman DJ, Pettigrew HM, Blair A, Hoover RN, Cohen JL. 1991. Retrospective cohort mortality study of workers at an aircraft maintenance facility. I. Epidemiological results. British Journal of Industrial Medicine 48(8):515–530.
Staines A, Cartwright RA. 1993. Hairy cell leukaemia: Descriptive epidemiology and a case-control study. British Journal of Haematology 85(4):714–717.
Steenland K, Palu S. 1999. Cohort mortality study of 57,000 painters and other union members: A 15 year update. Occupational and Environmental Medicine 56(5):315–321.
Stemhagen A, Slade J, Altman R, Bill J. 1983. Occupational risk factors and liver cancer. A retrospective case-control study of primary liver cancer in New Jersey. American Journal of Epidemiology 117(4):443–454.
Stern FB, Waxweiler RA, Beaumont JJ, Lee ST, Rinsky RA, Zumwalde RD, Halperin WE, Bierbaum PJ, Landrigan PJ, Murray WE. 1986. A case-control study of leukemia at a naval nuclear shipyard. American Journal of Epidemiology 123(6):980–992.
Stewart PA, Lee JS, Marano DE, Spirtas R, Forbes CD, Blair A. 1991. Retrospective cohort mortality study of workers at an aircraft maintenance facility. II. Exposures and their assessment. British Journal of Industrial Medicine 48(8):531–537.
Stockwell HG, Matanoski GM. 1985. A case-control study of lung cancer in painters. Journal of Occupational Medicine 27(2):125–126.
Svensson BG, Nise G, Englander V, Attewell R, Skerfving S, Moller T. 1990. Deaths and tumours among rotogravure printers exposed to toluene. British Journal of Industrial Medicine 47(6):372–379.
Tatham L, Tolbert P, Kjeldsberg C. 1997. Occupational risk factors for subgroups of non-Hodgkin’s lymphoma. Epidemiology 8(5):551–558.
Teschke K, Morgan MS, Checkoway H, Franklin G, Spinelli JJ, Van BG, Weiss NS. 1997. Surveillance of nasal and bladder cancer to locate sources of exposure to occupational carcinogens. Occupational and Environmental Medicine 54(6):443–451.
Teta MJ, Perlman GD, Ott MG. 1992. Mortality study of ethanol and isopropanol production workers at two facilities. Scandinavian Journal of Work, Environment and Health 18(2):90–96.
Thomas TL, Stewart PA, Stemhagen A, Correa P, Norman SA, Bleecker ML, Hoover RN. 1987. Risk of astrocytic brain tumors associated with occupational chemical exposures. A case-referent study. Scandinavian Journal of Work, Environment and Health 13(5):417–423.
Tomenson JA, Bonner SM, Heijne CG, Farrar DG, Cummings TF. 1997. Mortality of workers exposed to methylene chloride employed at a plant producing cellulose triacetate film base. Occupational and Environmental Medicine 54(7):470–476.
Tsai SP, Wen CP, Weiss NS, Wong O, McClellan WA, Gibson RL. 1983. Retrospective mortality and medical surveillance studies of workers in benzene areas of refineries. Journal of Occupational Medicine 25(9):685–692.
US Surgeon General. 1985 The Health Consequences of Smoking: Cancer and Chronic Lung Disease in the Workplace: A Report of the Surgeon General. Rockville, MD: Department of Health and Human Services.
Vamvakas S, Bruning T, Thomasson B, Lammert M, Baumuller A, Bolt HM, Dekant W, Birner G, Henschler D, Ulm K. 1998. Renal cell cancer correlated with occupational exposure to trichloroethene. Journal of Cancer Research and Clinical Oncology 124(7):374–382.
Van den Berghe H, Louwagie A, Broeckaert-Van Orshoven A, David G, Verwilghen R. 1979. Chromosome analysis in two unusual malignant blood disorders presumably induced by benzene. Blood 53(4):558–566.
van Steensel-Moll HA, Valkenburg HA, van Zanen GE. 1985. Childhood leukemia and parental occupation. A register-based case-control study. American Journal of Epidemiology 121(2):216–224.
Vaughan TL, Stewart PA, Davis S, Thomas DB. 1997. Work in dry-cleaning and the incidence of cancer of the oral cavity, larynx, and oesophagus. Occupational and Environmental Medicine 54(9):692–695.
Viadana E, Bross ID. 1972. Leukemia and occupations. Preventive Medicine 1(4):513–521.
Vineis P, Magnani C. 1985. Occupation and bladder cancer in males: A case-control study. International Journal of Cancer 35(5):599–606.
Walker JT, Bloom TF, Stern FB, Okun AH, Fingerhut MA, Halperin WE. 1993. Mortality of workers employed in shoe manufacturing. Scandinavian Journal of Work, Environment and Health 19(2):89–95.
Wallace J. 1996. Phenol. In: Kirk RE, Kroschwitz JI, Howe-Grant M, eds. Encyclopedia of Chemical Technology. Vol. 18. 4th ed. New York: John Wiley & Sons.
Waxweiler RJ, Smith AH, Falk H, Tyroler HA. 1981. Excess lung cancer risk in a synthetic chemicals plant. Environmental Health Perspectives 41:159–165.
Webler T, Brown HS. 1993. Exposure to tetrachloroethylene via contaminated drinking water pipes in Massachusetts: A predictive model. Archives of Environmental Health 48(5):293–297.
Weiderpass E, Pukkala E, Kauppinen T, Mutanen P, Paakkulainen H, Vasama-Neuvonen K, Boffetta P, Partanen T. 1999. Breast cancer and occupational exposures in women in Finland. American Journal of Industrial Medicine 36(1):48–53.
Wen CP, Tsai SP, Weiss NS, Gibson RL, Wong O, McClellan WA. 1985. Long-term mortality study of oil refinery workers. IV. Exposure to the lubricating-dewaxing process. Journal of the National Cancer Institute 74(1):11–18.
West RR, Stafford DA, Farrow A, Jacobs A. 1995. Occupational and environmental exposures and myelodysplasia: A case-control study. Leukemia Research 19(2):127–139.
West RR, Stafford DA, White AD, Bowen DT, Padua RA. 2000. Cytogenetic abnormalities in the myelodysplastic syndromes and occupational or environmental exposure. Blood 95(6):2093–2097.
Wiebelt H, Becker N. 1999. Mortality in a cohort of toluene exposed employees (rotogravure printing plant workers). Journal of Occupational and Environmental Medicine 41(12):1134–1139.
Wilcosky TC, Checkoway H, Marshall EG, Tyroler HA. 1984. Cancer mortality and solvent exposures in the rubber industry. American Industrial Hygiene Association Journal 45(12):809–811.
Wolf PH, Andjelkovich D, Smith A, Tyroler H. 1981. A case-control study of leukemia in the U.S. rubber industry. Journal of Occupational Medicine 23(2):103–108.
Wong O. 1987a. An industry wide mortality study of chemical workers occupationally exposed to benzene. I. General results. British Journal of Industrial Medicine 44(6):365–381.
Wong O. 1987b. An industry wide mortality study of chemical workers occupationally exposed to benzene. II. Dose response analyses. British Journal of Industrial Medicine 44(6):382–395.
Wong O. 1995. Risk of acute myeloid leukaemia and multiple myeloma in workers exposed to benzene. Occupational and Environmental Medicine 52(6):380–384.
Wong O, Harris F, Smith TJ. 1993. Health effects of gasoline exposure. II. Mortality patterns of distribution workers in the United States. Environmental Health Perspectives 101(Suppl 6):63–76.
Yin SN, Li GL, Tain FD, Fu ZI, Jin C, Chen YJ, Luo SJ, Ye PZ, Zhang JZ, Wang GC, et al. 1987. Leukaemia in benzene workers: A retrospective cohort study. British Journal of Industrial Medicine 44(2):124–128.
Yin SN, Li GL, Tain FD, Fu ZI, Jin C, Chen YJ, Luo SJ, Ye PZ, Zhang JZ, Wang GC, Zhang XC, Wu HN, Zhong QC. 1989. A retrospective cohort study of leukemia and other cancers in benzene workers. Environmental Health Perspectives 82:207–213.
Yin SN, Linet MS, Hayes RB, Li GL, Dosemeci M, Wang YZ, Chow WH, Jiang ZL, Wacholder S, Zhang WU, et al. 1994. Cohort study among workers exposed to benzene in China: I. General methods and resources. American Journal of Industrial Medicine 26(3):383–400.
Yin SN, Hayes RB, Linet MS, Li GL, Dosemeci M, Travis LB, Li CY, Zhang ZN, Li DG, Chow WH, Wacholder S, Wang YZ, Jiang ZL, Dai TR, Zhang WY, Chao XJ, Ye PZ, Kou QR, Zhang XC, Lin XF, Meng JF, Ding CY, Zho JS, Blot WJ. 1996a. A cohort study of cancer among benzene-exposed workers in China: Overall results. American Journal of Industrial Medicine 29(3):227–235.
Yin SN, Hayes RB, Linet MS, Li GL, Dosemeci M, Travis LB, Zhang ZN, Li DG, Chow WH, Wacholder S, Blot WJ. 1996b. An expanded cohort study of cancer among benzene-exposed workers in China. Benzene Study Group. Environmental Health Perspectives 104(Suppl 6):1339–1341.
Zack M, Cannon S, Loyd D, Heath CW Jr, Falletta JM, Jones B, Housworth J, Crowley S. 1980. Cancer in children of parents exposed to hydrocarbon-related industries and occupations. American Journal of Epidemiology 111(3):329–336.