Environmental factors are considered key determinants of cardiovascular disease. Although lifestyle choices such as smoking, diet, and exercise are viewed as major environmental influences, the contribution of pollutants and environmental chemicals is less clear. Accumulating evidence suggests that exposure to pollutants and chemicals could elevate the risk of cardiovascular disease. Many epidemiological studies report that exposure to fine particles present in ambient air is associated with an increase in cardiovascular mortality. Statistically significant relationships between particulate air pollution and ischemic heart disease, arrhythmias, and heart failure have been reported. Animal studies show that exposure to ambient air particles increases peripheral thrombosis and atherosclerotic lesion formation. Exposures to arsenic, lead, cadmium, pollutant gases, solvents, and pesticides have also been linked to increased incidence of cardiovascular disease. Mechanistically, these effects have been attributed to changes in the synthesis or reactivity of nitric oxide that may be caused by environmental oxidants or increased endogenous production of reactive oxygen species. Additional studies are urgently needed to: identify the contribution of individual pollutants to specific aspects of cardiovascular disease; establish causality; elucidate the underlying physiological and molecular mechanisms; estimate the relative susceptibility of diseased and healthy individuals and that of specific population groups; and determine whether pollutant exposure are risk correlates, that is, whether they influence major risk factors, such as hypertension, cholesterol, or diabetes, or whether they contribute to the absolute risk of heart disease. Collectively, these investigations could contribute to the emergent field of environmental cardiology.

Environmental Cardiology Studying Mechanistic Links Between Pollution and Heart Disease

An international, interdisciplinary working group of expert scientists met in June 2004 to develop IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans (IARC Monographs) on formaldehyde, 2-butoxyethanol, and 1-tert-butoxy-2-propanol. Each IARC Monograph includes a critical review of the pertinent scientific literature and an evaluation of an agent’s potential to cause cancer in humans. After a thorough discussion of the epidemiologic, experimental, and other relevant data, the working group concluded that formaldehyde is carcinogenic to humans, based on sufficient evidence in humans and in experimental animals. In the epidemiologic studies, there was sufficient evidence that formaldehyde causes nasopharyngeal cancer, “strong but not sufficient” evidence of leukemia, and limited evidence of sinonasal cancer. The working group also concluded that 2-butoxyethanol and 1-tert-butoxy-2-propanol are not classifiable as to their carcinogenicity to humans, each having limited evidence in experimental animals and inadequate evidence in humans. These three evaluations and the supporting data will be-published as Volume 88 of the IARC Monographs.

Meeting Report: Summary of IARC Monographs on Formaldehyde, 2-Butoxyethanol, and 1-tert-Butoxy-2-Propanol

Recent findings on the genetic toxicology of benzene, toluene, xylenes and phenols

This is the first of two articles reviewing the epidemiologic research on cardiovascular diseases (CVD) and the work environment. It deals with a number of nonchemical factors, ie, physical inactivity at work, stressors at work, shift work, noise, cold, heat, and electromagnetic fields and waves. First the methodological quality of each of the empirical studies is assessed on the basis of epidemiologic criteria. Then the research literature on each of the aforementioned factors of the work environment is evaluated. It is concluded that the hypothesis of a causal relationship between physical inactivity at work and risk of CVD is substantially supported by the literature. As regards work stressors and shift work, several good studies have been published during the last 10 years strongly suggesting a causal relationship. Other studies have shown a relationship between noise and elevated blood pressure, but the quality of this literature is low. Heat and cold appear to have an acute effect on the incidence of CVD, but the possible chronic effect has seldom been investigated. Concerning electromagnetic fields and waves, it is concluded that more research is needed. The study of CVD and work ought to play a bigger role in research in the fields of occupational medicine and cardiovascular epidemiology in the future.

Cardiovascular diseases and the work environment. A critical review of the epidemiologic literature on nonchemical factors.

Formaldehyde is an economically important chemical, to which more than 2 million U.S. workers are occupationally exposed. Substantially more people are exposed to formaldehyde environmentally, as it is generated by automobile engines, is a component of tobacco smoke and is released from household products, including furniture, particleboard, plywood, and carpeting. The International Agency for Research on Cancer (IARC) recently classified formaldehyde as a human carcinogen that causes nasopharyngeal cancer and also concluded that there is "strong but not sufficient evidence for a causal association between leukemia and occupational exposure to formaldehyde". Here, we review the epidemiological studies published to date on formaldehyde-exposed workers and professionals in relation to lymphohematopoietic malignances. In a new meta-analysis of these studies, focusing on occupations known to have high formaldehyde exposure, we show that summary relative risks (RRs) were elevated in 15 studies of leukemia (RR=1.54; confidence interval (CI), 1.18-2.00) with the highest relative risks seen in the six studies of myeloid leukemia (RR=1.90; 95% CI, 1.31-2.76). The biological plausibility of this observed association is discussed and potential mechanisms proposed. We hypothesize that formaldehyde may act on bone marrow directly or, alternatively, may cause leukemia by damaging the hematopoietic stem or early progenitor cells that are located in the circulating blood or nasal passages, which then travel to the bone marrow and become leukemic stem cells. To test these hypotheses, we recommend that future studies apply biomarkers validated for other chemical leukemogens to the study of formaldehyde.

Formaldehyde exposure and leukemia: a new meta-analysis and potential mechanisms

In a study of the mortality of Ontario undertakers, a cohort of 1,477 men first licensed during 1928 through 1957 was followed up until the end of 1977. Numbers of observed and expected deaths were determined for the period 1950 through 1977, using mortality rates of Ontario men as the standard. In all, 319 persons had died, compared with 322 expected. Ontario undertakers were not at increased risk of death from cancers at sites of contact with formaldehyde. Cirrhosis of the liver (standardized mortality ratio, 238) and chronic rheumatic heart disease (standardized mortality ratio, 199) were the only causes of death found to be significantly in excess. The data are discussed in the context of current epidemiologic information on the mortality experience of persons exposed to formaldehyde.

The mortality of Ontario undertakers and a review of formaldehyde-related mortality studies.

A matched case-control study was conducted for 72 cases of leukemia occurring among employees of four rubber and tire manufacturing companies during the period from 1964 to 1973, to determine if certain environmental exposures were related to the risk of developing leukemia. Earlier studies conducted in one company had shown an association of lymphatic leukemia with a work history of possible solvent exposure, and the results of the present study suggest that the association is weaker than previously described. However, recently acquired detailed environmental information reported elsewhere tends to support the initial finding at this company. Further studies are required to fully resolve this issue. A finding was the lack of association in the order three companies. In addition, lymphatic leukemia was found to be associated with work experience in general service jobs for the two larger companies from which a majority (89%) of the cases derive. Intervals from exposure death peaked at 27 to 38 years. No elevated risk for myeloid leukemia was found.

A case-control study of leukemia in the U.S. rubber industry.

To determine whether the carcinogenicity of dinitrotoluene (DNT) in rodent bioassays was predictive for humans, we examined the mortality experience of exposed workers at two ammunition plants. Cohorts of 156 and 301 men who had worked a month or more during the 1940s and 1950s at jobs with opportunity for substantial DNT exposure were followed through the end of 1980. Numbers of expected deaths and standardized mortality ratios (SMRs) were computed, using mortality rates of US white males as the standard. No evidence of a carcinogenic effect was found, but unsuspected excesses of mortality from ischemic heart disease were noted at both plants (SMRs) 131 and 143; 95% confidence limits 65 to 234 and 107 to 187, respectively). Deaths from ischemic heart disease remained high even when compared with expected numbers derived using mortality rates of the counties in which the plants were located. Additional analyses revealed evidence of a 15-year latent period and suggested a relationship with duration and intensity of exposure. Epidemiologic investigations of other heavily exposed populations are needed to confirm the etiologic significance of the association between DNT and heart disease described here.

Heart disease in workers exposed to dinitrotoluene

In this case-control study the detailed employment histories of 121 rubber plant employees who died of lung cancer from 1964 through 1973 were compared to those of 448 plant employees (controls) who died of other causes during the same calendar period. All subjects were white male hourly employees. Lung cancer cases and controls were matched individually on year of birth and year of first hire at the plant. Results of matched analyses indicated that there was no association between lung cancer mortality and employment in either rubber compounding and mixing jobs or curing jobs. Men who had worked for at least five years in rubber reclaim operations, where there was potentially heavy exposure to particulates and fumes, experienced a twofold increase in lung cancer risk. In addition, there was a 70% excess of lung cancer risk among men employed in making special products, where the primary production activity was fuel cell manufacturing. The latter two findings were marginally statistically significant.

A case-control study of employment experience and lung cancer among rubber workers.

This report presents the findings of a case-control study of lung cancer among workers at a rubber manufacturing plant. Detailed work histories of 40 lung cancer deaths, which occurred during 1977 and 1978, were compared with those of 146 controls who were individually matched to cases on age, sex, and race; 66 of the controls were also matched on year of first hire. Elevated odds ratios were noted for different durations of employment in four work areas: Reclaim Operation, Chemicals, Special Products Manufacture, and Curing Preparation. A clear trend of increasing odds ratios with increasing durations of exposure was observed for the first three of these work areas. Several chemicals used in these processes are known respiratory system hazards. The results of this study suggest an association between lung cancer mortality risk and employment in Reclaim Operation, Chemicals, and Special Products Manufacture. A moderate excess risk was observed in these areas among both smokers and nonsmokers, although the risk was greater among the smokers.

Dragana A. Andjelkovich

Papers

The mortality of Ontario undertakers and a review of formaldehyde-related mortality studies.

A case-control study of leukemia in the U.S. rubber industry.

Heart disease in workers exposed to dinitrotoluene

A case-control study of employment experience and lung cancer among rubber workers.

Lung cancer case-control study in a rubber manufacturing plant.