Proxyfan acts as a neutral antagonist of histamine H3 receptors in the feeding-related hypothalamic ventromedial nucleus.

BACKGROUND AND PURPOSE: Centrally acting histamine H(3) receptor ligands are proposed as potential treatments for obesity, although the value of inverse agonists at these receptors is still debated. Functional inhibition of H(3) autoreceptors activates neurones in a hypothalamic 'satiety' centre. The H(3) receptor antagonist, proxyfan was used as a tool to assess the action of histaminergic compounds in this model. EXPERIMENTAL APPROACH: We compared the actions of histamine on feeding with those of an H(3) receptor agonist (imetit) and inverse agonist (thioperamide) in rats and mice. Sites of action were identified by immunohistochemistry and the hypothalamic ventromedial nucleus (VMN) was investigated using electrophysiological techniques. KEY RESULTS: Central histamine or thioperamide decreased fast-induced feeding, whereas imetit increased feeding. Systemic thioperamide entered the brain to activate hypothalamic feeding centres and to reduce feeding without causing any adverse behaviours. Thioperamide activated neurones in the VMN through an action on histamine autoreceptors, whilst imetit had the opposite effect. Proxyfan administered alone did not affect either feeding or electrical activity. However, it blocked the actions of both thioperamide and imetit, acting as a neutral antagonist in this system. CONCLUSIONS AND IMPLICATIONS: The H(3) receptor inverse agonist, thioperamide, potently reduced appetite without adverse behavioural effects. This action was blocked by proxyfan, acting as a neutral antagonist in this model and, therefore, this compound is useful in determining the selectivity of H(3) receptor-directed drugs. A major action of thioperamide is through presynaptic autoreceptors, inducing stimulation by endogenous histamine of postsynaptic H(1 ) receptors on anorectic hypothalamic neurones.

Lifestyle-related factors and environmental agents causing cancer: an overview.

The increasing incidence of a variety of cancers after the Second World War confronts scientists with the question of their origin. In Western countries, expansion and ageing of the population as well as progress in cancer detection using new diagnostic and screening tests cannot fully account for the observed growing incidence of cancer. Our hypothesis is that environmental factors play a more important role in cancer genesis than it is usually agreed. (1) Over the last 2-3 decades, alcohol consumption and tobacco smoking in men have significantly decreased in Western Europe and North America. (2) Obesity is increasing in many countries, but the growing incidence of cancer also concerns cancers not related to obesity nor to other known lifestyle-related factors. (3) There is evidence that the environment has changed over the time period preceding the recent rise in cancer incidence, and that this change, still continuing, included the accumulation of many new carcinogenic factors in the environment. (4) Genetic susceptibility to cancer due to genetic polymorphism cannot have changed over one generation and actually favours the role of exogenous factors through gene-environment interactions. (5) Age is not the unique factor to be considered since the rising incidence of cancers is seen across all age categories, including children, and adolescents. (6) The fetus is specifically vulnerable to exogenous factors. A fetal exposure during a critical time window may explain why current epidemiological studies may still be negative in adults. We therefore propose that the involuntary exposure to many carcinogens in the environment, including microorganisms (viruses, bacteria and parasites), radiations (radioactivity, UV and pulsed electromagnetic fields) and many xenochemicals, may account for the recent growing incidence of cancer and therefore that the risk attributable to environmental carcinogen may be far higher than it is usually agreed. Of major concern are: outdoor air pollution by carbon particles associated with polycyclic aromatic hydrocarbons; indoor air pollution by environmental tobacco smoke, formaldehyde and volatile organic compounds such as benzene and 1,3 butadiene, which may particularly affect children and food contamination by food additives and by carcinogenic contaminants such as nitrates, pesticides, dioxins and other organochlorines. In addition, carcinogenic metals and metalloids, pharmaceutical medicines and some ingredients and contaminants in cosmetics may be involved. Although the risk fraction attributable to environmental factors is still unknown, this long list of carcinogenic and especially mutagenic factors supports our working hypothesis according to which numerous cancers may in fact be caused by the recent modification of our environment.

The multitude and diversity of environmental carcinogens.

We have recently proposed that lifestyle-related factors, screening and aging cannot fully account for the present overall growing incidence of cancer. In order to propose the concept that in addition to lifestyle related factors, exogenous environmental factors may play a more important role in carcinogenesis than it is expected, and may therefore account for the growing incidence of cancer, we overview herein environmental factors, rated as certainly or potentially carcinogenic by the International Agency for Research on Cancer (IARC). We thus analyze the carcinogenic effect of microorganisms (including viruses), radiations (including radioactivity, UV and pulsed electromagnetic fields) and xenochemicals. Chemicals related to environmental pollution appear to be of critical importance, since they can induce occupational cancers as well as other cancers. Of major concerns are: outdoor air pollution by carbon particles associated with polycyclic aromatic hydrocarbons; indoor air pollution by environmental tobacco smoke, formaldehyde and volatile organic compounds such as benzene and 1,3 butadiene, which may particularly affect children, and food pollution by food additives and by carcinogenic contaminants such as nitrates, pesticides, dioxins and other organochlorines. In addition, carcinogenic metals and metalloids, pharmaceutical medicines and cosmetics may be involved. Although the risk fraction attributable to environmental factors is still unknown, this long list of carcinogenic and especially mutagenic factors supports our working hypothesis according to which numerous cancers may in fact be caused by the recent modification of our environment.

The growing incidence of cancer: role of lifestyle and screening detection (Review).

The increasing incidence of a variety of cancers after the Second World War confronts scientists with the question of their origin. In Western countries, expansion and ageing of the population, as well as progress in cancer detection using new diagnostic and screening tests cannot fully account for the observed growing incidence of cancer. Our hypothesis is that environmental factors play a more important role in cancer genesis than it is usually agreed: i) over the last 2-3 decades, alcohol consumption and tobacco smoking in men have significantly decreased; ii) obesity is increasing in many countries, but the growing incidence of cancer also concerns cancers not related to obesity nor to other lifestyle-related factors; iii) there is evidence that the environment has changed over the same time scale as the recent rise in cancer incidence, and that this change included the accumulation of many new carcinogenic factors in the environment; iv) genetic susceptibility to cancer due to genetic polymorphism cannot have changed over one generation and actually favours the role of exogenous factors through gene-environment interactions; v) age is not the unique factor to be considered since the rising incidence of cancers is seen across all age categories, including children; vi) the fetus is specifically vulnerable to exogenous factors. A fetal exposure during a critical window period may explain why current epidemiological studies may be negative in adults. We therefore propose that the involuntary exposure to many carcinogens in the environment contributes to the rising trend in cancer incidence.

Age at any full-term pregnancy and breast cancer risk.

The authors analyzed data from two multistate, population-based case-control studies to investigate the association between age at any full-term pregnancy (FP) and breast cancer risk. Study subjects included breast cancer cases aged 20-79 years identified from four statewide cancer registries and randomly selected controls interviewed from 1988 to 1996. Complete information on a comprehensive set of risk factors for breast cancer was available for 9,891 cases and 12,271 controls. The large number of subjects enabled simultaneous adjustment of the covariates and efficient application of various modeling approaches. Overall, each 5-year increase in age at first FP was associated with an odds ratio of 1.07 (95% confidence interval (CI): 1.01, 1.13) for breast cancer. The corresponding estimates were odds ratio = 1.02 (95% CI: 1.00, 1.05) for age at second through ninth FPs. For age at last FP, the effect estimate (odds ratio = 1.01, 95% CI: 0.97, 1.06) was indistinguishable from that for other FPs after the first. In this analysis, a modest and transient increase in breast cancer risk after childbirth was also observed. The relatively greater effect of age at first FP is consistent with the existence of a long-term effect of early first FP on the differentiation of mammary cells, causing them to become less susceptible to carcinogenesis.

The health risks of decommissioning nuclear facilities.

The health risks facing workers involved in decommissioning nuclear facilities are a critical concern as the nuclear weapons complex and nuclear power plants begin to be dismantled. In addition to risks from exposure to radioactive materials, there are risks from other common industrial materials like crystalline silica dust and asbestos. We discuss these issues in the context of recent research on the risk of low-level ionizing radiation, the classification of crystalline silica as a carcinogen, and early experience with decommissioning nuclear facilities in the United States. Health and safety advocates will need to be vigilant to prevent worker exposure.

Leukemia in petroleum refinery workers: a review of recent studies.

A previous review of the published epidemiologic literature on cancer risk in workers in the petrochemical industry indicated excess risks of leukemia and several other cancers. Here we update this review, focusing on the risk of hematologic cancers (for example, leukemia and lymphoma) reported in studies of oil refinery workers published in the last ten years. Limitations of recent studies are discussed, including the dilution of highly exposed groups of workers with workers with little or no exposure. We consider the evidence for a "safe level" or threshold of benzene exposure in the light of its ability to cause several types of damage, including damage to stem cells which may cause a variety of malignancies. We conclude that there is evidence of a slight increase in mortality from leukemia among oil refinery workers, particularly among those employed before 1950. And continuing exposures to benzene and other carcinogens occurring in this industry should be controlled.

The decline in U.S. cancer mortality from 1991 to 1995: what's behind the numbers?

In 1996, a series of articles and news stories about cancer mortality in the United States proclaimed a "turning point in the 25-year war on cancer." While these articles and stories pointed to a recent decline in overall cancer mortality, they missed some important points about increases in specific types. They also ignored the politics behind the emphasis on smoking and diet as the main contributors to the cancer rates and the racial disparities in the U.S. data. In addition, recent articles on the decline in cancer mortality fail to note the much sharper decline in heart disease mortality. Continued efforts to reduce carcinogenic exposures at work and in the environment are needed to truly reduce the cancer burden.

Health status of Persian Gulf War veterans: self-reported symptoms, environmental exposures and the effect of stress.

BACKGROUND: Most US troops returned home from the Persian Gulf War (PGW) by Spring 1991 and many began reporting increased health symptoms and medical problems soon after. This investigation examines the relationships between several Gulf-service environmental exposures and health symptom reporting, and the role of traumatic psychological stress on the exposure-health symptom relationships. METHODS: Stratified, random samples of two cohorts of PGW veterans, from the New England area (n = 220) and from the New Orleans area (n = 71), were selected from larger cohorts being followed longitudinally since arrival home from the Gulf. A group of PGW-era veterans deployed to Germany (n = 50) served as a comparison group. The study protocol included questionnaires, a neuropsychological test battery, an environmental interview, and psychological diagnostic interviews. This report focuses on self-reported health symptoms and exposures of participants who completed a 52-item health symptom checklist and a checklist of environmental exposures. RESULTS: The prevalence of reported symptoms was greater in both Persian Gulf-deployed cohorts compared to the Germany cohort. Analyses of the body-system symptom scores (BSS), weighted to account for sampling design, and adjusted by age, sex, and education, indicated that Persian Gulf-deployed veterans were more likely to report neurological, pulmonary, gastrointestinal, cardiac, dermatological, musculoskeletal, psychological and neuropsychological system symptoms than Germany veterans. Using a priori hypotheses about the toxicant effects of exposure to specific toxicants, the relationships between self-reported exposures and body-system symptom groupings were examined through multiple regression analyses, controlling for war-zone exposure and post-traumatic stress disorder (PTSD). Self-reported exposures to pesticides, debris from Scuds, chemical and biological warfare (CBW) agents, and smoke from tent heaters each were significantly related to increased reporting of specific predicted BSS groupings. CONCLUSIONS: Veterans deployed to the Persian Gulf have higher self-reported prevalence of health symptoms compared to PGW veterans who were deployed only as far as Germany. Several Gulf-service environmental exposures are associated with increased health symptom reporting involving predicted body-systems, after adjusting for war-zone stressor exposures and PTSD.

Physical activity in usual occupation and risk of breast cancer (United States).

We have used data from a large population-based case-control study in the United States to evaluate the effect of occupational physical activity on breast cancer risk. Women diagnosed with breast cancer identified from four state cancer registries, and controls randomly selected from lists of licensed drivers or Medicare beneficiaries, were interviewed by telephone for information on usual occupation and other factors. We classified usual occupation into one of four categories of physical activity. After excluding subjects for whom a strength rating could not be assigned, we had a final sample size of 4,863 cases and 6,783 controls. Using conditional logistic regression models, we calculated adjusted odds ratios (OR) and 95 percent confidence intervals (CI) for occupations having light, medium, and heavy activity compared with sedentary ones. Women with heavy-activity occupations had a lower risk of breast cancer than women with sedentary jobs (OR = 0.82, CI = 0.63-1.08), as did women with jobs with medium activity (OR = 0.86, CI = 0.77-0.97) or light activity (OR = 0.92, CI = 0.84-1.01). There was a significant decreasing trend in the ORs from sedentary to heavy work (P = 0.007). Although limited by exposure misclassification, these data are consistent with the hypothesis that physical activity reduces the risk of breast cancer.

Variation in female breast cancer risk by occupation.

Data from a population-based case control study were used to estimate occupation-specific relative risks for female breast cancer, adjusted for established breast cancer risk factors. Breast cancer cases under age 75 were identified from tumor registries in four states. Controls were randomly selected from driver's license and Medicare beneficiary lists. Information on usual occupation and risk factors was obtained by telephone interview. Odds ratios from logistic regression adjusted for age, state, body mass index, benign breast disease, family history of breast cancer, menopausal status, age at menarche, parity, age of first birth, lactation history, education, and alcohol consumption were calculated for each of 26 occupational groups. Complete occupational information was obtained for 6,835 cases and 9,453 controls. Of 26 occupational groups, only "administrative support occupations" had a statistically significantly increased risk of breast cancer (OR = 1.15, 95% CI 1.06-1.24). In these data, no specific occupational group had an unusual risk of breast cancer. Increased risks reported elsewhere for nurses and teachers were not corroborated.

Occupational exposure to 60-hertz magnetic fields and risk of breast cancer in women.

We used data from a large population-based case-control study to test the hypothesis that women whose "usual occupation" entailed exposure to higher than background 60-Hz magnetic fields had a higher risk of breast cancer than women without such exposure. Breast cancer cases were identified from four statewide tumor registries, and controls were randomly selected from lists of licensed drivers and Medicare beneficiaries. Information on usual occupation and breast cancer risk factors was obtained by telephone interview. We calculated adjusted odds ratios from logistic regression models for women holding occupations with potential for low, medium, or high magnetic field exposure, compared with background exposure. There was a modest increase in risk for women with potential for high exposure [odds ratio (OR) = 1.43; 95% confidence interval (CI) = 0.99-2.09], and no increase for women with potential for medium (OR = 1.09; 95% CI = 0.83-1.42) or low (OR = 1.02; 95% CI = 0.91-1.15) exposure The risk among premenopausal women in the highest-exposure category was higher (OR = 1.98; 95% CI = 1.04-3.78) than for postmenopausal women (OR = 1.33; 95% CI = 0.82-2.17).