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Drug and environmental exposure histories in selective patient populations.

Drug histories and environmental exposures are an important part of all medical histories and are particularly significant in specific at-risk primary care patient populations such as obstetrical patients, primary care genetic referrals, and pediatric patients being evaluated in developmental centers. A review of genetic referrals made by primary care physicians to a satellite genetics clinic over a one-year period showed that 29 percent of all referrals had a significant history of single drug exposure, single environmental exposure, or multiple environmental and drug exposures. Drug and environmental exposures must be an important consideration in all at-risk groups.

Drug Prescriptions

Analysis of human exposure to benzo(a)pyrene via inhalation and food ingestion in the Total Human Environmental Exposure Study (THEES).

The Total Human Environmental Exposure Study (THEES) focuses on benzo(a)pyrene (BaP) as an example of a combustion-generated polycyclic aromatic hydrocarbon (PAH) compound. Primary pathways for environmental exposures to BaP are inhalation and ingestion. This program of field studies was conducted in Phillipsburg, New Jersey, a small, industrial city in the Delaware River valley. The study protocols included direct monitoring of BaP exposures via inhalation and ingestion pathways during three separate periods, each lasting 14 days. BaP concentrations in air were sampled at outdoor and in-home locations, with personal air sampling added during the latter two phases. Cooked food samples from each household were acquired, using a constant portion "second plate" of each meal prepared at home. Ambient levels were 4-10 times higher during the cold months compared with the late summer study period. Space heating and regional aerosol were major contributors to community levels of BaP in the air during the wintertime. Penetration of outdoor air, cooking activities, combustion appliances, and cigarette smoke were important sources of indoor air exposures. Cooking activities, besides releasing BaP-enriched particles indoors, produced food imbued with BaP and added substantially to exposure via the ingestion route. Among the study subjects, the range and magnitude of dietary exposures (2 to 500 ng/d) were much greater than for inhalation (10 to 50 ng/d). Nevertheless, there were ample individual cases where inhalation of BaP was the predominant exposure route. Indoor air BaP levels were closely correlated with ambient levels in most of the homes. For some individuals, measured personal air BaP exposures were adequately predicted by time-weighting of microenvironmental (i.e., outdoor and in-home) concentrations. However, enormously high exposures for ingestion or inhalation were detected only by direct observation, not from microenvironmental data.

Administration, Inhalation

Altitude and allergy to house-dust mites. A paradigm of the influence of environmental exposure on allergic sensitization.

To further investigate the possibility of a cause and effect relationship between exposure to house-dust mite (HDM) allergens and respiratory disease associated with dust mite sensitivity, we compared schoolchildren living in the Alps, where exposure to HDM is low, with those living at sea level, where it is high. The study included 933 schoolchildren from the fourth and fifth grades. The protocol included the standardized 1978 American Thoracic Society (ATS) questionnaire for children, skin testing using common aero-allergens and controls, and antigenic measurements of dust samples from mattresses (Group I antigen). The prevalence of asthma with positive skin test to HDM and the overall prevalence of positive skin test to HDM were significantly lower in mountain schoolchildren. The mean geometric HDM antigenic level in mattresses was much lower in the Alps (0.36 micrograms/g dust) than at sea level (15.8 micrograms/g dust). In contrast, the prevalence of hay fever and positive skin test to grass pollens as well as the overall prevalence of positive skin tests to grass pollens were significantly higher in the Alps. These data illustrate a striking relationship between exposure to environmental allergens and atopic sensitization.

Altitude

Environmental exposures with decreased risks for lung cancer?

The case for a decreased risk of lung cancer after exposure to environmental agents is evaluated using toxicological and epidemiological data. Experimental evidence demonstrates that exposure to substances which produce an inflammatory response in the lung, such as bacterial endotoxins, causes an increase in the secretion of inflammatory mediators and substances with a particular effect on tumour cells such as tumour necrosis factor (TNF). Other irritant agents, such as tobacco smoke, may also induce an activation of macrophages at low levels of exposure. Epidemiological evidence from several studies suggests that people exposed to dusts containing bacterial endotoxins have a lower lung cancer incidence than those who are unexposed. There are also some data suggesting that in certain ethnic groups, females smoking a small number of cigarettes/day, might have a lower risk for lung cancer than non-smokers. These data provide support for a hypothesis that low-dose exposures to some air pollutants might result in a decreased risk of lung cancer.

Cause of Death

Environmental exposure to tobacco smoke and lung function in young adults.

The relationship between lung function and environmental exposure to tobacco smoke (passive smoking) was studied in 293 nonsmoking young men and women, 15 to 35 yr of age. A self-administered mailed questionnaire was used to assess the lifetime environmental exposure to cigarette smoke at home and at work for each subject. Lung function information used here had been gathered in the course of a previous study of the determinants of lung function in early adulthood. In men, maximal midexpiratory flow rate (FEF25-75) decreased in relation to an index of cumulative lifetime environmental exposure to tobacco smoke at home, after taking into account the effects of cumulative exposure at work as well as age, height, body size, respiratory pressures, and cooking fuels used at home. The components of this exposure index most closely related to the reduction in FEF25-75 were maternal smoking habits and exposure to second-hand smoke during childhood. In women, the diffusing capacity of the lung (DLCO) decreased in relation to cumulative exposure to tobacco smoke at work, after accounting for the effects of cumulative lifetime exposure at home and the other factors mentioned above. These findings contribute to the gathering evidence that environmental exposure to tobacco smoke is harmful to respiratory health, and suggest that the effects are not insignificant. For instance, the FEF25-75 of a young man 20 yr of age who had never smoked and always lived at home would be 800 ml less if both his parents smoked than if they did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent

The relationship between blood pressure and environmental exposure to lead and cadmium in Belgium.

The question whether in the general population environmental exposure to lead and cadmium influences blood pressure after controlling for confounding factors remains debated. The environmental exposure of the Belgian population to both lead and cadmium is high as compared with other countries. The Cadmibel Cooperative Study was therefore designed to elucidate whether environmental exposure to lead and cadmium has any effect on blood pressure and renal function in the population at large. Before embarking on the large Cadmibel project, a small study was conducted. Blood pressure and the 24-hr urinary excretion of cadmium (CdU) and lead (PbU) were determined in a random 4% sample of the population of a small Belgian town. CdU averaged 0.27 micrograms/24 hr in 46 youths (mean age 14 +/- 3 years, +/- SD), increased with age, and was higher in 57 adult men (age 41 +/- 14 years), as compared with 59 adult women (age 39 +/- 14 years) (1.05 vs. 0.81 micrograms/24 hr; p less than 0.01). PbU averaged 5.8 micrograms/24 hr in youths and similarly increased with age; adult men excreted more lead than women (13.3 vs. 8.3 micrograms/24 hr; p less than 0.001). Among men, manual workers excreted more cadmium (1.4 vs. 0.8 micrograms/24 hr; p less than 0.05) but a similar amount of lead (7.0 vs. 6.9 micrograms/24 hr) as compared with office workers. In simple regression analysis, CdU was positively correlated with both systolic (r = 0.30; p less than 0.05) and diastolic (r = 0.38; p less than 0.01) blood pressure in women.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent

Environmental exposures in cytogenetically defined subsets of acute nonlymphocytic leukemia.

Three previous investigations have reported a relationship between clonal chromosome abnormalities in marrow of patients with acute nonlymphocytic leukemia and employment in occupations involving mutagenic chemicals, but the effects of other exposures were not described. Environmental exposure profiles, gathered by questionnaire, were therefore compared using a case-control study design in 235 newly diagnosed patients with acute nonlymphocytic leukemia: 126 with abnormal and 109 with normal karyotypes. The univariate odds ratio for occupation at diagnosis was 4.6, which, when adjusted for demographic and other exposures by logistic regression, was reduced to 2.5 (95% confidence interval, 0.5 to 12.8). Adjusted point estimates for other exposures were 4.3 (1.4 to 13.3) for prior cytotoxic therapy, 1.7 (0.9 to 3.1) for cigarette smoking, and 1.9 (1.0 to 3.4) for alcohol use. Dose-response relationships were present for both tobacco and alcohol consumption. Associations between specific abnormalities (+8, -7I-7q, [corrected] inv16, t[8;21]) and certain exposures were also present. These results suggest that life-style exposures may be associated with cytogenetic lesions in persons with acute nonlymphocytic leukemia.

Alcohol Drinking

Adjusting occupational exposure limits for moonlighting, overtime, and environmental exposures.

A mathematical model is used to predict relative body burdens of inhaled contaminants in workers who work two jobs or overtime, or who experience off-the-job exposure to air contaminants. Expected "peak" or maximum body burdens from multiple exposures are compared to those expected from the "normal" occupational exposure on which TLVs and Permissible Exposure Limits (PELs) arebased (five 8-hour days per week with zero off-the-job exposure). The model is designed to predict what adjustments to the TLVs and PELs are necessary to avoid accumulation of excess peak body burdens of contaminants from the additional exposures incurred. The general application of models to determine occupational exposure limits is reviewed, and several models are compared.

Air Pollutants

Is histological subtype a marker for environmental exposures in acute myelogenous leukemia?

The association between occupational and other environmental exposures was evaluated in 60 acute myelogenous leukemia cases and controls. Odds ratios and 95% confidence intervals for prior cytotoxic therapy and benzene exposure, adjusted for age, sex, and race by logistic regression, were 3.7 (0.7, 19.9) and 2.6 (0.4, 15.2), respectively. No other work-related associations, including employment in electrical occupations, were present. Other associations were suggestive but may have been due to biases in control selection or small numbers of subjects. The risks for prior cytotoxic therapy (odds ratio = 10.2) and benzene exposure (odds ratio = 11.4) were concentrated in 13 patients with French-American-British M4 leukemia; no environmental exposures were associated with French-American-British subtypes M1 and M2. These findings support the concept that French-American-British histological subtypes of AML may have different etiologies.

Antineoplastic Agents

Proteomic signatures and predictive modeling of cadmium-associated anxiety in middle-aged and elderly populations: an environmental exposure association study.

BACKGROUND: Emerging evidence implicates environmental contaminants such as cadmium (Cd) as modifiable risk factors for anxiety. Despite growing recognition of heavy metal toxicity in neuropsychiatric disorders, the molecular mechanisms linking environmental exposure to anxiety pathogenesis remain poorly understood. METHODS: Based on the established cohort of individuals with cognitive impairment in cadmium-contaminated areas, this cross-sectional association study enrolled 50 middle-aged and elderly hospitalized patients from these regions, adhering to the STROBE guidelines. Blood concentrations of cadmium (Cd), lead (Pb), and mercury (Hg) were analyzed in relation to anxiety severity assessed via the Hamilton Anxiety Rating Scale (HAMA). Plasma proteomic profiling was performed using data-independent acquisition (DIA) quantitative technology with an LC-MS/MS platform (timsTOF Pro, Bruker Daltonics), systematically characterizing 2,531 proteins across all samples. Machine learning techniques, specifically XGBoost and LASSO, were employed to identify biomarkers that were subsequently validated through mediation analysis and animal experiments, allowing for the screening of key protein signatures. Finally, clinical variables were integrated to construct a comprehensive model, which was then thoroughly evaluated. RESULTS: Anxious individuals exhibited significantly higher blood Cd levels than controls (&#x3b2;&#x2009;=&#x2009;0.50, 95% CI: 0.07-0.93, p&#x2009;<&#x2009;0.01), with anxiety positively correlating with depression (r&#x2009;=&#x2009;0.62, p&#x2009;=&#x2009;0.003) and inversely with ApoE3 genotype prevalence. Proteomics identified 120 differentially expressed proteins in anxious patients, enriched in oxidative phosphorylation and neurodegenerative pathways. CCDC126 emerged as a cadmium-associated biomarker, validated in rat models exposed to Cd. Combining CCDC126, blood Cd, Pb, and hypertension, a clinical prediction model achieved robust discrimination (AUC&#x2009;=&#x2009;0.80, validation cohort). CONCLUSIONS: This first integrative environmental-proteomic study highlights cadmium's synergistic role in anxiety pathophysiology and psychiatric comorbidity. The predictive model offers translatable potential for early risk stratification, while CCDC126 provides mechanistic insights for targeted interventions in populations exposed to environmental pollutants.

Cadmium

Extrapolation of laboratory findings to risks from environmental exposures: male reproductive effects of ethylene oxide.

The extrapolation of human risk from laboratory findings is based on physiologic and biochemical similarities between humans and test animals. While these extrapolations can be based on correlations and empiric relationships, such relationships must be derived for each agent and new set of exposure conditions. The complexity and diversity of environmental exposures severely limit the number of situations in which this may be done. An alternative approach is to use linked pharmacokinetic and pharmacodynamic models to estimate the tissue concentrations and subsequent effects associated with a given type of exposure. This approach has the advantage of allowing a determination of the tissue levels of the agent and of its effects for different time profiles of exposure and routes of entry. It permits comparisons of animal studies that use different experimental protocols. The utility of this approach was illustrated by quantitatively extrapolating from laboratory studies of male mice to mutational risk of male sterilizer operators exposed to ethylene oxide. This approach puts severe data demands on the researcher building models: extensive physiologic, biochemical and metabolic data must be available or estimable for body compartments; time-course and dose-response data must be available on the effects; and environmental exposure profiles must be available. However, it permits a degree of coordination of laboratory and epidemiologic studies that has rarely been possible. It also identifies potential new human risks, and a way of formulating testable hypotheses about human effects that are directly derived from laboratory data. Thus, this approach offers an exciting opportunity for better characterization of human effects and potential risks.

Animals

Health effects of environmental exposure to cadmium: objectives, design and organization of the Cadmibel Study: a cross-sectional morbidity study carried out in Belgium from 1985 to 1989.

Cadmium is a cumulative environmental pollutant. For the general population mainly exposed by the oral route and through tobacco smoke inhalation, the kidney is the critical organ. Belgium is the principal producer of cadmium in Europe, and certain areas of the country are polluted by cadmium mainly because of past emissions from nonferrous industries. Preliminary studies carried out in one polluted area have suggested that environmental pollution might lead to an increased uptake of cadmium by the human body and possibly to health effects. Thus, a large-scale morbidity study has been initiated to assess the validity of this hypothesis. The present paper describes the protocol of this study. Its main objectives are to determine to what extent environmental exposure to cadmium resulting from industrial emissions may lead to accumulation of the metal in the human organism; to establish whether or not environmental exposure may induce renal changes and/or influence blood pressure; and to assess the acceptable internal dose of cadmium for the general population. The study design takes advantage of the fact that biological indicators of exposure, body burden, and early nephrotoxic effects of cadmium are available, which increase the likelihood of detecting a cause-effect relationship.

Adult

Osmium: an appraisal of environmental exposure.

In the U.S., the chief source of new osmium is copper refining, where this metal is produced as a byproduct. Probably less than 10% of the osmium in the original copper ore is recovered, and 1000-3000 oz troy of osmium is lost each year to the environment as the toxic, volatile tetroxide from copper smelters. In 1971, about 2000 oz troy of osmium was domestically refined, most of which was from secondary sources. An additional 4169 oz troy of osmium was toll-refined. Major uses for osmium tetroxide identified are for catalysis, especially in steroid synthesis, and for tissue staining. Minor uses of osmium metal are for electrical contacts and for imparting hardness to alloys for mechanical pivots, etc. Unreclaimed osmium tetroxide that reaches wastewater streams is probably rapidly reduced by organic matter to nontoxic osmium dioxide or osmium metal, which would settle out in the sediment of the water course. Waste osmium metal, itself innocuous and chemically resistant, would be oxidized to the toxic tetroxide if incinerated. Because of the small amounts used and their wide dispersal, the amounts of osmium tetroxide in wastewater and air should pose no hazard to man or the environment. The chief acute toxic effects of osmium tetroxide are well known and include eye and respiratory-tract damage. Few data are available that provide information on possible effects of nonacute exposure resulting from environmental contamination by osmium. However, workers continually exposed to osmium tetroxide vapors (refiners and histologists) and rheumatoid arthritis patients who have received intra-articular injections of osmic acid solutions have shown no apparent damage from exposure to low levels of osmium.

Animals

Does environmental exposure to cadmium represent a health risk? Conclusions from the Cadmibel study.

Cadmium is a very dispersive pollutant which has progressively accumulated in the environment mainly in the areas where nonferrous smelters have been in operation. An important toxicological feature of cadmium is its exceptionally long biological half-life in the human body. For the general population mainly exposed to cadmium by the diet and smoking, the kidney is the main target organ. Some studies have also suggested that cadmium might play a role in the pathogenesis of hypertension. A cross-sectional study (called Cadmibel) was undertaken to assess whether environmental pollution by cadmium in Belgium might represent a health risk. This paper does not present the detailed results of this study which are published elsewhere but simply report its main conclusions. A total number of 2327 subjects (stratified according to age and sex) was randomly sampled in two urban (Liège and Charleroi) and two rural (Hechtel-Eksel and Noorderkempen) areas, with different environmental pollution by cadmium. After allowing for the various factors known to influence cadmium accumulation, it was estimated that the cadmium body burden of the residents of the most polluted district (Noorderkempen) was 50 to 85% higher than in the less polluted areas. No statistical association was found between environmental exposure to cadmium and blood pressure elevation or the prevalence of cardiovascular diseases. However, the study has shown that the environmental exposure of the general population to cadmium may induce slight renal tubular dysfunction and may probably also affect cadmium homeostasis. The probability of tubular dysfunction (as assessed by sensitive tests) is about 10% when cadmium in urine reaches 2 micrograms/day. The morbidity associated with the changes in the renal proximal tubule and the calcium metabolism observed when the body burden of cadmium exceeds this value remains to be assessed.

Adult

Mineral fiber content of lung tissue in patients with environmental exposures: household contacts vs. building occupants.

Analysis of tissue mineral fiber content in patients with environmental exposures has seldom been reported in the past. Our studies of six household contacts of asbestos workers indicate that these individuals often have pulmonary asbestos concentrations similar to some occupationally exposed individuals. In contrast, our studies of four occupants of buildings with asbestos-containing materials indicate that these individuals often have pulmonary asbestos burdens indistinguishable from the general nonoccupationally exposed population. However, one such building occupant exposed for many years and who later developed pleural mesothelioma was studied in detail, and it was concluded that her exposure as a teacher's aide in a school building containing acoustical plaster was the likely cause of her mesothelioma.

Adult

The Total Human Environmental Exposure Study (THEES) to benzo(a)pyrene: comparison of the inhalation and food pathways.

The assessment of human exposure to an environmental contaminant requires the measurement of levels present in each pathway of possible contact. In this paper, the design considerations and Phase I results of a human exposure study focused on Benzo(a)pyrene (BaP) are discussed. This study site, located in Phillipsburg, New Jersey, is a city that contains a metal pipe foundry, which is a suspected major source of BaP. Three outdoor PM-10 samplers (used to collect BaP-containing particles with an aerodynamic size of less than or equal to 10 micron) were located in residential areas surrounding the foundry. Ten homes were sampled indoors for PM-10. Some homes have indoor combustion sources, e.g., cigarette smoke or a coal burning stove. The indoor and outdoor samples were 24 hr in duration. The mean outdoor concentration of BaP was 0.9 ng/m3, and the indoor concentrations ranged from 0.1-8.1 ng/m3. Food samples were acquired from family meals each day. They represented a one-third portion of each meal eaten at home. The range of BaP per gram of wet weight of food was between 0.004 and 1.2 ng/g. Of the 20 wk of exposure (10 x 2 wk), 10 had higher food exposures and the other 10 had higher inhalation exposures. Of the two groups, the higher food exposures usually had a greater number of ng of BaP/wk. The dominance of one or the other pathway appeared to depend upon personal eating habits and indoor combustion source use. In some instances, outdoor air pollution led to a major portion of indoor air BaP exposures. Water appears to be a minor source of BaP exposures in the study area.

Air Pollutants

Thrombocytopenia associated with environmental exposure to polyurethane.

Few chemicals in the environment have been implicated as causes of isolated thrombocytopenia, and the evidence is usually less than convincing because the patients were not rechallenged with the chemical in vivo. In the present paper, a child is reported with the onset of thrombocytopenia in temporal association with environmental exposure to polyurethane. Five years after the initial thrombocytopenia had resolved, an inadvertent in vivo rechallenge with environmental polyurethane resulted in recurrence of the thrombocytopenia. This recurrence, together with the fact that only 1-4% of cases of idiopathic thrombocytopenic purpura in children recur, provided strong evidence for a causal role for the polyurethane exposure in this patient's thrombocytopenia. In summary, environmental exposure to polyurethane should be considered in the differential diagnosis of acquired thrombocytopenia in childhood.

Child, Preschool