Meryl H. Karol

Current state of the science: health effects and indoor environmental quality.

Our understanding of the relationship between human health and the indoor environment continues to evolve. Previous research on health and indoor environments has tended to concentrate on discrete pollutant sources and exposures and on specific disease processes. Recently, efforts have been made to characterize more fully the complex interactions between the health of occupants and the interior spaces they inhabit. In this article we review recent advances in source characterization, exposure assessment, health effects associated with indoor exposures, and intervention research related to indoor environments. Advances in source characterization include a better understanding of how chemicals are transported and processed within spaces and the role that other factors such as lighting and building design may play in determining health. Efforts are under way to improve our ability to measure exposures, but this remains a challenge, particularly for biological agents. Researchers are also examining the effects of multiple exposures as well as the effects of exposures on vulnerable populations such as children and the elderly. In addition, a number of investigators are also studying the effects of modifying building design, materials, and operations on occupant health. Identification of research priorities should include input from building designers, operators, and the public health community.

Concentration-dependent immunologic response to toluene diisocyanate (TDI) following inhalation exposure

Little is known concerning industrial exposure conditions which lead to development of allergic sensitivity in exposed workers. This study investigated the relationship between exposure concentration and the induction of antibodies and sensitivity in a guinea pig animal model for inhalation exposure to isocyanates (Karol et al., Toxicol. Appl. Pharmacol. 53, 260-270, 1980). Groups of guinea pigs were exposed, via inhalation, to TDI concentrations ranging from 0.12 to 10 ppm. Exposure was for 3 hr/day on 5 consecutive days. Beginning on Day 22, animals were evaluated for TDI-specific antibodies, skin sensitivity, and pulmonary sensitivity to TDI. No antibodies were detected in animals exposed to 0.12 ppm TDI, whereas 55% of animals exposed to 0.36 ppm TDI or greater displayed TDI-specific antibodies in their sera. Exposure to higher TDI concentrations resulted in both a greater percentage of animals producing antibodies and higher antibody titers. Pulmonary sensitivity, assessed by bronchial provocation challenge with TDI-protein antigen, was not detected in animals exposed to 0.12 ppm TDI but was present in guinea pigs exposed to TDI concentrations of 0.36 ppm or greater. However, exposure concentrations higher than 2 ppm were pneumotoxic and resulted in few pulmonary hypersensitivity reactions. Exposure of animals to 0.02 ppm TDI for 15 weeks did not result in either dermal sensitivity, pulmonary sensitivity, or production of TDI-specific antibody. The exposure protocol, as well as the exposure concentration, was important for establishment of sensitivity. Recognition of the concentration-response relationship governing immune reaction to inhaled TDI should permit establishment of safe airborne exposure levels for industrial workers to prevent sensitization.

Respiratory effects of inhaled isocyanates

Numerous industrial chemicals are known to cause allergic reactions in the lung. Prominent among such chemicals are isocyanates, the starting material in the production of polyurethanes. In view of the extensive worldwide production of isocyanates (1.5 million metric tons per year), and the diversity of products manufactured from isocyanates (i.e., cars, airplanes, furniture, bedding, etc.) there is considerable potential for adverse health effects associated with exposure to isocyanates. Syndromes of immediate respiratory reactivity, delayed-onset sensitivity, and hypersensitivity pneumonitis have all been associated with isocyanate exposure. However, little is known concerning how sensitivity develops, which individuals are most likely to become sensitized, or how to best detect early sensitivity. Answers to such questions are beginning to emerge from the recent development of animal models of lung sensitivity. These models will be discussed together with their application to clinical situations.

Diisocyanate asthma: clinical aspects and immunopathogenesis.

Diisocyanates, highly reactive chemicals used in the production of polyurethanes, are currently the most frequently reported cause of chemically induced occupational asthma and their use continues to rise. The prevalence of diisocyanate asthma among exposed workers is estimated to range from 5% to 15%. Routes of exposure include the respiratory tract and skin. Workplace exposures are difficult to quantify and control, and there is no simple diagnostic test for the disease. This review considers recent concepts in exposure. clinical aspects and pathogenesis of the disease. The pathogenesis of diisocyanate asthma remains unclear, with evidence supporting both immunological and nonimmunological mechanisms. Knowledge of the chemical reactivity of diisocyanates, the target biomolecules, and the cellular sites of reaction are fundamental to understanding diisocyanate toxicity and disease. Recent findings of chemical interactions with biological nucleophiles will be described. The importance of diisocyanate-adducted biomolecules will be emphasized and their potential contributions to pathogenesis discussed. It is anticipated that greater understanding of the immunopathogenesis of diisocyanate asthma, including the initial cell/diisocyanate reactions, should lead to clinically useful markers of exposure and early disease.

Tolyl-specific IgE antibodies in workers with hypersensitivity to toluene diisocyanate

Incorporation of a p-tolyl (mono) isocyanate-human serum albumin (TMI-HSA) antigen conjugate into a solid phase radioimmunoassay permitted detection of tolyl-specific IgE antibodies in 3 of 4 workers with clinical hypersensitivity to toluene diisocyanate (TDI). By comparison 19 TDI-exposed, non-sensitized workers had antibody titers similar to those found in normal adults. High titers of tolyl-specific IgE antibodies were not correlated with high levels of total serum IgE. Use of the monofunctional isocyanate in place of TDI in antigen preparation prevented cross-linking of antigen protein, an effect usually associated with TDI, and also assured that tolyl groups were sterically exposed. TMI-HSA antigens may prove beneficial in serological or cutaneous evaluation of TDI-sensitized workers.

Dermal contact with toluene diisocyanate (TDI) produces respiratory tract hypersensitivity in guinea pigs

Abstract The occurrence of pulmonary hypersensitivity to TDI in industrial workers has been well documented. It is generally assumed that sensitivity results from inhalation of TDI vapors in the workplace. This has been supported by an animal model for pulmonary sensitivity based on repeated inhalation of TDI (Karol et al. , 1980). Industrial workers are also exposed to TDI through skin contact frequently as a result of spills or splashes. In the current study the possibility of dermal exposures resulting in pulmonary sensitivity was investigated using guinea pigs as an animal model. TDI in concentrations ranging from 1 to 100% was applied to dorsal sites on guinea pigs. Skin sensitivity (contact sensitivity) to TDI was apparent by the seventh day following exposure. After fourteen days, animals were additionally evaluated for TDI sensitivity by serologic analysis and by bronchial provocation challenge. Antibodies to TDI were detected using passive cutaneous anaphylaxis, double diffusion in gel, and radiolabeled antigen binding (Farr) assays. Antibodies were specific for TDI and showed little, if any, cross-reactivity with hexamethylene diisocyanate (HDI), diphenylmethane diisocyanate (MDI), or dicyclohexylmethane diisocyanate (hydrogenated MDI). Respiratory hypersensitivity to TDI could be demonstrated by inhalation challenge with 0.005 ppm TDI, or aerosols of either TDI-protein conjugates or conjugates of p -tolyl isocyanate with protein. The development of respiratory hypersensitivity as a result of dermal contact with TDI emphasizes the importance of careful workplace practices and suggests reevaluation of the role of inhalation and/or dermal contact in causing pulmonary sensitization of workers.

Immunologic sensitization and pulmonary hypersensitivity by repeated inhalation of aromatic isocyanates

Previously, we have described an animal model for hapten-specific pulmonary hypersensitivity in which immunologic sensitization was accomplished by repeated inhalation of purified hapten-protein conjugates. The present study reports successful sensitization of animals by inhalation of p-tolyl isocyanate (TMI) or toluene diisocyanate (TDI) on 5 consecutive days. Within 2 weeks antibodies specific for tolyl (mono- or di-) isocyanate were detected using both passive cutaneous anaphylaxis and gel diffusion assays. Antibodies to TMI reacted with TMI-protein conjugates but did not react with conjugates containing TDI, n-hexyl isocyanate, or phenyl isocyanate. By contrast, antibodies to TDI cross-reacted with TMI-protein and phenyl isocyanate-protein antigens, but did not cross-react with conjugate antigens which contained hexyl isocyanate as the haptenic group. Animals sensitized to TMI displayed TMI-specific respiratory hypersensitivity, recognized by a respiratory response upon challenge with a TMI-protein conjugate. Utilization of the animal model to establish dose-response and threshold concentration relationships may provide a means to establish safe exposure levels for industrial workers exposed to reactive chemicals which may act as haptens.

The Potential Adverse Health Effects of Dental Amalgam

There is significant public concern about the potential health effects of exposure to mercury vapour (Hg0) released from dental amalgam restorations. The purpose of this article is to provide information about the toxicokinetics of Hg0, evaluate the findings from the recent scientific and medical literature, and identify research gaps that when filled may definitively support or refute the hypothesis that dental amalgam causes adverse health effects.Dental amalgam is a widely used restorative dental material that was introduced over 150 years ago. Most standard dental amalgam formulations contain approximately 50% elemental mercury. Experimental evidence consistently demonstrates that Hg0 is released from dental amalgam restorations and is absorbed by the human body. Numerous studies report positive correlations between the number of dental amalgam restorations or surfaces and urine mercury concentrations in non-occupationally exposed individuals. Although of public concern, it is currently unclear what adverse health effects are caused by the levels of Hg0 released from this restoration material. Historically, studies of occupationally exposed individuals have provided consistent information about the relationship between exposure to Hg0 and adverse effects reflecting both nervous system and renal dysfunction. Workers are usually exposed to substantially higher Hg0 levels than individuals with dental amalgam restorations and are typically exposed 8 hours per day for 20–30 years, whereas persons with dental amalgam restorations are exposed 24 hours per day over some portion of a lifetime. This review has uncovered no convincing evidence pointing to any adverse health effects that are attributable to dental amalgam restorations besides hypersensitivity in some individuals.

Improving indoor environmental quality for public health: impediments and policy recommendations.

Background People in modern societies spend more than 90% of their time indoors. Hence, indoor environmental quality (IEQ) has a significant impact on public health. In this article we describe health risks associated with indoor environments, illuminate barriers to overcoming these risks, and provide policy recommendations to achieve healthier indoor environments. Objectives The weight of evidence suggests that indoor environmental contaminants pose significant public health risks, particularly among children and the poor, and the societal costs of illnesses related to indoor environments are considerable. Despite the evidence of harm to human health, poor indoor environments are generally difficult to regulate and not of sufficient concern to the general public. We discuss several reasons for this lack of concern about IEQ, focusing specifically on home environments. Discussion Economics plays a large role both in political inaction and individual-level indifference. Because little effort has been made to quantify the value of the societal and individual costs of poor housing quality, as well as the benefits achievable by simple interventions, policymakers lack motivation to act on IEQ. Similarly, individual homeowners lack the incentive to remediate homes, as other problems may be more pressing than home environmental quality. Conclusions Although the problem of IEQ involves multiple stakeholders and multiple levels of governance, it is possible to establish economic incentives that would set the wheels in motion for action at all levels to achieve healthy home environments. Also important are education and information dissemination on the public health risks associated with indoor environments. These recommendations are intended for all decision makers who have an influence in developing policy to improve indoor environmental quality.

Isocyanate-conjugated human lung epithelial cell proteins: A link between exposure and asthma?

BACKGROUND Isocyanates are a group of highly reactive cross-linking chemicals that cause airway inflammation and asthma in exposed individuals. Isocyanates have been detected along the airway epithelia of exposed workers and animals, prompting the hypothesis that isocyanates can directly bind to epithelial cell proteins. OBJECTIVE We tested the hypothesis that hexamethylene diisocyanate (HDI) binds directly to lung epithelial cell proteins and initiated studies to evaluate the immunostimulatory potential of HDI-conjugated lung epithelial cell proteins. METHODS Human lung epithelial cell lines were exposed to vapor- and liquid-phase HDI, and the cellular proteins were analyzed for HDI conjugation by Western blotting and tested for the ability to induce lymphocyte proliferation in vitro. RESULTS A number of epithelial cell polypeptides, ranging from 25 to 110 kd in apparent molecular weight, were conjugated with HDI after exposure of the human lung epithelial cell lines (A549 and NCI-H292) to HDI concentrations greater than 0.005% (vol/vol) in the liquid phase. Vapor-phase HDI exposure resulted in a more restricted HDI conjugation pattern, with major HDI-conjugated polypeptides migrating at 47, 71, and 91 kd. HDI-conjugated epithelial cell proteins specifically stimulated proliferation of PBMCs from subjects with isocyanate-induced asthma but not HDI-exposed nonasthmatic individuals or atopic subjects with nonisocyanate-related asthma. CONCLUSIONS The data demonstrate that epithelial cell proteins readily react with HDI and that HDI-conjugated epithelial cell proteins can stimulate lymphocyte proliferation. Further characterization and evaluation of HDI-conjugated epithelial cell proteins will elucidate their potential role in the pathogenesis of isocyanate-induced asthma.