Poison severity score and sequential organ failure assessment score: Carbon monoxide poisoning prognosis.

PURPOSE: We aimed to examine the utility of the Poison Severity Score (PSS) and Sequential Organ Failure Assessment (SOFA) score as early prognostic predictors of short-term outcomes in patients with carbon monoxide (CO) poisoning. We hypothesized that both the PSS and the SOFA score would be useful prognostic tools. METHODS: This was retrospective observational study of patients with CO poisoning who presented to the emergency department and were admitted for more than 24 hours. We calculated PSS, the initial SOFA score, a second (2nd) SOFA score, and a 24-hour delta SOFA score. The primary outcome was reported as the cerebral performance category (CPC) scale score at discharge. We classified those with CPC 1-2 as the good outcome group and those with CPC 3-5 as the poor outcome group. RESULTS: This study included 192 patients: 174 (90.6%) belonged to the good outcome group, whereas 18 (9.4%) belonged to the poor outcome group. The PSS (1.00 [0.00, 1.00] vs 3.00 [3.00, 3.00], p < 0.001), initial SOFA (1.00 [0.00, 2.00] vs 4.00 [3.25, 6.00], p < 0.001), 2nd SOFA score (0.00 [0.00, 1.00] vs 4.00 [3.00, 7.00], p < 0.001), and 24-hour delta SOFA score (-1.00 [-1.00, 0.00] vs 0.00 [-1.00, 1.00], p = 0.047) of the good outcome group were significantly higher than those of the poor outcome group. The areas under the receiver operating characteristic curve for PSS and the initial SOFA and 2nd SOFA scores were 0.977 (95% confidence interval [CI] 0.944-0.993), 0.945 (95% CI 0.903-0.973), and 0.978 (95% CI 0.947-0.994), respectively. CONCLUSION: The PSS, initial SOFA score, and 2nd SOFA score predict acute poor outcome accurately in patients with CO poisoning.

Characterization of Carbon Monoxide Exposure During Hurricane Sandy and Subsequent Nor'easter.

OBJECTIVE: Carbon monoxide (CO) is an odorless, colorless gas produced by fossil fuel combustion. On October 29, 2012, Hurricane Sandy moved ashore near Atlantic City, New Jersey, causing widespread morbidity and mortality, $30 to $50 billion in economic damage, and 8.5 million households to be without power. The combination of power outages and unusually low temperatures led people to use alternate power sources, placing many at risk for CO exposure. METHODS: We examined Hurricane Sandy-related CO exposures from multiple perspectives to help identify risk factors and develop strategies to prevent future exposures. This report combined data from 3 separate sources (health departments, poison centers via the National Poison Data System, and state and local public information officers). RESULTS: Results indicated that the number of CO exposures in the wake of Hurricane Sandy was significantly greater than in previous years. The persons affected were mostly females and those in younger age categories and, despite messaging, most CO exposures occurred from improper generator use. CONCLUSIONS: Our findings emphasize the continued importance of CO-related communication and ongoing surveillance of CO exposures to support public health response and prevention during and after disasters. Additionally, regional poison centers can be a critical resource for potential on-site management, public health promotion, and disaster-related CO exposure surveillance. (Disaster Med Public Health Preparedness. 2017;11:562-567).

Risk assessment in combustion toxicology: Should carbon dioxide be recognized as a modifier of toxicity or separate toxicological entity?

To characterize the accumulated hazards associated with the inhalation of gases typical of combustion products, a time-integrated value known as the fractional effective dose (FED) is used. This FED is maintained by the International Organization for Standardization (ISO) and made publicly available as the Standard ISO 13571. The current FED calculation related to asphyxiant gases is based on non-human primate data to estimate the 50% probability of humans to be incapacitated or not being able to execute any escape paradigm from fires. The objective of this paper was to compare two to calculate FEDs of the most common mixture of asphyxiant fire gases CO, HCN, and CO2. The first was based on the current ISO 13571 (draft) standard, the alternative second method applied the conceptual principles established for the derivation of Acute Emergency Response Planning Guideline values. The alternative approach applied one third of the non-lethal threshold concentration (LC01) as the most suitable and robust Point of Departure (POD) to estimate the threshold characterizing 'impairment of escape' in the absence of post-exposure mortality. The hyperventilation correction factor for CO2 of ISO 13571 was replaced by a separate term that accounts for the inherent acute toxicity of CO2. This analysis supports the conclusion that the current ISO 13571 standard misjudges the impact of the acute toxicity elicited by concentrations of CO2 exceeding ≈6%. While underestimating the hazards attributable to CO2, the hyperventilation adjustment factor suggested by this standard is biased to markedly overestimate the hazards assigned to CO and HCN in fire effluents.

Association between ambient air pollution and proliferation of umbilical cord blood cells.

It has been established as a common knowledge that ambient air pollution (AAP) has an adverse effect on human health. The pathophysiological mechanism of this impact is likely to be related to the oxidative stress. In the current study we estimate the association between AAP and cell proliferation (CP) of umbilical cord blood cells, representing maternal organism most proximal to the fetal body. Blood samples were tested for proliferation in 292 enrolled Arab-Bedouin women at delivery (July 2012-March 2013). The estimates of AAP were defined by a hybrid satellite based model predicting both PM2.5 (particles<2.5µm in diameter) and PM10 (particles<10µm in diameter) as well as monitoring stations for gaseous air pollutants. Risk estimates of pollution exposure were adjusted to medical history, household risk factors and meteorological factors on the day of delivery or one week prior. Ambient ozone (O3) levels on 1, 2, 3and 4 days prior to delivery were associated with lower CP (Prevalence ratio (PR)=0.92, 0.92, 0.93, 0.93, respectively). Increase in inter-quartile range (IOR) of PM2.5 one day before delivery was associated with 9% increase in CP levels (PR=1.09). The positive direction in association was changed to negative association with CP for PM2.5 levels measured at more distant time periods (PR=0.90 and 0.93 for lags 5 and 6 days, respectively). Investigation of PM10 levels indicated a similar pattern (PR=1.05 for pollution values recorded one day before delivery and 0.93 and 0.95 for lags of 5 and 6 days, respectively). Carbon monoxide (CO) levels were associated with lower CP on the day of delivery and 1day prior (PR=0.92 and PR=0.94). To conclude, the levels of cell proliferation of umbilical cord blood cells appear to be associated with the AAP. More studies are needed to support our findings.

Assessment of Functional Disturbances in the Central Nervous System Caused by Severe Carbon Monoxide Poisoning in Rats.

An experimental model was developed for assessment of disturbances in CNS functions of laboratory animals caused by severe carbon monoxide poisoning. Normalization of the state of experimental rats after acute poisoning was accompanied by the development of cognitive abnormalities. Disturbances in the long-term memory were observed on days 1 and 14 after CO poisoning, while abnormalities in the short-term memory developed on days 1, 7, and 14. Learning impairment were recorded on day 8, while the training course began on day 7.

Risks, risk assessment and risk competence in toxicology.

Understanding the toxic effects of xenobiotics requires sound knowledge of physiology and biochemistry. The often described lack of understanding pharmacology/toxicology is therefore primarily caused by the general absence of the necessary fundamental knowledge. Since toxic effects depend on exposure (or dosage) assessing the risks arising from toxic substances also requires quantitative reasoning. Typically public discussions nearly always neglect quantitative aspects and laypersons tend to disregard dose-effect-relationships. One of the main reasons for such disregard is the fact that exposures often occur at extremely low concentrations that can only be perceived intellectually but not by the human senses. However, thresholds in the low exposure range are often scientifically disputed. At the same time, ignorance towards known dangers is wide-spread. Thus, enhancing the risk competence of laypersons will have to be initially restricted to increasing the awareness of existing problems.

Part 1. Assessment of carcinogenicity and biologic responses in rats after lifetime inhalation of new-technology diesel exhaust in the ACES bioassay.

The Health Effects Institute and its partners conceived and funded a program to characterize the emissions from heavy-duty diesel engines compliant with the 2007 and 2010 on-road emissions standards in the United States and to evaluate indicators of lung toxicity in rats and mice exposed repeatedly to 2007-compliant new-technology diesel exhaust (NTDE*). The a priori hypothesis of this Advanced Collaborative Emissions Study (ACES) was that 2007-compliant on-road diesel emissions "... will not cause an increase in tumor formation or substantial toxic effects in rats and mice at the highest concentration of exhaust that can be used ... although some biological effects may occur." This hypothesis was tested at the Lovelace Respiratory Research Institute (LRRI) by exposing rats by chronic inhalation as a carcinogenicity bioassay. Indicators of pulmonary toxicity in rats were measured after 1, 3, 12, 24, and 28-30 months of exposure. Similar indicators of pulmonary toxicity were measured in mice, as an interspecies comparison of the effects of subchronic exposure, after 1 and 3 months of exposure. A previous HEI report (Mauderly and McDonald 2012) described the operation of the engine and exposure systems and the characteristics of the exposure atmospheres during system commissioning. Another HEI report described the biologic responses in mice and rats after subchronic exposure to NTDE (McDonald et al. 2012). The primary motivation for the present chronic study was to evaluate the effects of NTDE in rats in the context of previous studies that had shown neoplastic lung lesions in rats exposed chronically to traditional technology diesel exhaust (TDE) (i.e., exhaust from diesel engines built before the 2007 U.S. requirements went into effect). The hypothesis was largely based on the marked reduction of diesel particulate matter (DPM) in NTDE compared with emissions from older diesel engine and fuel technologies, although other emissions were also reduced. The DPM component of TDE was considered the primary driver of lung tumorigenesis in rats exposed chronically to historical diesel emissions. Emissions from a 2007-compliant, 500-horsepower-class engine and after treatment system operated on a variable-duty cycle were used to generate the animal inhalation test atmospheres. Four groups were exposed to one of three concentrations (dilutions) of exhaust combined with crankcase emissions, or to clean air as a negative control. Dilutions of exhaust were set to yield average integrated concentrations of 4.2, 0.8, and 0.1 ppm nitrogen dioxide (NO2). Exposure atmospheres were analyzed by daily measurements of key effects of NTDE in the present study were generally consistent with those observed previously in rats exposed chronically to NO2 alone. This suggests that NO2 may have been the primary driver of the biologic responses to NTDE in the present study. There was little evidence of effects characteristic of rats exposed chronically to high concentrations of DPM in TDE, such as an extensive accumulation of DPM within alveolar macrophages and inflammation leading to neoplastic transformation of epithelia and lung tumors. components and periodic detailed physical-chemical characterizations. Exposures were conducted 16 hours/day (overnight, during the rats' most active period), 5 days/week. Responses to exposure were evaluated via hematology, serum chemistry, bronchoalveolar lavage (BAL), lung cell proliferation, histopathology, and pulmonary function. The exposures were accomplished as planned, with average integrated exposure concentrations within 20% of the target dilutions. The major components from exhaust were the gaseous inorganic compounds, nitrogen monoxide (NO), NO2, and carbon monoxide (CO). Minor components included low concentrations of DPM and volatile and semi-volatile organic compounds (VOCs and SVOCs). Among the more than 100 biologic response variables evaluated, the majority showed no significant difference from control as a result of exposure to NTDE. The major outcome of this study was the absence of pre-neoplastic lung lesions, primary lung neoplasia, or neoplasia of any type attributable to NTDE exposure. The lung lesions that did occur were minimal to mild, occurred only at the highest exposure level, and were characterized by an increased number and prominence of basophilic epithelial cells (considered reactive or regenerative) lining distal terminal bronchioles, alveolar ducts, and adjacent alveoli (termed in this report "Hyperplasia; Epithelial; Periacinar"), which often had a minimal increase in subjacent fibrous stroma (termed "Fibrosis; Interstitial; Periacinar"). Slight epithelial metaplastic change to a cuboidal morphology, often demonstrating cilia, was also noted in some animals (termed "Bronchiolization"). In addition to the epithelial proliferation, there was occasionally a subtle accumulation of pulmonary alveolar macrophages (termed "Accumulation; Macrophage") in affected areas. The findings in the lung progressed slightly from 3 to 12 months, without further progression between 12 months and the final sacrifice at 28 or 30 months. In addition to the histologic findings, there were biochemical changes in the lung tissue and lavage fluid that indicated mild inflammation and oxidative stress. Generally, these findings were observed only at the highest exposure level. There was also a mild progressive decrease in pulmonary function, which was more consistent in females than males. Limited nasal epithelial changes resulted from NTDE exposure, including increases in minor olfactory epithelial degeneration, hyperplasia, and/or metaplasia. Increases in these findings were present primarily at the highest exposure level, and their minor and variable nature renders their biologic significance uncertain. Overall, the findings of this study demonstrated markedly less severe biologic responses to NTDE than observed previously in rats exposed similarly to TDE. Further, the effects of NTDE in the present study were generally consistent with those observed previously in rats exposed chronically to NO2 alone. This suggests that NO2 may have been the primary driver of the biologic responses to NTDE in the present study. There was little evidence of effects characteristic of rats exposed chronically to high concentrations of DPM in TDE, such as an extensive accumulation of DPM within alveolar macrophages and inflammation leading to neoplastic transformation of epithelia and lung tumors.

The burden of disease related to indoor air in the Netherlands: do different methods lead to different results?

BACKGROUND: Dutch policy makers needed a knowledge base for prioritising control of different indoor air pollutants. Several burden of disease (BoD) estimates were available, but it was not known if they could be applied to The Netherlands. OBJECTIVES: To quantify the BoD related to indoor air in The Netherlands, and to compare the outcomes with a previous study (EnVIE), which used a different BoD methodology. RESULTS: The largest BoD was attributable to environmental tobacco smoke. The next most important indoor air pollutants were radon and thoron from soils and building materials, followed by dampness and carbon monoxide (CO). Formaldehyde exposure did not contribute to the total BoD, according to our estimates. The EnVIE estimate was three times higher, and the most important indoor air pollutants by BoD were combustion products from outdoor sources, bioaerosols due to dampness and by outdoor sources, volatile organic compounds, radon from soils, pathogens and CO. The differences in estimates were primarily caused by the different selection or definition of substances in indoor air, rather than the differing BoD methodology. CONCLUSIONS: Indoor air exposure is associated with a considerable BoD in The Netherlands; approximately 1500 healthy life years per 1 million inhabitants are lost due to 1 year of exposure. The results from the different BoD studies examined here are difficult to compare--even the relative order of most important pollutants depends on choices and assumptions in the assessment. A careful evaluation of BoD estimates is required before they can be used in policy making.

Evaluation of an exposure assessment used in epidemiological studies of diesel exhaust and lung cancer in underground mines.

NIOSH/NCI (National Institute of Occupational Safety and Health and National Cancer Institute) developed exposure estimates for respirable elemental carbon (REC) as a surrogate for exposure to diesel exhaust (DE) for different jobs in eight underground mines by year beginning in the 1940s-1960s when diesel equipment was first introduced into these mines. These estimates played a key role in subsequent epidemiological analyses of the potential relationship between exposure to DE and lung cancer conducted in these mines. We report here on a reanalysis of some of the data from this exposure assessment. Because samples of REC were limited primarily to 1998-2001, NIOSH/NCI used carbon monoxide (CO) as a surrogate for REC. In addition, because CO samples were limited, particularly in the earlier years, they used the ratio of diesel horsepower (HP) to the mine air exhaust rate as a surrogate for CO. There are considerable uncertainties connected with each of these surrogate-based steps. The estimates of HP appear to involve considerable uncertainty, although we had no data upon which to evaluate the magnitude of this uncertainty. A sizable percentage (45%) of the CO samples used in the HP to CO model was below the detection limit which required NIOSH/NCI to assign CO values to these samples. In their preferred REC estimates, NIOSH/NCI assumed a linear relation between C0 and REC, although they provided no credible support for that assumption. Their assumption of a stable relationship between HP and CO also is questionable, and our reanalysis found a statistically significant relationship in only one-half of the mines. We re-estimated yearly REC exposures mainly using NIOSH/NCI methods but with some important differences: (i) rather than simply assuming a linear relationship, we used data from the mines to estimate the CO-REC relationship; (ii) we used a different method for assigning values to nondetect CO measurements; and (iii) we took account of statistical uncertainty to estimate bounds for REC exposures. This exercise yielded significantly different exposure estimates than estimated by NIOSH/NCI. However, this analysis did not incorporate the full range of uncertainty in REC exposures because of additional uncertainties in the assumptions underlying the modeling and in the underlying data (e.g. HP and mine exhaust rates). Estimating historical exposures in a cohort is generally a very difficult undertaking. However, this should not prevent one from recognizing the uncertainty in the resulting estimates in any use made of them.

Fluctuation analysis-based risk assessment for respiratory virus activity and air pollution associated asthma incidence.

Asthma is a growing epidemic worldwide. Exacerbations of asthma have been associated with bacterial and viral respiratory tract infections and air pollution. We correlated the asthma admission rates with fluctuations in respiratory virus activity and traffic-related air pollution, namely particulate matter with an aerodynamic diameter ≤ 10 µm (PM10), nitrogen dioxide (NO2), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3). A probabilistic risk assessment framework was developed based on a detrended fluctuation analysis to predict future respiratory virus and air pollutant associated asthma incidence. Results indicated a strong association between asthma admission rate and influenza (r=0.80, p<0.05) and SO2 level (r=0.73, p<0.05) in Taiwan in the period 2001-2008. No significant correlation was found for asthma admission and PM10, O3, NO2, and CO. The proposed fluctuation analysis provides a simple correlation exponent describing the complex interactions of respiratory viruses and air pollutants with asthma. This study revealed that there was a 95% probability of having exceeded 2987 asthma admissions per 100,000 population. It was unlikely (30% probability) that the asthma admission rate exceeded 3492 per 100,000 population. The probability of asthma admission risk can be limited to below 50% by keeping the correlation exponent of influenza to below 0.9. We concluded that fluctuation analysis based risk assessment provides a novel predictor of asthma incidence.

Columba livia as a sentinel species for the assessment of urban air genotoxicity.

This study explored the comet assay as a possible tool to assess genotoxicity in erythrocytes of Columba livia to detect genotoxic effects induced by exposure to urban air pollution. Fieldwork was conducted between June 2004 and June 2005 in the city of Milan, Italy, by sampling pigeons in different areas almost twice a week. Six air contaminants-CO, PM10, NO(2), O(3) (ozone), SO(2), and C6H6-plus polycyclic aromatic hydrocarbons (PAHs) in fine particles, temperature, and ultraviolet index, were considered. Genotoxicity levels, expressed as %DNA migrated, tail moment, and damage index (DI), were always higher in wild pigeons than in pigeons living indoors (controls). Animals exposed to urban air showed significant differences from season to season, and the genotoxic parameters presented the highest values in summer (45.30% +/- 1.40% %DNA migrated, 12.73 +/- 0.80 tail moment, and 22.30 +/- 0.15 x DI x 10(-1)); regression analyses showed a positive relation between DI and O(3) concentrations (P < 0.001). The use of the comet assay DI parameter as a rapid assessment of incipient genotoxic risk by pollution, as measured in C. livia living in urban areas, is also discussed.

Air quality biomonitoring: assessment of air pollution genotoxicity in the Province of Novara (North Italy) by using Trifolium repens L. and molecular markers.

Mixed air pollutants are considered a major cause of DNA damage in living species. In this study Trifolium repens L. cv Regal was used as a bioindicator to assess the genotoxicity of air stressors in the Italian province of Novara. Two on-site biomonitoring experiments were performed during the spring and autumn of 2004. Test plants were exposed at 19 monitoring sites distributed homogeneously throughout the province, and each experiment lasted for a period of 6 weeks. Genotoxicity was evaluated with Amplified Fragment Length Polymorphism (AFLP) molecular markers. The results show the predominantly rural central-west region of the Novara Province to have the worst air quality with regard to genotoxicity. Analyses of geomorphology, land use and climatic factors suggest that the compromised air quality in the region could be attributed to wind strength and direction, transporting pollution from vehicular traffic on the A4 highway and from the urban/industrialized centres of Novara and Vercelli. Plant growth, changes in plant photochemical efficiency and the presence of ozone related leaf injuries were also measured to better interpret the results of genotoxicity. Statistical analyses show that although climatic factors such as light intensity and temperature influence plant growth, they do not contribute to atmospheric stressor-induced DNA damage. Further analyses indicated that, as expected, a mixture of genotoxic and non-genotoxic pollutants coexist in the Novara Province troposphere, and that the elevated ozone concentrations experienced during the study may have contributed to the DNA damage in the tested plants by enhancing genotoxicity via interaction with other air stressors.

Does socio-demographic status influence the effect of pollens and molds on hospitalization for asthma? Results from a time-series study in 10 Canadian cities.

PURPOSE: Social status influences asthma morbidity but the mechanisms are not well understood. To determine if sociodemographics influence the susceptibility to ambient aeroallergens, we determined the association between daily hospitalizations for asthma and daily concentrations of ambient pollens and molds in 10 large Canadian cities. METHODS: Daily time-series analyses were performed and results were adjusted for day of the week, temperature, barometric pressure, relative humidity, ozone, carbon monoxide, sulfur dioxide, and nitrogen dioxide. Results were then stratified by age, gender, and neighborhood family education and income. RESULTS: There appeared to be age and gender interactions in the relation between aeroallergens and asthma. An increase in basidiomycetes equivalent to its mean value, about 300/m3, increased asthma admissions for younger males (under 13 years of age) by 9.3% (95% CI, 4.8%, 13.8%) vs. 4.2% (95% CI, - 0.1%, 8.5%) for older males. The reverse was true among females with increased effect in the older age group: 2.3% (95% CI, 1.2%, 5.8%) in those under 13 years vs. 7.1% (95% CI, 4.1%, 10.1%) for older females. Associations were seen between aeroallergens and asthma hospitalization in the lowest but not the highest education group. CONCLUSIONS: Our results suggest that younger males and those within less educated families may be more vulnerable to aeroallergens as reflected by hospitalization for asthma.

Assessment of occupational exposures in foundries.

The working environment of foundries is hazardous and characterized by multiple simultaneous chemical and physical hazards exposure. In the present work, four foundries, namely; El Nasr Casting and Ramsis foundry in Alexandria and Misr Spinning and Weaving and Misr Rayon Companies in Kafr El-Dawar in Behira have been surveyed. Levels of total and respirable dust, free silica % in total dust and lead concentration in total and respirable dust; NO2, SO2 and CO concentrations; noise and heat stress levels have been determined in the present work utilizing recommended standard methods and direct reading calibrated instruments. The results of the present study revealed; 1. The levels of total dust and respirable dust taken at the four companies and at all operations are within threshold limit values, except at knockout and cleaning operation at El Nasr company. 2. Free silica concentration in total dust at all operations in all the companies are within threshold limit values, except at moulding, melting and knockout and cleaning operations in El Nasr Company. 3. Lead concentrations in total and respirable dust at melting and pouring in Misr Reyon Company are within threshold limit values. 4. Gases comprising NO2, SO2 and CO levels are within threshold limits in melting and pouring in all companies for the former two whereas CO levels in Misr spinning and weaving company are higher than threshold limit values. 5. Noise levels in knockout and cleaning operation at the four companies are exceeding threshold limit values. 6. Heat stress levels in melting and pouring operation in El Nasr and in pouring operation in Ramsis are higher than maximum allowable permissible levels. The present work is a massive survey, which highlights the occupational hazards in Egyptian foundries.

Noninvasive ambulatory assessment of cardiac function in healthy men exposed to carbon monoxide during upper and lower body exercise.

Very little is known about the cardiovascular responses of exercising individuals when exposed to carbon monoxide (CO). Sixteen healthy nonsmoking men aged 18-29 years participated in the study. Using a combination of exposures to CO by breathing from a bag or in an environmental chamber, subjects performed a randomized sequence of brief (5 min) multi-level treadmill and hand-crank exercises on different days at less than 2% carboxyhemoglobin (COHb) and after attaining target levels of 5%, 10%, 15%, and 20% COHb. To assess cardiac function changes we employed noninvasive impedance cardiography (ICG) and three-lead electrocardiograms (ECG). The ICG was used to estimate cardiac output, stroke volume, heart rate, cardiac contractility, and time-to-peak ejection time. The ECG was used to assess myocardial irritability and ischemia, and changes in cardiac rhythm. The results showed that the cardiovascular system compensated for the reduced O2-carrying capacity of the blood by augmenting heart rate, cardiac contractility, and cardiac output for both upper-body and lower-body exercise. While this mechanism served well in submaximal exercise, the enhanced cardiovascular response to exercise was not without physiological costs because it began to fail at moderate levels of CO exposure and exercise. We concluded that young, apparently healthy men can perform submaximal upper and lower-body exercise without overt impairment of cardiovascular function after CO exposures attaining 20% COHb.

Assessing the relevance of rodent data on chemical interactions for health risk assessment purposes: a case study with dichloromethane-toluene mixture.

Several descriptive studies have reported the occurrence of infra-additive and supra-additive toxic interactions in rodents given high doses of chemicals by routes different from anticipated human exposures. In order to assess the relevance of such rodent data on chemical interactions for humans, the route, species, and dose extrapolations need to be conducted on the basis of proven/hypothetical interaction mechanisms. The present study initially developed a physiologically based model of the toxicological interaction reported in rats receiving high oral doses of dichloromethane (DCM) and toluene (TOL). This predictive model was then used to asses the relevance of DCM-TOL interaction for humans exposed to threshold limit values (TLVs) of these chemicals, following the conduct of the various, essential extrapolations (i.e., rat to human, oral to inhalation, high dose to low dose). The interaction modeling approach involved (i) obtaining validated rat and human physiologically based pharmacokinetic (PBPK) models for TOL and DCM from the literature, and (ii) linking them via the modified Michaelis-Menten equation accounting for hypothetical mechanisms of interactions (no interaction, competitive inhibition, noncompetitive inhibition, and uncompetitive inhibition). Of the various interaction mechanisms investigated, the noncompetitive and uncompetitive metabolic inhibitions were found to adequately describe the reduction of carboxyhemoglobinemia (COHB) observed in rats during combined exposures (18.8 mmol/kg TOL, +6.2 mmol/kg DCM, po; 0.005 mmol/kg TOL, ip +5000 ppm DCM, 1 hr). The simulation model, based on noncompetitive and uncompetitive inhibition mechanisms, suggests that only < 10% reduction in the area under the COHB vs time curve (AUCCOHB) is likely to occur in humans exposed to the current TLVs of DCM and TOL (compared to AUCCOHB resulting from an 8-hr exposure to TLV of DCM alone). The present modeling approach, based on hypothetical mechanisms of interaction, then indicates that rodent data on DCM-TOL interaction are not relevant for humans, particularly with respect to the COHB effect. The application of this kind of a predictive modeling approach should be useful in screening the available reports on chemical interactions for identifying those of greater concern at relevant human exposure levels (RfD, RfC, TLV).

Assessment of health effects of fluctuating concentrations using simplified pharmacokinetic algorithms.

The purpose of this study was to develop a simple, practical method to improve the accuracy of assessing health effects by determining the concentration patterns inside the body resulting from fluctuating external pollutant concentrations. Linear pharmacokinetic processes were assumed, and the attenuations of the high- and low-frequency components of the external pattern when entering through the "biological window" were determined. Similar attenuations also were determined for the "time-averaged sampling window." It was shown that when the averaging time was less than 1/4 of the biological half-life, no information of biological significance was lost. Thus, a simple arithmetic step equation was proposed to convert external time-averaged concentrations to "biologically effective concentrations" proportional to internal concentrations. Calculations could readily be made in real time by a monitoring instrument, or even with a pocket calculator. Another simple algorithm was proposed for determining a "biological damage parameter" representative of cumulative damage if the body repair process is slow. Finally, simple algorithms were proposed for calculating body burdens from total absorbed mass rates, a procedure that should be useful for pollutants such as lead that may enter the body through multiple pathways. Results were compared with experimental and hypothetical data to show their utility.

[Use of dispersion analysis in the assessment of combined effect of low levels of carbon monoxide and psychoemotional stress in chronic experiment]. / Ispol'zovanie dispersionnogo analiza pri otsenke éffektov sochetannogo deistviia nizkikh urovnei monooksida ugleroda i psikhoémotsial'nogo stressa v khronicheskom éksperimente.

The article deals with evaluation of joint effects by means of dispersion analysis. The experimental study covered joint effects caused by low levels of carbon oxide (MAC and those 3 times lower) and specific psychoemotional stress in white rats. The studied parameters described activities of the central nervous, cardiovascular and immune systems. Dispersion analysis helped to reveal predominant role of the stress in the joint effects on the cardiovascular and central nervous systems, prevalent role of carbon oxide in the joint effects on the immune system.

In situ assessment of the rat heart during chronic carbon monoxide exposure using nuclear magnetic resonance imaging.

Ventricular hypertrophy induced in male Sprague-Dawley rats by inhalation of 500 ppm carbon monoxide (40% carboxyhemoglobin level) for 0-62 days was assessed by contiguous 2-mm thick axial cardiac cross-sections, using 32 accumulated averages of ungated fast-scan gradient-recalled nuclear magnetic resonance (NMR) images. Following final imaging, the rats were sacrificed and the hematocrit and heart mass were determined. The mean outside diameter of the left ventricle plus interventricular septum (LV + S) showed a strong correlation (r = 0.73, P less than 0.01) with the duration of CO exposure, while the correlation coefficients for the LV + S lumen diameter and wall thickness were marginally significant. The mean pleural space diameter also increased significantly (r = 0.64, P less than 0.05) with the duration of CO exposure. The ratio of the LV + S wall thickness and the lumen radius was 0.53 in the rats exposed to CO for 0-8 days; this value did not change with longer CO exposure. The LV + S outside and lumen diameter showed significant correlations to the hematocrit (r = 0.72, p less than 0.05 and r = 0.66, P less than 0.05, respectively), and the LV + S outside diameter correlated with the increase in the LV + S mass (r = 0.72, P less than 0.05). The results achieved with NMR imaging are consistent with past morphometric studies of CO-induced ventricular hypertrophy, where heart dimensions were determined in relaxed frozen tissue, and corroborate the eccentric nature of CO-induced ventricular hypertrophy.