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Query: UMLS:C0010200 (cough)
 23,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Uncertainty in risk assessment can be reduced by increasing the use of relevant data specific to the particular xenobiotic and exposed organism. We describe the development of a preliminary, mechanism-based exposure response model for chloroform hepatotoxicity consistig of toxicokinetic (TK) and toxicodynamic (TD) submodels. The TK submodel is based on an existing physiologically based toxicokinetic (PBTK) model for chloroform. The TD submodel consists of an empirical function linking tissue dose, defined by the PBTK model, with hepatocyte killing and subsequent regenerative cellular replication. Chloroform-induced cell killing was inferred quantitatively from dose-response hepatic labelling index studies conducted in female B6C3F1 mice and male F344 rats. The overall model was scaled to humans by conventional scaling of the TK submodel and by using the TD submodel as is, i.e. as developed from the rodent data. The resulting human model was used to analyze a case of human poisoning which developed after repeated ingestion of large doses of cough syrup containing chloroform and alcohol. The model predicted the observed toxic response after the capacity for chloroform metabolism was increased by a factor of 3 from the value estimated using human liver microsomes. This is an acceptable adjustment of this parameter, given the uncertainty associated with the extrapolation from microsomes and the coexposure to alcohol. This preliminary result is encouraging, suggesting that the model, at its current stage of development, is able to approximate actual human risks of hepatotoxicity from chloroform exposure. The extensive use of data on chloroform TK and cytolethality-induced regenerative cellular replication for model development suggests that the model has reduced uncertainty relative to the current U.S. EPA oral reference dose (RfD) calculation for chloroform, which does not use any mechanistic or dose-response data.
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PMID:Biologically based dose response model for hepatic toxicity: a mechanistically based replacement for traditional estimates of noncancer risk. 859 60

Air pollution produces adverse health effects. The consequences of lifelong daily exposures to atmospheric pollutants upon the respiratory apparatus of healthy children are of considerable clinical importance. We investigated the association between exposure to a highly polluted urban environment with a complex mixture of air pollutants-ozone and particulate matter the predominant ones-and chest x-ray abnormalities in 59 healthy Mexican children who are lifelong residents of Southwest Metropolitan Mexico City (SWMMC), with a negative history of tobacco exposure and respiratory illnesses. Their clinical results and x-ray findings were compared to those of 19 Mexican control children, residents of a low-pollution area, with a similar negative history of tobacco exposure and respiratory illnesses. Ozone concentrations in SWMMC exceeded the U.S. Environmental Protection Agency (U.S. EPA) National Ambient Air Quality Standard (NAAQS) for O(3): 0.08 ppm as 1-h maximal concentration, not to be exceeded more than 4 times a year, on 71% of days in 1986 and 95% in 1997, with values as high as 0.48 ppm. Ozone maximal peaks are usually recorded between 2 and 5 pm coinciding with children's outdoor physical activities. Children in the control group reported no upper or lower respiratory symptomatology. Every SWMMC child complained of upper and/or lower respiratory symptoms, including epistaxis, nasal dryness and crusting, cough, shortness of breath, and chest discomfort. Children aged 7-13 yr had the most symptomatology, while 5- to 6-year olds and adolescents with the lowest number of statistically significant outdoor exposure hours had less respiratory symptoms. Bilateral symmetric mild lung hyperinflation was significantly associated with exposure to the SWMMC atmosphere (p = .0004). Chronic and sustained inhalation of a complex mixture of air pollutants, including ozone and particulate matter (PM), is associated with lung hyperinflation, suggestive of small airway disease, in a population of clinically healthy children and adolescents. Small airways are a target of air pollutants in SWMMC children, with ozone and PM being most likely responsible, based on experimental animal, controlled-chamber, and epidemiological data available. Our main concern is the potential likelihood for the development of chronic lung disease in this highly exposed population.
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PMID:Exposure to air pollution is associated with lung hyperinflation in healthy children and adolescents in Southwest Mexico City: a pilot study. 1088 Jan 43