Biomedical subjects

T J Keefe

Publications and source records attributed to T J Keefe.

At least 19 recordsLinked to original sources

PubMed2003

Comparison of urban and rural non-fatal injury: the results of a statewide survey.

OBJECTIVES: This study compared the epidemiology of non-fatal injury among urban and rural residents of Colorado. DESIGN: A stratified probability sample with random digit dial methods was used to survey Colorado residents by telephone regarding injuries experienced in the last 12 months. Questions on the cause of the injury, the activity at the time of the injury, and the place of injury were based on the Nordic Medico Statistical Committee's (NOMESCO) classification of external causes of injuries. SUBJECTS: A total of 1425 urban and 1275 rural Colorado residents aged 18 and older were interviewed. RESULTS: Age, gender, marital status, and rural residency were found to increase the odds of self reported injury. The adjusted odds ratio for self reported injury was 1.3 (95% confidence interval (CI) 1.01 to 1.68) for rural compared with urban residents. Rural residence (odds ratio 1.02, 95% CI 0.51 to 7.01) was not a risk factor for injury among the highest risk group, those who were single and never married. No differences in injury characteristics were found by urban-rural status. CONCLUSIONS: The increased odds of self reported injury among rural residents were not explained by differences in the causes of injury or other injury characteristics. The differences in the importance of rural residence in increased odds of injury by marital status warrants further understanding and may be important in the development of injury prevention programs. Based on comparison with a similar survey, the NOMESCO coding system appears to be a viable alternative survey tool for gathering information on injury characteristics.

Adolescent↗

PubMed2002

Nonadditive hepatic tumor promoting effects by a mixture of two structurally different polychlorinated biphenyls in female rat livers.

This study evaluates and quantifies the interactive hepatic tumor promoting effects of two PCBs, the Ah receptor agonist PCB 126 (3,3',4,4',5-pentachlorobiphenyl) and the constitutive androstane receptor (CAR) agonist PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl). Promotion of altered hepatic foci was evaluated utilizing a medium-term 8-week bioassay for promoters of hepatocarcinogenesis. The assay employs placental glutathione-S-transferase positive (GST-P+) liver cell foci as markers of preneoplasia in female Fischer 344 rats treated with the known initiator diethylnitrosamine followed by partial hepatectomy and by gavage exposure to test chemicals. GST-P+ foci were quantified by histomorphometry and were reported as areas and numbers of GST-P+ foci within the area of liver examined. For PCB 126, the doses were 0.1, 1.0, and 10 microg/kg body weight. For PCB 153, the doses were 10, 100, 1000, 5000, and 10,000 microg/kg body weight. Combined PCB 126 and 153 exposures were 0.1 + 10, 1 + 100, 10 + 1000, 10 + 5000, and 10 + 10,000 microg/kg, respectively. Individual PCB treatment resulted in dose dependent increases in liver and adipose concentrations. Hepatic PCB 153 levels were significantly increased (p < 0.01) after combined exposure. Treatment with PCB 126 or PCB 153 alone resulted in a significant (p < 0.01) dose dependent increase in GST-P+ foci area and number compared with controls. Treatment with the mixture of PCB 126 and 153 resulted in antagonistic GST-P+ focus formation (p < 0.001) for both foci area and number. The less than additive effect was present at all 5 PCB 126/PCB 153 dose combinations, including the low doses of PCB 126 and 153 that did not show significant promotional activity alone.

Adipose Tissue↗

PubMed2001

Effects of malathion on survival, growth, development, and equilibrium posture of bullfrog tadpoles (Rana catesbeiana).

Bullfrog (Rana catesbeiana) tadpoles were exposed to malathion in water in a 28-d static renewal test. The effects of malathion on survival, growth, development, and loss of equilibrium posture were determined. Survival was significantly decreased at malathion concentrations of 2,500 micrograms/L and higher. Development of tadpoles was delayed significantly by malathion exposure as indicated by a dose-related decrease in developmental stage over time. Development of tadpoles in the 1,000-microgram/L and higher treatment groups was significantly delayed from that observed in the control. The effects of malathion on developmental stage suggest that malathion may decrease thyroid function in tadpoles, as it does in other species. Maintenance of equilibrium posture following agitation of the test containers was significantly impaired in tadpoles in all the malathion treatment groups (500 to 3,000 micrograms/L) relative to the control. Maintenance of equilibrium posture was thus the most sensitive end point measured in this study. Loss of equilibrium posture could increase predation losses and decrease feeding in populations of bullfrog tadpoles in the field. However, concentrations of malathion that produced adverse effects in our study are higher than published, measured concentrations found in wetlands or streams.

Animals↗

PubMed2000

Agricultural work-related injuries among farmers in Hubei, People's Republic of China.

OBJECTIVES: This population-based study evaluated patterns of and risk factors for, agricultural injuries among farmers in the People's Republic of China. METHODS: A multistage sample of 1500 Chinese farmers was selected from 14 villages. Face-to-face interviews with 1358 farmers were conducted between July 1997 and September 1997 (response rate = 91%). Agricultural work-related injuries that occurred in the previous 24 months and the associated factors were evaluated. RESULTS: A total of 33% of the farmers reported at least 1 work-related injury in the 24 months before the survey. Major external causes of the injuries were hand tools (50%), falls (26%), and heavy falling objects (10%). The statistically significant risk factors for injury were low family income, 1 to 6 school years of education, self-reported pesticide exposure, tension in relationships with neighbors, and stress in life. The most notable result was the relation between self-reported pesticide exposure and injury, with farmers with greater pesticide exposure at significantly greater risk for injury. CONCLUSIONS: The results of this study indicated that injuries occurring among Chinese farmers may have unique patterns and potential risk factors.

Accidents, Occupational↗

PubMed1999

Lack of promotional effects of groundwater contaminant mixtures on the induction of preneoplastic foci in rat liver.

F344 rats were exposed to drinking water mixtures of seven of the most common groundwater contaminants associated with hazardous waste sites [arsenic, benzene, chloroform, chromium, lead, phenol, and trichloroethylene (TCE)] as the full mixture or submixtures of the organic and/or inorganic chemicals. The lowest concentrations (1x) of the individual chemicals were environmentally realistic and below what would be expected to induce significant short-term toxicity. This study was intended to determine if previously reported increases in localized hepatocellular proliferation in response to these chemicals might be correlated with increased risk for hepatocarcinogenesis. Rats were exposed via a drinking water solution to the full seven- chemical mixture (at 1x and 10x concentrations), submixtures of the organic or inorganic chemicals (at 10x concentrations), a mixture of TCE, lead, and chloroform (TLC submixture at 10x and 100x concentrations), or deionized water as a control. The rats were evaluated for promotion of placental glutathione-S-transferase (GST-P) positive preneoplastic liver cell foci after diethylnitrosamine (DEN) initiation and partial hepatectomy. Focus formation, cell proliferation, and apoptosis were evaluated after exposure to DEN or saline controls, the chemical mixtures or deionized water controls, or combinations of these treatments. The total number and area of GST-P positive foci in DEN-treated rats exposed to the full seven-chemical mixture was increased as compared with the DEN-water controls, but this was statistically significant only for total focus area in the 1x dose group. In DEN-treated rats, the inorganic or TLC submixtures resulted in a significant reduction in number and area of GST-P positive foci. Focus area also was decreased in the organic submixture-treated group, but not significantly. Hepatocellular proliferation was not significantly changed in the chemical mixture saline groups as compared with the mixture water controls. After DEN treatment, however, cell proliferation was significantly decreased after the 10x seven-chemical and organic mixture treatments and the 100x TLC mixture treatment. Different groups showed either increased or decreased apoptotic rates which did not correlate well with proliferation rates or focus formation. Mixtures of these seven chemicals, therefore, did not appear to act as promoters of hepatic foci at environmentally relevant concentrations, and some mixture combinations appeared to decrease promotional activity.

Animals↗

PubMed1999

Reduced excretion of a melatonin metabolite in workers exposed to 60 Hz magnetic fields.

The effects of occupational 60 Hz magnetic field and ambient light exposures on the pineal hormone, melatonin, were studied in 142 male electric utility workers in Colorado, 1995-1996. Melatonin was assessed by radioimmunoassay of its metabolite, 6-hydroxymelatonin sulfate (6-OHMS), in post-work shift urine samples. Personal magnetic field and light exposures were measured over 3 consecutive days using EMDEX C meters adapted with light sensors. Two independent components of magnetic field exposure, intensity (geometric time weighted average) and temporal stability (standardized rate of change metric or RCMS), were analyzed for their effects on creatinine-adjusted 6-OHMS concentrations (6-OHMS/cr) after adjustment for age, month, and light exposure. Geometric mean magnetic field exposures were not associated with 6-OHMS/cr excretion. Men in the highest quartile of temporally stable magnetic field exposure had lower 6-OHMS/cr concentrations on the second and third days compared with those in the lowest quartile. Light exposure modified the magnetic field effect. A progressive decrease in mean 6-OHMS/cr concentrations in response to temporally stable magnetic fields was observed in subjects with low workplace light exposures (predominantly office workers), whereas those with high ambient light exposure showed negligible magnetic field effects. Melatonin suppression may be useful for understanding human biologic responses to magnetic field exposures.

Adult↗

PubMed1999

Back pain and agricultural work among farmers: an analysis of the Colorado Farm Family Health and Hazard Surveillance Survey.

BACKGROUND: Back pain is the most prevalent occupational health problem experienced by much of the world's workforce. However, agricultural work-related back pain occurring among US farmers working on small operations or family farms is usually not included in surveillance. With data collected by Colorado Farm Family Health and Hazard Surveillance Survey, this study reports characteristics of and risk factors for back pain among adult farmers living in eight Colorado counties. METHODS: A stratified probability sample of 500 farms was selected in proportion to the number of farms in study areas. During the 4-year period from 1993 through 1996, 458 farms were enrolled in the study and 759 farmers were interviewed using a questionnaire. Information on self-reported back pain and potential risk factors among 742 white farmers was evaluated and reported here. RESULTS: A total of 194 farmers (26.2%) reported to have had at least one episode of back pain lasting for 1 week or more. Males had a slightly higher prevalence of back pain than females (28.6% vs. 22.5%) and the lower back was the predominantly affected part of body among both males and females. In 45.4% of males and 43.9% of females back pain was brought on by repeated activities. Males' activities at work were more likely to cause back pain while females' activities at home were more likely to cause back pain. Three factors were found to be significantly associated with back pain: being depressed (odds ratio (OR) = 3.68, 95% confidence interval (CI) = 2.23-6.09), farming/ranching as main activities (OR = 1.66, CI = 1.17-2.36), and worked in agriculture for 10 to 29 years (OR = 1.62, CI = 1.14-2.30). CONCLUSIONS: Our analyses indicate that back pain is an occupational health problem among farmers on small operations or family farms and that back pain affected males and females differently. The finding of significant positive associations between depression, farming activities, and back pain warrants further attention.

Adult↗

PubMed1998

Association of semen quality and occupational factors: comparison of case-control analysis and analysis of continuous variables.

OBJECTIVE: To compare two statistical approaches, case-control and analysis of continuous parameters of semen, in examining the relationship between occupational exposures and male reproductive function. DESIGN: Case-control study. SETTING: Males providing semen samples at a university infertility clinic. PATIENT(S): Nonvasectomized males who provided at least one semen sample at an infertility clinic. MAIN OUTCOME MEASURE(S): Standard clinical semen analysis. RESULT(S): Analyses using a dichotomous dependent variable did not uncover significant associations between any occupational factor and infertility case status. However, linear models incorporating continuous variables identified a number of occupational factors that were associated with specific parameters of semen. A reduction in percentage of progressive sperm and an increase in percentage of coiled tail sperm defects in welders, compared with unexposed subjects, were found. Significant dose-response relationships between level of perceived job stress and percentage of progressive sperm, total motile count, morphology, abnormal heads, and coiled tail defects were found. CONCLUSION(S): The findings suggest that subtle changes in semen variables, possibly associated with workplace exposure, may be detected only with parametric analyses of continuous variables of semen.

Adult↗

PubMed1998

Nocturnal excretion of a urinary melatonin metabolite among electric utility workers.

OBJECTIVES: The effects of 60-Hz magnetic field and ambient light exposures on the pineal hormone melatonin were studied among electric utility workers. METHODS: Personal exposure was measured at 15-second intervals over 3 consecutive 24-hour periods. Exposure metrics based on magnetic field intensity, intermittence, or temporal stability were calculated for periods of work, home, and sleep. A rate-of-change metric (RCM) was used to estimate intermittence, and the standardized RCM (RCMS = RCM/standard deviation) was used to evaluate temporal stability. The effects of magnetic field exposure on total overnight 6-hydroxymelatonin sulfate (6-OHMS) excretion and creatinine-adjusted nocturnal 6-OHMS (6-OHMS/cr) concentration were analyzed with adjustment for age, month, and light exposure. RESULTS: Magnetic field intensity, intermittence, or cumulative exposure had little influence on nocturnal 6-OHMS excretion. Residential RCMS magnetic field exposures were associated with lower nocturnal 6-OHMS/cr concentrations. In multivariate statistical analyses, the interaction term for geometric mean and RCMS magnetic field exposures at home was associated with lower nocturnal 6-OHMS/cr and overnight 6-OHMS levels. Modest reductions in the mean 6-OHMS levels occurred after RCMS exposures during work. The greatest reductions occurred when RCMS exposures both at work and at home were combined; therefore the effects of temporally stable magnetic fields may be integrated over a large portion of the day. CONCLUSIONS: Results from this study provide evidence that temporally stable magnetic field exposures are associated with reduced nocturnal 6-OHMS excretion in humans.

Adult↗

PubMed1998

Characterization of plasma immunoglobulin G concentrations of llamas.

OBJECTIVE: To develop appropriate reference ranges for plasma IgG concentrations of llamas. ANIMALS: 643 llamas on 5 farms. PROCEDURE: Plasma IgG concentration was measured by using a single radial immunodiffusion assay kit. Farm of origin, age, body condition score, and sex were recorded for each llama. The effect of each factor on plasma IgG concentration was evaluated separately, using ANOVA; the association between age and IgG concentration was evaluated, using linear regression. Multivariable regression models were developed to examine concurrent effects of age, sex, body condition score, farm, and various interactions on IgG concentration. RESULTS: The IgG concentrations were between 127 and 3,969 mg/dl. In llamas < 12 months old, farm of origin accounted for 29% of variability for IgG concentration. Reference range for plasma IgG concentrations in llamas < 12 months old was 391 to 2,357 mg/dl; for llamas > 12 but < 28 months old was 771 to 2,796 mg/dl; and for llamas > 28 months old was 570 to 3,264 mg/dl. These ranges were applicable only for the kit used in this study. CONCLUSIONS: Healthy llamas have a wide range of IgG concentrations. Determinants of IgG concentration are multifactorial, and their importance varies with age of the llamas. CLINICAL IMPLICATIONS: The wide range of IgG concentrations observed in healthy llamas and the influence that age and farm may have on IgG concentrations indicate that a result for one specific llama should be interpreted in relation to those of its herdmates.

Aging↗

PubMed1998

Mortality in beagles irradiated during prenatal and postnatal development. I. Contribution of non-neoplastic diseases.

To evaluate the lifetime health effects of exposure to ionizing radiation during development, 1,680 beagles received whole-body exposures to 60Co gamma rays or sham exposures. Eight groups of 120 dogs each received mean doses of 15.6-17.5 or 80.8-88.3 cGy in early, mid- or late gestation, at 8, 28 or 55 days after breeding, or at 2 days after birth. Another group of 120 dogs received a mean dose of 82.6 cGy as 70-day-old juveniles and one group of 240 dogs received a mean dose of 81.2 cGy as 365-day-old young adults. Sham irradiations were given to 360 controls. Sexes were equally represented. There was no significant effect of irradiation on mean survival times in any groups. In 1,343 dogs allowed to live out their life span, chronic renal disease was a common cause of mortality, and irradiation in the late fetal or juvenile periods potentiated this disease, resulting in increased mortality due to renal failure. This was consistent with earlier findings of the high radiosensitivity of the kidney in the perinatal period. Hypothyroidism associated with atrophic thyroiditis was decreased by irradiation, a finding contrary to expectation and not easily explained. Diabetes mellitus was increased by irradiation in the mid- and late gestation and juvenile periods, a finding which is intriguing based on early reports of a similar finding in atomic bomb survivors. Though convulsive seizures were a common cause of mortality in the dogs, there was no evidence for increased risk associated with prenatal irradiation as has been reported in humans. Genetic analyses indicated that renal disease, hypothyroidism, diabetes mellitus and convulsive seizures all had a heritable component, but that this did not influence or bias the radiation responses evaluated.

Age Factors↗

PubMed1998

Mortality in beagles irradiated during prenatal and postnatal development. II. Contribution of benign and malignant neoplasia.

To evaluate the lifetime carcinogenic hazards of exposure to ionizing radiation during development, 1,680 beagles received whole-body exposures to 60Co gamma rays or sham exposures. Eight groups of 120 dogs each received mean doses of 15.6-17.5 or 80.8-88.3 cGy in early, mid- or late gestation, at 8, 28 or 55 days postcoitus or at 2 days after birth. Another group of 120 dogs received a mean dose of 82.6 cGy as 70-day-old juveniles and one group of 240 dogs received a mean dose of 81.2 cGy as 365-day-old young adults. Sham irradiations were given to 360 controls. Sexes were equally represented. In 1,343 dogs allowed to live out their life span, neoplasia was a major disease, contributing to mortality in 40% of the dogs. There was a significant increase in benign and malignant neoplasms occurring in young dogs (<4 years old), including fatal malignancies, after irradiation in the perinatal (late fetal and neonatal) periods. The lifetime incidence of fatal neoplasms was also increased in dogs irradiated perinatally. Three malignancies-lymphomas, hemangiosarcomas and mammary carcinomas-accounted for 51% of all fatal tumors. There was an apparent lifetime increase and earlier onset of lymphomas in dogs exposed as fetuses. Fatal hemangiosarcomas were increased in dogs irradiated early and late in gestation. Fatal mammary carcinomas were not increased by irradiation, although non-fatal carcinomas were increased after perinatal exposure. Myeloproliferative disorders and central nervous system astrocytomas appeared to be increased in perinatally irradiated dogs. These data suggest that irradiation in both the fetal and neonatal periods is associated with increased early onset and lifetime cancer risk.

Animals↗

PubMed1997

Multicenter clinical comparison of sedative and analgesic effects of medetomidine and xylazine in dogs.

OBJECTIVE: To evaluate analgesic and sedative effects of medetomidine hydrochloride in dogs and to compare effects with those of xylazine hydrochloride. DESIGN: Randomized, controlled trial. ANIMALS: 184 dogs that required sedation or analgesia for completion of minor diagnostic or therapeutic procedures. PROCEDURE: Dogs were sedated with medetomidine, i.v. (750 micrograms/m2 of body surface area) or i.m. (1,000 micrograms/m2) or with xylazine, i.v. (1.1 mg/kg 10.5 mg/lb] of body weight) or i.m. (2.2 mg/kg [1 mg/lb]). Sedative effects were measured by scoring posture and response to noise. Durations of effects were determined by measuring time intervals between drug administration and changes in posture. Analgesic effects were measured by determining toe-pinch pressure needed to elicit a withdrawal response. Clinicians rated sedative and analgesic effects and ease with which diagnostic or therapeutic procedures could be performed. RESULTS: Posture and response to noise scores were significantly higher for dogs given medetomidine, i.m., than for dogs given xylazine, i.m., and for dogs given medetomidine, i.v., than for dogs given xylazine, i.v. Time to regaining sternal recumbency and time to regaining ability to stand were longest after i.m. administration of medetomidine. Toe-pinch pressures were not significantly different among groups. Clinicians rated overall analgesic and sedative effects as excellent significantly more often after administration of medetomidine than after administration of xylazine. Prevalence of adverse effects did not differ among groups. CLINICAL IMPLICATIONS: Medetomidine and xylazine, at doses tested, were effective and safe, but results of subjective measurements indicated that medetomidine provided better sedation and analgesia than did xylazine. Specific alpha 2-adrenergic antagonists (atipamezole, yohimbine) are available for control of adverse cardiovascular effects.

Analgesics, Non-Narcotic↗

PubMed1997

Comparison of organochlorine pesticide and polychlorinated biphenyl residues in human breast adipose tissue and serum.

The presence of organochlorine pesticides, such as p,p'-DDT[2,2-bis(p-chlorophenyl)-1,1,1-trichloroethanel, and of polychlorinated biphenyls (PCBs) in human serum and adipose tissue has been reported in many studies over the last four decades. Recently, debate has heightened concerning the link of these compounds to breast cancer. To clarify and resolve this issue, accurate analytical residue data must be obtained. Separation of the organochlorine pesticides from the PCBs in breast tissue is critical to obtaining valid residue data. Based on methods refined in the Analytical Laboratory at Colorado State University, accurate residue levels were established for nine individual PCB congeners and eight organochlorine pesticides. The breast adipose tissue method used was a modification of the Mills et al. and de Faubert Maunder et al. methods. The serum method employed was a modification of the Burse et al. method. Both breast adipose tissue and serum from 36 women were analyzed, and correlations of the residues from the two substrates were evaluated. Serum concentrations of p,p'-DDE, the primary metabolite of p,p'-DDT, were correlated (alpha = .05) with the concentrations of p,p'-DDE in human breast adipose tissue (r = .808). Serum concentrations of the PCB congener BZ 153 were also significantly correlated to the human breast adipose tissue concentrations of BZ 153 (r = .377). No significant relationship was found between serum concentrations and tissue residues for 15 of the 17 compounds analyzed. This lack of correlation between breast adipose tissue and serum, as well as an absence of the compound residues in serum, emphasized that adipose tissue should be analyzed in addition to serum to fully understand the relationship of the organochlorine compounds to breast cancer.

Adipose Tissue↗

PubMed1997

Childhood injury deaths: rural and urban differences, Colorado 1980-8.

OBJECTIVES: The purpose of this study is to describe and compare the distribution of injury deaths among rural and urban Colorado children that occurred between 1980-8. METHOD: Death certificates coded E800-E969 were obtained for children who were 0-14 years of age at death between 1980-8 and who were Colorado residents. Average annual rates were computed for rural and urban children, separately by gender. The 1980 census was used to compute rates. Rate ratios were calculated to summarize information related to specific external causes of deaths, contrasting rural and urban children. These differences were evaluated using Z tests. RESULTS: Statistically significant elevated risks were found along rural children for motor vehicle injury deaths. Firearms were involved more often in rural deaths among unintentional injury deaths of children older than 4 years of age, and among homicide related deaths of children 5 years and younger. All rural children who committed suicide used a firearm. CONCLUSIONS: Comparisons between rural and urban injury deaths provide important information that can be used to guide prevention strategies. For example, in Colorado, a child restraint law, passed in 1984, covered children under 4 years of age or under 40 pounds. It was not until 1995, however, that legislation was passed requiring restraint of children 5-16 years of age. Traditionally, rural residents are slower to accept new ideas and to alter current practices than urban residents.

Adolescent↗

PubMed1997

Kinetic gait analysis assessment of meloxicam efficacy in a sodium urate-induced synovitis model in dogs.

OBJECTIVE: To examine the ability of meloxicam, a cyclooxygenase inhibitor, to mediate the effects of sodium urate-induced acute stifle synovitis in dogs. ANIMALS: 12 clinically normal adult hound-type dogs. PROCEDURE: A blinded, randomized, controlled single crossover design study was performed to determine the efficacy of meloxicam, using 2 dosage groups. In 2 experimental phases, dogs, according to group, received meloxicam (0.1 or 0.5 mg/kg of body weight) or matched volume of meloxicam vehicle, with a washout period of 21 to 28 days between phases. Blood samples for hematologic and biochemical analysis, as well as synovial fluid or cytologic analysis, were collected immediately before and approximately 24 hours after articular challenge of dogs under propofol anesthesia. Ground reaction forces (GRF) and subjective clinical scores were determined before and at 4, 8, 12, and 24 hours after articular challenge. Vertical force data included peak force, impulse, limb loading, and unloading rates. Craniocaudal data were divided into braking and propulsion phases and consisted of peak force and associated impulses. RESULTS: Except for propulsion impulse at 24 hours, all GRF variables were significantly greater at all post-synovitis induction times in the group receiving the high meloxicam dose. Significant differences in all GRF variables were seen at various times between the low-dose meloxicam group and the corresponding control group, and between the low- and high-dose meloxicam groups. Similar significance was seen in the subjective clinical evaluations. Strong correlations existed between the subjective and objective data. CONCLUSIONS: Meloxicam was effective in attenuating the effects of sodium urate-induced acute synovitis in dogs. Kinetic gait data provided an objective measurement of lameness in an experimentally induced arthritis model and quantified lameness improvements in response to medication with a nonsteroidal anti-inflammatory drug.

Animals↗

PubMed1996

Incorporating Monte Carlo simulation into physiologically based pharmacokinetic models using advanced continuous simulation language (ACSL): a computational method.

Biologically based models with physiological parameters are becoming more popular as a tool to estimate target tissue doses from chemical exposures. However, the majority of current physiologically based pharmacokinetic (PBPK) models do not take into account the uncertainty and/or variability within the various model parameters. Consideration of uncertainty is important to evaluate the predictive ability and complexity of a model as well as identification of parameters which contribute disproportionately to variability in model output. In order to estimate the uncertainty in PBPK model output, a versatile and simple computational method is presented which can be readily incorporated into the majority of PBPK models without extensive additions to model computer code. In this paper, a separate computer program for Monte Carlo simulation is furnished that randomly samples values for model parameters and writes them into a run-time language (command file) format which can then be utilized to execute individual PBPK models. Modifications to the PBPK model allow the desired output to be written to a data file for statistical analysis. The method presented in this paper is applied to a simple PBPK model for benzene disposition.

Algorithms↗

PubMed1996

Variability in biological exposure indices using physiologically based pharmacokinetic modeling and Monte Carlo simulation.

By using physiologically based pharmacokinetic (PBPK) modeling coupled with Monte Carlo simulation, the interindividual variability in the concentrations of chemicals in a worker's exhaled breath and urine were estimated and compared with existing biological exposure indices (BEIs). The PBPK model simulated an exposure regimen similar to a typical workday, while exposure concentrations were set to equal the ambient threshold limit values (TLVs) of six industrial solvents (benzene, chloroform, carbon tetrachloride, methylene chloride, methyl chloroform, and trichloroethylene). Based on model predictions incorporating interindividual variability, the percentage of population protected was derived using TLVs as the basis for worker protection. Results showed that current BEIs may not protect the majority or all of the workers in an occupational setting. For instance, current end-expired air indices for benzene and methyl chloroform protect 95% and less than 10% of the worker population, respectively. Urinary metabolite concentrations for benzene, methyl chloroform, and trichloroethylene were also estimated. The current BEI recommendation for phenol metabolite concentration at the end-of-shift sampling interval was estimated to protect 68% of the worker population, while trichloroacetic acid (TCAA) and trichloroethanol (TCOH) concentrations for methyl chloroform exposure were estimated to protect 54% and 97%, respectively. The recommended concentration of TCAA in urine as a determinant of trichloroethylene exposure protects an estimated 84% of the workers. Although many of the existing BEIs considered appear to protect a majority of the worker population, an inconsistent proportion of the population is protected. The information presented in this study may provide a new approach for administrative decisions establishing BEIs and allow uniform application of biological monitoring among different chemicals.

Humans↗