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Biomedical subjects

K Crump

Publications and source records attributed to K Crump.

17 recordsLinked to original sources
PubMed2003

Lung cancer mortality among chromate production workers.

AIMS: To assess mortality in 1997 among 493 former workers of a US chromate production plant employed for at least one year between 1940 and 1972. METHODS: Cohort members were followed for mortality to 31 December 1997. Standardised mortality ratios (SMRs) were calculated for selected cause specific categories of death including lung cancer. Lung cancer mortality was investigated further by calculation of SMRs stratified by year of hire, duration of employment, time since hire, and categories of cumulative exposure to Cr(VI). RESULTS: Including 51 deaths due to lung cancer, 303 deaths occurred. SMRs were significantly increased for all causes combined (SMR = 129), all cancers combined (SMR = 155), and lung cancer (SMR = 241). A trend test showed a strong relation between lung cancer mortality and cumulative hexavalent exposure. Lung cancer mortality was increased for the highest cumulative exposure categories (> or =1.05 to <2.70 mg/m(3)-years, SMR = 365; > or =2.70 to 23 mg/m(3)-years, SMR = 463), but not for the first three exposure groups. Significantly increased SMRs were also found for year of hire before 1960, 20 or more years of exposed employment, and latency of 20 or more years. CONCLUSIONS: The finding of an increased risk of lung cancer mortality associated with Cr(VI) exposure is consistent with previous reports. Stratified analysis of lung cancer mortality by cumulative exposure suggests a possible threshold effect, as risk is significantly increased only at exposure levels over 1.05 mg/m(3)-years. Though a threshold is consistent with published toxicological evidence, this finding must be interpreted cautiously because the data are also consistent with a linear dose response.

Adolescent↗
PubMed2001

Evaluating the evidence for hormesis: a statistical perspective.

It is possible to account for hormesis under current regulatory guidelines by invoking criteria for departure from default risk assessment procedures. However, past experience suggests that it will be difficult to amass enough evidence for hormesis in an individual case to permit departure from default procedures. Accordingly, hormesis is likely to be important in agency risk assessments only if guidelines are modified to incorporate hormesis as a default assumption. This could be appropriate if hormesis is determined to be a universal or near-universal phenomenon. Although there is ample evidence that hormesis occurs in many specific situations, the overall prevalence of hormesis is very difficult to evaluate based on currently available data. The lack of a valid statistical test for hormesis is a major limitation when evaluating evidence for hormesis. The attempts at estimating the prevalence of hormesis reviewed herein did not adequately control for false positives and/or may have had inadequate power to detect hormesis. Some suggestions are made for constructing a database and analyzing the data therein that would provide more readily interpretable information on the prevalence of hormesis.

Animals↗
PubMed2000

Determination of a site-specific reference dose for methylmercury for fish-eating populations.

Environmental risk-management decisions in the U.S. involving potential exposures to methylmercury currently use a reference dose (RfD) developed by the U.S. Environmental Protection Agency (USEPA). This RfD is based on retrospective studies of an acute poisoning incident in Iraq in which grain contaminated with a methylmercury fungicide was inadvertently used in the baking of bread. The exposures, which were relatively high but lasted only a few months, were associated with neurological effects in both adults (primarily paresthesia) and infants (late walking, late talking, etc.). It is generally believed that the developing fetus represents a particularly sensitive subpopulation for the neurological effects of methylmercury. The USEPA derived an RfD of 0.1 microg/kg/day based on benchmark dose (BMD) modeling of the combined neurological endpoints reported for children exposed in utero. This RfD included an uncertainty factor of 10 to consider human pharmacokinetic variability and database limitations (lack of data on multigeneration effects or possible long-term sequelae of perinatal exposure). Alcoa signed an Administrative Order of Consent for the conduct of a remedial investigation/feasibility study (RI/FS) at their Point Comfort Operations and the adjacent Lavaca Bay in Texas to address the effects of historical discharges of mercury-containing wastewater. In cooperation with the Texas Natural Resource Conservation Commission and USEPA Region VI, Alcoa conducted a baseline risk assessment to assess potential risk to human health and the environment. As a part of this assessment. Alcoa pursued the development of a site-specific RfD for methylmercury to specifically address the potential human health effects associated with the ingestion of contaminated finfish and shellfish from Lavaca Bay. Application of the published USEPA RfD to this site is problematic; while the study underlying the RfD represented acute exposure to relatively high concentrations of methylmercury, the exposures of concern for the Point Comfort site are from the chronic consumption of relatively low concentrations of methylmercury in fish. Since the publication of the USEPA RfD, several analyses of chronic exposure to methylmercury in fish-eating populations have been reported. The purpose of the analysis reported here was to evaluate the possibility of deriving an RfD for methylmercury, specifically for the case of fish ingestion, on the basis of these new studies. In order to better support the risk-management decisions associated with developing a remediation approach for the site in question, the analysis was designed to provide information on the distribution of acceptable ingestion rates across a population, which could reasonably be expected to be consistent with the results of the epidemiological studies of other fish-eating populations. Based on a review of the available literature on the effects of methylmercury, a study conducted with a population in the Seychelles Islands was selected as the critical study for this analysis. The exposures to methylmercury in this population result from chronic, multigenerational ingestion of contaminated fish. This prospective study was carefully conducted and analyzed, included a large cohort of mother-infant pairs, and was relatively free of confounding factors. The results of this study are essentially negative, and a no-observed-adverse-effect level (NOAEL) derived from the estimated exposures has recently been used by the Agency for Toxic Substances and Disease Registry (ATSDR) as the basis for a chronic oral minimal risk level (MRL) for methylmercury. In spite of the fact that no statistically significant effects were observed in this study, the data as reported are suitable for dose-response analysis using the BMD method. Evaluation of the BMD method used in this analysis, as well as in the current USEPA RfD, has demonstrated that the resulting 95% lower bound on the 10% benchmark dose (BMDL) represents a conservative estimate of the traditional NOAEL, and that it is superior to the use of "average" or "grouped" exposure estimates when dose-response information is available, as is the case for the Seychelles study. A more recent study in the Faroe Islands, which did report statistically significant associations between methylmercury exposure and neurological effects, could not be used for dose-response modeling due to inadequate reporting of the data and confounding from co-exposure to polychlorinated biphenyls (PCBs). BMD modeling over the wide range of neurological endpoints reported in the Seychelles study yielded a lowest BMDL for methylmercury in maternal hair of 21 ppm. This BMDL was then converted to an expected distribution of daily ingestion rates across a population using Monte Carlo analysis with a physiologically based pharmacokinetic (PBPK) model to evaluate the impact of interindividual variability. The resulting distribution of ingestion rates at the BMDL had a geometric mean of 1.60 microg/kg/day with a geometric standard deviation of 1.33; the 1st, 5th, and 10th percentiles of the distribution were 0.86, 1.04, and 1.15 microg/kg/day. In place of the use of an uncertainty factor of 3 for pharmacokinetic variability, as is done in the current RfD, one of these lower percentiles of the daily ingestion rate distribution provides a scientifically based, conservative basis for taking into consideration the impact of pharmacokinetic variability across the population. On the other hand, it was felt that an uncertainty factor of 3 for database limitations should be used in the current analysis. Although there can be high confidence in the benchmark-estimated NOAEL of 21 ppm in the Seychelles study, some results in the New Zealand and Faroe Islands studies could be construed to suggest the possibility of effects at maternal hair concentrations below 10 ppm. In addition, while concerns regarding the possibility of chronic sequelae are not supported by the available data, neither can they be absolutely ruled out. The use of an uncertainty factor of 3 is equivalent to using a NOAEL of 7 ppm in maternal hair, which provides additional protection against the possibility that effects could occur at lower concentrations in some populations. Based on the analysis described above, the distribution of acceptable daily ingestion rates (RfDs) recommended to serve as the basis for site-specific risk-management decisions at Alcoa's Point Comfort Operations ranges from approximately 0.3 to 1.1 microg/kg/day, with a population median (50th percentile) of 0.5 microg/kg/day. By analogy with USEPA guidelines for the use of percentiles in applications of distributions in exposure assessments, the 10th percentile provides a reasonably conservative measure. On this basis, a site-specific RfD of 0.4 microg/kg/day is recommended.

Adult↗
PubMed1995

Reanalysis of dose-response data from the Iraqi methylmercury poisoning episode.

Applying a hockey stick parametric dose-response model to data on late or retarded development in Iraqi children exposed in utero to methylmercury, with mercury (Hg) exposure characterized by the peak Hg concentration in mothers' hair during pregnancy, Cox et al. calculated the "best statistical estimate" of the threshold for health effects as 10 ppm Hg in hair with a 95% range of uncertainty of between 0 and 13.6 ppm. A new application of the hockey stick model to the Iraqi data shows, however, that the statistical upper limit of the threshold based on the hockey stick model could be as high as 255 ppm. Furthermore, the maximum likelihood estimate of the threshold using a different parametric model is virtually zero. These and other analyses demonstrate that threshold estimates based on parametric models exhibit high statistical variability and model dependency, and are highly sensitive to the precise definition of an abnormal response. Consequently, they are not a reliable basis for setting a reference dose (RfD) for methylmercury. Benchmark analyses and statistical analyses useful for deriving NOAELs are also presented. We believe these latter analyses--particularly the benchmark analyses--generally form a sounder basis for determining RfDs than the type of hockey stick analysis presented by Cox et al. However, the acute nature of the exposures, as well as other limitations in the Iraqi data suggest that other data may be more appropriate for determining acceptable human exposures to methylmercury.

Child↗
PubMed1994

Death following colchicine poisoning.

A 45-year-old male was admitted to hospital after 2 to 3 days of vomiting, nausea, and diarrhea following an apparent overdose of colchicine tables. During hospitalization his white blood cell count fell dramatically. At death, 33 h following initial hospitalization, pleural effusion with bilateral bronchopneumonia was evident, together with numerous bacterial colonies and marked hypocellularity of bone marrow and reduced megakaryocytes, erythroid, and myeloid cells. The most striking histological findings were numerous metaphasic mitotic figures in gastric and small bowel epithelia. Colchicine was detected, confirmed by high pressure liquid chromatography with photodiode array detection, and quantitated in antemortem plasma collected 3.3 h following hospitalization and in postmortem blood and bile. Colchicine was not detected in liver, vitreous humor, or stomach contents.

Bile↗
PubMed1993

Simultaneous determination of 6-monoacetylmorphine, morphine and codeine in urine using high-performance liquid chromatography with combined ultraviolet and electrochemical detection.

A method is described for the simultaneous determination of 6-monoacetylmorphine (6-MAM), morphine and codeine in post-mortem urine specimens using reversed-phase high-performance liquid chromatography with dual ultraviolet spectrophotometric and electrochemical detection. The limits of detection for a 1-ml urine sample were 0.04 mg/l for 6-MAM and 0.05 mg/l for both morphine and codeine. The presence of 6-MAM in urine indicates prior use of heroin and enables differentiation between morphine- and heroin-related deaths.

Chromatography, High Pressure Liquid↗
PubMed1992

A death involving probenecid.

A death following deliberate ingestion of approximately 75 g of probenecid in a 36-year-old man is described. Tissue concentrations of probenecid were highest in serum (710 mg/L) and liver (550 mg/kg). Probenecid was also detected in vitreous and bile. Ethanol was also detected in blood at 0.13 g/100 mL.

Adult↗
PubMed1991

Airborne concentrations of asbestos in 71 school buildings.

A total of 473 air samples from 71 schools scheduled for abatement (328 indoor static samples, 51 personal samples, and 94 outdoor samples) were analyzed by transmission electron microscopy techniques. Six measures of asbestos-in-air concentration were considered: (1) total asbestos structures per cubic centimeter: (2) chrysotile structures per cubic centimeter; (3) amphibole structures per cubic centimeter; (4) structures per cubic centimeter at least 0.5 micron long and at least five times wide; (5) structures per cubic centimeter at least 5 microns long; and (6) structures per cubic centimeter at least 5 microns long and at least 0.2 micron wide. The average concentration of chrysotile structures in indoor air samples was 0.017 structures/cm3; the average concentration of amphibole structures was 0.0015 structure/cm3. Ninety-five percent of structures found were chrysotile. The average concentrations of all structures were significantly higher indoors than outdoors (P less than 0.001). The average concentration of structures more than 5 microns long indoors was 0.00023 structure/cm3. None of the following factors were significantly correlated with asbestos concentrations in air: type of asbestos-containing materials (ACM) present, condition of ACM, accessibility of ACM to students, whether ACM were covered, air flow, or whether sweeping was noted during sample collection. In addition, asbestos-in-air concentrations were not significantly different in different types of schools (high, intermediate or elementary) or in schools constructed in different time periods. Lastly, there was no correlation between the mineral type of asbestos found in the air and the type found in samples of bulk material.

Air↗
PubMed1990

Exact statistical tests for any carcinogenic effect in animal bioassays. II. Age-adjusted tests.

Statistical methods are discussed for application in animal carcinogenesis bioassays that test a general null hypothesis that response frequencies are independent of the treatment level for all tumor endpoints, sexes, and species considered in the bioassay, conditional on survival. These methods are similar to those proposed earlier by Farrar and Crump (1988, Fundam, Appl. Toxicol. 11, 652-663) which involve test statistics that are functions of p values from multiple standard statistical hypothesis tests, and evaluation of significance using randomization. Refinements include the introduction of an exact incidental tumor test analogous to the asymptotic test of Hoel and Walburg (1972, J. Natl. Cancer Inst. 49, 361-372), which takes into account the possibility that any differences among treatment groups in response rates result from differences in survival that is independent of tumors. Additional consideration is given to selection of test statistics, and a test is proposed that is sensitive specifically to cases where the same tumor endpoints are affected in multiple sexes and species. Applications of the procedures to results of National Toxicology Program (NTP) bioassays concerning decabromodiphenyl oxide and iodinated glycerol illustrate the sensitivity of tests based on different test statistics to distinct alternative hypotheses. When compared with the qualitative conclusions of the NTP regarding the strength of evidence for a carcinogenic effect in the same bioassays, the results presented suggest that the methods can be useful in clarifying otherwise equivocal evidence for carcinogenicity. Various difficulties are discussed relevant to the construction of exact combined fatal and incidental tumor tests analogous to the tests of Peto et al. (1980, IARC Monogr. Suppl. 2).

Age Factors↗
PubMed1989

Evaluation of uncertainty in input parameters to pharmacokinetic models and the resulting uncertainty in output.

Physiologically-based pharmacokinetic (PBPK) models may be used to predict the concentrations of parent chemical or metabolites in tissues, resulting from specified chemical exposures. An important application of PBPK modeling is in assessment of carcinogenic risks to humans, based on animal data. The parameters of a PBPK model may include metabolic parameters, blood/air and tissue/blood partition coefficients, and physiological parameters, such as organ weights and blood flow rates. Uncertainty in estimates of these parameters results in uncertainty regarding tissue concentrations and resulting risks. Data are reviewed relevant to the quantification of these uncertainties, for a PBPK model-based risk assessment for tetrachloroethylene. Probability distributions are developed to express uncertainty in model parameters, and uncertainties are propagated by a sequence of operations that simulates processes recognized as contributing to estimates of human risk. Distributions of PBPK model output and human risk estimates are used to characterize uncertainty resulting from uncertainty in model parameters.

Animals↗
PubMed1989

Choice of dose measure for extrapolating carcinogenic risk from animals to humans: an empirical investigation of 23 chemicals.

When estimating carcinogenic risk in humans from animal data, animal to human extrapolation is often accomplished by assuming that humans and animals are equally sensitive when dose is measured appropriately in common units in both species. This paper reports on an empirical investigation of several dose units, based on data from 23 chemicals for which both animal and human data were available. The dose units were evaluated using a measure called "bias," which represents roughly the factor by which the TD25 calculated from animal data must be multiplied to correspond, on average, to the TD25 calculated from human data. (A TD25 is the average human dose rate per unit of body weight in mg kg-1 d-1, administered between ages 20 and 65, that would cause an extra lifetime cancer risk of 25%.) Biases of greater than one mean that estimates of human risk from animal data exceeded estimates made from human data. Five dose measures are evaluated in this paper; they are based on several risk assessment methods. The resulting ranges of biases are: dose rate per surface area in mg m-2 d-1, 2.1 to 12; dose rate per unit of body weight in mg kg-1 d-1, 0.36 to 1.6; parts per million in diet, 1.1 to 6.2; cumulative dose per unit of body weight in mg kg-1 per lifetime, 13 to 84; parts per million in air, 1.1 to 4.5. These findings suggest that all of these measures of dose except dose rate per unit of body weight tend to result in overestimation of human risk.

Administration, Inhalation↗
PubMed1985

Evaluation for compensation of asbestos-exposed individuals. II. Apportionment of risk for lung cancer and mesothelioma.

The incidence of lung cancer in the cigarette smoking population occupationally exposed to asbestos is inordinately high. A method for apportioning risk to these two agents has been developed. It utilizes degree of asbestos and smoking exposures; the time interval from onset and, where applicable, termination of both exposures; the time interval to diagnosis of lung cancer; and morphologic, physiologic, and radiological evidence of pulmonary fibrosis.

Adolescent↗
PubMedDate not supplied

Simultaneous HPLC gradient analysis of 15 benzodiazepines and selected metabolites in postmortem blood.

The simultaneous identification and quantitation of 15 benzodiazepines and selected metabolites in postmortem blood, serum, or liver homogenate is described. The assay involves extraction with diethylether, followed by an acid clean-up step of the ether. Chromatographic separation was achieved on a Nova-Pak phenyl 18 column using ultraviolet detection at 240 nm. A gradient HPLC system was developed to improve separation of nitro-reduction metabolites from the solvent front and endogenous peaks. The mobile phases consisted of a gradient from 15 to 28% acetonitrile in 40 mM potassium phosphate buffer. Within-run and day-to-day precision were generally 10-15%. The method described is sensitive and reproducible for the analysis of benzodiazepine concentrations in postmortem tissues.

Benzodiazepines↗