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Biomedical subjects

D Krewski

Publications and source records attributed to D Krewski.

At least 109 records · Page 6Linked to original sources
PubMed1986

Environmental health risk assessment: hexachlorobenzene.

The process of environmental health risk assessment may be described as a series of distinct stages, ranging from hazard identification and risk estimation to the selection and implementation of an appropriate risk management strategy. An important step in this process is the estimation of health risks at low levels of exposure. The toxicological and epidemiological data base on which such estimates are based are reviewed in the case of hexachlorobenzene (HCB), a persistent organochlorine pesticide, along with data on human exposure. This information is used to assess the potential human health risks attributable to HCB.

Animals↗
PubMed1985

Methylmercury-induced mitochondrial DNA synthesis in neural tissue of cats.

The association between selected neuropathological lesions and effects on mitochondrial and nuclear DNA synthesis was explored in cats exposed in vivo to methylmercuric chloride. Two groups of eight adult female cats ingested 0 or 176 micrograms Hg/kg body wt/day as methylmercuric chloride added daily to their diet. Treated animals and concurrent controls were sacrificed following the onset of clinical signs of toxicity, with the mean termination time being about 12 (range 7-15) weeks. Terminal Hg levels for the control and treated groups respectively were 0.16 +/- 0.02 and 12 +/- 1 ppm in the cerebrum and 0.16 +/- 0.01 and 14 +/- 1 ppm in blood. Hydroxyurea-resistant [3H]thymidine incorporation into DNA in cultured explants of cerebrum and cerebellum, as measured by scintillation counting of extracted DNA, was elevated for treated animals. Autoradiographic analysis indicated that the excess DNA synthesis was cytoplasmic, and deoxyribonuclease resistant, suggesting a mitochondrial DNA origin. The excess DNA synthesis was pronounced in cell types prone to neurodegeneration, specifically the Purkinje cells and the granular cell layer in the cerebellum and the large neurons in the cerebrum. Mitochondrial DNA from neural tissues of an additional five pairs of cats treated for 8 weeks was isolated from cesium chloride/ethidium bromide density gradients. Thymidine incorporation into mitochondrial DNA was greater in methylmercury-treated than control animals. These observations indicate that methylmercury affects mitochondrial DNA synthesis in vivo with a tissue specificity parallel to that of neuropathological lesions.

Animals↗
PubMed1984

Mutagenicity screening of foods. II. Results with fruits and vegetables.

A survey of the mutagenic potential of a wide variety of food products has been initiated with results for 28 different beverages reported previously [Stoltz et al, 1982b]. Here, results for samples of 46 widely consumed fruits and vegetables from six general categories are given. Each sample was concentrated and fractionated by polarity and solubility to give five fractions, each of which was assayed for mutagenic potential with Salmonella typhimurium TA98 and TA100. Although statistical analysis of the data resulted in positive findings for 22 fruit and vegetable samples, only six products (grapes, onions, peaches, raisins, raspberries, strawberries) demonstrated potent mutagenic activity.

Cooking↗
PubMed1984

Determining "safe" levels of exposure: safety factors or mathematical models?

The object of regulatory toxicology is to determine "safe" levels of human exposure to toxicants present in the environment. The traditional safety factor approach is compared to more recent mathematical modeling techniques, outlining the underlying assumptions and statistical properties of each procedure. Several linear extrapolation procedures are examined in detail using computer simulation, along with the impact of nonlinear kinetics on the extrapolation process.

Biotransformation↗
PubMed1983

The power and interpretation of the carcinogenicity bioassay.

Carcinogenicity is a major consideration in the assessment of risks due to environmental chemicals. The carcinogen bioassay therefore is a very important component of the battery of toxicological tests used in hazard evaluation. The strengths and limitations of this bioassay are discussed with emphasis upon the unresolved practical considerations, the interpretation of negative results, the significance of tumors induced in the presence of a high background incidence of naturally occurring tumors, and the difficulties in transspecies extrapolation. These factors, in combination with consideration of the biological mechanisms of chemical cancer induction, will be valuable in assessing the potential risk to man posed by individual chemicals.

Animals↗
PubMed1982

Mutagenicity screening of foods I. Results with beverages.

Following a number of recent reports on the presence of mutagens in certain foods, a general survey of the mutagenic potential of a wide variety of food products has been initiated. Here, results for samples of 28 widely consumed beverages from 13 general categories are reported. Each sample was concentrated and fractionated by polarity and solubility to give up to seven fractions, each of which was assayed for mutagenic potential with Salmonella typhimurium TA98 and TA100 +/- fortified liver homogenate. Fractions showing evidence of either mutagenicity or toxicity were retested at the same and lower concentrations. The utility of the fractionation procedure and the sensitivity of the screening strategy were established by assaying six beverages spiked with known mutagens prior to fractionation. Statistical analysis of the data resulted in positive findings for seven beverages, although confirmation of these results through analysis of a second sample was obtained only for red wine, grape juice, and instant coffee. The remaining 21 beverages showed no strong evidence of mutagenic activity. For those foods for which the variation among replicate plates was largest, the false-positive rate for the two-stage screening procedure employed was estimated to be less than 1% while the false-negative rate for a beverage inducing a threefold increase in the background mutation rate was conservatively estimated to be limited to 14%.

Beverages↗
PubMed1982

Toxicological procedures for assessing the carcinogenic potential of agricultural chemicals.

Pesticides and other agricultural chemicals are now widely used throughout the world as a means of improving crop yields in order to meet the increasing demands being placed upon the global food supply. In Canada, the use of such chemicals is controlled through government regulations established jointly by the Department of Agriculture and the Department of National Health & Welfare. Such regulations require a detailed evaluation of the toxicological characteristics of the chemical prior to its being cleared for use. In this paper, procedures for assessing the carcinogenic potential of agricultural and other chemicals are discussed. Consideration is given to both the classical long-term in vivo carcinogen bioassay in rodent or other species and the more recently developed short-term in vitro tests based on genetic alterations in bacterial and other test systems.

Animals↗
PubMedDate not supplied

Sources of variation in the mutagenic potency of complex chemical mixtures based on the Salmonella/microsome assay.

Twenty laboratories worldwide participated in a collaborative trial sponsored by the International Programme on Chemical Safety on the mutagenicity of complex mixtures as expressed in the Salmonella/microsome assay. The U.S. National Institute of Standards and Technology provided homogeneous reference samples of urban air and diesel particles and a coal tar solution to each participating laboratory, along with samples of benzo[a]pyrene and 1-nitropyrene which served as positive controls. Mutagenic potency was characterized by the slope of the initial linear component of the dose-response curve. Analysis of variance revealed significant interlaboratory variation in mutagenic potency, which accounted for 57-96% of the total variance on a logarithmic scale, depending on the sample, strain and activation conditions. Variation among replicate extractions of organic material (required for the air and diesel particles) and among replicate bioassays within the same laboratory was also appreciable. The average potencies for air and diesel particles in laboratories using Soxhlet extracts were not significantly different from those in laboratories using sonication, although there was larger interlaboratory variation for the Soxhlet method. Repeatability (which approximates the coefficient of variation within laboratories) ranged from 18 to 40% for air and diesel particles extracted using sonication, depending on the strain and activation conditions. Repeatability of Soxhlet-extracted air and diesel particles, however, ranged from about 37 to 89% including outliers and from about 11 to 31% excluding outliers. Repeatability of the coal tar sample and the 2 positive controls was in the range 18-34%. Reproducibility (which approximates the coefficient of variation between laboratories) was generally at least twice repeatability, and exceeded 100% for Soxhlet-extracted air and diesel particles, as well as 1-nitropyrene. Reanalysis of the data omitting observations of more than 1500 revertants/plate generally had little effect on these results. Elimination of outlying observations had limited impact, with the exception of Soxhlet-extracted air and diesel particles. In this case, reproducibility of bioassay results was notably improved, due largely to the omission of results for replicate extractions which varied more than 5-fold within one laboratory. Normalization of the log potency slopes for the mixtures by the corresponding slopes for benzo[a]pyrene tended to reduce this variation, although variation was increased after normalization by 1-nitropyrene. Adjustment for the percentage of organic matter extracted from the air and diesel particulate samples had little effect on variation for sonication-extracted particles, whereas variation was reduced for diesel particles and increased for air particles for Soxhlet.

Air Pollutants↗
PubMedDate not supplied

Overview, conclusions, and recommendations of the IPCS collaborative study on complex mixtures.

The International Programme on Chemical Safety (IPCS) sponsored an international collaborative study to examine the variability associated with the extraction and bioassay of standard reference materials (SRMs) that are complex environmental mixtures provided by the U.S. National Institute of Standards and Technology (NIST). The study was also intended to evaluate the feasibility of establishing bioassay reference values and ranges for the SRMs. Twenty laboratories from North America, Europe, and Japan participated in the study. As part of the mandatory core protocol, each laboratory extracted the organic material from two particulate samples and bioassayed these extracts. A coal tar polycyclic aromatic hydrocarbon (PAH) solution and two mutagenic control compounds were also subjected to bioassay without prior extraction by the participating laboratories. The bioassay used was the Salmonella/microsomal plate incorporation assay. For the optional portion of the study, a laboratory was free to use the SRMs for any type of exploratory research. The primary purpose of the required portion of the study was to estimate the intra- and inter-laboratory variability in mutagenic potencies of the test materials and to determine whether or not the NIST mixtures could be used as reference materials by others performing the Salmonella assay. Repeatability (intra-laboratory variance) of the bioassay results ranged from 16% to 88% depending on the SRM and the bioassay conditions (tester strain and metabolic activation), whereas reproducibility (inter-laboratory variance) ranged from 33% to 152%. Between-laboratory variability was the main source of variation accounting for approximately 55-95% of the total variation for the three environmental samples. Variation in the mutagenic potency of the control compounds was comparable, with the exception of 1-nitropyrene for which the reproducibility ranged from 127% to 132%. In summary, NIST SRMs provided useful materials for an international inter-laboratory study of complex mixtures. By establishing both intra- and inter-laboratory variance for the mutagenicity results for these materials, the usefulness of these SRMs as reference materials for the Salmonella bioassay was established, critical procedures within the bioassay protocol were identified, and recommendations for future efforts were delineated.

International Cooperation↗
PubMedDate not supplied

Saccharin: a toxicological and historical perspective.

Saccharin, first synthesized in 1879, eventually became popular as an inexpensive substitute for sugar, particularly as a non-caloric sweetner. The dispute concerning the safety of saccharin for human consumption is almost as old as saccharin itself. In this article, the history concerning the uses of saccharin and the accompanying controversy are reviewed. In addition, the spectrum of toxicological and epidemiological studies to which saccharin has been subjected are also examined. While the toxicological data indicate that saccharin is probably the agent solely responsible for the bladder tumors observed in second generation male rats, the epidemiological studies provide, at best, an equivocal relationship between the consumption of saccharin and bladder cancer. A benefit-risk evaluation for saccharin showed few, if any documentable benefits from the use of saccharin and much genuine uncertainty concerning the potential risks for ingestion by man. This element of genuine uncertainty as to the extent of human risk posed to man is the crux of saccharin's past and its foreseeable future.

Animals↗
PubMedDate not supplied

A comparison of statistical methods for low dose extrapolation utilizing time-to-tumor data.

The assessment of health risks due to low levels of exposure to potential environmental hazards based on the results of toxicological experiments necessarily involves extrapolation of results obtained at relatively high doses to the low dose region of interest. In this paper, different statistical extrapolation procedures which take into account both time-to-response and the presence of competing risks are compared using a large simulated data base. The study was designed to cover a range of plausible dose response models as well as to assess the effects of competing risks, background response, latency and experimental design on the performance of the different extrapolation procedures. It was found that point estimates of risk in the low dose region may differ from the actual risk by a factor of 1000 or more in certain situations, even when precise information on the time of occurrence of the particular lesion of interest is available. Although linearized upper confidence limits on risk can be highly conservative when the underlying dose response curve is sublinear in the low dose region, they were found not to exceed the actual risk in the low dose region by more than a factor of 10 in those cases where the underlying dose response curve was linear at low doses.

Animals↗
PubMedDate not supplied

Reanalysis of the Harvard Six Cities Study, part I: validation and replication.

Because the results of the Harvard Six Cities Study played a critical role in the establishment of the current U.S. ambient air quality objective for fine particles (PM(2.5)), the U.S. Environmental Protection Agency, industry, and nongovernmental organizations called for an independent reanalysis of this study to validate the original findings reported by Dockery and colleagues in the New England Journal of Medicine (vol. 329, pp. 1753-1759) in 1993. Validation of the original findings was accomplished by a detailed statistical audit and replication of original results. With the exception of occupational exposure to dust (14 discrepancies of 249 questionnaires located for evaluation) and fumes (15/249), date of death (2/250), and cause of death (2/250), the audit identified no discrepancies between the original questionnaires and death certificates in the audit sample and the analytic file used by the original investigators. The data quality audit identified a computer programming problem that had resulted in early censorship in 5 of the 6 cities, which resulted in the loss of approximately 1% of the reported person-years of follow-up; the reanalysis team updated the Six Cities cohort to include the missing person-years of observation, resulting in the addition of 928 person-years of observation and 14 deaths. The reanalysis team was able to reproduce virtually all of the original numerical results, including the 26% increase in all-cause mortality in the most polluted city (Stubenville, OH) as compared to the least polluted city (Portage, WI). The audit and validation of the Harvard Six Cities Study conducted by the reanalysis team generally confirmed the quality of the data and the numerical results reported by the original investigators. The discrepancies noted during the audit were not of epidemiologic importance, and did not substantively alter the original risk estimates associated with particulate air pollution, nor the main conclusions reached by the original investigators.

Air Pollutants↗
PubMedDate not supplied

Reanalysis of the Harvard Six Cities Study, part II: sensitivity analysis.

Following the validation and replication of the Harvard Six Cities Study (Krewski et al., this issue), we conducted a wide range of sensitivity analyses to explore the observed associations between long-term exposure to fine particle or sulfate air pollution and mortality. We examined the impact of alternative risk models on estimates of risk, taking into account covariates not included in the original analyses. These risk models provided a basis for identifying covariates that may confound or modify the association between fine particle or sulfate air pollution and mortality, and for identifying sensitive population subgroups. The possibility of confounding due to occupational exposures was also investigated. Residence histories were coded for the study subjects and were used to examine temporal patterns of exposure and risk. Our sensitivity analyses showed the mortality risk estimates for fine particle and sulfate air pollution to be highly robust against alternative risk models of the Cox proportional hazards family, including models with additional covariates from the original questionnaires not included in the original published analyses. There was limited evidence of departures from the proportional hazards assumption. Flexible exposure-response models provided some evidence of departures from linearity at both low and high sulfate concentrations. Incorporating information on changes over time in cigarette smoking and body mass index had little effect on the association between fine particles and mortality. There was limited evidence of variation in risk with attained age, gender, smoking status, occupational exposure to dust and fumes, marital status, heart or lung diseases, or lung function. However, air pollution risk did appear to decreasing with increasing educational attainment. Extensive adjustment for occupation using aggregate indices of occupational "dirtiness" and occupational exposure to known lung carcinogens had little impact on the mortality risks associated with particulate air pollution. Our evaluation of population mobility indicated that relatively few subjects moved from their original city of residence. Attempts to identify critical exposure time windows were limited by the lack of marked interindividual variation in temporal exposure patterns throughout the study period. Overall, this extensive sensitivity analysis both supported the conclusions reached by the original investigators and demonstrated the robustness of these conclusions to alternative analytic approaches.

Age Factors↗