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D Krewski

Publications and source records attributed to D Krewski.

At least 73 records · Page 4Linked to original sources
PubMed1995

Cancer risk due to occupational exposure to polycyclic aromatic hydrocarbons.

Polycyclic aromatic hydrocarbons (PAHs) demonstrate carcinogenic activity in animal models. Although some epidemiologic studies have implicated PAHs as risk factors for human cancer, the evidence reported to date has not been consistent. The purpose of this report is to describe the associations between occupational exposure to PAHs in the workplace and each of 14 types of cancer. A population-based, case-control study was carried out in Montreal to investigate associations between a large variety of environmental and occupational exposures on the one hand, and several types of cancer on the other. A detailed job history was obtained from each subject along with information on a number of potential confounders. Each job history was reviewed by a team of experts, who used this information to construct a corresponding history of occupational exposures. Among the PAH exposures considered were benzo(a)pyrene (B(a)P) and five categories of PAHs defined on the basis of the source material, namely, wood, petroleum, coal, other sources, and any source. Altogether, 3,730 cancer patients and 533 population controls were interviewed and their job exposure histories coded. For each of 14 types of cancer analyzed, three control groups were available: other cancer patients, population controls, and the pooled set of cancer and population controls. The associations between 14 cancer types and 6 PAH exposures were analyzed using logistic regression methods. For most types of cancer evaluated, there was no evidence of excess risk due to PAHs at the levels encountered in the occupations in which PAH exposure has been prevalent in the Montreal area. For a few cancer sites--the esophagus, the pancreas, and the prostate gland--there were suggestions of excess risk; these observations are noteworthy hypotheses for further investigation. For lung cancer, there appeared to be an increased risk due to PAHs among nonsmokers and light smokers, but not among heavy smokers.

Adult↗
PubMed1995

Associations between cigarette smoking and each of 21 types of cancer: a multi-site case-control study.

BACKGROUND: Although the effects of cigarette smoking on cancer risk have been well documented, there remain several outstanding issues to be clarified, including the determination of which types of cancer are associated with smoking and estimation of the magnitude of the effect of smoking on different types of cancer. A further issue is whether the effects seen elsewhere can be demonstrated in Canada, where tobacco products differ somewhat from those in other countries. METHODS: A case-control study was undertaken in Montreal to investigate the associations between a large number of environmental and occupational exposures on the one hand, and several types of cancer on the other. Between 1979 and 1985, interviews were carried out with incident male cases of 21 types of cancer, including 15 anatomical sites and six histological subtypes. The interview was designed to obtain detailed information on smoking histories, job histories, and other potential confounders. Altogether, 3730 cancer patients and 533 population controls were interviewed. For each type of cancer analysed, two control groups were used: population controls and cancer controls (selected from among other cancer patients). The purpose of the present analysis is to estimate the relative risk of each of 21 types of cancer in relation to smoking and to estimate the percentage of cancer cases attributable to cigarette smoking. RESULTS: Separate analyses conducted with the two control groups produced similar results. Of the many sites of cancer examined, the following were not associated with cigarette smoking: colon, rectum, liver, prostate, kidney and skin (melanoma). Within the lymphoreticular system, there was no excess risk of Hodgkin's lymphoma, although the results for non-Hodgkin's lymphoma were weakly suggestive of an association with smoking. The following sites were clearly associated with smoking: lung (odds ratio [OR] = 12.1), bladder (OR = 2.4), oesophagus (OR = 2.4), stomach (OR = 1.7), and pancreas (OR = 1.6). Population attributable risk percentages due to smoking were 90% for lung, 53% for bladder, 54% for oesophagus, 35% for stomach, and 33% for pancreas. CONCLUSIONS: Of the 21 types of cancer examined, the following were associated with smoking among men in Montreal: lung (including all major histological subtypes), bladder (and its main histological subtypes), oesophagus, stomach and pancreas. Smoking likely accounts for a large proportion of cancers occurring at these sites.

Adult↗
PubMed1995

A simple data transformation for estimating benchmark doses in developmental toxicity experiments.

Developmental anomalies induced by toxic chemicals may be identified using laboratory experiments with rats, mice or rabbits. Multinomial responses of fetuses from the same mother are often positively correlated, resulting in overdispersion relative to multinomial variation. In this article, a simple data transformation based on the concept of generalized design effects due to Rao-Scott is proposed for dose-response modeling of developmental toxicity. After scaling the original multinomial data using the average design effect, standard methods for analysis of uncorrelated multinomial data can be applied. Benchmark doses derived using this approach are comparable to those obtained using generalized estimating equations with an extended Dirichlet-trinomial covariance function to describe the dispersion of the original data. This empirical agreement, coupled with a large sample theoretical justification of the Rao-Scott transformation, confirms the applicability of the statistical methods proposed in this article for developmental toxicity risk assessment.

Abnormalities, Drug-Induced↗
PubMed1995

Uncertainty, variability, and sensitivity analysis in physiological pharmacokinetic models.

Physiologically based pharmacokinetic (PBPK) models are now commonly used to predict the dose of toxic metabolites of chemical substances reaching target tissues. A typical PBPK model can involve 20 or more physiological, physiochemical, and biochemical parameters, each of which is estimated with some degree of error. In this article, methods for assessing the impact of uncertainty in the parameter values on prediction of tissue dose are proposed, along with methods for identifying those parameters to which predictions of tissue doses are most sensitive. Many of the model parameters are related to body weight, which is assumed to vary in accordance with a doubly truncated normal distribution. The application of the proposed methods is illustrated using a PBPK model for benzene.

Animals↗
PubMed1994

Case-control study of residential radon and lung cancer in Winnipeg, Manitoba, Canada.

A case-control study of lung cancer in relation to exposure to radon in homes in Winnipeg, Manitoba, Canada, was conducted during 1983-1990. In total, 738 individuals with histologically confirmed incident cases of lung cancer were interviewed, along with 738 controls matched on age (+/- 5 years) and sex. Radon dosimeters were placed in all residences in which the study subjects had reported living within the Winnipeg metropolitan area for at least 1 year. Radon dosimetry was done by means of integrated alpha-track measurements over a 1-year period. In the homes monitored, the average level of radon-222 was about 120 becquerels (Bq)/m3 in the bedroom area and 200 Bq/m3 in the basement. After adjusting for cigarette smoking and education, no increase in the relative risk for any of the histologic types of lung cancer observed among the cases was detected in relation to cumulative exposure to radon.

Adult↗
PubMed1994

Effects of low ambient levels of ozone and sulfates on the frequency of respiratory admissions to Ontario hospitals.

To investigate the acute respiratory health effects of ambient air pollution, the number of emergency of urgent daily respiratory admissions to 168 acute care hospitals in Ontario were related to estimates of exposure to ozone and sulfates in the vicinity of each hospital. Ozone levels were obtained from 22 monitoring stations maintained by the Ontario Ministry of the Environment for the period January 1, 1983 to December 31, 1988. Daily levels of sulfates were recorded at nine monitoring stations representing three different networks operated by the Ontario Ministry of the Environment and Environment Canada. Positive and statistically significant associations were found between hospital admissions and both ozone and sulfates recorded on the day of admission and up to 3 days prior to the date of admission. Five percent of daily respiratory admissions in the months of May to August were associated with ozone, with sulfates accounting for an additional 1% of these admissions. Ozone was a stronger predictor of admissions than sulfates. Positive and statistically significant (P < 0.05) associations were observed between the ozone-sulfate pollution mix and admissions for asthma, chronic obstructive pulmonary disease, and infections. Positive associations were also found in all age groups, with the largest impact on infants (15% of admissions associated with the ozone-sulfate pollution mix) and the least effects on the elderly (4%). Temperature had no effect on the air pollution-admission relationship. Ozone (lagged 1 day) and sulfates (lagged 1 day) displayed a positive association with respiratory admissions for 91 and 100% of the 168 acute care hospitals, respectively. Air pollution was not related to a class of nonrespiratory admissions, which served as a negative control, nor was it related to admissions in the winter months of December to March, when ozone and sulfate levels are low and when people spend a considerable amount of time indoors.

Adolescent↗
PubMed1994

Are the apparent effects of cigarette smoking on lung and bladder cancers due to uncontrolled confounding by occupational exposures?

It has been suggested that the well known associations between smoking and cancer may in part reflect inadequately controlled confounding due to occupational exposures. The purpose of the present analysis is to describe the association between cigarette smoking and both lung and bladder cancers, taking into account the potential confounding effects of over 300 covariates, most of which represent occupational exposures. A population-based case-control study was undertaken in Montreal to investigate the associations between a large variety of environmental and occupational exposures, on the one hand, and several types of cancer, on the other. Interviews were carried out with male incident cases of several sites of cancer, including 857 lung cancers and 484 bladder cancers. A group of non-smoking-related cancers, comprising 1,707 interviewed subjects, was used as one control group. Additionally, 533 population controls were interviewed and constituted a second control group. Interview information included detailed lifetime smoking histories, job histories, and other potential confounders. Each job history was reviewed by a team of experts who translated it into a history of occupational exposures. These occupational exposures, as well as nonoccupational covariates, were treated as potential confounders in the analysis of cigarette smoking effects. Regardless of whether population controls or cancer controls were used, the odds ratio (OR) between smoking and lung cancer (ranging from 12 to 16 for ever vs never smokers) was not materially affected by adjustment for occupational exposures. The odds ratios for bladder cancer (ranging from 2 to 3) were also unaffected by confounding due to occupational exposures.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Applications of multinomial dose-response models in developmental toxicity risk assessment.

Reproductive and developmental anomalies induced by toxic chemicals may be identified using laboratory experiments with small mammalian species such as rats, mice, and rabbits. In this paper, dose-response models for correlated multinomial data arising in studies of developmental toxicity are discussed. These models provide a joint characterization of dose-response relationships for both embryolethality and teratogenicity. Generalized estimating equations are used for model fitting, incorporating overdispersion relative to the multinomial variation due to correlation among littermates. The fitted dose-response models are used to estimate benchmark doses in a series of experiments conducted by the U.S. National Toxicology Program. Joint analysis of prenatal death and fetal malformation using an extended Dirichlet-trinomial covariance function to characterize overdispersion appears to have statistical and computational advantages over separate analysis of these two end points. Benchmark doses based on overall toxicity are below the minimum of those for prenatal death and fetal malformation and may, thus, be preferred for risk assessment purposes.

Abnormalities, Drug-Induced↗
PubMed1994

Tests for trend in developmental toxicity experiments with correlated binary data.

In this article, the operating characteristics of recently proposed tests for trend in correlated binary data arising in laboratory studies of developmental toxicity are examined using both computer-generated and experimental data. Specifically, we consider adjusted Cochran-Armitge tests based on the Rao-Scott transformation which are of the same general form as that for uncorrelated data. In addition, generalized score tests based on generalized estimating equations allowing for extrabinomial variation in the data are discussed. Specific forms of these statistics demonstrating favorable type I and type II error rates are identified and recommended for use in practice. The application of these tests is illustrated using data from studies of developmental toxicity that have been reported in the literature.

Abnormalities, Drug-Induced↗
PubMed1994

Applications of physiologic pharmacokinetic modeling in carcinogenic risk assessment.

The use of physiologically based pharmacokinetic (PBPK) models has been proposed as a means of estimating the dose of the reactive metabolites of carcinogenic xenobiotics reaching target tissues, thereby affording an opportunity to base estimates of potential cancer risk on tissue dose rather than external levels of exposure. In this article, we demonstrate how a PBPK model can be constructed by specifying mass-balance equations for each physiological compartment included in the model. In general, this leads to a system of nonlinear partial differential equations with which to characterize the compartment system. These equations then can be solved numerically to determine the concentration of metabolites in each compartment as functions of time. In the special case of a linear pharmacokinetic system, we present simple closed-form expressions for the area under the concentration-time curves (AUC) in individual tissue compartments. A general relationship between the AUC in blood and other tissue compartments is also established. These results are of use in identifying those parameters in the models that characterize the integrated tissue dose, and which should therefore be the primary focus of sensitivity analyses. Applications of PBPK modeling for purposes of tissue dosimetry are reviewed, including models developed for methylene chloride, ethylene oxide, 1,4-dioxane, 1-nitropyrene, as well as polychlorinated biphenyls, dioxins, and furans. Special considerations in PBPK modeling related to aging, topical absorption, pregnancy, and mixed exposures are discussed. The linkage between pharmacokinetic models used for tissue dosimetry and pharmacodynamic models for neoplastic transformation of stem cells in the target tissue is explored.

Animals↗
PubMed1993

Physiological pharmacokinetics and cancer risk assessment.

There has been considerable progress in recent years in developing physiological models for the pharmacokinetics of toxic chemicals and in the application of these models in cancer risk assessment. Physiological pharmacokinetic models consist of a number of individual compartments, based on the anatomy and physiology of the mammalian organism of interest, and include specific parameters for metabolism, tissue binding, and tissue reactivity. Because of the correspondence between these compartments and specific tissues or groups of tissues, these models are particularly useful for predicting the doses of biologically active forms of toxic chemicals at target tissues under a wide variety of exposure conditions and in different animal species, including humans. Due to their explicit characterization of the biological processes governing pharmacokinetic behaviour, these models permit more accurate predictions of the dose of active metabolites reaching target tissues in exposed humans and hence of potential cancer risk. In addition, physiological models also permit a more direct evaluation of the impact of parameter uncertainty and inter-individual variability in cancer risk assessment. In this article, we review recent developments in physiologic pharmacokinetic modeling for selected chemicals and the application of these models in carcinogenic risk assessment. We examine the use of these models in integrating diverse information on pharmacokinetics and pharmacodynamics and discuss challenges in extending these pharmacokinetic models to reflect more accurately the biological events involved in the induction of cancer by different chemicals.

Carcinogens↗
PubMed1993

AMESFIT: a microcomputer program for fitting linear-exponential dose-response models in the Ames Salmonella assay.

The Ames Salmonella/microsome assay remains the most widely used microbial test for genotoxicity. In this article, we describe a microcomputer program developed to fit a linear-exponential dose-response model to Ames assay data for established mutagens. The model includes a linear term to describe the mutagenic effects of the test agent at low to moderate doses and an exponential attenuation factor to accommodate downturns at high doses due to cytotoxicity. Quasi-likelihood methods are used to obtain estimates of the unknown model parameters, thereby avoiding the need to fully specify the distribution of the experimental data. This method of estimation also allows for extra-Poisson variation that is characteristic of counts of mutant colonies of bacteria observed in the Ames assay. The particular linear-exponential model used here was developed for use in the analysis of a recent large-scale collaborative trial using the Ames assay sponsored by the International Programme on Chemical Safety. The use of our program is illustrated using sample data sets taken from that collaborative study.

Dose-Response Relationship, Drug↗
PubMed1993

An overview of the report: correlation between carcinogenic potency and the maximum tolerated dose: implications for risk assessment.

Current practice in carcinogen bioassay calls for exposure of experimental animals at doses up to and including the maximum tolerated dose (MTD). Such studies have been used to compute measures of carcinogenic potency such as the TD50 as well as unit risk factors such as q1 * for predicting low-dose risks. Recent studies have indicated that these measures of carcinogenic potency are highly correlated with the MTD. Carcinogenic potency has also been shown to be correlated with indicators of mutagenicity and toxicity. Correlation of the MTDs for rats and mice implies a corresponding correlation in TD50 values for these two species. The implications of these results for cancer risk assessment are examined in light of the large variation in potency among chemicals known to induce tumors in rodents.

Animals↗
PubMed1993

A Weibull model for the estimation of tumorigenic potency.

In this paper, a new method of estimating tumorigenic potency is proposed that takes into account information on survival and, when available, the underlying cause of death. Specifically, Weibull distributions are used to describe the time to tumor occurrence (X), the time to death as a result of tumor occurrence (Y), and the time of death from causes other than tumor occurrence (Z). The distributions of X and Y are related via a lethality parameter p lying between 0 (incidental tumors) and 1 (rapidly fatal tumors). The index of tumorigenic potency is defined as the dose inducing a specified excess tumor response rate (in the range of 25%-50%) following exposure for an extended period encompassing most of the expected lifespan. Application of the proposed method is illustrated using several data sets taken from the literature.

2-Acetylaminofluorene↗
PubMed1993

Modeling the Ames Salmonella/microsome assay.

Of the many short-term tests for mutagenicity that have been proposed in recent years, the Ames Salmonella/microsome assay is the single most widely used and most thoroughly validated in vitro test system. This assay uses cells cultured in a soft agar containing a trace amount of histidine to allow growth of auxotrophic bacteria, and is designed to detect reverse mutations from auxotrophic cells to histidine-independent prototrophic cells. In this paper, statistical models that have been proposed for the analysis of Ames test data are reviewed, including those of a mechanistic and empirical nature. An extension to the class of biologically based models derived by Margolin, Kaplan, and Zeiger (1981, Proceedings of the National Academy of Sciences 78, 3779-3783) is proposed by allowing for diffusion of histidine within the plate agar. Quasi-likelihood methods for estimating the model parameters are presented, and applied to 1,120 data sets from a recent collaborative trial sponsored by the International Programme on Chemical Safety.

Animals↗
PubMed1993

Radon, cigarette smoke, and lung cancer: a re-analysis of the Colorado Plateau uranium miners' data.

Much of our knowledge regarding the interaction of radon and tobacco smoke in the etiology of human lung cancer derives from studies of uranium miners. In this article, we present a re-analysis of lung cancer mortality in the Colorado Plateau miners' cohort within the framework of the two-mutation clonal expansion model of carcinogenesis. This analysis takes into account the patterns of exposure to radon and cigarette smoke experienced by individuals in the cohort. A simultaneous re-analysis of the British doctors' cohort indicated that those model parameters relating to the effects of tobacco were comparable in the two data sets. We found no evidence of interaction between radon and tobacco smoke with respect to their joint effect on the first or second stage mutation rates or on the rate of proliferation of initiated cells. The age-specific relative risks associated with joint exposure to radon and cigarette smoke, however, were supra-additive but submultiplicative. The analysis also confirmed that fractionation of radon exposures leads to higher lung cancer risks. Finally, we present some estimates of lung cancer risk from environmental radon exposure for non-smokers and smokers.

Adult↗
PubMed1992

Cancer risk assessment with intermittent exposure.

Applications of methods for carcinogenic risk assessment often focus on estimating lifetime cancer risk. With intermittent or time-dependent exposures, lifetime risk is often approximated on the basis of a lifetime average daily dose (LADD). In this article, we show that there exists a lifetime equivalent constant dose (LECD) which leads to the same lifetime risk as the actual time-dependent exposure pattern. The ratio C = LECD/LADD then provides a measure of accuracy of risk estimates based on the LADD, as well as a basis for correcting such estimates. Theoretical results derived under the classical multistage model and the two-stage birth-death-mutation model suggest that the maximum value of C, which represents the factor by which the LADD may lead to underestimates of risk, will often lie in the range of 2- to 5-fold. The practical application of these results is illustrated in the case of astronauts subjected to relatively short-term exposure to volatile organics in a closed space station environment, and in the case of the ingestion of pesticide residues in food where consumption patterns vary with age.

Adult↗