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Biomedical subjects

M E Meek

Publications and source records attributed to M E Meek.

18 recordsLinked to original sources
PubMed2003

Releases from copper smelters and refineries and zinc plants in Canada: human health exposure and risk characterization.

In these assessments of releases from copper smelters and refineries and from zinc plants as Priority Substances under the Canadian Environmental Protection Act (CEPA), available data were critically evaluated to determine if environmental exposure to selected components of these releases poses a risk to human health. The data on airborne levels of a variety of toxic substances near these facilities in Canada were obtained from the companies or provinces and systematically analyzed. Monitoring of ambient air near the Canadian copper smelters and refineries and zinc plants indicates that releases from these facilities result in increased potential for inhalation exposure of local human populations to several components of releases (As, Cd, Cr, Ni, Pb, SO(2) and PM(10)). Airborne levels in the vicinity of these metal-processing operations overlap those associated with cardiorespiratory effects for PM(10), and exceed health-based guidelines for SO(2) and, near some facilities, Pb. In addition, the margin between levels of As, Cd, Cr and Ni near these facilities in Canada and carcinogenic potency for each of these metals is relatively small near copper smelters, larger near copper refineries, and intermediate near zinc plants. On this basis, the risk to human health from environmental exposure to releases from these facilities is considered to be high compared with other Priority Substances assessed under CEPA, especially for facilities where copper is smelted.

Air Pollutants↗
PubMed2003

Assessing the dose-dependency of allometric scaling performance using physiologically based pharmacokinetic modeling.

The performance of allometric scaling of dose as a power of body weight under a variety of extrapolation conditions with respect to species, route, exposure intensity, and mechanism/mode of action, remains untested in many cases. In this paper, animal-human internal dose ratio comparisons have been developed for 12 chemicals (benzene, carbon tetrachloride, chloroform, diisopropylfluorophosphate, ethanol, ethylene oxide, methylene chloride, methylmercury, styrene, tetrachloroethene, trichloroethene, and vinyl chloride). This group of predominantly volatile and lipophilic chemicals was selected on the basis that their kinetics have been well-studied and can be predicted in mice, rats, and humans using physiologically based pharmacokinetic (PBPK) models. PBPK model predictions were compared to the allometric scaling predictions for interspecies extrapolation. Recommendations for the application of the allometric scaling are made with reference to internal dose measure (mode of action) and concentration level. The results of this assessment generally support the use of scaling factors recommended in the published literature, which includes scaling factors of 1.0 for risk assessments in which toxicity is attributed to the parent chemical or stable metabolite, and -0.75 for dose-response assessments in which toxicity is attributed to the formation of a reactive metabolite from an inhaled compound. A scaling factor of 0.75 is recommended for dose-response assessments of orally administered compounds in which toxicity is attributed to the parent chemical or stable metabolite and 1.0 for risk assessments in which toxicity is attributed to the formation of a reactive metabolite from a compound administered by the oral route. A dose-dependency in the results suggests that the scaling factors appropriate at high exposures may differ from those at low exposures, primarily due to the impact of saturable metabolism.

Administration, Inhalation↗
PubMed2002

Guidelines for application of chemical-specific adjustment factors in dose/concentration-response assessment.

This manuscript addresses guidance in the use of kinetic and dynamic data to inform quantitatively extrapolations for interspecies differences and human variability in dose-response assessment developed in a project of the International Programme on Chemical Safety (IPCS) initiative on Harmonisation of Approaches to the Assessment of Risk from Exposure to Chemicals. The guidance has been developed and refined through a series of planning and technical meetings and larger workshops of a broad range of participants from academia, government agencies and the private sector. The guidance for adequacy of data for replacement of common defaults for interspecies differences and human variability is presented in the context of several generic categories including: determination of the active chemical species, choice of the appropriate metric (kinetic components) or endpoint (dynamic components) and nature of experimental data, the latter which includes reference to the relevance of population, route and dose and the adequacy of the number of subjects/samples. The principal objective of this guidance developed primarily as a resource for risk assessors, is to foster better understanding of the components of and criteria for adequacy of chemical-specific data to quantitate interspecies differences and human variability in kinetics and dynamics. It is anticipated that this guidance will also encourage the development of appropriate data and facilitate their incorporation in a consistent fashion in dose-response assessment for regulatory purposes (IPCS, 2001).

Algorithms↗
PubMed2001

Health risk assessment of 1,3-butadiene as a Priority Substance in Canada.

1,3-Butadiene was included in the second list of Priority Substances to be assessed under the Canadian Environmental Protection Act. Potential hazards to human health were characterized on the basis of critical examination of available data on health effects in experimental animals and occupationally exposed human populations, as well as information on mode of action. Based on consideration of all relevant data identified as of April 1998, butadiene was considered highly likely to be carcinogenic to humans, and likely to be a somatic and germ cell genotoxicant in humans. In addition, butadiene may also be a reproductive toxicant in humans. Estimates of the potency of butadiene to induce these effects have been derived on the basis of quantitation of observed exposure-response relationships for the purposes of characterization of risk to the general population in Canada exposed to butadiene in the ambient environment.

Animals↗
PubMed2000

Lessons learned in applying the U.S. EPA proposed cancer guidelines to specific compounds.

An expert panel was convened to evaluate the U.S. Environmental Protection Agency's "Proposed Guidelines for Carcinogen Risk Assessment" through their application to data sets for chloroform (CHCl3) and dichloroacetic acid (DCA). The panel also commented on perceived strengths and limitations encountered in applying the guidelines to these specific compounds. This latter aspect of the panel's activities is the focus of this perspective. The panel was very enthusiastic about the evolution of these proposed guidelines, which represent a major step forward from earlier EPA guidance on cancer-risk assessment. These new guidelines provide the latitude to consider diverse scientific data and allow considerable flexibility in dose-response assessments, depending on the chemical's mode of action. They serve as a very useful template for incorporating state-of-the-art science into carcinogen risk assessments. In addition, the new guidelines promote harmonization of methodologies for cancer- and noncancer-risk assessments. While new guidance on the qualitative decisions ensuing from the determination of mode of action is relatively straightforward, the description of the quantitative implementation of various risk-assessment options requires additional development. Specific areas needing clarification include: (1) the decision criteria for judging the adequacy of the weight of evidence for any particular mode of action; (2) the role of mode of action in guiding development of toxicokinetic, biologically based or case-specific models; (3) the manner in which mode of action and other technical considerations provide guidance on margin-of-exposure calculations; (4) the relative roles of the risk manager versus the risk assessor in evaluating the margin of exposure; and (5 ) the influence of mode of action in harmonizing cancer and noncancer risk assessment methodologies. These points are elaborated as recommendations for improvements to any revisions. In general, the incorporation of examples of quantitative assessments for specific chemicals would strengthen the guidelines. Clearly, any revisions should retain the emphasis present in these draft guidelines on flexibility in the use of scientific information with individual compounds, while simultaneously improving the description of the processes by which these mode-of-action data are organized and interpreted.

Animals↗
PubMed1998

Relevance of carcinogenicity bioassays in mice in assessing potential health risks associated with exposure to methylene chloride.

Considerable research has been conducted to identify possible mechanisms of the carcinogenicity of methylene chloride in rodents, and to ascertain whether the observed increased incidences of liver and lung tumours in mice exposed to this substance, are relevant in assessing the potential hazards and risks to human health. On the basis of a study that purported to show qualitative differences between murine and human tissues, in the subcellular localization of the Theta-class glutathione S-transferase enzyme responsible for converting methylene chloride to a putative highly unstable, but reactive genotoxic metabolite, it was suggested that the mouse is an inappropriate model for human health risk assessment. However, other studies conducted in vitro with intact cells do not support the hypothesis that a putatively reactive metabolite of methylene chloride must be generated only within the nucleus in order to be able to interact with genomic DNA. Moreover, investigations employing semi-quantitative methods of mRNA hybridization are not convincing in identifying the subcellular localization of active Theta class glutathione S-transferase, and do not support the hypothesis of the differential subcellular localization of this enzyme within the nucleus of mouse, but not human cells. There is therefore, insufficient evidence to support the view that qualitative differences between humans and mice in the subcellular distribution of Theta-class glutathione S-transferase, renders carcinogenicity studies conducted with mice irrelevant in human hazard identification and risk assessment.

Animals↗
PubMed1996

Is ingested inorganic arsenic a "threshold" carcinogen?

Ingested inorganic arsenic (As) is known to be a human carcinogen. An intriguing question is whether there is a threshold for the carcinogenic effects of As, i.e., is there a level below which it does not induce the development of cancer(s)? This Roundtable will discuss the United States Environmental Protection Agency's As risk assessment using the Taiwan data from different viewpoints. It will also consider the hypothesis that there is a threshold for As and data for or against this hypothesis. For example, some scientists believe that epidemiological data cannot answer this question, while others feel that different study designs and larger sampling will provide adequate data. Reasons for each position are given. This Roundtable discussion demonstrates the controversy surrounding the use of the Taiwan data for risk assessment.

Arsenic Poisoning↗
PubMed1995

Approach to health risk determination for metals and their compounds under the Canadian Environmental Protection Act.

The Canadian Environmental Protection Act (CEPA) authorizes the Ministers of the Environment and of Health in Canada to investigate a wide variety of substances that may contaminate the environment and cause adverse effects on the environment and/or on human health. Under the Act, assessments have been completed for 44 environmental contaminants on the first Priority Substances List, including four metals and their compounds. The principles developed for the assessment of risk to human health for priority substances under CEPA are outlined, with specific emphasis on the metals. These include general aspects such as estimation of total exposure from all media, the development of exposure potency indices for carcinogens in lieu of low-dose risk estimates, and incorporation of toxicokinetic and toxicodynamic data, where available, to modify traditionally adopted uncertainty factors for development of tolerable intakes, or concentrations, for nonneoplastic effects. Aspects of the approach to human health risk assessment more specific to the metals considered under CEPA (i.e., arsenic, cadmium, chromium, and nickel) and implications for the subsequent strategic options process are also addressed, including the extent to which various chemical forms could be assessed (i.e., speciation) and essentiality.

Adolescent↗
PubMed1995

Speciation in health risk assessments of metals: evaluation of effects associated with forms present in the environment.

Because metals occur in various forms in the environment, speciation is an issue which must be addressed in regulatory health risk assessment programs. The manner in which speciation was addressed in a federal program in Canada is discussed in this article. Under the Canadian Environmental Protection Act, four metals, including arsenic, cadmium, chromium, and nickel, and their compounds were assessed as priority substances to determine the risk to human health associated with exposure to levels present in the general environment in Canada. The extent to which the speciation of these metals could be considered in these assessments was largely determined by the nature of available data. Very few data were identified on speciation in environmental media to which humans are exposed. Based on available data on health effects, it was possible to conduct assessments on only one form each of arsenic and cadmium (i.e., inorganic arsenic and inorganic cadmium), two forms of chromium (trivalent and hexavalent), and four forms of inorganic nickel (oxidic, sulfidic, soluble, and metallic.

Canada↗
PubMed1983

An investigation of the penetration of ingested asbestos into the normal and abnormal intestinal mucosa of the rat.

To characterize the tissue response associated with the presence of asbestos fibres in the gastro-intestinal wall, duodenal tissues of Wistar rats were examined by light microscopy following injection of a suspension containing amosite fibres into the wall of the duodenum. Intestinal tissues were also examined by light microscopy following oral administration of amosite for 5 days to healthy animals and for up to 7 days to animals with induced gastro-intestinal ulcers. Injection of amosite into the wall of the gastro-intestinal tract resulted in granulomatous lesions characterized by large numbers of macrophages containing crystals with the polarizing characteristics of amosite fibres. Examination by polarizing light microscopy following ingestion of asbestos revealed no such lesions or other histopathological abnormalities in the gut wall of the healthy animals and no intracellular fibres were observed in the animals with ulcers. Light microscopy, therefore, yielded no pathological evidence of widespread transmigration of asbestos from the gastro-intestinal tract of rats, even under conditions of mucosal loss. Further studies involving analysis by electron microscopy are under way.

Administration, Oral↗
PubMed1983

Transmigration of ingested asbestos.

There has been speculation that the ingestion of asbestos in food and drinking water may play some role in the etiology of cancer of the gastrointestinal (GI) tract. An important question in the evaluation of the possible human cancer risk associated with asbestos ingestion is whether fibers can penetrate into and through the GI tract in sufficient numbers to cause adverse systemic or local effects. Factors that complicate interpretation of the available data on the transmigration of ingested asbestos are discussed, and the preliminary results of our ongoing investigation of the penetration of amosite fibers into the normal and abnormal intestinal mucosa of the Wistar rat are reported.

Animals↗
PubMed1983

Asbestos in drinking water: a Canadian view.

For several years now, public health professionals have been faced with evaluating the potential hazards associated with the ingestion of asbestos in food and drinking water. In Canada, this is a subject of particular concern, because of the widespread occurrence of chrysotile asbestos in drinking water supplies. The results of available Canadian monitoring and epidemiologic studies of asbestos in drinking water are reviewed and discussed in light of other published work. It is concluded that the risk to health associated with the ingestion of asbestos, at the levels found in municipal drinking water supplies, is so small that it cannot be detected by currently available epidemiologic techniques.

Asbestos↗
PubMedDate not supplied

Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data.

A complete mode of action human relevance analysis--as distinct from mode of action (MOA) analysis alone--depends on robust information on the animal MOA, as well as systematic comparison of the animal data with corresponding information from humans. In November 2003, the International Life Sciences Institute's Risk Science Institute (ILSI RSI) published a 2-year study using animal and human MOA information to generate a four-part Human Relevance Framework (HRF) for systematic and transparent analysis of MOA data and information. Based mainly on non-DNA-reactive carcinogens, the HRF features a "concordance" analysis of MOA information from both animal and human sources, with a focus on determining the appropriate role for each MOA data set in human risk assessment. With MOA information increasingly available for risk assessment purposes, this article illustrates the further applicability of the HRF for reproductive, developmental, neurologic, and renal endpoints, as well as cancer. Based on qualitative and quantitative MOA considerations, the MOA/human relevance analysis also contributes to identifying data needs and issues essential for the dose-response and exposure assessment steps in the overall risk assessment.

Aging↗
PubMedDate not supplied

Mode of action: oxalate crystal-induced renal tubule degeneration and glycolic acid-induced dysmorphogenesis--renal and developmental effects of ethylene glycol.

Ethylene glycol can cause both renal and developmental toxicity, with metabolism playing a key role in the mode of action (MOA) for each form of toxicity. Renal toxicity is ascribed to the terminal metabolite oxalic acid, which precipitates in the kidney in the form of calcium oxalate crystals and is believed to cause physical damage to the renal tubules. The human relevance of the renal toxicity of ethylene glycol is indicated by the similarity between animals and humans of metabolic pathways, the observation of renal oxalate crystals in toxicity studies in experimental animals and human poisonings, and cases of human kidney and bladder stones related to dietary oxalates and oxalate precursors. High-dose gavage exposures to ethylene glycol also cause axial skeletal defects in rodents (but not rabbits), with the intermediary metabolite, glycolic acid, identified as the causative agent. However, the mechanism by which glycolic acid perturbs development has not been investigated sufficiently to develop a plausible hypothesis of mode of action, nor have any cases of ethylene glycol-induced developmental effects been reported in humans. Given this, and the variations in sensitivity between animal species in response, the relevance to humans of ethylene glycol-induced developmental toxicity in animals is unknown at this time.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Chloroform: exposure estimation, hazard characterization, and exposure-response analysis.

Chloroform has been assessed as a Priority Substance under the Canadian Environmental Protection Act. The general population in Canada is exposed to chloroform principally through inhalation of indoor air, particularly during showering, and through ingestion of tap water. Data on concentrations of chloroform in various media were sufficient to serve as the basis for development of deterministic and probabilistic estimates of exposure for the general population in Canada. On the basis of data acquired principally in studies in experimental animals, chloroform causes hepatic and renal tumors in mice and renal tumors in rats. The weight of evidence indicates that chloroform is likely carcinogenic only at concentrations that induce the obligatory precursor lesions of cytotoxicity and proliferative regenerative response. Since this cytotoxicity is primarily related to rates of formation of reactive, oxidative metabolites, dose response has been characterized in the context of rates of formation of reactive metabolites in the target tissue. Results presented here are from a "hybrid" physiologically based pharmacokinetic (PBPK) animal model that was revised to permit its extension to humans. The relevant measure of exposure response, namely, the mean rate of metabolism in humans associated with a 5% increase in tumor risk (TC05), was estimated on the basis of this PBPK model and compared with tissue dose measures resulting from 24-h multimedia exposure scenarios for Canadians based on midpoint and 95th percentiles for concentrations in outdoor air, indoor air, air in the shower compartment, air in the bathroom after showering, tap water, and food. Nonneoplastic effects observed most consistently at lowest concentrations or doses following repeated exposures of rats and mice to chloroform are cytotoxicity and regenerative proliferation. As for cancer, target organs are the liver and kidney. In addition, chloroform has induced nasal lesions in rats and mice exposed by both inhalation and ingestion at lowest concentrations or doses. The mean rate of metabolism associated with a 5% increase in fatty cysts estimated on the basis of the PBPK model was compared with tissue dose measures resulting from the scenarios already described, and lowest concentrations reported to induce cellular proliferation in the nasal cavities of rats and mice were compared directly with midpoint and 95th percentile estimates of concentrations of chloroform in indoor air in Canada. The degree of confidence in the underlying database and uncertainties in estimates of exposure and in characterization of hazard and dose response are delineated.

Air Pollutants↗
PubMedDate not supplied

1,3-Butadiene: exposure estimation, hazard characterization, and exposure-response analysis.

1,3-Butadiene has been assessed as a Priority Substance under the Canadian Environmental Protection Act. The general population in Canada is exposed to 1,3-butadiene primarily through ambient air. Inhaled 1,3-butadiene is carcinogenic in both mice and rats, inducing tumors at multiple sites at all concentrations tested in all identified studies. In addition, 1,3-butadiene is genotoxic in both somatic and germ cells of rodents. It also induces adverse effects in the reproductive organs of female mice at relatively low concentrations. The greater sensitivity in mice than in rats to induction of these effects by 1,3-butadiene is likely related to species differences in metabolism to active epoxide metabolites. Exposure to 1,3-butadiene in the occupational environment has been associated with the induction of leukemia; there is also some limited evidence that 1,3-butadiene is genotoxic in exposed workers. Therefore, in view of the weight of evidence of available epidemiological and toxicological data, 1,3-butadiene is considered highly likely to be carcinogenic, and likely to be genotoxic, in humans. Estimates of the potency of butadiene to induce cancer have been derived on the basis of both epidemiological investigation and bioassays in mice and rats. Potencies to induce ovarian effects have been estimated on the basis of studies in mice. Uncertainties have been delineated, and, while there are clear species differences in metabolism, estimates of potency to induce effects are considered justifiably conservative in view of the likely variability in metabolism across the population related to genetic polymorphism for enzymes for the critical metabolic pathway.

Animals↗
PubMedDate not supplied

Inhaled formaldehyde: exposure estimation, hazard characterization, and exposure-response analysis.

Formaldehyde has been assessed as a Priority Substance under the Canadian Environmental Protection Act. Probabilistic estimates of exposure of the general population in Canada to formaldehyde in ambient and indoor air are presented. Critical health effects include sensory irritation and the potential to induce tumors in the upper respiratory tract (the nasal region in rodents and potentially the lungs of humans). The majority of the general population is exposed to airborne concentrations of formaldehyde less than those typically associated with sensory irritation (i.e., 0.1 mg/m3). Based primarily upon data derived from laboratory studies, the inhalation of formaldehyde under conditions that induce cytotoxicity and sustained regenerative proliferation within the respiratory tract is considered to present a carcinogenic hazard to humans. At airborne levels for which the prevalence of sensory irritation is minimal (i.e., 0.1 mg/m3), risks of respiratory-tract cancers for the general population estimated on the basis of a biologically motivated case-specific model are exceedingly low. This biologically motivated case-specific model incorporates two-stage clonal expansion and is supported by dosimetry calculations from computational fluid dynamics analyses of formaldehyde flux in various regions of the nose and single-path modeling for the lower respiratory tract. The degree of confidence in the underlying database and uncertainties in estimates of exposure and in characterization of hazard and dose response are delineated.

Air Pollutants↗