Interspecies extrapolation of toxicity data.
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Animals↗
Biomedical subjects
D Krewski
Publications and source records attributed to D Krewski.
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↗
Carcinogenic mixtures.
Human populations are generally exposed simultaneously to a number of toxicants present in the environment, including complex mixtures of unknown and variable origin. While scientific methods for evaluating the potential carcinogenic risks of pure compounds are relatively well established, methods for assessing the risks of complex mixtures are somewhat less developed. This article provides a report of a recent workshop on carcinogenic mixtures sponsored by the Committee on Toxicology of the U.S. National Research Council, in which toxicological, epidemiological, and statistical approaches to carcinogenic risk assessment for mixtures were discussed. Complex mixtures, such as diesel emissions and tobacco smoke, have been shown to have carcinogenic potential. Bioassay-directed fractionation based on short-term screening test for genotoxicity has also been used in identifying carcinogenic components of mixtures. Both toxicological and epidemiological studies have identified clear interactions between chemical carcinogens, including synergistic effects at moderate to high doses. To date, laboratory studies have demonstrated over 900 interactions involving nearly 200 chemical carcinogens. At lower doses, theoretical arguments suggest that risks may be near additive. Thus, additivity at low doses has been invoked as as a working hypothesis by regulatory authorities in the absence of evidence to the contrary. Future studies of the joint effects of carcinogenic agents may serve to elucidate the mechanisms by which interactions occur at higher doses.
Animals↗
Dose-response relationships in carcinogenesis.
Considerable information on the carcinogenic potential of chemical and radiological agents has accumulated from the epidemiological and toxicological studies conducted to date. In this article, we discuss dose-response relationships in carcinogenesis from both empirical and theoretical points of view. Emphasis is placed on the application of biologically based models to describe observed dose-response relationships for exposure to single and multiple agents known to increase cancer risk. The implications of these observations for inferences about possible mechanisms of carcinogenesis are explored.
Animals↗
On the use of historical control data to estimate dose response trends in quantal bioassay.
New tests for trend in proportions, in the presence of historical control data, are proposed. One such test is a simple score statistic based on a binomial likelihood for the "current" study and beta-binomial likelihoods for each historical control series. A closely related trend statistic based on estimating equations is also proposed. Trend statistics that allow overdispersed proportions in the current study are also developed, including a version of Tarone's (1982, Biometrics 38, 215-220) test that acknowledges sampling variation in the beta distribution parameters, and a trend statistic based on estimating equations. Each such trend test is evaluated with respect to size and power under both binomial and beta-binomial sampling conditions for the current study, and illustrations are provided.
Analysis of Variance↗
Additive and multiplicative relative risk in the two-stage clonal expansion model of carcinogenesis.
The effects of exposure to two carcinogens are explored within the context of the two-stage clonal expansion model of carcinogenesis. This biologically based model provides a useful framework for the quantitative description of carcinogenesis, and for defining carcinogenic agents that act as initiators, promoters, and completers. This paper addresses the combined effects of simultaneous lifetime exposure to two carcinogens as well as nonoverlapping partial lifetime exposure to each agent. Whereas the age-specific relative risk for exposure to two initiators or two completers is additive, a multiplicative relative risk model holds for exposure to an initiator and a completer, or to a promoter and a completer. Exposure to two promoters yields supra-multiplicative relative risk. Exposure to an initiator and promoter leads to multiplicative and supra-multiplicative relative risks for simultaneous lifetime and nonoverlapping partial lifetime exposures, respectively. Although departures from the additive relative risk model may thus occur at moderate to high doses, conditions are identified under which additivity will provide a good approximation to the joint risk at low doses. The methods of analysis used in this paper can also be used to determine the joint effects of exposure to two carcinogens which may affect more than one stage (initiation, promotion, completion) of the process of carcinogenesis. In general, the joint effects of exposure to such agents depends on the relative magnitude of the effects on individual stages.
Animals↗
A model-free approach to low-dose extrapolation.
Estimates of risk associated with exposure to low levels of carcinogenic substances present in the environment are generally obtained by linear extrapolation from higher exposure levels at which risks can be estimated directly. In this paper, we examine the scientific basis for the assumption of low-dose linearity in carcinogenic risk assessment and the different statistical methods that have been proposed for linear extrapolation. A model-free approach to linear extrapolation is described and illustrated using epidemiological data on radiation carcinogenesis. The statistical properties of this method are empirically assessed using 572 selected sets of bioassay data.
Carcinogens, Environmental↗
Role of epidemiology in health risk assessment.
Human health risk assessment has been the object of systematic study in recent years, with formal models of risk assessment and risk management having been proposed by several national and international health agencies. The particular model developed by the Environmental Health Directorate of Health and Welfare Canada was examined in some detail and used to focus on the role of epidemiology in the overall process of risk assessment. In addition to providing information fundamental to the identification of environmental carcinogens and the estimation of carcinogenic risks, epidemiology may also play a role in shaping risk perception and in improving risk communication practices. Taken collectively, epidemiologic data on health risks provide a basis for improved disease surveillance and prioritization of public health concerns. Both descriptive and analytic epidemiologic protocols may be used to gather information on disease etiology. Because of the potential for bias and confounding in observational studies of human populations, epidemiological data should be subjected to careful evaluation in accordance with established criteria before a causal relationship between exposure and disease is inferred. Toxicological studies using nonhuman test systems may be used to avoid these problems, but at the expense of obtaining indirect information on human health risks. Nonetheless, toxicological data provide an important complement to epidemiological data, providing information on potential health risks in advance of human exposure and offering a means of indirectly assessing risks in situations where human studies fail to provide informative results. The complementary roles of epidemiology and toxicology in health risk assessment were examined using four case studies. While the epidemiological evidence linking tobacco consumption to lung cancer is now unequivocal, the corresponding data on involuntary smoking, although strongly suggestive of increasing the relative risk of lung cancer, requires further confirmation before providing the same degree of evidence as now exists for active smoking. At present, the best estimates suggest that overall mortality attributable to active smoking may exceed that due to passive smoking by roughly 100-fold. Despite this large difference in health impact, passive smoking continues to be the focus of much public concern, in part because of the involuntary nature of the risk involved. Because of the abundance of good epidemiological data on tobacco, toxicology has assumed a secondary role in defining the health risks associated with smoking. In contrast, while epidemiological studies with saccharin and formaldehyde have provided unequivocal evidence of carcinogenic effects in animals exposed to high doses, thereby raising concerns over potential human carcinogenicity.(ABSTRACT TRUNCATED AT 400 WORDS)
Canada↗
Quantitative factors in chemical carcinogenesis: variation in carcinogenic potency.
The quantitative assessment of toxicological data on the carcinogenic potential of chemicals requires consideration of a number of factors, including mathematical models of the mechanism of carcinogenic action and pharmacokinetic models for the metabolic activation of the parent compound to its reactive metabolite. In this article, the use of such models in estimating carcinogenic potency and in predicting risks at low levels of exposure is discussed, along with other factors involved in the evaluation of carcinogen bioassay data. The Carcinogenic Potency Database (CPDB) established by Gold et al. (1984, Environ. Health Perspect. 58, 9-322) is used to illustrate the application of quantitative approaches to carcinogenic risk assessment and to examine the variation in the potency of chemical carcinogens. Based on an analysis of 585 experiments selected from the CPDB, the risk-specific (10(-6) doses (RSDs) obtained by linear extrapolation from the TD50 were generally within a factor of 5-10 of those derived from the linearized multistage model. The RSDs obtained by linear extrapolation from the TD50 are roughly log-normally distributed with a median of about 20-90 ng/kg/day, depending on the subset of the CPDB considered. This distribution has been used by Rulis (1986, in Food Protection Technology (C. W. Felix, Ed.), pp. 29-37, Lewis, Chelsea, MI) to explore the concept of a threshold of regulation for chemical carcinogens present in the environment at low levels.
Animals↗
Measuring carcinogenic potency.
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Animals↗
Carcinogenic potency and interspecies extrapolation.
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Animals↗
Cancer risks due to occupational exposure to formaldehyde: results of a multi-site case-control study in Montreal.
A case-control study was undertaken in Montreal to investigate the possible associations between occupational exposures and cancers of the following sites: oesophagus, stomach, colo-rectum, liver, pancreas, lung, prostate, bladder, kidney, melanoma and lymphoid tissue. In total, 3,726 cancer patients and 533 population controls were interviewed to obtain detailed lifetime job histories and information on potential confounders. Each job history was translated into a history of occupational exposures. Because of current concerns about formaldehyde carcinogenicity, we carried out a special analysis of the association between exposure to formaldehyde and each type of cancer covered by this study. Separate statistical analyses were carried out for each type of cancer using population controls as well as a control series drawn from among the other cancer sites in the study. Although nearly a quarter of all subjects had undergone occupational exposure to formaldehyde, the levels of exposure were in general quite low. There was no persuasive evidence of an increased risk of any type of cancer among men exposed to these levels of formaldehyde. However, the possibility of a small increase in risk could not be ruled out.
Adult↗
Statistical issues in the analysis of the long-term carcinogenicity bioassay in small rodents: an empirical evaluation of statistical decision rules.
Data on 49 randomly selected studies from the NCI/NTP Carcinogenesis Bioassay Program were reanalyzed using four statistical decision rules to classify substances as either being negative or falling into one of three categories indicating increasing evidence of oncogenicity. The data available for analysis were the crude marginal counts of numbers of animals with specified lesions, as well as the number of animals surviving at the time the studies were terminated. Statistical analysis was based primarily on the Cochran-Armitage test for linear trend in proportions, with and without the use of historical control information. If only concurrent controls were used, classifications of carcinogenicity obtained in between 34 and 57% of the studies, depending on the decision rule used. The incorporation of historical control information into the Cochran-Armitage test statistic led to almost universal findings of carcinogenicity. The data base assembled here was used to estimate false negative and false positive rates for each of the four decision rules.
Animals↗
Pharmacokinetics of methylmercury in the blood of monkeys (Macaca fascicularis).
Statistical analysis of the blood mercury profiles of groups of two and four adult female cynomolgus monkeys (Macaca fascicularis) given single oral doses of 500 micrograms and 50 microCi (25.3 micrograms) methylmercury/kg body wt, respectively, indicates that a two-compartment model best describes the absorption and elimination of methylmercury in blood. Absorption was largely complete within 6 hr, and the half-time of methylmercury during the terminal elimination phase ranged from 10 to 15 days. In addition, three groups of five adult female cynomolgus monkeys were dosed with methylmercury every Monday, Wednesday, and Friday for periods up to 2 years at effective doses of 10, 25, or 50 micrograms methylmercury/kg body wt/day. The average blood levels at steady state were estimated to be 0.27 +/- 0.02, 0.69 +/- 0.03, and 1.51 +/- 0.08 ppm, respectively, with average time taken to achieve 95% of the steady-state blood level being about 92 days. The steady-state blood levels obtained via extrapolation of the results from the two single-dose experiments were significantly different from those actually achieved, indicating that the average steady-state blood levels under chronic dosing conditions may not be accurately estimated on the basis of short-term experiments. The data were also used to examine the impact of different dosing intervals on variation in blood mercury levels.
Animals↗
Statistical considerations in the interpretation of negative carcinogenicity data.
The regulation of toxic substances present in the environment requires that carcinogens be distinguished from noncarcinogens on the strength of the available toxicological and epidemiological evidence for carcinogenicity. In this article, we consider the difficulties associated with establishing strong evidence against carcinogenicity. In particular, the ability of both animal and human studies to detect small increases in tumor occurrence rates is evaluated in statistical terms. Consideration is also given to resolving apparent conflicts between the toxicological and the epidemiological sources of data.
Animals↗
Recent developments in carcinogenic risk assessment.
In this paper, recent developments in the quantitative assessment of carcinogenic risks based on toxicological and epidemiological data are reviewed. In particular, model-free approaches to low-dose risk assessment which involve only the assumption of low-dose linearity are considered. Measures of carcinogenic potency which avoid the need to extrapolate to low doses are also described. The allometric bases for converting risk estimates between species are then discussed. Pharmacokinetic models for determining the dose delivered to the target tissue are examined, and the implications of using such models in extrapolating between doses, of exposure, and species are examined. The application of these concepts in chemical and radiation carcinogenesis is illustrated by means of brief case studies of methylene chloride and Rn. Biologically motivated cancer models based on the initiation-promotion-progression theory of carcinogenesis are discussed and compared with the classical multistage model. The estimation of risks with time-dependent exposure patterns is considered, and conditions under which the use of a time-weighted average dose is appropriate are identified. Finally, the estimation of carcinogenic risks posed by exposure to complex mixtures is explored.
Animals↗
Carcinogenic risk assessment of complex mixtures.
Although procedures for assessing the carcinogenic risks associated with exposure to individual chemicals are relatively well developed, risk assessment methods for mixtures of chemicals are still in the developmental stage. In this paper, we examine the difficulties in assessing the risks of exposure to complex mixtures, with special reference to the potential for synergistic effects among the components of the mixture. Statistical models for describing the joint action of multiple exposures are reviewed, and their implications for low-dose risk assessment are examined. The potential use of pharmacokinetic models to describe the metabolism of mixtures is also considered. Application of these results in regulating mixtures of carcinogenic substances is illustrated using examples involving multiple contaminants in drinking water and polycyclic aromatic hydrocarbons produced from combustion sources.
Carcinogenicity Tests↗
Long-term toxicity of hexachlorobenzene.
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Animals↗