摘要:

We fit lognormal distributions to data collected in a national survey for both total water intake and tap water intake by children and adults for these age groups in years: 0

ISSN:0272-4332    

DOI:10.1111/j.1539-6924.1992.tb01312.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

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 tests 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 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 do

ISSN:0272-4332    

DOI:10.1111/j.1539-6924.1992.tb01313.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

The use of average qualitative concordance between two bioassay endpoints is considered, with emphasis directed at agreement between rats and mice from results of long‐term carcinogenicity studies. It is noted that concordance varies as a function of the underlying potency or toxicity of the chemicals over which the averaging is performed. Thus, the averaging process dilutes large observed concordances from potent chemicals, and possibly inflates lower observed concordances from weakly active chemicals. Stratification over some measure of potency is suggested as a method for taking these effects into account. Statistical simulations of concordance analyses limited to low‐potency ranges are employed to examine the concordance measure in greater detail. It is seen that at low potencies, observed concordance is consistently underestimated, reaching maximum levels of only about

ISSN:0272-4332    

DOI:10.1111/j.1539-6924.1992.tb01314.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Estimates have been made of the cancer potency of aflatoxin exposure among the U.S. population. Risk modeling is used to assess the dose‐response relationship between aflatoxin exposure and primary liver cancer, controlling for hepatitis B virus (HBV), based on data provided by the Yehet al.study in China.(1)A relative risk model is proposed as a more appropriate alternative to the additive (“absolute” risk) model for transportation of risk coefficients between populations with different baseline rates. Several general relative risk models were examined; the exponential model provided the best fit. The Poisson regression method was used to fit the relative risk model to the grouped data. The effects of exposure to aflatoxin (AFB1) and hepatitis B infection were both found to be statistically significant. The risk of death from liver cancer for those exposed to AFB1relative to the unexposed population, increases by 0.05% per ng/kg/day exposure of AFB1(p<0.001). The results also indicated a 25‐fold increase in the risk of death from liver cancer among those infected with hepatitis B virus, relative to noncarriers (p<0.0001). With a hepatitis prevalence rate of 1%, the aflatoxin intake level associated with liver cancer lifetime excess risk of 1 × 10−5for the U.S. population was estimated as 253 ng/day, based on a liver cancer baseline rate of 3.4 /

ISSN:0272-4332    

DOI:10.1111/j.1539-6924.1992.tb01315.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

One of the challenges of introducing greater biological realism into stochastic models of cancer induction is to find a way to represent thehomeostatic controlof the normal cell population over its own size without complicating the analysis too much to obtain useful results. Current two‐stage models of carcinogenesis typically ignore homeostatic control. Instead, a deterministic growth path is specified for the population of “normal” cells, while the population of “initiated” cells is assumed to grow randomly according to a birth‐death process with random immigrations from the normal population. This paper introduces a simple model of homeostatically controlled cell division for mature tissues, in which the size of the nonmalignant population remains essentially constant over time. Growth of the nonmalignant cell population (normal and initiated cells) is restricted by allowing cells to divide only to fill the “openings” left by cells that die or differentiate, thus maintaining the constant size of the nonmalignant cell population. The fundamental technical insight from this model is thatrandom walks, rather than birth‐and‐death processes, are the appropriate stochastic processes for describing the kinetics of the initiated cell population. Qualitative and analytic results are presented, drawn from the mathematical theories of random walks and diffusion processes, that describe the probability of spontaneous extinction and the size distribution of surviving initiated populations when the death/differentiation rates of normal and initiated cells are known. The constraint that the nonmalignant population size must remain approximately constant leads to much simpler analytic formulas and approximations, flowing directly from random walk theory, than in previous birth‐death models. As in other stochastic models, our analysis implies that individual susceptibility to carcinogens affecting the second (malignant) transformation rate should follow an age‐dependent frequency distribution in a population of initially identical individuals; hence, individual risks are heterogeneous even in the absence of individual differences in exposure patterns or pharmacokinetics. A theoretical formula is developed for the approximate frequency distribution of individual susceptibilities in a population exposed to a simple initiator/

ISSN:0272-4332    

DOI:10.1111/j.1539-6924.1992.tb01316.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Because of the inherent complexity of biological systems, there is often a choice between a number of apparently equally applicable physiologically based models to describe uptake and metabolism processes in toxicology or risk assessment. These models may fit the particular data sets of interest equally well, but may give quite different parameter estimates or predictions under different (extrapolated) conditions. Such competing models can be discriminated by a number of methods, including potential refutation by means of strategic experiments, and their ability to suitably incorporate all relevant physiological processes. For illustration, three currently used models for steady‐state hepatic elimination—the venous equilibration model, the parallel tube model, and the distributed sinusoidal perfusion model—are reviewed and compared with particular reference to their application in the area of risk assessment. The ability of each of the models to describe and incorporate such physiological processes as protein binding, precursor‐metabolite relations and hepatic zones of elimination, capillary recruitment, capillary heterogeneity, and intrahepatic shunting is discussed. Differences between the models in hepatic parameter estimation, extrapolation to different conditions, and interspecies scaling are discussed, and criteria for choosing one model over the others are presented. In this case, the distributed model provides the most general framework for describing physiological processes taking place in the liver, and has so far not been experimentally refuted, as have the other two models. These simpler models may, however, provide useful bounds on parameter estimates and on extrapolations and risk asse

ISSN:0272-4332    

DOI:10.1111/j.1539-6924.1992.tb01317.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

ISSN:0272-4332    

DOI:10.1111/j.1539-6924.1992.tb01318.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

ISSN:0272-4332    

DOI:10.1111/j.1539-6924.1992.tb01319.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Book reviewed in this article.Chemical Exposures: Low Levels and High StakesBy Nicholas A. Ashford and Claudia S. MillerSignificance and Treatment of Volatile Organic Compounds in Water SuppliesEdited by N. M. Ram, R. F. Christman, and K. P. CantorActive and Passive Smoking Hazards in the WorkplaceBy Judith A. DouvilleUncertainty in Environmental Health Risk AssessmentBy Kenneth T. BogenPractical Applications of Quantitative Structure‐Activity Relationships (QSAR) in Environmental Chemistry and ToxicologyEdited by W. Karcher and J. Devillers BostonHandbook of Environmental Fate and Exposure Data for Organic Chemicals, Vol II. SolventsEdited by Philip H. HowardWhat Happened? Diagnosing Unfamiliar Real‐Life SituationsBy A.J.M. GroenewegenOccupational and Environmental Safety Engineering and ManagementBy H.R. Kavianian and C.A. WentzHealth and Medical Aspects of Diaster PreparednessEdited by John C. DuffyChemicals in the Human Food ChainEdited by Carl K. Winter, James N. Seiber, and Carole F. NucktonDevelopmental Toxicology: Risk Assessment and the FutureEdited by Ronald D.

ISSN:0272-4332    

DOI:10.1111/j.1539-6924.1992.tb01320.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY