Epidemiologic-hygienic aspects of the assessment of carcinogenic risk in methacrylate production

The authors studied oncologic mortality among the workers exposed to some acryl monomers. The oncologic risk was estimated for the individuals exposed to acrylonitrile, methyl methacrylate, methyl- and butyl acrylate, methacrylic acid. Occurrence of the malignancies appeared to depend on the dose of methyl methacrylate.     

Statistical issues in biological radiation dosimetry for risk assessment using stable chromosome aberrations

Biological dosimeters are useful for epidemiologic risk assessment in populations exposed to catastrophic nuclear events and as a means of validating physical dosimetry in radiation workers. Application requires knowledge of the magnitude of uncertainty in the biological dose estimates and an understanding of potential statistical pitfalls arising from their use. This paper describes the statistical aspects of biological dosimetry in general and presents a detailed analysis in the specific case of dosimetry for risk assessment using stable chromosome aberration frequency. Biological dose estimates may be obtained from a dose-response curve, but negative estimates can result and adjustment must be made for regression bias due to imprecise estimation when the estimates are used in regression analyses. Posterior-mean estimates, derived as the mean of the distribution of true doses compatible with a given value of the biological endpoint, have several desirable properties: they are nonnegative, less sensitive to extreme skewness in the true dose distribution, and implicitly adjusted to avoid regression bias. The methods necessitate approximating the true-dose distribution in the population in which biological dosimetry is being applied, which calls for careful consideration of this distribution through other information. An important question addressed here is to what extent the methods are robust to misspecification of this distribution, because in many applications of biological dosimetry it cannot be characterized well. The findings suggest that dosimetry based solely on stable chromosome aberration frequency may be useful for population-based risk assessment.     

Benzidine mechanistic data and risk assessment: species- and organ-specific metabolic activation

The aromatic amine benzidine (BZ) has produced various tumors, including liver tumors, in mice, rats and hamsters. BZ forms DNA adducts in rodent liver, and it is positive in most genotoxicity tests. Only bladder tumors are produced in dogs and in humans who have been occupationally exposed, possibly related to the slow rate of liver detoxification by acetylation, allowing activation of BZ or its metabolites in urine. Despite these differences, risk assessment for humans, based on liver tumors in mice, was approximately predictive of the incidence of bladder tumors observed in industrially exposed humans.     

Statistical methods applied in retrospective risk assessment of endometrial adenocarcinoma occurrence

A retrospective study about frequency of occurrence of endometrial adenocarcinoma in postmenopausal women which are associated with diabetes mellitus, overweight and hypertension was performed. The aim of the study was to have risk factors for carcinoma of endometrium estimated. The nonparametric statistics such as: 2 x 2 table chi 2/Phi2 test, observed versus expected chi 2 test and estimation of relative risk were applicable. A retrospective study (from 1991 to 1993) of 2887 patients of Institute of Obstetrics and Gynecology University School of Poznań with pathological sign and symptoms was performed.     

城市暴雨内涝情景模拟与灾害风险评估

Scenado modelling and the risk assessment of natural disasters is one of the hot-spots in disaster research. However, up until now, urban natural disaster risk assessments lack common procedures and programmes. This paper selects rainstorm waterlogging as a disaster to research, which is one of the most frequently occurring hazards for most cities in China. As an example, we used a small-scale integrated methodology to assess risks relating to rainstorm waterlogging hazards in the Jing'an District of Shanghai. Based on the basic concept of disaster risk, this paper applies scenario modelling to express the risk of small-scale urban rainstorm waterlogging disasters in different return periods. Through this analysis of vulnerability and exposure, we simulate different disaster scenarios and propose a comprehensive analysis method and procedure for small-scale urban storm waterlogging disaster risk assessments. A grid-based Geographical Information System (GIS) approach,including an urban terrain model, an urban rainfall model and an urban drainage model, was applied to simulate inundation area and depth. Stage-damage curves for residential buildings and contents were then generated by the loss data of waterlogging from field surveys, which were further applied to analyse vulnerability, exposure and loss assessment. Finally, the ex-ceedance probability curve for disaster damage was constructed using the damage of each simulated event and the respective exceedance probabilities. A framework was also devel-oped for coupling the waterlogging risk with the risk planning and management through the exceedance probability curve and annual average waterlogging loss. This is a new explora-tion for small-scale urban natural disaster scenario simulation and risk assessment.     

The use of toxicologic data in mechanistic risk assessment: 1,3-butadiene as a case study

The National Research Council (NRC) recently published a report. Science and Judgment in Risk Assessment, that critiqued the current approaches to characterizing human cancer risks from exposure to chemicals. One issue raised in the report relates to the use of default options for quantitation of cancer risks. Default options are general guidelines that can be used for risk assessment when specific information about a chemical is absent. Research on 1,3-butadiene represents an interesting case study in which existing knowledge on this chemical indicates that two default options may no longer be tenable: (1) humans are as sensitive as the most sensitive animal species, and (2) the rate of metabolism is a function of body surface area rather than inherent species differences in metabolic capacity. Butadiene, a major commodity chemical used in the production of synthetic rubber, is listed as one of 189 hazardous air pollutants under the 1990 Clean Air Act Amendments. Butadiene is a carcinogen in rats and mice, with mice being substantially more sensitive than rats. The extent to which butadiene poses a cancer risk to humans exposed to this chemical is uncertain. Butadiene requires metabolic activation to DNA-reactive epoxides to exert its mutagenic and carcinogenic effects. Research is directed toward obtaining a better understanding of the cancer risks of butadiene in humans by evaluating species-dependent differences in the formation of the toxic butadiene epoxide metabolites, epoxybutene and diepoxybutane. The data include in-vitro studies on butadiene metabolism using tissues from humans, rats, and mice as well as experimental data and physiological model predictions for butadiene in blood and butadiene epoxides in blood, lung, and liver after exposure of rats and mice to inhaled butadiene. The findings suggest that humans are more like rats and less like mice regarding the formation of butadiene epoxides. The research approach employed can be a useful strategy for developing mechanistic and toxicokinetic data to supplant default options used in carcinogen risk assessments for butadiene.     

A brief history of the use of laboratory animals for the prediction of carcinogenic risk for man with a note on needs for the future

This review discusses developments during the last 60 years in the field of carcinogenicity testing based on the use of laboratory animals. Improvements that have occurred in the quality of animals and in the way in which tests are conducted are considered, along with the importance of distinguishing between fatal and incidental tumours. Still to be faced is a need to control calorie intake in the course of carcinogenicity testing. A necessity for a better understanding of how disturbances of physiological and/or hormonal status can predispose to tumour development and for more comparative metabolism studies is stressed. Recognition of the fact that thresholds exist for carcinogenesis by non-genotoxic compounds poses a need for avoiding unrealistically high levels of exposure and for more and better information on how different species metabolise test agents.     

Statistical modeling of carcinogenic risks in dogs that inhaled 238PuO2

Combined analyses of data on 260 life-span beagle dogs that inhaled 238PuO2 at the Inhalation Toxicology Research Institute (ITRI) and at Pacific Northwest National Laboratory (PNNL) were conducted. The hazard functions (age-specific risks) for incidence of lung, bone and liver tumors were modeled as a function of cumulative radiation dose, and estimates of lifetime risks based on the combined data were developed. For lung tumors, linear-quadratic functions provided an adequate fit to the data from both laboratories, and linear functions provided an adequate fit when analyses were restricted to doses less than 20 Gy. The estimated risk coefficients for these functions were significantly larger when based on ITRI data compared to PNNL data, and dosimetry biases are a possible explanation for this difference. There was also evidence that the bone tumor response functions differed for the two laboratories, although these differences occurred primarily at high doses. These functions were clearly nonlinear (even when restricted to average skeletal doses less than 1 Gy), and evidence of radiation-induced bone tumors was found for doses less than 0.5 Gy in both laboratories. Liver tumor risks were similar for the two laboratories, and linear functions provided an adequate fit to these data. Lifetime risk estimates for lung and bone tumors derived from these data had wide confidence intervals, but were consistent with estimates currently used in radiation protection. The dog-based lifetime liver tumor risk estimate was an order of magnitude larger than that used in radiation protection, but the latter also carries large uncertainties. The application of common statistical methodology to data from two studies has allowed the identification of differences in these studies and has provided a basis for common risk estimates based on both data sets.     

Present systems and future needs for risk assessment of veterinary biologicals in Australia: the perspective of the regulator

The increasing range and complexity of biologicals, and the greater demand for these products, have resulted in a greater volume of trade in animal-based biological material. This has given rise, in turn, to many approaches to the regulation of importation of these materials, as countries seek protection against the introduction of disease. Harmonization of these regulatory approaches would contribute significantly to the availability of veterinary biologicals, to their manufacture and trade, and to disease security. Australia has developed systems for the categorisation and evaluation of biologicals, control by import permits, and specific procedures at point-of-entry and in institutions where these products are used. Computerised records and precedents assist in evaluation and in the issuing of permits. Recognition that some materials must be subject to further control has led to a system of registration of institutions based on levels of biosecurity, and approved use and disposal programmes. Institutions vary from high-security animal health laboratories to human in vitro fertilisation clinics, which use animal-derived media and materials. Such institutions are regulated through quality assurance contracts. Quarantine authorities have linkages with other agencies which have an interest in these products. These linkages reflect the administrative structures of government in Australia, and provide for management of all forms of risk. The author describes these systems and overviews their biological basis.     

Statistical issues in periodontal research

In the past 10 to 12 years, there have been several statistical issues identified in periodontal research which require and have generated non-standard or new statistical approaches. The purpose of this paper is to give an overview of these issues and approaches. Three general categories of issues are described: (i) statistical methods for detecting when disease progression occurs, and biological theories and corresponding statistical models which attempt to describe how the disease progresses; (ii) design issues in studies of therapeutic efficacy; and (iii) analytic issues arising from periodontal data analysis.     

Statistical methods for describing temporal order in longitudinal research

BACKGROUND: Although traditional epidemiological statistical methods (e.g., logistic regression) are useful for describing predictive relationships in longitudinal panel studies in which changes in risk factor levels occur before change in the outcome variable, more sophisticated statistical methods must be used when the temporal order between variables is unknown. METHODS: Using national survey data, the current study shows how log-linear models and discrete-time survival analysis can be used to test for temporal order. The relationship between marijuana use and friends' use of marijuana is examined to illustrate these methods. RESULTS: Using traditional analytic strategies, it appears that friends use and marijuana use are predictive of each other. However, valid tests for temporal order reveal that both variables change concurrently, so there is no temporal order between these variables; rather, these variables tend to change concurrently. CONCLUSION: In many current areas of research, temporal order between theoretically important variables is unknown and traditional analytic strategies will yield misleading results. The fundamental problem with prior approaches is that no estimate of concurrent change is made. Without an estimate of concurrent change, estimates of prediction will be biased. The current study illustrates valid methods that can be used to describe temporal orderings.     

Phenobarbital mechanistic data and risk assessment: enzyme induction, enhanced cell proliferation, and tumor promotion

Chronic exposure to high doses of phenobarbital (PB) causes hepatocellular adenomas in both mice and rats and hepatocellular carcinomas in some strains of mice. Long-term PB therapy has not been found to cause human tumors. PB is not DNA reactive, and most genotoxicity tests have yielded negative results. PB has been extensively studied as an epigenetic, rodent liver tumor promoter. At exposures causing rodent liver tumors, PB has measurable effects on hepatocytes: PB inhibits cell-to-cell communication; PB induces enzymes, including P450 cytochromes; PB stimulates proliferation and inhibits apoptosis of hepatocytes in neoplastic foci. Threshold exposures for some of these endpoints coincide with the threshold exposure for tumorigenesis.     

Modeling epidemiologic studies of occupational cohorts for the quantitative assessment of carcinogenic hazards

Epidemiologic studies of occupational cohorts have played a major role in the quantitative assessment of risks associated with several carcinogenic hazards and are likely to play an increasingly important role in this area. Relatively little attention has been given in either the epidemiologic or the risk assessment literature to the development of appropriate methods for modeling epidemiologic data for quantitative risk assessment (QRA). The purpose of this paper is to review currently available methods for modeling epidemiologic data for risk assessment. The focus of this paper is on methods for use with retrospective cohort mortality studies of occupational groups for estimating cancer risk, since these are the data most commonly used when epidemiologic information is used for QRA. Both empirical (e.g., Poisson regression and Cox proportionate hazards model) and biologic (e.g., two-stage models) models are considered. Analyses of a study of lung cancer among workers exposed to cadmium are used to illustrate these modeling methods. Based on this example it is demonstrated that the selection of a particular model may have a large influence on the resulting estimates of risk.     

Butylated hydroxyanisole mechanistic data and risk assessment: conditional species-specific cytotoxicity, enhanced cell proliferation, and tumor promotion

Butylated hydroxyanisole (BHA), at high doses, has been found to induce forestomach squamous cell carcinomas in rodents, but not glandular cell or other types of neoplasms. BHA is not DNA-reactive, and the epigenetic mechanism of tumor formation involves cytotoxicity and enhanced cell proliferation, which are mostly reversible. Humans lack a forestomach and, therefore, are predicted to be much less sensitive than rodents to the effects of BHA. Also, the exposures to humans are well below doses producing the epigenetic effects in rodents. It has been concluded that BHA is an agent whose rodent carcinogenicity is conditionally species-specific and not relevant to humans.     

Initiation-promotion model for assessment of carcinogenicity: medium-term liver bioassay in rats for rapid detection of carcinogenic agents

Sarcomatoid Carcinomas are rare tumors composed of mixed malignant epithelial and mesenchymal cells. Only one case is reported in the colon, up to date. We describe the second case in an 86-year-old woman. The tumor, replacing the intestinal wall, consisted of carcinomatous and sarcomatous areas. The former was composed of differentiated superficial adenocarcinoma and of infiltrating epithelioid undifferentiated solid portion. The latter was mostly composed of undifferentiated spindle cells with focal chondrosarcomatous and pleomorphic anaplastic areas. A strong Cytocheratin (CK) and Epithelial Membrane Antigen (EMA) immunoreactivity (IR) with focal CA 125 positivity was detected in differentiated adenocarcinomatous areas. Solid carcinoma-like areas coexpressed CK and Vimentin (VIM). The sarcomatous spindle-cell component of the tumor was largely VIM positive, with focal CK IR. Both polyclonal and monoclonal antibodies for Carcino-Embryonic Antigen (CEA) did not display any reaction.     

Statistical modelling of breast cancer incidence and mortality rates in Scotland

The interpretation of time trends in disease rates can be facilitated using estimable contrasts from age-period-cohort models. Cohort and period trends in breast cancer incidence and mortality rates in Scotland were investigated using contrasts that measure the changes in the linear trends. These contrasts were compared with estimates obtained from mortality rates in the USA and Japan. A significant moderation of both breast cancer incidence and mortality rates was observed in Scotland, associated with cohorts of women born after the Second World War compared with women born between the two world wars. The moderation of breast cancer mortality among cohorts born after 1925 compared with cohorts born before 1925 that was observed in the USA and Japan was also observed in this study. This moderation is not present in the incidence rates. The relative decline in the risk of breast cancer seen in younger cohorts seems to be contradictory to the temporal pattern present among breast cancer risk factors. It may well be that the alteration of eating patterns as a result of rationing in the wartime and immediate post-war period, and the subsequent influence on certain breast cancer risk factors probably produced by such changes, may have had some influence on the development of healthier girls and women. Such speculation could be addressed in a well-designed epidemiological study. There have been no changes in the mortality rate trends with period in Scotland, although the changes in the incidence rate trends with period are consistent with an increase in registration coverage.     

Dose-response assessment for developmental toxicity. III. Statistical models

Although quantitative modeling has been central to cancer risk assessment for years, the concept of dose-response modeling for developmental effects is relatively new. The benchmark dose (BMD) approach has been proposed for use with developmental (as well as other noncancer) endpoints for determining reference doses and reference concentrations. Statistical models appropriate for representing the unique features of developmental toxicity testing have been developed and applied (K. Rai and J. Van Ryzin, 1985, Biometrics 41, 1-9; L. Kupper, C. Portier, M. Hogan, and E. Yamamoto, 1986, Biometrics 42, 85-98; R. Kodell, R. Howe, J. Chen, and D. Gaylor, 1991, Risk Anal. 11, 583-590). Generalizations of those models (designated the RVR, LOG, and NCTR models, respectively) account for the correlations among observations in individual fetuses or implant within litters; the potential for variables other than dose, such as litter size, to affect the probability of adverse outcome; and the possibility of a threshold dose below which background response rates are unaltered. The generalized models were applied to a database of 607 endpoints with significant dose-related increases in response rate. It was determined that the models were generally capable of fitting the observed dose-response patterns, with the LOG model appearing to be superior with respect to fit. A significant contributor to the ability of the LOG model to fit the data was its flexibility with respect to the representation of the dependence of response probability on litter size, a trait not shared by the other two models. Litter size appeared to be a significant covariable for predicting response rates, even when intralitter correlation was accounted for by assuming a beta-binomial distribution for the observations among individual fetuses. In contrast, a threshold dose parameter did not appear to be necessary to adequately describe the observed dose-response patterns. BMD estimates (corresponding to 5% additional risk) from all three models were similar to one another and to BMDs estimated from other, generic dose-response models (not specifically designed for developmental toxicity testing) that modeled average proportion of fetuses affected. The BMDs at the 5% level of risk were similar to no observed adverse effect levels determined by statistical tests of trend. Greater emphasis on and further examination of dose-response modeling for developmental toxicity testing are needed; biologically based approaches that consider the continuum of developmental effects induced in such tests should be encouraged.     

Clinical risk assessment for mental health nurses

This article proposes a risk management cycle for mental health nurses, it can be used as a guide to assessing and managing the risk of harm associated with people with mental health problems alongside systematic approaches to planning care.