Trichloroethylene and Human Cancer

Evidence to suggest that trichloroethylene may be a human carcinogen comes mainly from two small epidemiological studies with supporting evidence from human toxicity and genotoxicity studies and from rodent cancer bioassays. Careful analysis of these data reveal marked inconsistencies between the data, differences in the conclusions drawn by various authorities reviewing the same data and, for certain key human studies, a complete absence of exposure data. Much of the rodent cancer data may be dismissed as not indicative of a human hazard because the tumors result from either peroxisome proliferation, or as a consequence of exceptionally high metabolic rates that are found uniquely in mouse tissues, or because the tumors only occur in the presence of overt toxicity. A common mechanism invoked to account for the development of renal tumors in both rats and humans is unproven, there is contrary evidence to suggest that this mechanism does not result in renal cancer, and alternative mechanisms have been proposed. Overall, the uncertainty and lack of consistency throughout the trichloroethylene studies, whether they are in humans, in animals, or in tests in vitro, lead to the conclusion that it would be wholly inappropriate to classify trichloroethylene as a human carcinogen.     

Trichloroethylene Carcinogenic Potency

Mention of tradename, specific equipment, or proprietary product does not constitute a guarantee or warranty by the State of California or imply approval to the exclusion of other products. The conclusions reached herein represent those of the author and do not necessarily represent those of the State of California. Current U.S. regulatory policy regarding the carcinogenic potential of trichloroethylene (TCE) in humans is conflicting. Weight-of-evidence considerations show either no or inconsistent associations between chronic TCE exposure and excess human cancer risk. Occupational exposure limits are so great (538,000 µg/m³) that daily absorbed doses are greater than the rodent no observed adverse effect level (NOAEL). Using the regulatory strength-of-evidence approach, recommended ambient air concentration limits (1.1 µg/m³) are derived using the default linearized multistage model. The latter assumes a radiomimetic mode of action, a highly questionable assumption in light of published TCE mechanism of action data. Given the current state of U.S. regulatory policy on this material, credible analyses of the data are needed from neutral nongovernmental organizations.     

A Review of the Epidemiology of Trichloroethylene and Kidney Cancer

The occupational epidemiological studies of trichloroethylene (TCE) exposure and kidney cancer are reviewed. Seven occupational cohort studies, conducted in the U.S., Finland, and Sweden involving over 130,000 workers, do not report statistically increased risks of kidney cancer among TCE-exposed workers. These studies were based on well-defined cohorts and exposure assessments involving urine biomonitoring or some type of job exposure matrix. In contrast, two German studies reported eight- to eleven-fold increased risks for renal cancer among TCE-exposed workers. However, numerous methodological and analytical shortcomings severely limit any interpretation of the German studies. We conclude that the more reliable epidemiologic data do not support a causal relationship between kidney cancer and TCE exposure.     

Application of Kinetic and Dynamic Data for Antihistamines to Risk Characterization in Sensitive Populations

A major goal of risk assessment is to protect the health of individuals who may be more sensitive than the general population. This study compared human phar-macokinetic and pharmacodynamic data in sensitive groups (i.e., children, the elderly, diseased states, and poor metabolizers) versus young, healthy adults for the antihistamines cetirizine, fexofenadine, loratadine, azelastine, ebastine, chlorpheniramine, and diphenhydramine. The default components (3.16 each for kinetic and dynamic aspects) of the intraspecies uncertainty factor were adjusted with compound specific data for the antihistamines. The majority (16 of 18) of the composite factors (kinetics X dynamics) for the sensitive groups were less than 10. Children had the lowest composite factors for antihistamines, ranging from 1.1 to 6.3. Application of kinetic and dynamic data for antihistamines to the Renwick/International Programme on Chemical Safety (IPCS) scheme can aid in characterizing the extent of variability in sensitive populations, thereby reducing the uncertainty associated with the risk assessment of sensitive populations.     

Framework for Human Health Risk Assessment

The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the USEPA. The U.S. Government has the right to retain a nonexclusive royalty-free license in and to any copyright covering this article. The U.S. Environmental Protection Agency has recognized the need to develop a framework for human health risk assessment that puts a perspective on the approaches in practice throughout the Agency. In response, the USEPA's Risk Assessment Forum has begun the process of developing a framework for human health risk assessment. This paper provides some additional background to the previous review of the framework efforts and notes the Agency's extramural efforts to begin the process of integrating and harmonizing risk assessment approaches for all human health endpoints.     

Harmonization: Developing Consistent Guidelines for Applying Mode of Action and Dosimetry Information to Cancer and Noncancer Risk Assessment

The 1983 book, Risk Assessment in the Federal Government: Managing the Process, recommended developing consistent inference guidelines for cancer risk assessment. Over the last 15 years, extensive guidance have been provided for hazard assessment for cancer and other endpoints. However, as noted in several recent reports, much less progress has occurred in developing consistent guidelines for quantitative dose response assessment methodologies. This paper proposes an approach for dose response assessment guided by consideration of mode of action (pharmacodynamics) and tissue dosimetry (pharmacokinetics). As articulated here, this systematic process involves eight steps in which available information is integrated, leading first to quantitative analyses of dose response behaviors in the test species followed by quantitative analyses of relevant human exposures. The process should be equally appropriate for both cancer and noncancer endpoints. The eight steps describe the necessary procedures for incorporating mechanistic data and provide multiple options based upon the mode of action by which the chemical causes the toxicity. Given the range of issues involved in developing such a procedure, we have simply sketched the process, focusing on major approaches for using toxicological data and on major options; many details remain to be filled in. However, consistent with the revised carcinogen risk assessment guidance (USEPA, 1996c), we propose a process that would ultimately utilize biologically based or chemical specific pharmacokinetic and pharmacodynamic models as the backbone of these analyses. In the nearer term, these approaches will be combined with analysis of data using more empirical models including options intended for use in the absence of detailed information. A major emphasis in developing any harmonized process is distinguishing policy decisions from those decisions that are affected by the quality and quantity of toxicological data. Identification of data limitations also identifies areas where further study should reduce uncertainty in the final risk evaluations. A flexible dose response assessment procedure is needed to insure that sound toxicological study results are appropriately used to influence risk management decision-making and to encourage the conduct of toxicological studies oriented toward application for dose response assessments.     

Radiation Hormesis and Cancer

Despite the long history of radiation hormesis and the public health concerns with low-level exposures to ionizing radiation, there has been surprisingly little formal evaluation of whether hormetic effects are displayed with respect to radiation exposure and cancer incidence (i.e., reduced cancer risk at low radiation doses compared to controls, enhanced cancer risk at higher doses) until relatively recently. This paper reviews data relevant to the question of radiation hormesis and cancer with particular emphasis on experimental studies in animal models exposed to low levels of ionizing radiation. Data exist that provide evidence both consistent with and/or supportive of radiation hormesis. Other biomedical research provides potentially important mechanistic insight: low dose exposures have the capacity to activate immune function to prevent the occurrence of tumor development and metastasis; low doses of radiation have been shown to reduce mutagenic responses and induce endogenous antioxidant responses. These findings are consistent with epidemiological data suggesting an inverse relationship between background radiation and cancer incidence and with occupational epidemiological investigations in which low-dose exposure groups display markedly lower standardized mortality rates than the referent or control group.     

Using the RESRAD Code to Assess Human Exposure Risk to 226Ra, 232Th,and 40K in Soil

This article evaluates the health risk raised by exposure to naturally occurring radionuclides in soil around Khak-Sefid, Ramsar, Iran, which is an area of high natural background radiation. A high purity germanium detector was used to determine levels of radionuclides in soil samples and the cancer morbidity risk for a hypothetical resident farmer was evaluated using the RESidual RADioactivity (RESRAD) code. The average activity concentrations of ²²⁶Ra, ²³²Th, and ⁴⁰K were found to be 13,201 ± 391, 27.9 ± 2.4, and 415.5 ± 16 Bq/kg, respectively. The maximum assessed cancer morbidity risks were calculated from external and internal exposure pathways as 4.73 × 10^?2 and 3.40 × 10^?2 for ²²⁶Ra, 1.41 × 10^?4 and 7.88 × 10^?5 for ²³²Th, and 1.3 × 10^?4 and 4.233 × 10^?4 for ⁴⁰K. The RESRAD calculations also showed total cancer morbidity risks from external gamma and plant ingestion pathways were more important than from other exposure pathways. A sensitivity analysis was also performed to determine the input parameter values in the risk assessment process. In general, due to the high calculated risk of ²²⁶Ra compared with ²³²Th and ⁴⁰K it can be the major source of concern for human heath in the study area.     

Characterization of bacteriocin bificin C6165: a novel bacteriocin

Aims

To purify and primarily characterize an anti‐Alicyclobacillus bacteriocin produced by Bifidobacterium animalis subsp. animalis CICC 6165, suggested to be named bificin C6165.

Methods and Results

During purification of the bificin C6165, optimal recovery was achieved with ammonium sulfate precipitation followed by two chromatographic steps. Mass spectrometry analyses revealed a distinctive peak corresponding to a molecular mass of 3395·1 Da. This bacteriocin was heat stable, effective after refrigerated storage and freeze–thaw cycles. The primary mode of action of bificin C6165 is most probably due to pore formation, as indicated by the efflux of K⁺ from metabolically active cells of Alicyclobacillus acidoterrestris. In the presence of 10 mmol l^?1 gadolinium, bificin C6165 did not affect cells of Alicyclobacillus acidoterrestris. This suggests that the mode of action of bificin C6165 relies on a net negatively charged cell surface.

Conclusions

Bificin C6165 is indeed a novel bacteriocin and it exhibited remarkable potency for Alicyclobacillus control.

Significance and Impact of the Study

Application of bacteriocins in preservation of fruit juices has seldom been studied. Bificin C6165 may be an alternative method to control juice spoilage by this Alicyclobacillus acidoterrestris and meet increasing consumer demand for nature and artificial chemical additive‐free food products.     

Chemical Contamination of Aquatic Organisms from an Urbanized River in the New York/New Jersey Harbor Estuary

The lower 6 miles of the tidal Passaic River, part of the New York/New Jersey (NY/NJ) Harbor Estuary system, are contaminated with a variety of organic and inorganic chemicals as a result of more than 150 years of heavy industrialization and urbanization. The River's ecology is substantially degraded due to habitat removal/alteration, and the organisms that reside in or utilize the River are exposed to and bioaccumulate chemicals from sediments and food web interactions. We quantify in this study the extent and magnitude of chemical contamination in several fish species (representing a range of trophic levels) and blue crab (Callinectes sapidus). In addition, the concentration of several contaminants of concern are compared to concentrations in similar organisms from other areas of the NY/NJ Harbor Estuary, as well as available tissue-based toxicological effects benchmarks that are reported in the literature. The results suggest that a variety of contaminants are present at elevated levels in each of the species collected from the River. Several contaminants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), total DDT (2,2-bis[4-chlorophenyl]1,1-dichloroethene), copper, and mercury are present at average concentrations that exceed those from other waterways in the NY/NJ Harbor Estuary. However, the concentrations of contaminants in the River, with few exceptions do not exceed available toxic effects levels as reported in the literature for these or similar fish and crustaceans. This suggests that toxicological risks from bioaccumulative contaminants in the lower Passaic River are limited to select contaminants and species.     

Health Risk Assessment of Domestic Roof Water Harvesting Using Failure Mode and Effects Analysis: Evidence from Nagaur,Rajasthan, India

This article is crafted around assessment and analysis of health risks associated with domestic rooftop water harvesting in India, with the prime objective of bringing to the forefront the deterrent issues and challenges in rainwater harvesting in general and domestic rooftop water harvesting in particular. This is based on a study on health risk assessment of a domestic rooftop water harvesting project conducted in the Nagaur district of Rajasthan, India, providing a critical reflection and exemplifying the prevalent scenario in the arid regions of the world. The methodology used for deriving the conclusions is failure mode and effects analysis. A set of risks were graded according to their severity based on their risk priority number scores evolved, including various contaminants polluting the harvested rainwater. The findings bear implications for planning of reconstructive changes to be incorporated and thus providing the necessary outlook for effective alleviation of the deterrents and make rainwater harvesting the premium solution for realization of the Millennium Development Goals by providing access to safe drinking water to the populace chiefly in the developing countries where the problem of scarce safe water is grave.     

Extrapolation in Risk Assessment: Improving the Quantification of Uncertainty,and Improving Information to Reduce the Uncertainty

Risk assessments inevitably extrapolate from the known to the unknown. The resulting calculation of risk involves two fundamental kinds of uncertainty: uncertainty owing to intrinsically unpredictable (random) components of the future events, and uncertainty owing to imperfect prediction formulas (parameter uncertainty and error in model structure) that are used to predict the component that we think is predictable. Both types of uncertainty weigh heavily both in health and ecological risk assessments. Our first responsibility in conducting risk assessments is to ensure that the reported risks correctly reflect our actual level of uncertainty (of both types). The statistical methods that lend themselves to correct quantification of the uncertainty are also effective for combining different sources of information. One way to reduce uncertainty is to use all the available data. To further sharpen future risk assessments, it is useful to partition the uncertainty between the random component and the component due to parameter uncertainty, so that we can quantify the expected reduction in uncertainty that can be achieved by investing in a given amount of future data. An example is developed to illustrate the potential for use of comparative data, from toxicity testing on other species or other chemicals, to improve the estimates of low-effect concentration in a particular case with sparse case-specific data.     

Short Communication: Characterization and succession of yeast populations associated with spontaneous fermentations during the production of Brazilian sugar-cane aguardente

A succession of yeasts was observed during fermentation of aguardente with Saccharomyces cerevisiae being the predominant species. Candida sake, Kluyveromyces marxianus var. drosophilarum and apiculate yeasts were also frequent. Transient yeast species were found in variable numbers, probably due to the daily addition of sugar-cane juice. Killer yeasts were isolated and may have a role in the exclusion of some transient and contaminant species.     

Contested Etiology: Cancer Risk Among Two Anatolian Populations in Turkey and Europe

This paper discusses the different explanatory models and the contested perceptions of cancer etiology among residents of two Anatolian villages and migrants from these villages in Turkey, Sweden, and Germany. These communities suffer from an endemic, deadly cancer called mesothelioma, the cause of which is associated with exposure to an environmental carcinogenic substance, erionite, which is present in large deposits in the ground, in the stones, and white stucco that the villagers used to build their homes, and in the air in the form of dust. However, an examination of patients' disease trends, experiences, and local explanations has led to new investigations of possible familial risk cofactors. This paper selectively focuses on different aspects of cancer risk and its manifested metaphors, aesthetics, and perceptions. The different categories of cancer risk freely interact, derive an important part of their meaning from the context of the doctor-cancer patient relationship, and are created and navigated by the cancer narrative.     

Restoring Wild Salmon to the Pacific Northwest: Framing the Risk Question

In the Pacific Northwest of the United States, it is urgent to assess accurately the various options proposed to restore wild salmon. For the past 150 years, a variety of analytic approaches have been employed to assess the ecological consequences of salmon management options. Each approach provided useful information to decision makers, but each also suffered from limitations, some relatively minor, others sufficient to undermine any potential utility. Risk assessment has become the most widely used analytic approach to evaluate environmental policy options. To date its use in ecological policy has been largely constrained to evaluating relatively simple technical questions (e.g., regulatory actions associated with specific chemicals or hazardous waste sites). Recently, however, there has been interest in applying risk assessment to more complex ecological policy problems (e.g., the decline of wild salmon in the Pacific Northwest). Although its use has become commonplace and widely accepted, especially among regulatory and land management agencies, risk assessment remains contentious. The most heated debates revolve around delineating the specific meaning of risk; that is, framing the risk “question” to be answered.     

Breast cancer in the personal genomics era

Breast cancer is a heterogeneous disease with a complex etiology that develops from different cellular lineages, progresses along multiple molecular pathways, and demonstrates wide variability in response to treatment. The "standard of care" approach to breast cancer treatment in which all patients receive similar interventions is rapidly being replaced by personalized medicine, based on molecular characteristics of individual patients. Both inherited and somatic genomic variation is providing useful information for customizing treatment regimens for breast cancer to maximize efficacy and minimize adverse side effects. In this article, we review (1) hereditary breast cancer and current use of inherited susceptibility genes in patient management; (2) the potential of newly-identified breast cancer-susceptibility variants for improving risk assessment; (3) advantages and disadvantages of direct-to-consumer testing; (4) molecular characterization of sporadic breast cancer through immunohistochemistry and gene expression profiling and opportunities for personalized prognostics; and (5) pharmacogenomic influences on the effectiveness of current breast cancer treatments. Molecular genomics has the potential to revolutionize clinical practice and improve the lives of women with breast cancer.