The Weight of Evidence Does Not Support the Listing of Styrene as “Reasonably Anticipated to be a Human Carcinogen” in NTP's Twelfth Report on Carcinogens

Styrene was listed as “reasonably anticipated to be a human carcinogen” in the twelfth edition of the National Toxicology Program's Report on Carcinogens based on what we contend are erroneous findings of limited evidence of carcinogenicity in humans, sufficient evidence of carcinogenicity in experimental animals, and supporting mechanistic data. The epidemiology studies show no consistent increased incidence of, or mortality from, any type of cancer. In animal studies, increased incidence rates of mostly benign tumors have been observed only in certain strains of one species (mice) and at one tissue site (lung). The lack of concordance of tumor incidence and tumor type among animals (even within the same species) and humans indicates that there has been no particular cancer consistently observed among all available studies. The only plausible mechanism for styrene-induced carcinogenesis—a non-genotoxic mode of action that is specific to the mouse lung—is not relevant to humans. As a whole, the evidence does not support the characterization of styrene as “reasonably anticipated to be a human carcinogen,” and styrene should not be listed in the Report on Carcinogens.     

Trichloroethylene in the Environment: Public Health Concerns

The Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxi-cological profiles for hazardous substances found at waste sites and elsewhere in the environment. In 1997 the agency updated its toxicological profile for trichloroethylene and included new and expanded information on the health effects associated with exposures to trichloroethylene. Several endpoints of concern are described in the profile. However, in this paper only results from studies reporting developmental and carcinogenic effects from trichloroethylene exposures in human and experimental animal studies are summarized and evaluated. Based on its assessment of the available studies and limitations in the reported findings, ATSDR has determined there is limited but suggestive evidence that developmental effects may be a concern for some persons exposed to TCE in drinking water. Moreover, developmental effects may be the most sensitive of all non-cancer health effects associated with trichloroethylene exposures. Significant questions remain about the likely mode(s) of action for TCE-induced carcinogenesis in humans and the basis for differences in pharmacokinetics handling of TCE across animal strains and sex. However, on the basis of animal data and the suggestive, yet inconclusive, human data available, ATSDR has determined that cancer should be an effect of concern for people exposed to TCE in the environment. ATSDR agrees that the available literature supports the premise that TCE is “reasonably anticipated to be a human carcinogen” as defined by the U.S. National Toxicology Program.     

An Assessment of the Carcinogenic Potential of Trichloroethylene in Humans

Controversy surrounds the assessments of carcinogenic potential associated with human exposure to trichloroethylene (TCE). The American Conference of Governmental Industrial Hygienists states that TCE is “not suspected to be a human carcinogen.” In contrast, the International Agency for Research on Cancer has classified TCE as a probable human carcinogen, based primarily on the results of animal toxicity studies. Chronic high-dose TCE exposures cause hepatic and pulmonary tumors in mice and renal tumors in rats. Human epidemiology studies, however, do not support a causal association between exposure to TCE at environmentally relevant levels and cancers of the lung, liver, or kidney. The apparent discrepancy between the animal data and the human data can be explained by (1) differences in TCE exposure levels between laboratory animals and humans, (2) species-specific differences in TCE metabolism, and (3) other species-specific mechanisms involved in the development of cancer in rodents. This paper critically assesses the experimental and epidemiological data relevant to the carcinogenic potential of TCE. From the analysis, we conclude that TCE exposure at concentrations likely to be encountered in most environmental media is not likely to cause liver, lung, or kidney cancers in humans.     

自发性树鼩乳腺肿瘤的特性(英文)

乳腺癌是严重危害女性健康的常见恶性肿瘤,建立合适的乳腺癌动物模型对于研究人类乳腺癌的生物学机制及发展新的防治方法至关重要。相对于常用的啮齿类动物,树鼩(Tupaia belangeri chinensis,tree shrew)因在进化层次上更接近于人类而可用于建立更适合的乳腺癌模型。该文详细了介绍一例树鼩自发性乳头状良性乳腺肿瘤。免疫组化结果显示该例肿瘤孕激素受体阳性且Ki-67阳性细胞比例显著增加;而活化的Caspase3阳性细胞比例较低;且肿瘤的形态和病理与人导管内乳头状肿瘤非常接近。提示利用树鼩建立乳腺肿瘤模型的可行性。     

Strategies for integrating disparate social information

Social information use is widespread in the animal kingdom, helping individuals rapidly acquire useful knowledge and adjust to novel circumstances. In humans, the highly interconnected world provides ample opportunities to benefit from social information but also requires navigating complex social environments with people holding disparate or conflicting views. It is, however, still largely unclear how people integrate information from multiple social sources that (dis)agree with them, and among each other. We address this issue in three steps. First, we present a judgement task in which participants could adjust their judgements after observing the judgements of three peers. We experimentally varied the distribution of this social information, systematically manipulating its variance (extent of agreement among peers) and its skewness (peer judgements clustering either near or far from the participant''s judgement). As expected, higher variance among peers reduced their impact on behaviour. Importantly, observing a single peer confirming a participant''s own judgement markedly decreased the influence of other—more distant—peers. Second, we develop a framework for modelling the cognitive processes underlying the integration of disparate social information, combining Bayesian updating with simple heuristics. Our model accurately accounts for observed adjustment strategies and reveals that people particularly heed social information that confirms personal judgements. Moreover, the model exposes strong inter-individual differences in strategy use. Third, using simulations, we explore the possible implications of the observed strategies for belief updating. These simulations show how confirmation-based weighting can hamper the influence of disparate social information, exacerbate filter bubble effects and deepen group polarization. Overall, our results clarify what aspects of the social environment are, and are not, conducive to changing people''s minds.     

Do All Dogs Go to Heaven? Investigating the Association between Demographic Characteristics and Beliefs about Animal Afterlife

The purpose of this research was to explore American’s beliefs about animal afterlife based on key demographic factors such as sex, race/ethnicity, age, geographic region, religion/faith, and pet ownership. We attained a large and diverse sample of respondents (n = 800) using Amazon’s Mechanical Turk, and attempted to make the data fairly representative of the United States population by applying post-stratification weights based on auxiliary statistics obtained from US Census data. Results of the study suggest that many people perceive animal lives as similarly sacred as human lives. Evidence also suggests that one’s membership in a particular demographic category may have considerable bearing on views about animal afterlife. The authors recommend veterinarians remain cognizant that some people extend their own views on issues such as spirituality to their pets and those beliefs and values can impact veterinary care and decision-making.     

Murine tumor suppressor models

Tumor suppressor genes have been shown to be necessary for proper maintenance of cell growth control. Inactivation of these genes in the germline of humans is linked to inherited cancer predisposition. Moreover, sporadically arising human tumors often have somatic mutations in tumor suppressor genes. During the past few years, advances in molecular and cellular biology have led to the creation of animal models that have germline mutations of various tumor suppressor genes. Such mice potentially represent important animal models for familial cancer predisposition syndromes, and the study of the tumorigenesis process has been greatly assisted by their development. Such models have also demonstrated the importance of tumor suppressor function in embryonic development. In this review, we describe mice with inactivated germline tumor suppressor genes that are genetically analogous to 10 different inherited cancer syndromes in humans. We describe the variable usefulness of the mutant mice as models for human disease.     

ADAMTS proteases and cancer

ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are complex extracellular proteases that have been related to both oncogenic and tumor-protective functions. These enzymes can be secreted by cancer and stromal cells and may contribute to modify the tumor microenvironment by multiple mechanisms. Thus, ADAMTSs can cleave or interact with a wide range of extracellular matrix components or regulatory factors, and therefore affect cell adhesion, migration, proliferation and angiogenesis. The balance of protumor versus antitumor effects of ADAMTSs may depend on the nature of their substrates or interacting-partners upon secretion from the cell. Moreover, different ADAMTS genes have been found overexpressed, mutated or epigenetically silenced in tumors from different origins, suggesting the direct impact of these metalloproteases in cancer development. However, despite the important advances on the tumor biology of ADAMTSs in recent years, more mechanistic and functional studies are necessary to fully understand how these proteases can influence tumor microenvironment to potentiate cancer growth or to induce tumor regression. This review outlines current and emerging connections between ADAMTSs and cancer.     

Multiple primary malignant neoplasms in England and Wales, 1971-1981

In the period 1971-81, more than 1.9 million persons were registered with a malignant neoplasm among the 49.2 million population of England and Wales. For 63,536 people, two or more tumor registrations (multiple tumor records) have arisen in that period. Because of the structure of the National Cancer Registration scheme, some errors in registration are inevitable, particularly duplicate registration of a single tumor by adjacent regional cancer registries. A pilot study showed that 61 percent of multiple records would represent true multiple primary malignancy, and that these records could be readily separated from registration errors. After abstraction of identifying codes from each tumor, 129,047 tumors involved in 63,536 multiple records were matched to the national cancer file, and the full data set extracted for successfully matched tumors. Person-years data were extracted for the 1.8 million tumors not involved in a multiple record. Eleven percent of multiple records were not completely matched, and a further 16 percent were excluded on SEER criteria, or as probable registration errors, leaving 46,155 multiple primary tumors for further analysis. Over 3 million person-years at risk of a second tumor were accrued. The overall risk of a second tumor at any site before age 85 was 0.77 for males and 0.80 for females, after exclusion of second tumors observed within 12 months of the first. The risk of a new primary apparently decreased with increasing duration of survival, a trend which may be due in part to under-registration of second tumors in the early 1970s and an improvement in linkage since 1971.     

The p53 tumor suppressor: Critical regulator of life & death in cancer

p53 is the most commonly mutated or deleted known gene in human cancer. The consequences of its disruption are profound, either in the germlines of patients with Li-Fraumeni Syndrome, or in mice with targeted gene knockouts. Abundant evidence suggests that p53 exerts regulation of cell cycle progression as well as apoptotic cell death, both in response to identical environmental or metabolic stressors. The specific decision of cell cycle arrest vs. death may underlie p53's differential ability to trigger death in cancer cells and arrest with repair in non-cancer cells, thus producing a therapeutic index pertinent to cancer therapy. Indeed, p53 status is likely to correlate with prognosis in many human cancers and in multiple animal tumor models. The mechanistic basis for p53's functions are still emerging, and will hopefully yield new therapeutic strategies applicable to treatment of the many poor-prognosis, p53-deficient human malignancies.     

An investigation of human-animal interactions and empathy as related to pet preference,ownership, attachment,and attitudes in children

ABSTRACT

Osgood's Semantic Differential technique was used with a sample of 12 animal names to see if they elicited responses that were distinctively characteristic, and therefore useful in uncovering connotative meaning. The 100 survey participants responded with unanimity to some species, whereas their responses to others were highly variable. Results disclosed a taxonomy of grouping animal names that differed from the normal zoological taxonomy. This suggests that the technique may be useful for discovering the connotations that animals have, and what various animal species may mean to people.     

Somatic mutations in stilbene estrogen-induced Syrian hamster kidney tumors identified by DNA fingerprinting

Kidney tumors from stilbene estrogen (diethylstilbestrol)-treated Syrian hamsters were screened for somatic genetic alterations by Random Amplified Polymorphic DNA-polymerase chain-reaction (RAPD-PCR) fingerprinting. Fingerprints from tumor tissue were generated by single arbitrary primers and compared with fingerprints for normal tissue from the same animal, as well as normal and tumor tissues from different animals. Sixty one of the arbitrary primers amplified 365 loci that contain approximately 476 kbp of the hamster genome. Among these amplified DNA fragments, 44 loci exhibited either qualitative or quantitative differences between the tumor tissues and normal kidney tissues. RAPD-PCR loci showing decreased and increased intensities in tumor tissue DNA relative to control DNA indicate that loci have undergone allelic losses and gains, respectively, in the stilbene estrogen-induced tumor cell genome. The presence or absence of the amplified DNA fragments indicate homozygous insertions or deletions in the kidney tumor DNA compared to the age-matched normal kidney tissue DNA. Seven of 44 mutated loci also were present in the kidney tissues adjacent to tumors (free of macroscopic tumors). The presence of mutated loci in uninvolved (non-tumor) surrounding tissue adjacent to tumors from stilbene estrogen-treated hamsters suggests that these mutations occurred in the early stages of carcinogenesis. The cloning and sequencing of RAPD amplified loci revealed that one mutated locus had significant sequence similarity with the hamster Cyp1A1 gene. The results show the ability of RAPD-PCR to detect and isolate, in a single step, DNA sequences representing genetic alterations in stilbene estrogen-induced cancer cells, including losses of heterozygosity, and homozygous deletion and insertion mutations. RAPD-PCR provides an alternative molecular approach for studying cancer cytogenetics in stilbene estrogen-induced tumors in humans and experimental models. Although the exact functional importance of mutated loci is unknown, this study indicates that these altered loci may participate during tumor progression in the kidney.     

A Humanized Leucine Zipper-TRAIL Hybrid Induces Apoptosis of Tumors both In Vitro and In Vivo

Evidence suggests that stimulating apoptosis in malignant cells without inflicting collateral damage to the host''s normal tissues is a promising cancer therapy. Chemo- and radiation therapies that, especially if combined, induce apoptosis in tumor cells have been used for treating cancer patients for decades. These treatments, however, are limited in their ability to discriminate between malignant and non-malignant cells and, therefore, produce substantial healthy tissue damage and subsequent toxic side-effects. In addition, as a result of these therapies, many tumor types acquire an apoptosis-resistant phenotype and become more aggressive and metastatic. Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) has been considered a promising and reliable selective inducer of apoptosis in cancerous cells. TRAIL, however, is not uniformly effective in cancer and multiple cancer cell types are considered resistant to natural TRAIL. To overcome this deficiency of TRAIL, we have earlier constructed a yeast-human hybrid leucine zipper-TRAIL in which the yeast GCN4-pII leucine zipper was fused to human TRAIL (GCN4-TRAIL). This construct exhibited a significantly improved anti-tumor apoptotic activity and safety, but is potentially immunogenic in humans. Here, we report a novel, potent, and fully human ATF7 leucine zipper-TRAIL (ATF7-TRAIL) fusion construct that is expected to have substantially lower immunogenicity. In solution, ATF7-TRAIL exists solely as a trimer with a Tm of 80°C and is active against cancer cells both in vitro and in vivo, in a mouse tumor xenograft model. Our data suggest that our re-engineered TRAIL is a promising candidate for further evaluation as an antitumor agent.     

Public Response to Official Information on Cancer and Cancer Clusters

Official information about cancer and cancer clusters from state health departments clashes with lay views. A few studies have covered site-specific communication by telephone and public meetings, and hypothetical messages, but not generic information actually provided. Public response to such information was probed with a random survey of New Jersey households (n = 327), part of a quasi-experiment contrasting the agency's cognitive message and an alternative message adding procedural and affective information. Respondents rated both information types as understandable, helpful, and trustworthy, particularly among those trusting the agency, agreeing with officials’ views of facts, and with low concern about local clusters. Anxiety about cancer, aversion to uncertainty, cancer experience, and familiarity with clusters or the agency did not affect responses. Agreeing with officially defined facts (knowledge) was associated with trust in the agency and concern about clusters, but scepticism about expert knowledge. Information exposure increased trust, belief in expert knowledge (except on whether cancers cluster), and (some) factual knowledge, but also increased self-reported concern among those already concerned. These findings suggest that, absent specific learning, people believe scientific information is understandable, helpful, and trustworthy when they already trust experts and institutions; people with prior distrust offer less positive evaluations.