Carcinogenicity

One of the principal applications of toxicology data is to inform risk assessments and support risk management decisions that are protective of human health. Ideally, a risk assessor would have available all of the relevant information on (a) the toxicity profile of the agent of interest; (b) its interactions with living systems; and (c) the known or projected exposure scenarios: to whom, how much, by which route(s), and how often. In practice, however, complete information is seldom available. Nonetheless, decisions still must be made. Screening-level assays and tools can provide support for many aspects of the risk assessment process, as long as the limitations of the tools are understood and to the extent that the added uncertainty the tools introduce into the process can be characterized and managed. Use of these tools for decision-making may be an end in itself for risk assessment and decision-making or a preliminary step to more extensive data collection and evaluation before assessments are undertaken or completed and risk management decisions made. This paper describes a framework for the application of screening tools for human health decision-making, although with some modest modification, it could be made applicable to environmental settings as well. The framework consists of problem formulation, development of a screening strategy based on an assessment of critical data needs, and a data analysis phase that employs weight-of-evidence criteria and uncertainty analyses, and leads to context-based decisions. Criteria for determining the appropriate screening tool(s) have been identified. The choice and use of the tool(s) will depend on the question and the level of uncertainty that may be appropriate for the context in which the decision is being made. The framework is iterative, in that users may refine the question(s) as they proceed. Several case studies illustrate how the framework may be used effectively to address specific questions for any endpoint of toxicity.

The potential mutagenicity and carcinogenicity of commercial PCBs has been investigated in both in vivo and in vitro systems and several conclusions can be drawn from these studies. (1) PCBs can covalently adduct DNA both in vivo and in vitro (using a source of metabolic activation); the more highly chlorinated biphenyls are poorly metabolized and these compounds tend to exhibit very low binding to DNA. Based on the structure-activity relationships for PCBs (Safe, 1984) it is unlikely that the more toxic compounds such as 3,3',4,4',5-penta- and 3,3',4,4',5,5'-hexachlorobiphenyl, would form covalent adducts with DNA. (2) PCB mixtures and individual compounds exhibit minimal mutagenic activity in most assay systems. (3) The more highly chlorinated PCB mixtures (i.e. greater than 50% Cl by weight) are hepatocarcinogens in rodents whereas data from a limited number of studies suggest that the lower chlorinated mixtures are not carcinogenic. (4) In some model systems,...

Licorice (or 'liquorice') is a plant of ancient origin and steeped in history. Licorice extracts and its principle component, glycyrrhizin, have extensive use in foods, tobacco and in both traditional and herbal medicine. As a result, there is a high level of use of licorice and glycyrrhizin in the US with an estimated consumption of 0.027-3.6 mg glycyrrhizin/kg/day. Both products have been approved for use in foods by most national and supranational regulatory agencies. Biochemical studies indicate that glycyrrhizinates inhibit 11beta-hydroxysteroid dehydrogenase, the enzyme responsible for inactivating cortisol. As a result, the continuous, high level exposure to glycyrrhizin compounds can produce hypermineralocorticoid-like effects in both animals and humans. These effects are reversible upon withdrawal of licorice or glycyrrhizin. Other in vivo and clinical studies have reported beneficial effects of both licorice and glycyrrhizin consumption including anti-ulcer, anti-v...

A Workshop sponsored by EURL ECVAM was held in Ispra, Italy in 2013 to consider whether the in vitro mammalian cell genotoxicity test results could complement and mitigate the implications of a positive Ames test response for the prediction of in vivo genotoxicity and carcinogenicity, and if patterns of results could be identified. Databases of Ames-positive chemicals that were tested for in vivo genotoxicity and/or carcinogenicity were collected from different sources and analysed individually (Kirkland et al., in this issue). Because there were overlaps and inconsistent test results among chemicals in the different databases, a combined database which eliminated the overlaps and evaluated the inconsistencies was considered preferable for addressing the above question. A database of >700 Ames-positive chemicals also tested in vivo was compiled, and the results in in vitro mammalian cell tests were analysed. Because the database was limited to Ames-positive chemicals, the majorit...

Concerns related to higher levels of acrylamide in processed carbohydrate-rich foods, especially in fried potato products, are well known. This article provides updates on various aspects of acrylamide in processed potato products including mechanisms of acrylamide formation and health risks due to its intake. Levels of reducing sugars in potatoes are considered as a main factor contributing towards the formation of acrylamide in processed potato products. Useful approaches in lowering the levels of reducing sugars such as use of suitable varieties, storage methods, storage temperature and duration of storage are described and discussed. Importance and practical utility of various steps before and during the processing that can contribute in reducing the final concentration of acrylamide are highlighted. Progress made and present status of potato processing industry in India are part of this article. The article describes varietal improvement and spread of short-term and long-term storage technologies in India and their contribution towards round the year availability of processing grade potatoes to the processing industries and how all this has helped in achieving reduced levels of acry-lamide in chips and French fries. Outcome and implications of cold-induced sweetening tolerance in potatoes are presented along with other management practices and strategies that can lower the acrylamide levels in processed potato products. Future lines of work have been suggested to make the consumption of fried potato products safer.

In 2006 the Massachusetts Toxics Use Reduction Institute conducted a study to determine if states could identify safer alternatives to five chemicals of concern. The chemicals investigated included di (2-ethylhexyl) phthalate (DEHP), formaldehyde, hexavalent chromium, lead and perchloroethylene. First, the Institute developed a methodology for assessing alternatives to these five chemicals that allowed it to quickly determine priority uses and alternatives to assess and to research the pertinent decision criteria, which included performance, technical, financial environmental and human health parameters. The methodology included important feedback from stakeholders in the state, which helped to focus and enhance the value of the work. Second, the Institute implemented the methodology over a ten month period. Based on the activities conducted by the Institute, safer alternatives were identified for each of the priority uses associated with the five chemicals studied. This report summ...

A biomaterial is "any substance (other than drugs) or combination of substances synthetic or natural in origin, which can be used for any period of time, as a whole or as a part of a system which treats, augments, or replaces any tissue, organ, or function of the body".
Biocompatibility is the ability of a material to perform with an appropriate host response in a specific application.
Host Response is the response of the host organism (local and systemic) to the implanted material or device.

Mutagenicity and carcinogenicity databases are crucial resources for toxicologists and regulators involved in chemicals risk assessment. Until recently, existing public toxicity databases have been constructed primarily as "look-up-tables" of existing data, and most often did not contain chemical structures. Concepts and technologies originated from the structure-activity relationships science have provided powerful tools to create new types of databases, where the effective linkage of chemical toxicity with chemical structure can facilitate and greatly enhance data gathering and hypothesis generation, by permitting: a) exploration across both chemical and biological domains; and b) structure-searchability through the data. This paper reviews the main public databases, together with the progress in the field of chemical relational databases, and presents the ISSCAN database on experimental chemical carcinogens.

Formaldehyde (FA) is a world high-production compound with numerous applications ranging from production of resins to medicines. Due to its sensitizing properties, irritating effects and potential cancer hazard FA is of great environmental health concern. Numerous studies in humans and experimental animals demonstrated that inhaled FA produced toxicity, genotoxicity, and cancer at distal sites. IARC, based on sufficient data, reclassified FA as a human carcinogen. The highest level of human exposure to this aldehyde occurs in occupational settings, namely, in pathology and anatomy laboratories, where FA is commonly used as a fixative and tissue preservative. Several studies consistently showed that the levels of airborne FA in anatomy laboratories exceeded recommended exposure criteria. In order to assess the genotoxic effects of chronic occupational exposure to FA, a group of pathology/anatomy workers was assessed using a micronucleus (MN) test and comet assay. The level of exposure to FA was also determined and the time-weighted average (TWA) of exposure was calculated for each subject. The TWA mean value for FA exposed workers was 0.43 ± 0.06 ppm, exceeding national and international recommended limit levels of 0.3 ppm. Both MN frequency and comet assay parameters were significantly higher in exposed subjects. Data obtained confirm a correlation between genetic damage and occupational exposure to FA. These data, along with recent implications of human carcinogenicity, point out the need for close monitoring of occupational exposure to FA. Implementation of security and hygiene measures as well as good practices campaigns may be crucial to decrease risk.

There is an issue in the EU classification of substances for carcinogenicity and for reproductive or developmental toxicity which has brought difficulties to those involved in the process. The issue lies in the inability of the classification system to distinguish between carcinogens and reproductive toxicants with different levels of concern. This has its origins in the early years of toxicology when it was thought that a relatively small number of chemicals would be either carcinogens or reproductive toxicants, but this has turned out not to be the case. This can cause problems in communicating to the users of chemicals, including the public, the nature of the hazard presented by chemicals. Processes have been developed within the classification system for setting specific concentration limits which assess the degree of hazard for carcinogens and reproductive toxicants as high, medium or low. However these categories are not otherwise used in classification. It is proposed that th...

In vitro models are currently not considered to be suitable replacements for animals in experiments to assess the multiple factors that underlie the development of cancer as a result of environmental exposure to chemicals. An evaluation was conducted on the potential use of normal keratinocytes, the SV40 T-antigen-immortalised keratinocyte cell line, SVpgC2a, and the carcinoma cell line, SqCC/Y1, alone and in combination, and under standardised serum-free culture conditions, to study oral cancer progression. In addition, features considered to be central to cancer development as a result of environmental exposure to chemicals, were analysed. Genomic expression, and enzymatic and functional data from the cell lines reflected many aspects of the transition of normal tissue epithelium, via dysplasia, to full malignancy. The composite cell line model develops aberrances in proliferation, terminal differentiation and apoptosis, in a similar manner to oral cancer progression in vivo. Tran...

Due to limited human exposure data, risk classification and the consequent regulation of exposure to potential carcinogens has conventionally relied mainly upon animal tests. However, several investigations have revealed animal carcinogenicity data to be lacking in human predictivity. To investigate the reasons for this, we surveyed 160 chemicals possessing animal but not human exposure data within the US Environmental Protection Agency chemicals database, but which had received human carcinogenicity assessments by 1 January 2004. We discovered the use of a wide variety of species, with rodents predominating, and of a wide variety of routes of administration, and that there were effects on a particularly wide variety of organ systems. The likely causes of the poor human predictivity of rodent carcinogenicity bioassays include: 1) the profound discordance of bioassay results between rodent species, strains and genders, and further, between rodents and human beings; 2) the variable, y...

The Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation has conducted a long-term bioassay on aspartame (APM), a widely used artificial sweetener. APM was administered with feed to 8-week-old Sprague-Dawley rats (100–150/sex/group), at concentrations of 100,000, 50,000, 10,000, 2,000, 400, 80, or 0 ppm. The treatment lasted until natural death, at which time all deceased animals underwent complete necropsy. Histopathologic evaluation of all pathologic lesions and of all organs and tissues collected was routinely performed on each animal of all experimental groups. The results of the study show for the first time that APM, in our experimental conditions, causes a) an increased incidence of malignant-tumor–bearing animals with a positive significant trend in males (p ≤ 0.05) and in females (p ≤ 0.01), in particular those females treated at 50,000 ppm (p ≤ 0.01); b) an increase in lymphomas and leukemias with a positive significant trend in both males (p ≤ 0.05) ...

Short- and medium-term rodent bioassays have been proposed under ICH guidelines for use in testing for the carcinogenic potential of pharmaceuticals. Further evaluation of these models is needed urgently and coordinated efforts are in progress worldwide to expand the available database. Models currently being investigated include transgenic mice (Tg-rasH2, Tg.AC, p53(+/-), XPA(-/-)) and neonatal mice. As more data become available on the performance of these assays, regulatory and industry scientists will be faced with the difficult challenge of determining how the performance (accuracy) of each assay will be measured and deciding which assays have value in the risk assessment process.

Discovered in the early 1800s, the use of cadmium and various cadmium salts started to become industrially important near the close of the 19th century, rapidly thereafter began to flourish, yet has diminished more recently. Most cadmium used in the United States is a byproduct from the smelting of zinc, lead, or copper ores, and is used to manufacture batteries. Carcinogenic activity of cadmium was discovered first in animals and only subsequently in humans. Cadmium and cadmium compounds have been classified as known human carcinogens by the International Agency for Research on Cancer and the National Toxicology Program based on epidemiologic studies showing a causal association with lung cancer, and possibly prostate cancer, and studies in experimental animals, demonstrating that cadmium causes tumors at multiple tissue sites, by various routes of exposure, and in several species and strains. Epidemiologic studies published since these evaluations suggest that cadmium is also asso...

A ε-caprolactama (CAP) é um monômero precursor de polímeros denominados nylon 6. Esses polímeros destinam-se à produção de tapetes, vestuário e materiais plásticos tais como equipamentos, sistemas e componentes automotivos, conectores, além de embalagens plásticas. Resíduos de CAP podem migrar de embalagens plásticas de nylon 6 para os alimentos. Diante disso, foi de interesse realizar uma revisão dos efeitos relativos à exposição à CAP e o seu impacto sobre a saúde humana. Estudos epidemiológicos indicam a possibilidade da CAP causar inflamações oculares e cutâneas, além de irritações no sistema respiratório. Pode ocorrer ainda hipotensão, taquicardia, palpitações, rinorréia, ressecamento nasal, efeitos geniturinários e sobre a reprodução como distúrbios nas funções menstrual e ovariana, e complicações no parto; além de problemas neurológicos e hematológicos. Estudos com animais são consistentes com tais relatos. Os estudos de genotoxicidade in vitro e in vivo por via oral e intrap...