Vincent James Cogliano

Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis.

Background: A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A–F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens. Objectives and Methods: IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens. Discussion: These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply. Conclusion: We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA’s Integrated Risk Information System Program and the U.S. National Toxicology Program. Citation: Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713–721; http://dx.doi.org/10.1289/ehp.1509912

The Emergence of Systematic Review in Toxicology

The Evidence-based Toxicology Collaboration hosted a workshop on “The Emergence of Systematic Review and Related Evidence-based Approaches in Toxicology,” on November 21, 2014 in Baltimore, Maryland. The workshop featured speakers from agencies and organizations applying systematic review approaches to questions in toxicology, speakers with experience in conducting systematic reviews in medicine and healthcare, and stakeholders in industry, government, academia, and non-governmental organizations. Based on the workshop presentations and discussion, here we address the state of systematic review methods in toxicology, historical antecedents in both medicine and toxicology, challenges to the translation of systematic review from medicine to toxicology, and thoughts on the way forward. We conclude with a recommendation that as various agencies and organizations adapt systematic review methods, they continue to work together to ensure that there is a harmonized process for how the basic elements of systematic review methods are applied in toxicology.

Quantitative cancer assessment for vinyl chloride : indications of early-life sensitivity

Complementary sources of information are analyzed to characterize the early-life cancer risk from inhaling vinyl chloride. A study of partial-lifetime exposures suggests that the lifetime cancer risk depends on age at exposure, with higher lifetime risks attributable to exposures at younger ages. Studies of newborn animal exposures further demonstrate that a brief exposure in newborns can, by the end of life, induce a higher incidence of tumors compared to long-term exposure occurring later in life, including tumor types not induced by exposure later in life. An empirical, quantitative approach is used to model early-life sensitivity to inhaled vinyl chloride, supplementing conventional approaches for estimating the increased cancer risk from lifetime exposure. A single estimate is not presumed to apply to the entire population; instead, the new approach makes distinctions about the cancer risks for different population segments. This assessment shows one way such information might be analyzed, presented, and used to assess actual exposure situations.

Trichloroethylene: Using New Information To Improve the Cancer Characterization

The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency. Assessments of TCEs potential to cause cancer in humans have had to address issues concerning the strength of the human evidence and the relevance of the animal tumors to humans. The epidemiological database now includes analyses of multiple studies and molecular information. A recent analysis strongly suggests that TCE may induce cancer in humans at multiple sites, including kidney, liver, and lympho-hematopoietic cancer. Molecular analyses have found mutations of the von Hippel-Lindau tumor suppressor gene in renal tumors of TCE-exposed individuals. The animal bioassays have been followed up with mechanistic studies that provide insight into TCEs possible modes of action at each tumor site. This information suggests that TCE may act through mechanisms that can be relevant to human cancers. The mechanistic information can also be used to identify risk factors that may make some people more susceptible to TCEs adverse effects, allowing a fuller characterization of TCEs cancer potential in different groups of people.

Lack of data drives uncertainty in PCB health risk assessments

Health risk assessments generally involve many extrapolations: for example, from animals to humans or from high doses to lower doses. Health risk assessments for PCBs involve all the usual uncertainties, plus additional uncertainties due to the nature of PCBs as a dynamic, complex mixture. Environmental processes alter PCB mixtures after release into the environment, so that people are exposed to mixtures that might not resemble the mixtures where there are toxicity data. This paper discusses the evolution of understanding in assessments of the cancer and noncancer effects of PCBs. It identifies where a lack of data in the past contributed to significant uncertainty and where new data subsequently altered the prevailing understanding of the toxicity of PCB mixtures, either qualitatively or quantitatively. Finally, the paper identifies some uncertainties remaining for current PCB health assessments, particularly those that result from a lack of data on exposure through nursing or on effects from inhalation of PCBs.