Radiation Adverse Outcome pathways (AOPs): examining priority questions from an international horizon-style exercise.

Purpose: The Organisation for Economic Co-operation and Development (OECD) Adverse Outcome Pathway (AOP) Development Programme is being explored in the radiation field, as an overarching framework to identify and prioritize research needs that best support strengthening of radiation risk assessment and risk management strategies. To advance the use of AOPs, an international horizon-style exercise (HSE) was initiated through the Radiation/Chemical AOP Joint Topical Group (JTG) formed by the OECD Nuclear Energy Agency (NEA) High-Level Group on Low Dose Research (HLG-LDR) under the auspices of the Committee on Radiological Protection and Public Health (CRPPH). The intent of the HSE was to identify key research questions for consideration in AOP development that would help to reduce uncertainties in estimating the health risks following exposures to low dose and low dose-rate ionizing radiation.

Radiation adverse outcome pathways (AOPs) are on the horizon: advancing radiation protection through an international Horizon-Style exercise.

Purpose: The Adverse Outcome Pathway (AOP) framework, a systematic tool that can link available mechanistic data with phenotypic outcomes of relevance to regulatory decision-making, is being explored in areas related to radiation risk assessment. To examine the challenges including the use of AOPs to support the radiation protection community, an international horizon-style exercise was initiated through the Organisation for Economic Co-operation and Development Nuclear Energy Agency High-Level Group on Low Dose Research Radiation/Chemical AOP Joint Topical Group. The objective of the HSE was to facilitate the collection of ideas from a range of experts, to short-list a set of priority research questions that could, if answered, improve the description of the radiation dose-response relationship for low dose/dose-rate exposures, as well as reduce uncertainties in estimating the risk of developing adverse health outcomes following such exposures.

Adverse outcome pathways, key events, and radiation risk assessment.

The overall aim of this contribution to the 'Second Bill Morgan Memorial Special Issue' is to provide a high-level review of a recent report developed by a Committee for the National Council on Radiation Protection and Measurements (NCRP) titled 'Approaches for Integrating Information from Radiation Biology and Epidemiology to Enhance Low-Dose Health Risk Assessment'. It derives from previous NCRP Reports and Commentaries that provide the case for integrating data from radiation biology studies (available and proposed) with epidemiological studies (also available and proposed) to develop Biologically-Based Dose-Response (BBDR) models. In this review, it is proposed for such models to leverage the adverse outcome pathways (AOP) and key events (KE) approach for better characterizing radiation-induced cancers and circulatory disease (as the example for a noncancer outcome).

Recent Epidemiologic Studies and the Linear No-Threshold Model For Radiation Protection-Considerations Regarding NCRP Commentary 27.

National Council on Radiation Protection and Measurements Commentary 27 examines recent epidemiologic data primarily from low-dose or low dose-rate studies of low linear-energy-transfer radiation and cancer to assess whether they support the linear no-threshold model as used in radiation protection. The commentary provides a critical review of low-dose or low dose-rate studies, most published within the last 10 y, that are applicable to current occupational, environmental, and medical radiation exposures. The strengths and weaknesses of the epidemiologic methods, dosimetry assessments, and statistical modeling of 29 epidemiologic studies of total solid cancer, leukemia, breast cancer, and thyroid cancer, as well as heritable effects and a few nonmalignant conditions, were evaluated.

International organizations, risk assessment and research-Why, what and how.

The process of setting radiation protection standards requires the interaction of a number of international and national organizations that in turn require the input of scientific and regulatory experts. Bill Morgan served in an expert capacity for several of these organizations particularly for the application of radiation biology data to risk assessment. He brought great enthusiasm and dedication to these committee efforts.

Can radiation research impact the estimation of risk?

Purpose: This review is a contribution to the memory of Dr William (Bill) Morgan and highlights an area of research and deliberation that he considered extremely important in support of the setting of protective radiation dose limits. Biological research has generally played a minor role in the estimation of adverse health outcomes following exposure to low doses and low dose rates of radiation. The reliance has been on the available, quite extensive data base of epidemiology studies.

The role of dose rate in radiation cancer risk: evaluating the effect of dose rate at the molecular, cellular and tissue levels using key events in critical pathways following exposure to low LET radiation.

Purpose: This review evaluates the role of dose rate on cell and molecular responses. It focuses on the influence of dose rate on key events in critical pathways in the development of cancer. This approach is similar to that used by the U.

Integrating basic radiobiological science and epidemiological studies: why and how.

There is quite an extensive set of epidemiology studies conducted for a range of different radiation exposure scenarios and in some cases at doses that can be considered to be in the low dose range (<100 mGy). In addition, there is an extensive literature on the effects of radiation at animal and cellular levels, as well as expanding knowledge of the underlying mechanisms of disease formation (both cancer and non-cancer). A significant concern is that these two areas of study have been linked rarely to support each other-to enhance low dose/low dose-rate extrapolation and reduction of uncertainty in risk estimates.

The use of mode of action information in risk assessment: quantitative key events/dose-response framework for modeling the dose-response for key events.

The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF) to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome.

An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B1, tamoxifen and vinyl chloride.

The framework analysis previously presented for using DNA adduct information in the risk assessment of chemical carcinogens was applied in a series of case studies which place the adduct information into context with the key events in carcinogenesis to determine whether they could be used to support a mutagenic mode of action (MOA) for the examined chemicals. Three data-rich chemicals, aflatoxin B1 (AFB1), tamoxifen (Tam) and vinyl chloride (VCl) were selected for this exercise. These chemicals were selected because they are known human carcinogens and have different characteristics: AFB1 forms a unique adduct and human exposure is through contaminated foods; Tam is a pharmaceutical given to women so that the dose and duration of exposure are known, forms unique adducts in rodents, and has both estrogenic and genotoxic properties; and VCl, to which there is industrial exposure, forms a number of adducts that are identical to endogenous adducts found in unexposed people.

Dose-response approaches for nuclear receptor-mediated modes of action for liver carcinogenicity: Results of a workshop.

A public workshop, organized by a Steering Committee of scientists from government, industry, universities and research organizations, was held at the National Institute of Environmental Health Sciences (NIEHS) in September, 2010. The workshop explored the dose-response implications of toxicant modes of action (MOA) mediated by nuclear receptors. The dominant paradigm in human health risk assessment has been linear extrapolation without a threshold for cancer, and estimation of sub-threshold doses for non-cancer and (in appropriate cases) cancer endpoints.

Uncertainties in estimating health risks associated with exposure to ionising radiation.

The information for the present discussion on the uncertainties associated with estimation of radiation risks and probability of disease causation was assembled for the recently published NCRP Report No. 171 on this topic. This memorandum provides a timely overview of the topic, given that quantitative uncertainty analysis is the state of the art in health risk assessment and given its potential importance to developments in radiation protection.

DNA reactivity as a mode of action and its relevance to cancer risk assessment.

The ability of a chemical to induce mutations has long been a driver in the cancer risk assessment process. The default strategy has been that mutagenic chemicals demonstrate linear cancer dose responses, especially at low exposure levels. In the absence of additional confounding information, this is a reasonable approach, because risk assessment is appropriately considered as being protective of human health.

The fractions of respiratory tract cells at risk in formaldehyde carcinogenesis.

Clonal growth modeling of carcinogenesis requires data on the number of cells at risk of becoming cancerous. We synthesized literature data to estimate the fraction of respiratory tract epithelial cells that are progenitor cells, and therefore at risk, in formaldehyde carcinogenesis for specific respiratory tract regions. We concluded that the progenitor cells for the transitional and respiratory epithelia of the nose are basal and nonciliated cells and Type II cells in the alveolar region.

A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens.

Quantitative methods for estimation of cancer risk have been developed for daily, lifetime human exposures. There are a variety of studies or methodologies available to address less-than-lifetime exposures. However, a common framework for evaluating risk from less-than-lifetime exposures (including short-term and/or intermittent exposures) does not exist, which could result in inconsistencies in risk assessment practice.

A review of biomonitoring studies measuring genotoxicity in humans exposed to hair dyes.

Hair dye ingredients frequently produce positive results in short-term in vitro genotoxicity tests, although results from in vivo assays are typically negative, especially for ingredients in use today. The use of hair dyes is quite widespread resulting in the exposure both for persons working in hairdressing salons and for individuals who have their hair dyed. This provides the opportunity to add to the data from standard in vitro and in vivo genotoxicity tests by investigating whether or not genotoxic responses are detected in such exposed individuals.

Reciprocal translocations in somatic and germ cells of mice chronically exposed by inhalation to ethylene oxide: implications for risk assessment.

Groups of male B6C3F1 mice were exposed by inhalation to 0, 25, 50, 100 or 200 p.p.m.

Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization.

The assessment of human cancer risk from chemical exposure requires the integration of diverse types of data. Such data involve effects at the cell and tissue levels. This report focuses on the specific utility of one type of data, namely DNA adducts.

Application of key events analysis to chemical carcinogens and noncarcinogens.

The existence of thresholds for toxicants is a matter of debate in chemical risk assessment and regulation. Current risk assessment methods are based on the assumption that, in the absence of sufficient data, carcinogenesis does not have a threshold, while noncarcinogenic endpoints are assumed to be thresholded. Advances in our fundamental understanding of the events that underlie toxicity are providing opportunities to address these assumptions about thresholds.

Impact of life stage and duration of exposure on arsenic-induced proliferative lesions and neoplasia in C3H mice.

Epidemiological studies suggest that chronic exposure to inorganic arsenic is associated with cancer of the skin, urinary bladder and lung as well as the kidney and liver. Previous experimental studies have demonstrated increased incidence of liver, lung, ovary, and uterine tumors in mice exposed to 85 ppm (approximately 8 mg/kg) inorganic arsenic during gestation. To further characterize age susceptibility to arsenic carcinogenesis we administered 85 ppm inorganic arsenic in drinking water to C3H mice during gestation, prior to pubescence and post-pubescence to compare proliferative lesion and tumor outcomes over a one-year exposure period.

Update on linear non-threshold dose-response model and implications for diagnostic radiology procedures.

Cancer risk estimates are used in the setting of radiation protection standards by international and national organizations, and for this purpose need to be developed for low doses of radiation. The approach has involved extrapolation from cancer mortality and incidence values at higher doses to predict the low-dose estimates. Such an extrapolation has generally involved the use of the linear non-threshold (LNT) theory.