A new approach to the classification of carcinogenicity.

Concern over substances that may cause cancer has led to various classification schemes to recognize carcinogenic threats and provide a basis to manage those threats. The least useful schemes have a binary choice that declares a substance carcinogenic or not. This overly simplistic approach ignores the complexity of cancer causation by considering neither how the substance causes cancer, nor the potency of that mode of action. Consequently, substances are classified simply as "carcinogenic", compromising the opportunity to properly manage these kinds of substances. It will likely be very difficult, if not impossible, to incorporate New Approach Methodologies (NAMs) into binary schemes. In this paper we propose a new approach cancer classification scheme that segregates substances by both mode of action and potency into three categories and, as a consequence, provides useful guidance in the regulation and management of substances with carcinogenic potential. Examples are given, including aflatoxin (category A), trichlorethylene (category B), and titanium dioxide (category C), which demonstrate the clear differentiation among these substances that generate appropriate levels of concern and management options.

The codification of hazard and its impact on the hazard versus risk controversy.

The long running controversy about the relative merits of hazard-based versus risk-based approaches has been investigated. There are three levels of hazard codification: level 1 divides chemicals into dichotomous bands of hazardous and non-hazardous; level 2 divides chemicals into bands of hazard based on severity and/or potency; and level 3 places each chemical on a continuum of hazard based on severity and/or potency. Any system which imposes compartments onto a continuum will give rise to issues at the boundaries, especially with only two compartments. Level 1 schemes are only justifiable if there is no variation in severity, or potency or if there is no threshold. This is the assumption implicit in GHS/EU classification for carcinogenicity, reproductive toxicity and mutagenicity. However, this assumption has been challenged. Codification level 2 hazard assessments offer a range of choices and reduce the built-in conflict inherent in the level 1 process. Level 3 assessments allow a full range of choices between the extremes and reduce the built-in conflict even more. The underlying reason for the controversy between hazard and risk is the use of level 1 hazard codification schemes in situations where there are ranges of severity and potency which require the use of level 2 or level 3 hazard codification. There is not a major difference between level 2 and level 3 codification, and they can both be used to select appropriate risk management options. Existing level 1 codification schemes should be reviewed and developed into level 2 schemes where appropriate.

Chemical carcinogenicity revisited 2: Current knowledge of carcinogenesis shows that categorization as a carcinogen or non-carcinogen is not scientifically credible.

Developments in the understanding of the etiology of cancer have undermined the 1970s concept that chemicals are either "carcinogens" or "non-carcinogens". The capacity to induce cancer should not be classified in an inflexible binary manner as present (carcinogen) or absent (non-carcinogen). Chemicals may induce cancer by three categories of mode of action: direct interaction with DNA or DNA replication including DNA repair and epigenetics; receptor-mediated induction of cell division; and non-specific induction of cell division. The long-term rodent bioassay is neither appropriate nor efficient to evaluate carcinogenic potential for humans and to inform risk management decisions. It is of questionable predicitiveness, expensive, time consuming, and uses hundreds of animals. Although it has been embedded in practice for over 50 years, it has only been used to evaluate less than 5% of chemicals that are in use. Furthermore, it is not reproducible because of the probabilisitic nature of the process it is evaluating combined with dose limiting toxicity, dose selection, and study design. The modes of action that lead to the induction of tumors are already considered under other hazardous property categories in classification (Mutagenicity/Genotoxicity and Target Organ Toxicity); a separate category for Carcinogenicity is not required and provides no additional public health protection.

Chemical carcinogenicity revisited 1: A unified theory of carcinogenicity based on contemporary knowledge.

Developments in the understanding of the etiology of cancer have profound implications for the way the carcinogenicity of chemicals is addressed. This paper proposes a unified theory of carcinogenesis that will illuminate better ways to evaluate and regulate chemicals. In the last four decades, we have come to understand that for a cell and a group of cells to begin the process of unrestrained growth that is defined as cancer, there must be changes in DNA that reprogram the cell from normal to abnormal. Cancer is the consequence of DNA coding errors that arise either directly from mutagenic events or indirectly from cell proliferation especially if sustained. Chemicals that act via direct interaction with DNA can induce cancer because they cause mutations which can be carried forward in dividing cells. Chemicals that act via non-genotoxic mechanisms must be dosed to maintain a proliferative environment so that the steps toward neoplasia have time to occur. Chemicals that induce increased cellular proliferation can be divided into two categories: those which act by a cellular receptor to induce cellular proliferation, and those which act via non-specific mechanisms such as cytotoxicity. This knowledge has implications for testing chemicals for carcinogenic potential and risk management.

Chemical carcinogenicity revisited 3: Risk assessment of carcinogenic potential based on the current state of knowledge of carcinogenesis in humans.

Over 50 years, we have learned a great deal about the biology that underpins cancer but our approach to testing chemicals for carcinogenic potential has not kept up. Only a small number of chemicals has been tested in animal-intensive, time consuming, and expensive long-term bioassays in rodents. We now recommend a transition from the bioassay to a decision-tree matrix that can be applied to a broader range of chemicals, with better predictivity, based on the premise that cancer is the consequence of DNA coding errors that arise either directly from mutagenic events or indirectly from sustained cell proliferation. The first step is in silico and in vitro assessment for mutagenic (DNA reactive) activity. If mutagenic, it is assumed to be carcinogenic unless evidence indicates otherwise. If the chemical does not show mutagenic potential, the next step is assessment of potential human exposure compared to the threshold for toxicological concern (TTC). If potential human exposure exceeds the TTC, then testing is done to look for effects associated with the key characteristics that are precursors to the carcinogenic process, such as increased cell proliferation, immunosuppression, or significant estrogenic activity. Protection of human health is achieved by limiting exposures to below NOEALs for these precursor effects. The decision tree matrix is animal-sparing, cost effective, and in step with our growing knowledge of the process of cancer formation.

Classification schemes for carcinogenicity based on hazard-identification have become outmoded and serve neither science nor society.

Classification schemes for carcinogenicity based solely on hazard-identification such as the IARC monograph process and the UN system adopted in the EU have become outmoded. They are based on a concept developed in the 1970s that chemicals could be divided into two classes: carcinogens and non-carcinogens. Categorization in this way places into the same category chemicals and agents with widely differing potencies and modes of action. This is how eating processed meat can fall into the same category as sulfur mustard gas. Approaches based on hazard and risk characterization present an integrated and balanced picture of hazard, dose response and exposure and allow informed risk management decisions to be taken. Because a risk-based decision framework fully considers hazard in the context of dose, potency, and exposure the unintended downsides of a hazard only approach are avoided, e.g., health scares, unnecessary economic costs, loss of beneficial products, adoption of strategies with greater health costs, and the diversion of public funds into unnecessary research. An initiative to agree upon a standardized, internationally acceptable methodology for carcinogen assessment is needed now. The approach should incorporate principles and concepts of existing international consensus-based frameworks including the WHO IPCS mode of action framework.

Key Elements for Judging the Quality of a Risk Assessment.

BACKGROUND: Many reports have been published that contain recommendations for improving the quality, transparency, and usefulness of decision making for risk assessments prepared by agencies of the U.S. federal government. A substantial measure of consensus has emerged regarding the characteristics that high-quality assessments should possess. OBJECTIVE: The goal was to summarize the key characteristics of a high-quality assessment as identified in the consensus-building process and to integrate them into a guide for use by decision makers, risk assessors, peer reviewers and other interested stakeholders to determine if an assessment meets the criteria for high quality. DISCUSSION: Most of the features cited in the guide are applicable to any type of assessment, whether it encompasses one, two, or all four phases of the risk-assessment paradigm; whether it is qualitative or quantitative; and whether it is screening level or highly sophisticated and complex. Other features are tailored to specific elements of an assessment. Just as agencies at all levels of government are responsible for determining the effectiveness of their programs, so too should they determine the effectiveness of their assessments used in support of their regulatory decisions. Furthermore, if a nongovernmental entity wishes to have its assessments considered in the governmental regulatory decision-making process, then these assessments should be judged in the same rigorous manner and be held to similar standards. CONCLUSIONS: The key characteristics of a high-quality assessment can be summarized and integrated into a guide for judging whether an assessment possesses the desired features of high quality, transparency, and usefulness. CITATION: Fenner-Crisp PA, Dellarco VL. 2016. Key elements for judging the quality of a risk assessment. Environ Health Perspect 124:1127-1135; http://dx.doi.org/10.1289/ehp.1510483.

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. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs.

Advancing human health risk assessment: integrating recent advisory committee recommendations.

Over the last dozen years, many national and international expert groups have considered specific improvements to risk assessment. Many of their stated recommendations are mutually supportive, but others appear conflicting, at least in an initial assessment. This review identifies areas of consensus and difference and recommends a practical, biology-centric course forward, which includes: (1) incorporating a clear problem formulation at the outset of the assessment with a level of complexity that is appropriate for informing the relevant risk management decision; (2) using toxicokinetics and toxicodynamic information to develop Chemical Specific Adjustment Factors (CSAF); (3) using mode of action (MOA) information and an understanding of the relevant biology as the key, central organizing principle for the risk assessment; (4) integrating MOA information into dose-response assessments using existing guidelines for non-cancer and cancer assessments; (5) using a tiered, iterative approach developed by the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) as a scientifically robust, fit-for-purpose approach for risk assessment of combined exposures (chemical mixtures); and (6) applying all of this knowledge to enable interpretation of human biomonitoring data in a risk context. While scientifically based defaults will remain important and useful when data on CSAF or MOA to refine an assessment are absent or insufficient, assessments should always strive to use these data. The use of available 21st century knowledge of biological processes, clinical findings, chemical interactions, and dose-response at the molecular, cellular, organ and organism levels will minimize the need for extrapolation and reliance on default approaches.

Mode of action: moving toward a more relevant and efficient assessment paradigm.

To advance the utility and predictability of safety evaluation, an integrated approach that relies on all existing knowledge to understand how agents perturb normal biological function or structure is needed to progress more focused evaluation strategies. The mode of action (MOA)-human relevance framework developed by the International Program for Chemical Safety and The International Life Sciences Institute provides a useful analytical approach where different lines of evidence (e.g., in vitro, in vivo) can be organized, linked, and integrated at different levels of biological organization into a more efficient, hypothesis-driven approach to safety evaluation. This framework provides a weight-of-evidence approach based on considerations for causality (as originally articulated by Bradford Hill), including dose response and temporal concordance, consistency, specificity, and biological plausibility and coherence. Once an animal MOA and its key events are established, qualitative and quantitative comparisons between experimental animals and humans are made based on the key events. This comparison enables a conclusion as to whether the MOA is likely operative in humans and, if so, whether it can result in a more refined hazard and dose-response assessment. This framework provides an important tool to promote and formalize the use of MOA data in safety evaluation regardless of whether the information comes from traditional or novel approaches, such as those recommended by the NRC in its 2007 report "Toxicity Testing in the 21st Century," which recommends moving away from traditional approaches of measuring adverse endpoints by using newer technologies to identify ways agents may considerably perturb cellular pathways to produce their toxicity.

Application of the International Life Sciences Institute Key Events Dose-Response Framework to food contaminants.

Contaminants are undesirable constituents in food. They may be formed during production of a processed food, present as a component in a source material, deliberately added to substitute for the proper substance, or the consequence of poor food-handling practices. Contaminants may be chemicals or pathogens. Chemicals generally degrade over time and become of less concern as a health threat. Pathogens have the ability to multiply, potentially resulting in an increased threat level. Formal structures have been lacking for systematically generating and evaluating hazard and exposure data for bioactive agents when problem situations arise. We need to know what the potential risk may be to determine whether intervention to reduce or eliminate contact with the contaminant is warranted. We need tools to aid us in assembling and assessing all available relevant information in an expeditious and scientifically sound manner. One such tool is the International Life Sciences Institute (ILSI) Key Events Dose-Response Framework (KEDRF). Developed as an extension of the WHO's International Program on Chemical Safety/ILSI mode of action/human relevance framework, it allows risk assessors to understand not only how a contaminant exerts its toxicity but also the dose response(s) for each key event and the ultimate outcome, including whether a threshold exists. This presentation will illustrate use of the KEDRF with case studies included in its development (chloroform and Listeriaonocytogenes) after its publication in the peer-reviewed scientific literature (chromium VI) and in a work in progress (3-monochloro-1, 2-propanediol).

Assessing the human carcinogenic potential of tetrahydrofuran: I. Mode of action and human relevance analysis of the male rat kidney tumor.

In 1998, the National Toxicology Program concluded that inhalation exposure to tetrahydrofuran resulted in increased incidences of renal adenomas and carcinomas (combined) in male F344 rats and of hepatocellular adenomas and carcinomas (combined) in female B6C3F1 mice. In the present paper, the bioassay results and additional information are evaluated using the IPCS/ILSI Mode of Action/Human Relevance Framework to determine if the data are sufficient to describe the possible mode(s) of action (MOA) underlying the reported results for the rat renal tumor and to determine if any of these modes of action could be operative in humans. Preliminary analysis of the rat renal tumor data and related information suggested that a MOA could be described, but questions remained concerning the role that chronic progressive nephropathy (CPN) may play in the development of the lesions. In 2009, a Pathology Working Group concluded that the rat renal lesions resulted primarily from regenerative processes associated with advanced CPN. The renal tumor finding is considered not relevant to humans and should not be considered in any further risk assessment efforts on this chemical. A companion paper describes a similar analysis of the female mouse liver tumor finding.

Agricultural chemical safety assessment: A multisector approach to the modernization of human safety requirements.

Better understanding of toxicological mechanisms, enhanced testing capabilities, and demands for more sophisticated data for safety and health risk assessment have generated international interest in improving the current testing paradigm for agricultural chemicals. To address this need, the ILSI Health and Environmental Sciences Institute convened a large and diverse group of international experts to develop a credible and viable testing approach that includes scientifically appropriate studies that are necessary without being redundant, and that emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. Benefits of the proposed approach include improved data for risk assessment, greater efficiency, use of fewer animals, and better use of resources. From the outset of this endeavor, it was unanimously agreed that a tiered approach should be designed to incorporate existing knowledge on the chemistry, toxicology, and actual human exposure scenarios of the compound, with integration of studies on metabolism/kinetics, life stages, and systemic toxicities. Three international task forces were charged with designing study types and endpoints on metabolism/kinetics, life stages, and systemic toxicities to be used in the tiered approach. This tiered testing proposal departs from the current standardized list of hazard studies used by many national authorities, and represents the first comprehensive effort of its kind to scientifically redesign the testing framework for agricultural chemicals.

A tiered approach to life stages testing for agricultural chemical safety assessment.

A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. The ACSA Life Stages Task Force proposes a tiered approach to toxicity testing that assesses a compound's potential to cause adverse effects on reproduction, and that assesses the nature and severity of effects during development and adolescence, with consideration of the sensitivity of the elderly. While incorporating many features from current guideline studies, the proposed approach includes a novel rat reproduction and developmental study with enhanced endpoints and a rabbit development study. All available data, including toxicokinetics, ADME data, and systemic toxicity information, are considered in the design and interpretation of studies. Compared to existing testing strategies, the proposed approach uses fewer animals, provides information on the young animal, and includes an estimation of human exposure potential for making decisions about the extent of testing required.

The human relevance of information on carcinogenic modes of action: overview.

Risk assessment policies and practice place increasing reliance on mode of action (MOA) data to inform conclusions about the human relevance of animal tumors. In June 2001, the Risk Science Institute of the International Life Sciences Institute formed a workgroup to study this issue. The workgroup divided into two subgroups, one developing and testing a "framework" for MOA relevance analysis and the other conducting an in-depth analysis of peroxisome proliferation-activated receptor (PPAR)alpha activation as the MOA for some animal carcinogens. This special issue of Critical Reviews in Toxicology presents the scientific reports emerging from this activity. These reports serve several purposes. For risk assessors in and out of government, they offer a new human relevance framework (HRF) that complements and extends existing guidance from other organizations. Regarding the specific MOA for peroxisome proliferating chemicals, these reports offer a state-of-the-science review of this important MOA and its role in tumorigenesis in three different tissues (liver, testis, and pancreas). The case studies in these reports present models for using MOA information to evaluate the hazard potential for humans. The cases also illustrate the substantial impact of a complete human relevance analysis, as distinct from an animal MOA analysis alone, on the nature and scope of risk assessment.

PPARalpha agonist-induced rodent tumors: modes of action and human relevance.

Widely varied chemicals--including certain herbicides, plasticizers, drugs, and natural products--induce peroxisome proliferation in rodent liver and other tissues. This phenomenon is characterized by increases in the volume density and fatty acid oxidation of these organelles, which contain hydrogen peroxide and fatty acid oxidation systems important in lipid metabolism. Research showing that some peroxisome proliferating chemicals are nongenotoxic animal carcinogens stimulated interest in developing mode of action (MOA) information to understand and explain the human relevance of animal tumors associated with these chemicals. Studies have demonstrated that a nuclear hormone receptor implicated in energy homeostasis, designated peroxisome proliferator-activated receptor alpha (PPARalpha), is an obligatory factor in peroxisome proliferation in rodent hepatocytes. This report provides an in-depth analysis of the state of the science on several topics critical to evaluating the relationship between the MOA for PPARalpha agonists and the human relevance of related animal tumors. Topics include a review of existing tumor bioassay data, data from animal and human sources relating to the MOA for PPARalpha agonists in several different tissues, and case studies on the potential human relevance of the animal MOA data. The summary of existing bioassay data discloses substantial species differences in response to peroxisome proliferators in vivo, with rodents more responsive than primates. Among the rat and mouse strains tested, both males and females develop tumors in response to exposure to a wide range of chemicals including DEHP and other phthalates, chlorinated paraffins, chlorinated solvents such as trichloroethylene and perchloroethylene, and certain pesticides and hypolipidemic pharmaceuticals. MOA data from three different rodent tissues--rat and mouse liver, rat pancreas, and rat testis--lead to several different postulated MOAs, some beginning with PPARalpha activation as a causal first step. For example, studies in rodent liver identified seven "key events," including three "causal events"--activation of PPARalpha, perturbation of cell proliferation and apoptosis, and selective clonal expansion--and a series of associative events involving peroxisome proliferation, hepatocyte oxidative stress, and Kupffer-cell-mediated events. Similar in-depth analysis for rat Leydig-cell tumors (LCTs) posits one MOA that begins with PPARalpha activation in the liver, but two possible pathways, one secondary to liver induction and the other direct inhibition of testicular testosterone biosynthesis. For this tumor, both proposed pathways involve changes in the metabolism and quantity of related hormones and hormone precursors. Key events in the postulated MOA for the third tumor type, pancreatic acinar-cell tumors (PACTs) in rats, also begin with PPARalpha activation in the liver, followed by changes in bile synthesis and composition. Using the new human relevance framework (HRF) (see companion article), case studies involving PPARalpha-related tumors in each of these three tissues produced a range of outcomes, depending partly on the quality and quantity of MOA data available from laboratory animals and related information from human data sources.