Toxicology and Epidemiology: Improving the Science with a Framework for Combining Toxicological and Epidemiological Evidence to Establish Causal Inference

Historically, toxicology has played a significant role in verifying conclusions drawn on the basis of epidemiological findings. Agents that were suggested to have a role in human diseases have been tested in animals to firmly establish a causative link. Bacterial pathogens are perhaps the oldest examples, and tobacco smoke and lung cancer and asbestos and mesothelioma provide two more recent examples. With the advent of toxicity testing guidelines and protocols, toxicology took on a role that was intended to anticipate or predict potential adverse effects in humans, and epidemiology, in many cases, served a role in verifying or negating these toxicological predictions. The coupled role of epidemiology and toxicology in discerning human health effects by environmental agents is obvious, but there is currently no systematic and transparent way to bring the data and analysis of the two disciplines together in a way that provides a unified view on an adverse causal relationship between an agent and a disease. In working to advance the interaction between the fields of toxicology and epidemiology, we propose here a five-step "Epid-Tox” process that would focus on: (1) collection of all relevant studies, (2) assessment of their quality, (3) evaluation of the weight of evidence, (4) assignment of a scalable conclusion, and (5) placement on a causal relationship grid. The causal relationship grid provides a clear view of how epidemiological and toxicological data intersect, permits straightforward conclusions with regard to a causal relationship between agent and effect, and can show how additional data can influence conclusions of causalit

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

Abstract 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

Abstract 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

Abstract 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

Mode of Action in Relevance of Rodent Liver Tumors to Human Cancer Risk

Hazard identification and risk assessment paradigms depend on the presumption of the similarity of rodents to humans, yet species specific responses, and the extrapolation of high-dose effects to lowdose exposures can affect the estimation of human risk from rodent data. As a consequence, a human relevance framework concept was developed by the International Programme on Chemical Safety (IPCS) and International Life Sciences Institute (ILSI) Risk Science Institute (RSI) with the central tenet being the identification of a mode of action (MOA). To perform a MOA analysis, the key biochemical, cellular, and molecular events need to first be established, and the temporal and dose-dependent concordance of each of the key events in the MOA can then be determined. The key events can be used to bridge species and dose for a given MOA. The next step in the MOA analysis is the assessment of biological plausibility for determining the relevance of the specified MOA in an animal model for human cancer risk based on kinetic and dynamic parameters. Using the framework approach, a MOA in animals could not be defined for metal overload. The MOA for phenobarbital (PB)-like P450 inducers was determined to be unlikely in humans after kinetic and dynamic factors were considered. In contrast, after these factors were considered with reference to estrogen, the conclusion was drawn that estrogen-induced tumors were plausible in humans. Finally, it was concluded that the induction of rodent liver tumors by porphyrogenic compounds followed a cytotoxic MOA, and that liver tumors formed as a result of sustained cytotoxicity and regenerative proliferation are considered relevant for evaluating human cancer risk if appropriate metabolism occurs in the animal models and in humans

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-022-03324-z

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